The psychological and human brain effects of music in combination with psychedelic drugs
This PhD thesis by Mendel Kaelen gives a great overview of the effect of psychedelics (LSD) and music on the brain.
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.
Research Summary of 'The psychological and human brain effects of music in combination with psychedelic drugs'
Introduction
Music has played a central role in psychedelic therapy since the earliest clinical trials of the 1950s and 1960s, with therapists consistently reporting that carefully selected music intensifies and guides the psychedelic experience in therapeutically beneficial ways. Despite this longstanding practice, little empirical research had directly investigated how music and psychedelics interact at the psychological or neurobiological level, nor what specific functions music might serve during psychedelic-assisted therapy. This thesis aimed to address that gap through four complementary studies examining the psychological and neural effects of music in combination with psychedelics — specifically LSD in healthy volunteers and psilocybin in patients with treatment-resistant depression — situated at the intersection of psychedelic neuroscience, the affective neuroscience of music, and emerging psychedelic therapy research.
Methods
Four studies were conducted using complementary designs. Study 1 was a double-blind, placebo-controlled crossover investigation of intravenous LSD versus placebo in healthy volunteers, measuring music-evoked emotions using the Geneva Emotional Music Scale (GEMS). Study 2 extended this design with 7T fMRI during music listening under LSD and placebo, analysing BOLD responses to acoustic features — particularly timbral complexity — and correlating activations with music-evoked emotion. Study 3 applied seed-based functional connectivity and dynamic causal modelling (DCM) to the same dataset, focussing on parahippocampal cortex (PHC) connectivity with visual cortex during music under LSD, and relating connectivity changes to mental imagery and autobiographical memory ratings. Study 4 was a qualitative interview study of patients undergoing psilocybin therapy for treatment-resistant depression, using structured post-session interviews analysed for themes relating to the subjective experience of music.
Results
Study 1 demonstrated that LSD significantly increased emotional responsiveness to music, with GEMS increases on wonder, transcendence, power, tenderness, nostalgia, peacefulness, and joyful activation; no significant increases in negatively valenced emotions (sadness, tension) were observed. Study 2 revealed that LSD amplified BOLD responses to timbral complexity specifically in the inferior frontal gyrus and precuneus, and these activations correlated significantly with music-evoked emotions of wonder. Study 3 showed that LSD and music together significantly increased PHC functional connectivity with bilateral visual cortex and left inferior frontal gyrus and insula. Dynamic causal modelling confirmed enhanced directional information flow from PHC to visual cortex, which correlated with increased complex visual imagery and personal memory recollection under LSD. Study 4 identified prominent qualitative themes from psilocybin therapy patients: music was welcomed as intensifying emotion and imagination, providing a sense of guidance and personal support, and inducing calming effects; the most common unwelcomed influence was an intensification of negative emotional states.
Discussion
Taken together, the four studies establish that psychedelics substantially alter neural processing of music and the emotions it evokes, with LSD amplifying activations in regions implicated in imaginative and autobiographical processing — inferior frontal gyrus, precuneus, and parahippocampal cortex — in response to timbral features. The connectivity finding provides a mechanistic account of why psychedelics and music together are particularly potent in evoking complex mental imagery and autobiographical memory retrieval, phenomena considered central to the therapeutic process in psychedelic-assisted treatment. The qualitative data from psilocybin therapy patients demonstrated that music serves multiple experiential functions simultaneously: guiding the emotional trajectory of the session, intensifying positive states, and facilitating openness to experience. These qualitative findings complement the neuroimaging data by grounding the mechanisms in the lived therapeutic context, supporting an account in which music's therapeutic functions are mediated by synergistic enhancement of emotional, imaginative, and autobiographical processing pathways.
Conclusion
Four studies demonstrate that psychedelics and music interact to produce specific psychological and neural effects extending beyond the independent effects of either alone. LSD intensifies music-evoked emotions — particularly wonder and transcendence — and amplifies neural responses to timbral features in regions implicated in imagination and autobiographical memory. The LSD–music interaction promotes information flow from the parahippocampal cortex to visual cortex, correlating with complex imagery and memory retrieval that may underlie therapeutic experiences during psychedelic-assisted treatment. Qualitative data from psilocybin therapy patients confirm that music guides, intensifies, and structures the therapeutic experience, providing a phenomenological account convergent with the neuroimaging findings.
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STATEMENT OF PUBLICATIONS
Parts of the data and the discussions presented in chapters 3 and 5 of this thesis have been previously published in Psychopharmacologyand in NeuropsychopharmacologyChapter 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 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.
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.
GLOSSARY
Psychedelics | The word psychedelic is derived from the Greek words psychḗ meaning "mind" or "soul", and dêlos, meaning "to manifest" or "make visible". Compounds considered "classic" psychedelics include psilocybin (the psychoactive constituent of magic mushrooms), LSD, mescaline (the psychoactive constituent of peyote and san pedro cacti) and DMT (a major psychoactive ingredient in the Amazonian brew ayahuasca). All these drugs share the property of being agonists at the serotonin 2A receptor and have phenomenological similarities. The use of the term 'psychedelics' in this paper refers to the classic psychedelics such as those listed above. Peak experience | Peak-experiences are characterized by a "transcending" of one's usual sense of selfhood, typically accompanied by emotions of wonder, blisfulnesss and awe. They are often are associated with a sensation of union or completeness, a sense of absence or resolution of inner conflict, and a sense of serenity, confidence and meaningful purpose in one's personal life. "Music may be a human invention, but if so, it resembles the ability to make and control fire: it is something we invented that transforms human life. Indeed, it is more remarkable than fire making in some ways, because not only is it a product of our brain's mental capacities, it also has the power to change the brain. It is thus emblematic of our species' unique ability to change the nature of ourselves." Psychedelic drugs and music have a profound capacity to alter consciousness, and have been used by humans for thousands of years and across various cultures. In recent years, increasing numbers of studies have assessed the psychotherapeutic potential of psychedelic drugs, commonly referred to as "psychedelic therapy". Within this approach, music is considered to be an important therapeutic component. The results of these studies are promising, yet so far, the function of music in psychedelic therapy has not been addressed. Increasing numbers of studies have examined how psychedelic drugs and music work in the brain separately, yet so far, no study has investigated how they work together. The research presented here was founded on the primary motivation to increase our understanding of the therapeutic functions of music in psychedelic therapy, by combining neuroscience and qualitative research methods. Because the subjective experiences of music that are often described under a psychedelic depict a remarkable profoundness, their combined study can prove fruitful as a new research paradigm in itself; one that may significantly advance our understanding of how the human brain processes music, and more broadly, how the human brain produces certain subjective states that are otherwise difficult to access under experimental conditions (e.g. peak experiences and emotional catharsis). This introduction chapter serves to introduce the reader to the rich history in which this topic is embedded, and to provide a comprehensive overview of the relevant academic literature. In the first half, this chapter will describe the historic use of psychedelics and music, the development of psychedelic therapy in the 1950s and 1960s, and the major perspectives that emerged from this work, including the original motivations for the use of music. In the second half, this chapter will review the recent clinical, psychopharmacological, and neuroscience literature on psychedelics and music, and converge into an outlining of the primary research questions this study aims to answer.
WHAT ARE PSYCHEDELICS?
The term psychedelic was first coined by the British psychiatrist Humphrey Osmond in conversation with the author Aldous Huxley in 1956. Osmond had introduced Huxley to the cacti-derived psychoactive drug mescaline in 1953, after which Huxley wrote the classic book The Doors of Perception to Heaven and Hell. Their research and their personal accounts with mescaline, and later with lysergic acid diethylamide (LSD), contributed to the then revolutionary idea in the psychiatric community that changes in mental states are due changes in neurochemistry. Humprhey and Huxley engaged in a quest to replace terms that were previously used for these compounds, such as psychoto-mimetic (i.e. psychosismimicking compounds) or hallucinogen (i.e. hallucination-inducing compounds), with a new term that they intended to be "more inclusive": a term that would not solely describe their ability to elicit psychosis-like symptoms or hallucinations, but also their ability to evoke experiences that have psychodynamic, aesthetic and spiritual significance. In a famous letter in 1956, Huxley sent Osmond the following rhyme: "To make this trivial world sublime, take half a gram of phanerothyme." Osmond responded to this by writing: "To fathom hell or soar angelic, just take a pinch of psychedelic." The word psychedelic was derived from combining the Greek words psychḗ, meaning "mind" or "soul", with dêlos, meaning "to manifest" or "to make visible". It refers to the notion that these compounds can bring into the awareness a wide spectrum of latent psychological content, that can both strongly positive or negative in emotional valence -hence the idea that they let the individual who takes them "fathom hell or soar angelic". Osmond presented the term "psychedelic" for the first time at a scientific conference in 1957, and Huxley illustrated this view in an elaboration on his personal experience with mescaline, in 1954, in his book The Doors of Perception: "But what I had expected did not happen. I had expected to lie with my eyes shut, looking at visions of many-colored geometries, of animated architectures, rich with gems and fabulously lovely, of landscapes with heroic figures, of symbolic dramas trembling perpetually on the verge of the ultimate revelation. But I had not reckoned, it was evident, with the idiosyncrasies of my mental make-up, the facts of my temperament, training and habits."Drugs considered "classic" psychedelics include lysergic acid diethylamide (LSD), psilocybin (the major psychoactive constituent of magic mushrooms), mescaline (a psychoactive constituent of peyote and San Pedro cacti) and DMT (a major psychoactive ingredient in the Amazonian brew ayahuasca). As will be discussed in greater detail in later paragraphs, all these compounds share the property of stimulating the serotonin 2A receptor. The use of the term "psychedelics" in this manuscript refers to these compounds or to the plants, mushrooms or cacti that naturally produce them. 1.2 Psychedelics and music in pre-historic times Both psychedelics and music share an interesting history, and one that may be more intertwined than separated. An introduction to the modern study of psychedelics and music may therefore not be complete without connecting it to their rich historical and cultural origins. The challenge with discussions of ancient history lies however in the tendency of the earth to decompose virtually anything in time. This not only renders controlled scientific experimentation impossible, but the little archaeological findings that are well-preserved and successfully uncovered are therefore precious, and also need to be viewed in that respect: They are likely to represent a mere minuscule fraction of everything that once has been. What can we therefore safely infer, without too much speculation, about the historical use of music and the historical consumption of psychedelics? For music, this task may be relatively simpler, as music-making can (but not necessarily) imply the crafting of musical instruments. Such artefacts are more likely to be preserved than, let's say, a mushroom. Various uncovered stones show modifications that indicate their use as rhythm instruments, such as rasping and drumming. Mammoth bones showing such signs were found along beaters and ivory rattles in Mezin, Ukraine, and dated to 20,000 years old. But the oldest artefacts that have been identified reliably as musical instruments are bone and ivory flutes found in Germany, and these are estimated to be more than 35.000 years old. Not only is this finding striking because of the age (i.e. these flutes were thus played in a period long before the onset of agricultural settlements, and in a time period where human cave-dwellers shared these untamed natural landscapes with other hominid species, such as Neanderthalers); but also, because these instruments are already evident of a remarkable sophistication. The separate holes allow the production of a broad repertoire of auditory pitches. This suggests that humans have likely engaged in musical activities for periods of time preceding the production of these advanced musical instruments. Indeed, instruments are not necessary to make music, and from records of hunter-gatherer societies across the globe it is clear that, for example, vocalisation and clapping play important roles in a variety of musical activities. In many of these aboriginal societies (e.g., Native Americans, Aka and Mbuti African pygmies, Australian aboriginals and Yupik Eskimos of Alaska), music has strong ceremonial functions, including social, celebratory, medicinal and -particularly frequent-shamanic. The pioneering ethnomusicologist Bruno Nettle was amongst the first to point this out in his book Music in Primitive Culture, where he writes: "Among many American Indian and some Paleo-Siberian tribes, composition is ordinarily relegated to shamans (medicine-men) or other individuals connected with religion in a particular way. Indeed, musical and religious specialisation are often correlated, and are probably the two activities of primitive life in which specialisation most commonly occurs."Nettle also documented the central role of music during shamanic ceremonies of Native American Indians that include the consumption of mescaline-containing cacti. This was soon followed by the documentation the ayahuasca-ceremonies in many tribes in South-America, the mushroom-ceremonies in Central America, Siberia and Papua New Guinea, the Ibogaineceremonies in west Africa, the Yopo -ceremonies in the Caribbean's, and so forth) -all of which are characterised by the prominent use of music during the ceremonies. Typically, this music consists of lengthily repeated and simple melodic structures, produced via chanting or whistling, and often has significant rhythmic properties, emphasised by the use of rattles, drums or clapping. This simplicity may be, and has been argued to be, ideally suited to support the strong introspective altered states of consciousness facilitated by these ceremonies. In these contexts, the music is often considered sacred, only to be used for this purpose, and is associated with the evoking of vivid eyes-closed imagery and powerful emotions. A good example for this is the singing of the "spirit-songs" or icaro's that are sung during ayahuasca-ceremonies, of which the anthropologist Marlene Dobkin De-Rios said the following: "We could only marvel at the pervasive presence of music in a variety of forms, as an integral part of the psychedelic experience [..] Shamans state that the music they create provokes special types of visions. Healers told me that the particular traditional melodies, icaros, that they choose to sing or whistle, would evoke visions they specifically desired their clients to have, to permit them to see the agent responsible for bewitchment, to resolve anxiety created in the wake of psychedelics use, and so on." (Dobkin deHow far do these traditions stretch back into human history? Evidence for the pre-historic use of psychedelic plants, cacti and mushrooms in combination with music-making is elusive. However, their use by hunter-gatherer societies in the modern era is suggestive for their use by earlier communities. Since their natural resources and tool-use are often similar, and thus likely remained static, and given that natural resources and tool-use define cultural lifestyles to a large degree, ceremonial constructs may be preserved for lengthy times too. This argument has been made for the archaeology of music, and can equally apply to the archaeology of psychedelics and their combined use with music-making. The ceremonial use of psycho-active plants and music is shown amongst many aboriginal societies on different continents, and may therefore be considered to be as central to human culture as is commonly argued for music alone. More direct archaeological evidence for the ceremonial consumption of psychedelic plants comes from various uncovered artefacts. Of these, the rock and cave art of the Tassili n Ajjer desert in Algeria, dated to be 7000 to 9000 years old, may be both the most ancient and the most mysterious association with psychedelic mushrooms. These include, and are not limited to, a feathered-headed bee-faced figure with mushrooms sprouting out of his body, smiling figures with mushroom-shaped hats running around with mushrooms in their hands, and female figures with round and colourful mushroom-capped faces. Some authors have argued that the vast amounts of geometric drawings found on cave-walls alongside these and other regions, supplements evidence for the authors of these drawings to be in an altered state. In a cave in Spain, painted rows of mushrooms were found, resembling locally growing psychedelic mushrooms, and dated to be 7000 years old. In North America, Texas, specimen of peyote found in caves and rock shelters were dated to be 5600 years old. Pipes with residues of burned DMTcontaining seeds in Argentinia were dated to be more than 4000 years old. Many mushroom-shaped stones were uncovered in Guatemala, and dated to be between 3000 to 2000 years old, alongside multitudes of artistic depictions of mushrooms and mushroom-eating figures on ceramics from the same regions and time-periods (. The Greek gods Persephone and Demeter are depicted sharing a mushroom, and are associated with the then highly popular mystery cult "Eleusis", in which the participants gathered to share a psycho-active drink called "Keykeon". The Eastern Vedic hymns are devotions to "Soma", the "king of all plants", which supposedly elevated the consumer to become godlike, and some Indian sects maintain the use psychedelic drugs as part of their rituals. Biblical traditions tell the story of Moses who guides the Israelites to find "Manna", "the bread of god", which appears as circular disks in the morning dew of the fields, and which would make god visible to the human eye after eating. Reviewing the various references to the historic consumption of psychedelics in the major spiritual traditions of today, is beyond the objectives of this thesis, but this discussion has sketched out a general message: The uncovering of the various artefacts and the conservation of psychedelic-and music-use in aboriginal societies today, suggest that musicmaking and the consumption of psychedelics are both ancient and universally human.
PSYCHEDELICS IN MODERN TIMES
Although Europe is home to various psycho-active plants and psilocybin-containing mushrooms, knowledge about psychedelics in modern times only started to break through into mainstream science in the first half of the 20 th century. Some argue that the infamous witch-hunts spanning the 15 th to the 18 th century in Europe played a role in eradicating ceremonial psychedelic-plant use. The sudden rise in interest in psychedelics in the 20 th century was catalysed by (1) the birth of ethnopharmacology, and (2) the discovery of LSD. One of the most significant contributions for the former, may be the work of Richard Evans Schultes. Via more than 450 publications in the early-and mid 20 th century, Schultes increased awareness within the western scientific community about the traditional usages of various psychedelic plants around the world. The discovery of LSD centres around Albert Hofmann and his work in Sandoz laboratories in Basel, Switzerland. In search for a novel blood circulatory stimulant, Hofmann synthesized a range of derivatives from ergot alkaloids in 1938, one of which being LSD-25. On 16 April 1943 Hofmann accidentally intoxicated himself while re-assessing his earlier works with LSD. He felt dizzy and went home. Three days later Hofmann intentionally ingested 250 mcg of LSD, to test whether it was this drug that caused the symptoms he experienced earlier. What he believed would be a miniscule dose, turned out to be what is now known as 10 times the amount of a threshold psychoactive dose. Hofmann described his experience as both frightening and fascinating. After reassurance of his physiological health by his doctor, he described how he experienced "an uninterrupted stream of fantastic pictures, extraordinary shapes with intense, kaleidoscope-like play of colours". But it was what he experienced the day after, that provided an inspiration for the many therapeutic investigations that would soon follow. Hofmann describes in his autobiography that he woke up the next day with a remarkable mental clarity, and wrote: "A sensation of well-being and renewed life flowed through me. The world was as if newly created. All my senses vibrated in a condition of highest sensitivity."Soon LSD was actively marketed under the name "delysid" to psychiatrists and researchers, as an adjunct for psychotherapy and as a tool to study psychosis. The subsequent paragraphs will provide an overview of the early scientific efforts that followed the discovery of LSD, and the perspectives that grew out of this on its therapeutic use and mechanisms.
DEVELOPMENT OF PSYCHEDELIC THERAPY IN THE 1950S AND 1960S
Claude and Ey, andmay have been the first to discuss the potential therapeutic use of psychedelics in the academic literature. The study byadministered mescaline to patients with "depersonalisation", and reported that the patients who demonstrated an improvement afterwards all shared a similar statement about their experience with mescaline: "I have seen that I can be as I used to be before."Regardless of the infancy of research with psychedelics at that time, this short description already depicted succinctly what would soon be viewed as a principal effect via which psychedelics act therapeutically: their ability to quickly and radically change a person's perspective, leading to sustained changes in outlook, personality, mood and behaviour. This section will examine the perspectives that were born out of psychiatric research with psychedelics in the 1950s and 1960s, and how this led to the central use of music during psychedelic therapy sessions.
THE FUNCTION OF THERAPEUTIC EXPERIENCES
Despite earlier reports on mescaline, it was the discovery of the psycho-active effects of LSD in 1943 that sparked a great international interest in the therapeutic potentials of psychedelics.were the first to report on the therapeutic use of LSD, describing the effects of LSD as increasing the patient's "expressiveness" and as "permitting re-examination of significant experiences of the past, which were sometimes relived with frightening realism". This was the beginning of numerous experiments on the therapeutic usage of psychedelics, culminating into an estimated 40.000 patients with mood-and addiction disorders to have been treated with LSD and other psychedelics by the late 1960s. Psychiatrists who performed these experiments noticed that psychedelics can produce diverse types of experiences across patients and sessions. The characteristic perceptual effects of psychedelics are well recognised, but it was other effects, in particular the effects on the individual's emotionality, that ignited the strongest motivation amongst psychiatrists to consider their therapeutic utility. These observations inspired the hypothesis that psychedelics work by weakening the usual psychological defence-mechanisms (also referred to as "ego dissolution"), and thereby uncover (usually "repressed") emotions, memories and thoughts. It was believed this effect of psychedelics would "speed up" psychotherapy.reported that under LSD "frequently whole sequences unroll before the patient's eyes as though they had been stored on microfilm".concluded from their observations that "LSD-25 has the astonishing quality of bringing into focus the patient's repressed emotional attitudes, conflicts, etc., and permits their re-activation".remarked that "emotions hitherto camouflaged were brought out, without the intense guilty fears that had kept them submerged".wrote: "The major dimension of drug-altered reactivity with therapeutic relevance is the affective or emotional sphere: intense, labile, personally meaningful emotionality is uniformly produced, with periodic episodes of overwhelming feeling."Researchers often pointed out the apparent unpredictability and diversity of the emotional effects engendered by psychedelics, and the challenges this brought for therapeutic work. LSD was found to be able to produce states of profound well-being, as well as states of immense anxiety; tranquil states of mind, as well as those riddled with confusion and paranoia; moments filled with intense euphoria, as well as episodes of explosive anger). These observations fuelled the emerging view in the psychiatric community that these compounds can produce psychosis-like symptoms. Corresponding to this view, in a series of initial clinical trials, LSD was administered to patients with severe alcoholism with the intention to experimentally induce a "psychosis-like state". It was thought that the LSD-state would to a large extent resemble the alcoholism-induced psychosis, Delerium Tremens (DT), and the hypothesis was that this experience would produce a "psychological shock" that would frighten patients away from their drinking behaviour. The outcomes of these experiments did however not confirm this hypothesis. First, compared to DT, LSD was found to differ markedly in its capacity to produce a "nebulous sense of wonderment", an increased "aesthetic appreciation" of music and art, an increased perception of "new values", and "a sense of quiet meditation". Secondly, out of the variety of experiences LSD could produce, it was not negative or "frightening" experiences that were associated with clinical improvements, but rather the opposite. Patients who showed the strongest improvements, were described to have a certain type of experience that was characterised by such enhanced feelings of "wonder" and a sense of "transcending" their usual sense of self."Nearly invariably, whenever dramatic personality change has been noted following the use of these drugs, it has been associated with this kind of experience, that is one called transcendental or visionary"Andnoted: "When therapeutic changes did occur, they were often of a qualitatively different order than those which occur in traditional psychotherapy. Under the influence of LSD, the individual goes through highly intense and unusual experiences which may very well change the way in which he views life"Psychedelics were found useful by psychiatrists not only for their acute psychological effects, but in particular for their capacity to facilitate enduring therapeutic change after the session, ranging from weeks, months, or longer. The type of experience under LSD that was found to promote such therapeutic changes most reliably, were argued to exhibit this "self-transcending" quality. It were these experiences that were thought to allow the individual to obtain a sudden shift in perspective on themselves, charged with emotionality, motivating a change in behaviour accordingly. The general consensus arose that it was not the drug, but the experience that the drug can facilitate, which is therapeutic. By the mid 1960s, researchers identified the types of experiences that were considered most therapeutic, and these can be roughly classified into two main categories: 1) Autobiographical experiences: characterised by an emotional "release" or "catharsis", the experience of vivid and emotionally charged personal memories and insights into one's own personal life. These experiences were often interpreted within a psychodynamic framework. 2) Peak experiences: characterised by a sense of dissolving or transcending one's sense of usual self, culminating into a sense of union, and feelings of bliss and spirituality. These experiences are sometimes also referred to as "spiritual-type experiences", "mystical-type experiences", or "psychedelic-peak experiences", and were often interpreted within a humanistic framework.
THE FUNCTION OF NON-DRUG VARIABLES TO FACILITATE THERAPEUTIC EXPERIENCES
An increased awareness emerged of the influence that non-drug variables have on determining the types of experiences patients undergo (i.e. variables other than the drug, such as social atmosphere, the music, the physical environment, etc.). This is now commonly referred to as the importance of "set and setting", where set refers to the mind-set of the individual, including its personality, mood and expectations, and setting refers to environment in which the drug is taken, including its interpersonal-and sensory-qualities. Psychiatrists began to experiment with a strategic design of non-drug variables in order to promote most desirable therapeutic experiences and outcomes. One leading example for this course in history was Humphrey Osmond, who arrived in 1951 at the Weyburn Mental Hospital in Canada, to be shocked by the "bleakness" of the institution. Osmond engaged with an architect, Kiyoshi Izumi, who, after his first personal experience with LSD, set off to design a new psychiatric hospital, that eventually was recognized by the World Health Organisation for its highly innovative quality.summarised the growing awareness on the significance of the setting as follows: "We had noted before from our studies of the psychotomimetic properties of this drug that the environment and particularly the attitude of the people around the person undergoing the LSD experience seemed to influence his reaction profoundly. […] The environment surrounding the patient taking LSD was changed by the addition of auditory stimuli, visual stimuli, emotional stimuli and a change in the attitude of the people in contact with the patient."A particular strong example of this attitude towards designing setting-variables in service of the therapeutic experience, is represented by the psychiatrist, who stated: "So far, as Dr. Abramson clearly outlined, we have used frames of reference in which LSD is used as an aid to psychotherapy. However, within our frame of reference […], psychotherapy is used as an aid to the LSD experience. Our objective is to give each patient a particular LSD experience. To this end, we use psychological and environmental tricks: sound and music; visual stimuli, such as paintings by Van Gogh; tactile stimuli, such as various smooth or rough objects for the patients to handle. We also take advantage of the heightened suggestibility of the subjects by using persuasion, suggestion, and reiterated demand, with the theme of hope and possibility of change."The increased emotional responsiveness under the drug, was not seen as an obstacle, but as an effect of the drug that can be utilised in service of therapeutic objectives. This was attempted by tailoring the design of non-drug variables such as the environment and the music being played, in such way that these variables become an active part of the therapeutic sessions. By the late 60s, the foundation of psychedelic therapy was characterised by a strong patient-centred approach, adapting setting-variables to patient's therapeutic needs, to maximise the occurrence of autobiographical-and peak experiences.
PSYCHOLYTIC THERAPY AND PSYCHEDELIC THERAPY
At that moment in time, by the late 1960s, broadly speaking two different therapeutic approaches had evolved via which these views manifested into practice: the "psycholytic" method, mainly practiced in Europe, and the "psychedelic" method, mainly practiced in the United States. These approaches differed in the dosages administered, the amount of sessions conducted, and the structure of the sessions themselves: 1. Psycholytic therapy was characterised by lower dosages, with the intention to preserve sufficient "ego-functioning" for the patient in order to actively engage with the therapist during the sessions. Generally speaking, the primary goal here was to use the drug as an adjunct to psychotherapy, with the emphasis on facilitating "autobiographical experiences". Typically, patients underwent multiple psychedelicassisted therapy sessions to reach the therapeutic objectives. Music was often used in psycholytic approaches, but more frequently intermitted by conversations or periods of silence. 2. Psychedelic therapy was characterised by higher dosages, with the intention to dissolve "ego-functioning", and for the individual to "immerse" fully in the unfolding experience. The primary goal here was to facilitate a "peak experience" that would result in enduring changes in personality, mood and behaviour. Typically, patients underwent one or a small number of sessions, and would listen to music for the majority of the time during these sessions -often with eyes closed to increase introspection. In practice, autobiographical-and peak experiences often co-occurred within both psycholytic and psychedelic methods, and within one session. A good example of this can be found in an excerpt from a case reported by, describing the treatment of a patient with alcoholism with a high dose of LSD (450 mcg). This excerpt demonstrates the use of various therapeutic elements that have been discussed here, such as the significance of both autobiographical and peak experiences, and how the therapists utilises non-drug variables to provide adequate therapeutic support: "I was now very conscious of the fact that the music was creating variations of great beauty in my mind. It was such beauty that words can't describe it. The word "magnificent" kept running through my mind. I felt that I was being overwhelmed by beauty. I stated that I was undergoing the most magnificent experience of my life. By this point, I had lost all sense of time. What seemed like an eternity later, but possibly only a minute or so in actual time, I became aware that my mood had changed. I suddenly saw myself near the bottom of a huge filthy pit. It seemed to be bottomless and was crawling with horrible things such as octopi and enormous, oddshaped frogs. I tried to crawl my way out of the pit and finally got near the top. Looking down, it was horrible -worse than I have ever visualized hell. Huge vats and casks containing whiskey were being poured into this slimy pit. It seemed that all the whiskey in the world was being dumped there. I began to cry. A feeling of deep guilt and remorse had come over me. The doctor had me sit up. In discussion with him, I realized the significance of this episode for my own experience with alcohol. After my crying spell, I felt relieved and cleaner inside. Once again I reclined on the couch. The music became more meaningful to me than anything I had ever heard before. A tremendous feeling of exaltation came over me. It kept growing in intensity. I felt rapture and ecstasy. Each moment I thought I had reached the zenith of rapture and joy; then the intensity and ecstasy would increase. It was overwhelming! There are no words to describe my feelings. Then, while I was in this state, all became still and quiet. A sense of cleanliness and purity swept over me. I was alone and at peace. At this precise moment, I felt that all was holy and pure. I felt humble and insignificant. I was completely awed! It was the greatest, most magnificent experience of my life. I knew then that life has meaning and riches and rewards. I felt as though I had been reborn. Probably never again will I undergo such an experience. But I don't care -once in a lifetime is more than any mortal can hope for. I then began to think about mankind in general. I realised that what I had experienced was potentially in everyone, and I felt compassion, warmth, and understanding for my fellow man. […] I cried. I remember wishing that my wife could be at my side, so I could tell her and show her how I now felt. I knew then that I had been throwing my life away, and that there was so much I could do to change things for the better."1.5 The use of music in psychedelic therapy in the 1950s and 1960s The realisation that non-drug variables (for example, the physical environment, the social environment, the mind-set and the music) assubstantially influence the patient's experience under a psychedelic, was typically explained as the result of a "weakening" effect of the drug on the patient's psychological defence mechanisms. This would lead to an enhanced suggestibility and emotional response to various types of stimuli from the environment. From early on in the scientific literature, descriptions appeared that called attention to the particularly remarkable influence of music.describes the relationship between ego-boundary dissolving effects of LSD and the intensified response to music as follows: "The most impressive feature in the experience of the non-rational system was the disappearance of all boundaries between individual entities, or, indeed, the disappearance of individuality as such.In this way, the meanings of certain musical phenomena (rhythms, intervals, etc.) were felt to have their exact equivalents in certain tensions or experiences of pressure, movement or position of certain parts of the body."In the efforts to provide optimal therapeutic support for patients via design of settingvariables, a striking consistency appeared in the literature around the use of music. Therapists frequently emphasized the significance of playing music. In general, the reasons to incorporate music within psychedelic therapy were described as (1) music's capacity to modulate emotion and mood, (2) music's capacity to evoke autobiographical memories and to stimulate the imagination, and (3) music's capacity to facilitate peak experiences. In what follows, these separate points will be discussed.
THE USE OF MUSIC TO FACILITATE EMOTION
The perceived value of the emotion-modulating effects of music are well described by, who stated that the patient's ability "to regain fully his emotional expressive abilities" under LSD, "negatively, and especially, positively" to be one of the most important therapeutic mechanisms within LSD-assisted psychotherapy. Holzinger continued to describe the main role of music as "to enhance this ability of the patient to express his feelings".wrote that music was used "initially to aid in relaxation", but that it was soon realised that music could support the therapy sessions in different ways too: "After repeated observations that music seemed to potentiate the drug action, it was used when there was no verbal exchange. Selections of the patient's choice or of a semi-classical nature were played during the early phase; certain piano concertos were used at the height of the experience".This point is illustrated especially clearly by, who reported the use of music to intentionally evoke emotionally intense experiences: "After the initial and usually apprehensive episode, an attempt is made to send the patient into an intense episode. Factors encouraging such an episode are: reassurance, selection of meaningful music, absolute quiet and privacy, with discouragement of any analysis and discussion of the episode while it is in progress."Hoffernoted that music can "be very helpful", but that music and other non-drug variables factors "must be looked upon as aids and not as objectives of the experience", and that the music should always be tailored to every patient's unique needs: "Some subjects find music intolerable and visual aids repulsive, and their wishes and feelings must be honoured. They find music extremely distracting and it prevents them from fully experiencing other components of the reaction."Hoffer continued to explain that the effects of LSD on altering the perception of music and the emotional response to music, can however be utilised strategically to facilitate intense emotional experiences with high therapeutic significance: "Very often, sounds which normally have no particular aesthetic appeal, were heard in a most unusual manner. Subjects who were indifferent to music, were enthralled by it. One of our subjects, a physicist, was overwhelmed by the beauty of music being played on an old scratchy record player. After a while he exclaimed "I wish they could play it as beautifully as I now hear it." The background noise of the record did not reduce his appreciation of the music. This property of the experience is very useful in bringing out the psychedelic reaction. Carefully selected music can be very powerful in altering the subject's mood and associations. One subject, an intellectual, cold physician, who was an alcoholic, did not have any emotional reaction to 300 mcg of LSD for about 2.5 hours. When Ave Maria was played, he seemed startled, then in a few minutes, became transfixed with emotion and began to cry. The song had suddenly taken him to his youth when he had been very happy. The music triggered of an emotional catharsis which completely altered a psychotomimetic to a psychedelic experience."
THE USE OF MUSIC TO FACILITATE AUTOBIOGRAPHICAL EXPERIENCES
As the previous section showed, the evoked emotionality by the music during the peak of the drug-effects were often found to be of autobiographical meaning. Psychiatrists typically reported a blending of vivid memories and personal thoughts with strong feelings, such as in the following statement by: "The immediate result of giving the LSD is to produce a deepening of the patient's emotional tone, a change in thinking, sometimes regression to an earlier emotional and intellectual period and the reliving of emotionally charged memories."The first clinical observations that patients under LSD remember past events in "frightening realism", and that not infrequently "whole sequences unroll before the patient's eyes as though they had been stored on microfilm", was a major incentive to explore LSD's potential therapeutic use further. Subsequently, music was found to be in particular helpful to exert a degree of guidance in this phenomenon. This is well summarised by, who said: "Music can be an effective stimulus in helping to bring out affectively charged memories and fantasies. We have found classical music generally best, although a great variety of different kinds of music can be effective, especially if the music can be selected in terms of specific aspects of the patient's emotions and background. Music was played throughout the sessions as "background" and sometimes with the instruction to "go with the music" and to have fantasies suggested by the music."The main view behind the significance of these autobiographical experiences, was that they facilitate a state of personal insightfulness, characterised by new perspectives on oneself and on one's life, that promote changes in the way the person subsequently lives his or her life. Smith et al 1959 described that "It is hoped by this method to make the experience a thought-provoking one rather than a frightening one". The authors illustrate their appraised therapeutic benefits from the effects of LSD and music via the report from a 39-old alcoholic patient, describing his therapy sessions with LSD as follows: "The experience I have had as a result of the drug was unique and most definitely constructive. It manifested itself in many ways, the most important being my ability to recall certain events, some pleasant, some very unpleasant. It allowed me to see myself as I really am, as a person who is first an egotistical deceitful procrastinator and have many more defects which I am aware of but, because of my lack of knowledge or something or other, have never been able to do anything about."1.5.3 The use of music to facilitate peak experiences Music played a particular central role in the "high-dose" psychedelic therapy approach. After administration of the drug, patients were typically encouraged to fully direct the attention inwards and listen to a music playlist for the subsequent 6 to 8 hours. This approach was heavily influenced by Helen Bonny, a music-therapist, and placed a significant emphasis on music's capacity to facilitate peak experiences: "The time of peak drug intensity when psychedelic peak experiences are most probable comes 3 to 5 hours after ingestion. The greatest effort is made to provide an optimal setting for this type of experience. It is for this period that there is the greatest agreement among therapists regarding the type of music to employ.As this is the most critical period of the session, a discussion of appropriate and inappropriate ways in which music can be used is especially important. In the repertoire designated as 'peak music' are certain selections which have been shown by experience to evoke powerful emotions and to aid greatly in facilitating the occurrence of peak experiences if played at the proper time. If these selections are played at an improper time, the potential effect can be wasted and a negative musical imprint for that particular selection may result."The use of music to facilitate peak experiences derived significant inspiration from humanistic psychology, and in particular the views pioneered byargued that peak experiences are integral to the lives of healthy self-actualising individuals. Maslow said the following about psychedelics: "In the last few years it has become quite clear that certain drugs called "psychedelic", especially LSD and psilocybin, give us some possibility of control in this realm of peak experiences. It looks as if these drugs often produce peak experiences in the right people under the right circumstances, so perhaps we needn't wait for them to occur by good fortune."At the time that the work bywas published, new government regulations were already put in place (by 1966 in the US, and by 1967 in Europe) that marked the beginning of a long hiatus in research with psychedelics. Although the intentions behind these regulations may have been to halt the growing uncontrolled use of psychedelics in society, what was truly halted was the scientific research. It took several decades for academic human research with psychedelics to restart. The subsequent paragraphs serve to provide an overview of this recent renaissance of modern research. It will show that the therapeutic approaches employed in modern studies with psychedelics, are heavily influenced, if not fully compatible, with the views that were developed by the 1960s as outlined above.
MODERN PSYCHOLOGICAL AND PSYCHOTHERAPEUTIC RESEARCH WITH PSYCHEDELICS
The level of interest today, in studying the therapeutic potential and the human neuroscience of psychedelics, stands in stark contrast to the almost complete absence of this research in the preceding decades. This revival is posing a number of important questions for the scientific and psychotherapeutic community. As was detailed in the previous section, psychedelic therapy differs from current treatment approaches on several major points. Compared with conventional pharmacotherapy (i.e. psychiatric medication), the strongest contrast is that in psychedelic therapy the aim is not to administer the compound repeatedly and continuously, but only on one or a few occasions, with the objective to facilitate sustained improvements (i.e. clinical remission that extends beyond the acute drug effects during the therapy sessions). Compared to conventional psychotherapy, the strongest contrast is, first of all, that a drug is administered, and secondly, that this drug has powerful acute subjective effects: The lengthily periods of introspection and intense emotionality facilitated by psychedelics do not merely aid the usual way psychotherapy is performed, but instead yield dramatic consequences on the way the therapeutic sessions are performed, including their structure, duration and the role of the therapists. The views that led to the development of the procedures that characterize psychedelic therapy sessions in the 1950s and 1960s, are to a large extend derived from direct clinical observations, case studies, or experiments that were not well-controlled. In addition, the practice was often informed by theoretical frameworks that are not always supported by sufficient scientific evidence. One example of this are psychodynamic hypotheses around ego-functioning, and the then-popular idea that psychedelics weaken "ego-defence mechanisms", resulting in a regression to an earlier emotional and intellectual mode of cognition. This has led to a therapeutic method that is construed from various concepts and assumptions that await empirically validation. Addressing this is important, given psychedelic therapy receives an increasing amount of empirical support for its safety and efficacy, and is being implemented at increasingly larger scales in the years ahead (i.e. larger numbers of therapists and patients will be working within this therapeutic framwork). Studies are therefore warranted that not only establish safety and efficacy of the procedures, but also scrutinise the assumptions inherent within these procedures and to further an empirically grounded development of the therapeutic working model. These considerations were a central motivation for the research presented in this thesis. Given the primacy of music during psychedelic therapy sessions, the focus was on studying the combined effects of psychedelics and music. In order to formulate the primary research questions this research aims to address, this section will provide an overview of the modern pre-clinical and clinical human research with psychedelics, and highlight how recent research has addressed some of the observations and interpretations reported in the 1950s and 1960s. In summary, these are (1) the variety of subjective effects of psychedelics (hence, leading to a need to structure the experience), (2) the effects of psychedelics on emotion and mood, 3) the effects of psychedelics on ego-functioning, (4) the capacity of psychedelics to evoke autobiographical experiences, and (5), the capacity of psychedelics to evoke peak experiences. This section will conclude with a review of the recent clinical trials with psychedelics. See table 1.1, for methodological details regarding these referenced studies.
THE VARIETY OF SUBJECTIVE EFFECTS OF PSYCHEDELICS
Several modern studies have investigated acute subjective effects of psychedelics in healthy volunteers using questionnaires and behavioural experiments, demonstrating that they can occasion changes in perception, cognition and emotionand in a dose-dependent manner. The acute subjective effects of psychedelics are often assessed via the altered state of consciousness questionnaire (ASC), that measures changes in distinct factors of conscious experience. One major factor of effects of psychedelics are changes in perception, including different sensory modalities (i.e. visual, auditory, tactile), but also changes in the perception of time. Imagination is often reported to be highly vivid, and eyes-closed imagery of an "elementary" nature (i.e. colours and patterns) and of a "complex" nature (i.e. concrete objects, landscapes or entities) are both common. Cognitive-and behavioural experiments have demonstrated that impaired attentionand response inhibitionafter psilocybin, enhanced divergent thinking after ayahuasca, and increased spread of semantic activation under LSD. Several studies have also assessed cognitive effects of psychedelics via self-report questionnaires, showing increased cognitive disorganisation, disordered thinking, muddled thinking, and insightfulness. In an effort to reconcile the "paradoxical" capacity of psychedelics to induce both "positive" effects (positive mood, enhanced creative thinking, insightfulness, etc.) and "negative" effects (impaired cognition, muddled thinking, etc.), these cognitive effects of psychedelics have been conceptualised as a modulatory effect on cognitive flexibility. Indirect support for the view that psychedelics enhance cognitive flexibility comes from a study that demonstrates psilocybin increases switching rate when attending ambiguous stimuli, and a study that demonstrated increased divergent thinking under ayahuasca. The effects of psychedelics on emotion will be discussed separately in the following paragraph. Together, these studies illustrate the diverse spectrum of subjective effects psychedelics can occasion. This variety, was one of the motivations in the 1950s and 1960s, to try to exert some degree of control over the experience via, for example, utilizing nondrug variables. Some recent studies show support for this, demonstrating that acute drug effects can be predicted by several factors other than drug dose, including the mind-set of the individual, and the individual's personality traits.
THE EFFECTS OF PSYCHEDELICS ON EMOTION AND MOOD
The effect of psychedelics on emotionality was an important motivation to investigate their therapeutic potential, and modern studies have demonstrated that psychedelics increase emotionality via different research paradigms. Using mood rating scales,showed significant increases in "emotional excitability" under psilocybindemonstrated increases in "happiness" under LSD. These findings were confirmed and corroborated bywho compared two separate dosing regimens (100 mcg and 200 mcg of LSD) and reported a doseresponse relationship for increases in emotional excitability, confirming earlier observations of dose-dependency on emotionality. The study byalso showed socio-emotional effects after LSD, such as increased closeness, trust and openness.performed behavioural assessments targeting changes in socio-emotional information processing under LSD, and reported impaired recognition of fearful and sad faces, but enhanced emotional empathy.reported a comparable emotionalinformation bias in a study showing that psilocybin produced a significant enhancement in positive mood and decreases accurate recognition of negative facial expression. A study bymay be interpreted along similar lines, by showing reduced feelings of social pain under psilocybin within in a behavioural social exclusion task.
THE EFFECTS OF PSYCHEDELICS ON EGO-FUNCTIONING
As was detailed in the introduction chapter, one major reported effect of psychedelics is a temporary dissolving of boundaries between self (i.e. the "me") and object (i.e. the "notme"). This effect has been referred to as disturbed ego-functioning, ego-disintegration or ego-dissolution, and was emphasised by many early researchers as an important underlying mechanism via which psychedelics may work therapeutically. It has recently been argued that, because of this effect, psychedelics represent an opportunity to study the mechanisms via which the human brain produces a coherent sense of self or ego. Important for the present discussion is the study by, who demonstrated construct validity for ego-dissolution, and specificity of ego-dissolution for the experiences with psychedelics, over experiences with alcohol or cocaine (which were associated with the opposite effect, i.e. "ego-inflation"). Earlier questionnaire studies have also indicated prominent effects of psychedelics on ego-functioning, in particular via high ratings on the distinct ASC factor "oceanic boundlessness", defined as "positively experienced derealisation and depersonalisation", and via increased ratings for "impaired control and cognition", an important marker for disturbed ego-functioning. Finally, ego-dissolution has been related to enhanced suggestibility under LSD-an effect that has also been prominently hypothesised in early research as a potential therapeutic action of psychedelics.
THE CAPACITY OF PSYCHEDELICS TO FACILITATE AUTOBIOGRAPHICAL EXPERIENCES
The capacity of psychedelics to facilitate autobiographical experiences has not given much attention yet in modern research.demonstrated increased vividness for autobiographical memories, and ratings in questionnaires that relate to autobiographical experiences, such as "I saw scenes from my past" are shown to be enhanced under psilocybin
THE CAPACITY OF PSYCHEDELICS TO FACILITATE PEAK EXPERIENCES
The capacity of psychedelics to facilitate peak experiences requires special attention, given the significant emphasis that was placed on its therapeutic value by early researchers in previous literature. Overall, pronounced subjective effects that are consistently reported include experiences of "blissful" emotions, a "sense of unity", and feelings of "spirituality", and these effects have been related to the ego-boundary dissolving effects of psychedelics. Although these studies suggest that psychedelics can produce subjective effects, that can be categorised under peak experiences, important work has been done by, who explicitly studied the occurrence of peak experiences under psychedelics, and tested early hypothesis that these experiences are associated with sustained changes (up to months/years) in mood, behaviour and personality. The hallmark study ofdemonstrated that psilocybin is able to facilitate peak experiences (named by the authors as "mystical-type experiences") with sustained personal meaning, in individuals who have never taken a psychedelic drug before. Subsequent studies replicated these findings and associated these experiences with enduring positive changes in outlook, personality and behaviour72% of the participants who received psilocybin for their first time reported the experience to be in their top 5 of most meaningful experiences in their lives, and 65% reported improved well-being 14 months afterwards.showed that only those individuals who experienced a strong, or "full" mystical-type experience, as defined by the Mystical Experience Questionnaire (MEQ), presented a significant increase in the personality trait "openness", 14 months after the experience. These studies provide support for the hypothesis brought forth by earlier research that psychedelics can facilitate peak experiences, and support the view that peak experiences are associated with sustained positive changes. In addition, the studies showed that enduring positive changes can be instantiated by administering psilocybin only once or on a few occasions, and that these changes can occur in constructs, such as personality traits, that are normally considered stable in adulthood.
CLINICAL TRIALS WITH PSYCHEDELICS
In recent years, a number of clinical studies have focussed on the treatment of addiction-and mood disorders, and end-of-life care, using psychedelic therapy. Studies for psychedelic therapy for treating addiction have been implemented for tobacco-dependence and alcoholdependence.conducted an open-label pilot study to the efficacy of psilocybin-assisted psychotherapy for smoking cessation, and included 15 participants that had an average of six previous quitting attempts, and who smoked on average of 19 cigarettes per day for 31 years. The study showed that 12 of 15 participants (80%) completely abstained from smoking at a 6-month follow-up, and 10 of 15 participants maintained abstinence at 12-month follow-up. At the 12-month follow-up, 13 participants (86.7%) rated their experience with psilocybin to be "among the five most personally meaningful and spiritually significant experiences of their lives". Furthermore, the participants who rated high on measures for mystical-type experiences, personal meaning and spiritual significance, also showed the strongest sustained reductions in craving (Garcia-Romeu,, supporting the hypothesis that positive therapy outcomes are mediated by peak experience.performed the first open-label pilot study to test safety and efficacy of treating ten patients with alcohol-dependence with psilocybin. Patients showed a significant increase in drinking-abstinence following psilocybin, and these reductions were maintained at a 36-week follow-up. The general intensity of drug-effects during the psilocybin experience significantly predicted reductions in drinking and in craving 5 weeks later. Finally,performed a meta-analysis on studies using LSD to treat alcoholism in the 1950s and 1960s, including six studies describing the treatment of 536 patients, and showed improvements up to 6 months after one dose of LSD. There are two open-label pilot studies that have assessed safety and efficacy of the use of psychedelics to treat major depression, one using the DMT-containing Amazonian plant-brew ayahuascaand one using psilocybinadministered ayahuasca to six patients with mild to severe depression and showed significant reductions in measures for depression up to 21 days after administration.administered psilocybin to patients with treatment resistant depression, who were in treatment on average of 18 years, and showed a 67% response rate (n=8) at 1 week after treatment with psilocybin, of which seven patients met the formal criteria for remission. Seven patients (58%) maintained their response for up to 3 months after the experience and five patients (42%) remained in full remission. Another application of psychedelic therapy concerns its use in end-of-life care, to improve quality of life in patients diagnosed with a terminal illness, by treating co-morbid diagnosis of anxiety-disorders and distress.administered psilocybin to twelve subjects with advanced-stage cancer who had a diagnosis of acute stress or anxiety disorder due their illness. The study showed significant improvements in mood at 6 months' prior the experience, but the effect-size was small, nor did the outcomes correlate with measures for peak experiences. The authors argue that the findings may reflect the relative low dose that was used (0.2 mg/kg), compared with dosages used by(approx. 0.5mg/kg)., provided two psychedelic therapy sessions with LSD to patients with end-of-life anxiety, and showed significant reductions in trait and state anxiety at the 2month and 12-month follow-up. The authors note, however that only 3 out of 8 patients in the experimental group, reduced anxiety-measures to a level below the diagnostic cut-off. In a separate 12-month follow-up study,reported that 66.7% reported that LSD facilitated access to emotions, deepened introspection and insights, and changed personality and values. The authors note that the observed therapeutic changes were "mainly dependent on a related encompassing of emotional experiences". The most comprehensive studies towards the efficacy of psychedelic therapy in end-of-life care, are two recent double-blind placebocontrolled clinical trials.showed acute improvements after high-dose sessions (30 mg/70 kg), with 80% of the 51 participants showing clinically significant decreases in depressed mood and anxiety at the 6-month follow-up.demonstrated clinically significant reductions in depression or anxiety after one dose of psilocybin (0.3 mg/kg) that sustained in 60-80% of participants at the 6.5 month follow-up. Finally, in a small open-label pilot-study,administered psilocybin to nine patients with obsessive compulsive disorder (OCD). Symptom severity was measured at baseline and at 4, 8 and 24 hours post-administration. All subjects demonstrated acute reductions in symptoms, ranging from 23% to 100% reduction. Compared to baseline, at 24hours post-administration 88.9% maintained a reduction in symptoms equal or larger than 25%, and 66.7% maintained a reduction in symptoms equal or larger than 50%. See appendix for study-details of these clinical trials.
SAFETY AND EFFICACY OF PSYCHEDELICS
The results of these clinical studies show a promising prospect. Although the sample-sizes are small, the fact that remission and abstinence has been maintained for long periods after a single or a few sessions, is "unheard of" in psychiatry. Particular notice must be given to the severity of the conditions of the patients in these studies, such as long-term drug-dependencyor treatment-resistance. Another important contribution of these pilot-studies is their demonstration of safety within patient populations. So far there are no adverse events reported, apart from temporary anxiety and thought confusion in some volunteers during the sessions. Needless to say, although the current data is suggesting a good safety-profile, the strict selection criteria and small study population sizes may have influenced these findings, and studies in larger populations are warranted. But the emerging picture suggests that psychedelics can be safely administered when appropriate guidelines are adhered. Indirect support for the safetyprofile of psychedelics comes from meta-analyses that showed mental health complications following psychedelic drug use amongst users to be rare (i.e. <0.1%) (Cohen and. In addition, decreased rates of suicidality and psychological distress were reported among individuals with a history of psychedelic drug useand there is no evidence for increased rates of mental health problems in populations who use psychedelics.
NEUROSCIENCE OF PSYCHEDELICS
To inform hypotheses and study-designs for the investigation of how psychedelics and music work in the brain in combination, an understanding of how they work separately is an important starting point. This section will provide an overview of early and modern neuroscience research of psychedelics. It will start with outlining the findings from neuroscience research with psychedelics at the microscopic level, i.e. the study of the interactions of psychedelics with neurotransmitter-systems in the brain, and then describe how this influences behaviour of neurons and their communication. This will serve as an introduction to the subsequent sections, which will review our current understanding on the effects of psychedelics on the macroscopic level, i.e. the changes produced by psychedelics in the behaviour of large populations or networks of neurons as measured by neuroimaging studies, and how these changes in brain function have been associated with some of the major psychological effects occasioned by psychedelics described previously.
PSYCHEDELICS ACT AS SEROTONIN 2A RECEPTOR AGONISTS
Almost a decade after the discovery of LSD, the presence of the neurotransmitter serotonin was discovered in the human brain. It was the structural similarity between LSD and serotonin that made researchers speculate about a role of serotonin in producing the behavioural and subjective effects of LSD. First, experiments proposed contradicting mechanistic models, of LSD being either an antagonistor an agonist) on the serotonin receptor system. What aided the research significantly, was the increased knowledge on the different serotonin receptor subtypes, and the development of selective serotonin antagonists. A series of studies using drug discrimination models in ratsand primates, showed that serotonin 2A antagonists, but not serotonin2C antagonists, blocked discriminative cues of psychedelics. Behavioural effects of psychedelics in mice, such as head twitching, have been successfully blocked by selective serotonin 2A antagonists and by knocking out genes encoding serotonin 2A receptors in mice. Radioligand binding studies show a 10 to 100-fold higher affinity of LSD for the serotonin 2 receptor family, compared to other serotonin receptor sub-types, and serotonin 2A receptor affinity across different types of psychedelic drugs correlates with their potency. However, ergotamide and lisuride do not produce behavioural or subjective effects like "classic" psychedelics such as LSD, yet they exhibit high serotonin 2A receptor affinity and agonist properties. This led to the identification of down-stream, intra-cellular signalling pathways that are recruited by psycho-active, but not by non-psychoactive serotonin2A agonists. Important evidence for the role of the serotonin 2A receptor in producing subjective effects of psychedelics was derived from human studies with serotonin 2A antagonists.showed that the effects of psilocybin are abolished when co-administered with the serotonin 2A receptor antagonists ketanserin and risperidone. Subsequently, serotonin2A antagonists are shown to block effects of psilocybin within various cognitive-and behavioural measures, including tasks for automatic response inhibition (prepulse / sensorimotor gating) and controlled response inhibition (semantic / stroop interference), and experiments that assessed emotional biases and positive mood. More recently, the effects of ayahuascaand of LSDwere successfully blocked by ketanserin too. Together, these studies provide a body of evidence that indicates that psychedelics produce their subjective effects via activation of the serotonin 2A receptor.
EXPRESSION AND ACTIVATION OF THE SEROTONIN 2A RECEPTOR
The serotonin 2A receptor is expressed throughout the neocortex, but is especially highly expressed in high-level association areas (defined in subsequent paragraph), including the posterior cingulate cortex, the anterior cingulate cortex, the medial temporal lobes and the insula. What are the effects of activating these receptors? Upon activation of the serotonin 2A receptor, the neuron's cell membrane depolarizes and becomes more excitable, i.e. more likely to fire in response to incoming action potentials. The outcome of this increased excitability depends on the type of neuron that is stimulated. The human neo-cortex is organised into distinct layers (six in total), and each layer is characterised by distinct cell types that are connected in a canonical fashion: distinct cell-types are forming a specific wiring-pattern, which is repeated, like the patterning of a tapestry, throughout the neo-cortex. The majority of serotonin 2A receptors are expressed on excitatory glutamatergic pyramidal neurons within the deep layer V of the cortex, and to a lesser extent on GABA-ergic inhibitory interneurons. The deep layer V pyramidal neurons form an "output", projecting to hierarchically subordinate regions, whereas deep layer 5 inhibitory interneurons provide local inhibition of pyramidal neuronal activity. The net-effect of increasing the excitability of both neuron-types may therefore be difficult to predict. Because interneuron-to-pyramidal-neuron communication orchestrates a meticulously balanced activation/deactivation of neuronal populations under normal conditions, one prediction is that increasing their excitability will have a desynchronizing or disordering effect on neuronal oscillations. The following sections will discuss the effects of serotonin 2A receptor activation on brain activity in more detail.
HUMAN NEUROIMAGING WITH PSYCHEDELICS: INTRODUCTION
The micro-level organisation outlined above provides the elementary building-blocks for the macro-level organisation of the human brain -a highly complex network encompassing an approximate 100 billion neurons, that are organised into functionally segregated regions and networks of regions. Brains construct internal working models of their environment that motivate behaviours accordingly. Because this environment is ever-changing, and a critical source for survival as well as it is a continuous source of challenges and threads, much of the human brain evolved into highly specialized functions that account for the complexity and flexibility needed to thrive. Understanding how the brain does this, is the ultimate goal of human neuroscience. Neuroimaging, in turn, is one of human neuroscience's most valuable tools to do so. Neuroimaging refers to the various techniques that allow the imaging of either the structural (anatomical) or functional (activity) characteristics of the nervous system. There are various modalities that allow the imaging of the living human brain, including electroencephalography (EEG), magnetoencephalography (MEG), direct recordings via implanted electrodes, positron emission tomography (PET), single photon emission tomography (SPECT), and magnetic resonance imaging (MRI). Each modality poses unique advantages and limitations, and in addition, the different experimental paradigms (e.g. the experimental scanning conditions) and the data-analyses techniques (i.e. the processing and drawing statistically-informed inferences from these measurements) add to the vast possibilities of how the human brain can be studied. An introduction into these paradigms, techniques and terminologies, and in particular those used in the research presented in this thesis, will be provided in the next chapter 2 (methodology). This section will focus primarily on providing an overview of human neuroimaging with psychedelics performed under resting state (task-free) conditions. These studies have produced important insights into how psychedelics change brain function, unconstrained by experimental conditions. Furthermore, these studies provide an important foundation from which to formulate the primary hypotheses in this study, that aim to understand how the way music is processed in the brain is changed under psychedelics.
HUMAN NEUROIMAGING WITH PSYCHEDELICS: EARLY RESEARCH
Reviewing early neuroimaging studies with LSD in the 1950s and 1960s presents a challenge, since both the technologies used and the methodological standards to statistically process and analyse complex time-series, have undergone significant advances over the last decades. Nevertheless, early studies that used direct depth EEG and scalp EEG to record spontaneous brain activity, have given important insights into possible brain mechanisms by which psychedelics may produce their subjective effects -of which some have been confirmed or indirectly supported by modern neuroimaging research. One of the most consistent observations of the early work may be a lowering of the power or amplitude of spontaneous brain activity after psychedelics. Decreases in the amplitude of spontaneous cortical activity are demonstrated after LSD and mescaline in rabbits, in cats, in rats, and in humans. Often these reductions in oscillatory power occurred in the alpha range and were accompanied by a simultaneous increase in the alpha frequency.performed a series of experiments utilising intracerebral recordings using depth EEG in patients with schizophrenia and convulsive disorders, and reported a "pronounced quieting effects" on brain activity, with simultaneous increases in infrequent recurrences of short bursts of "alpha-like discharges" in the visual cortex and deep in the temporal lobes. The authors reported that these sudden bursts of activity corresponded with the presence of eyes-closed visual hallucinations and the presence of music: "One patient had waxing and waning of the alpha-like spindles from the depths of the occipital region that corresponded with the rhythms of music. This appeared at the height of the mescaline effect but never appeared without music or in the control period with music" The neuroimaging studies in this period led researchers to hypothesise an important role for the temporal lobe system in producing the subjective effects of psychedelics. Animal work described disorganised activity within the hippocampus, and the disappearance of behavioural effects of LSD in chimpanzees whose temporal lobes have been removed.used depth electrodes to study the effects of LSD and mescaline on brain activity in humans, and associated disorganized activity within the hippocampus with the occurrences of visual hallucinations and emotionally charged memories.corroborated these findings by demonstrating that after surgical removal of temporal lobes in humans with epilepsy, LSD lost its effectiveness in producing changes in amplitude or frequency of cortical activity.
HUMAN NEUROIMAGING WITH PSYCHEDELICS: BRAIN ACTIVITY
Modern neuroimaging in animals is largely consistent with earlier work, showing pronounced reductions in oscillatory power across different frequency bands after administration of serotonin 2A agonists. In what follows, the aim is to provide a brief but comprehensive overview of the modern human neuroimaging research that has been done with psychedelics, with a focus on resting state neuroimaging paradigms. The earliest modern EEG study with a psychedelic may be the report by, who managed to perform field EEG recordings in participants of an ayahuasca ritual in Brazil. The study reported trend decreases in oscillatory power in the alpha and theta frequency bands, and trend increases in oscillatory power in the beta frequency bands.assessed the effects of ayahuasca on cortical activity using EGG in wellcontrolled experimental conditions, and confirmed earlier observations, showing broad-band power decreases in spontaneous brain activity after ayahuasca.assessed the effects of psilocybin on resting state brain activity using MEG, and showed significant decreases in oscillatory power across frequency bands, with particularly pronounced decreases in the alpha frequency range. These decreases appeared localised in the posterior cingulate cortex, and the magnitude of the decreases in alpha activity correlated positively with ratings for ego-dissolution. The finding that psychedelics decrease low-frequency oscillatory power in the human brain has since then been replicated with psilocybin, LSDand ayahuasca. Carhart-Harris et al (2016) replicated previous findings with psilocybin, showing reductions in alpha oscillatory power within the PCC under LSD to correlate with ratings of ego-dissolution.furthermore showed that decreases in oscillatory power under psilocybin extended into parahippocampal regions, which form part of the medial temporal lobe system. Previous studies measured effects of psychedelics on brain dynamics over one time-window during strongest drug effects. In contrast,recorded resting-state cortical activity with EEG for over 2 hours in 25 minute intervals, and indicated that ayahuasca reduced alpha power 50 minutes post-administration, but that alpha oscillatory power was restored back to normal levels in subsequent measures at later time-points, and then accompanied by significant increases in gamma power.reported increases in glucose metabolism in cortical and subcortical regions after psilocybin, including increases in the anterior cingulate cortex, the insula, the thalamus and the (medial and lateral) temporal lobes. These changes correlated with some of the subjective effects of psilocybin, such as visual hallucinations and ego dissolution, and in particular with increases in the cingulate cortex, medial temporal lobes and medial frontal lobes. Similarly,showed increased blood perfusion after ayahuasca in the anterior insula, the anterior cingulate, the left amygdala and parahippocampal gyrus. In contrast, the first fMRI study assessing acute effects of psilocybin by, showed decreases in the BOLD signal and in cerebral blood flow (ASL) in cortical and subcortical regions, and these decreases appeared in high-level association regions such as the medial prefrontal cortex and the precuneus (part of the default mode network (DMN)), and correlated with subjective effects of psilocybin. These findings have been replicated by Palhano Fontes et al, who showed decreases in the BOLD signal after ayahuasca in DMN regions under resting state conditions. These findings have been interpreted as a disorganising or disintegrating effect of psychedelics on the integrity of high-level brain regions. Accordingly,showed increased BOLD signal variability after psilocybin, with particularly pronounced changes within the hippocampi and the anterior cingulate cortex. In accord with these findings,showed that psilocybin and LSD produce significant increases in entropic brain activity, suggesting that brain activity becomes more disorganised, unpredictable or uncertain.
HUMAN NEUROIMAGING WITH PSYCHEDELICS: BRAIN CONNECTIVITY
An important advancement in neuroimaging is the study of functional integration, i.e. the communication between anatomically and functionally segregated brain regions, and recent studies have provided insights into how psychedelics affect functional connectivity using fMRI.demonstrated significant decoupling between the medial prefrontal cortex and the posterior cingulate cortex. This finding has since then been replicated with ayahuascaand with LSD. In addition,showed a decoupling of the medial temporal lobe areas from parietal lobes after psilocybinshowed decoupling of the parahippocampus (part of the medial temporal lobes) from the DMN after LSD. The medial prefrontal cortex, the posterior cingulate cortex and the medial temporal lobes are structurally wellconnected and show strong functional coupling under normal resting state conditions. These regions are important high-level association regions that function like "communication hubs" -central nodes in a network that receive and integrate information from many disperse and different functionally specialised brain regions. The pronounced reductions in functional connectivity between these regions facilitated by psychedelics suggests that a key mechanism via which psychedelics work in the brain is to dis-organise or dis-integrate the functional integrity of these high-level brain networks. This is in line with the body of evidence discussed previously indicating that psychedelics work by desynchronizing brain activity within high-level association cortices. In addition to studying changes of functional connectivity between different regions, valuable insights have emerged from studying changes in coupling between different brain networks. Two resting state brain networks that usually display anti-correlated or orthogonal activity, the DMN and the Task Positive Network (TPN), are shown to become positively coupled after psilocybinand after ayahuasca. Expanding on these findings,investigated thirteen separate resting state brain networks and reported marked increases after psilocybin between brain networks that are usually more strictly functionally segregated, in particularly for high-level association networks in which the serotonin 2A receptors are in highly expressed, i.e. the posterior cingulate cortex and the anterior cingulate cortex within the DMN. Similar findings were reported for LSD, including significant increased coupling between normally segregated brain networks, with simultaneous disintegrated activity within the networks themselves.assessed the effects of LSD on whole-brain functional connectivity density (FCD), which corresponds to the strength of correlated activity for each region with all other parts of the brain, i.e. high FCD values indicate high global connectivity. Key findings from this study are that FCD was increased within high-level association networks, such as the DMN and the salience network, and that FCD increases within the insula and the angular gyrus correlated with ego-dissolution.
NEUROSCIENCE RESEARCH WITH PSYCHEDELICS: SUMMARY
Taking these findings together, a picture emerges of psychedelics desynchronizing and disorganising neuronal activity via serotonin 2A receptor activation, and in particular within important hub-regions that form hierarchically high-level brain networks. Simultaneously, psychedelics facilitate an increased coupling between brain regions and networks that are normally more strictly functionally segregated. This "collapse" of the usual hierarchy of brain function, and the resulting decrease in the brain's modularity, may be a fundamental mechanism via which psychedelics produce their interesting subjective effects.
NEUROSCIENCE OF MUSIC
One key question that this research aims to address is how psychedelics change the way music is processed in the brain. To the author's knowledge, there is only one reference in previous literature on the effects of psychedelics and music on brain function, and that is the study bywho reported that the effect of music under mescaline was associated with "alpha-like spindles", which "never appeared without music or in the control period with music". A complete review of all neuroimaging research with music is beyond the present scope, but to formalise a working hypothesis, this section will provide an overview of the relevant studies that informed the present study's primary objectives: a discussion on the brain mechanisms of music-perception, music-evoked emotion, and music-evoked mental imagery.
HUMAN NEUROIMAGING OF MUSIC-PERCEPTION
Music is a highly dynamic and multi-dimensional stimulus, consisting of distinct acoustic features, such as pitch, loudness, tempo, rhythm and timbre. Accordingly, the neurobiological and cognitive processes involved in music-listening display a complex functional specialisation and a strong hierarchical organisation. This process serves the analysis of the spectral and temporal structures of the sound, and the linking of these patterns with high-level mental representations. Hereby, music attains its profound capacity to elicit thoughts, sensations and emotions. One of the central insights of the neuroimaging of music-listening, is that music recruits large-scale brain networks involved in attention, working memory, episodic memory, motor function and emotion. This has turned music into a valuable tool for cognitive neuroscience to study the functional organization of the human brain. This processing of music starts at the lowest levels of the brain's hierarchy, at the cochlea, where incoming auditory information is filtered, before being forwarded to the brainstem and the medial geniculate nucleus (MGN) -a region within the thalamus that is specialised into relaying auditory information to the auditory cortex. Within the auditory cortex, the processing of music starts by analysing music's "elementary" acoustic properties, such as the loudness, tempo, pitch and timbre. This process involves Heschl's gyrus, the superior temporal gyrus (STG) and the planum temporale, and these processes occur in parallel and are integrated progressively within the processing hierarchy. The linking of acoustic information with complex "high-level" mental representations, is associated with information exchange between these auditory cortices and the inferior frontal gyrus (IFG). The IFG, also termed Broca's area, plays an important role in auditory working-memory, and has been implicated as a critical area for the syntactical processing of sound, that both music and spoken language have in common.
HUMAN NEUROIMAGING OF MUSIC-EVOKED EMOTION
Music-evoked emotions are often described in the literature as "complex", since music not only evokes basic, "simple" emotions such as pleasure and fear, but often a mixture of emotions. Feelings of "nostalgia" or feelings of "wonder" are good example of such complex music-evoked emotion. The emotion-evoking effects of music are found to rely on the engagements of both limbic brain areas, such as the amygdala and the striatal system, and high-level association cortices, such as the insula the hippocampus and the orbitofrontal cortex. The ventral striatum is consistently activated to music, and several neuroimaging studies have associated the ventral striatum with music-evoked pleasure and the encoding of music-evoked reward. Of particular significance for the present study may be the notably high numbers of studies that implicate an important function of the medial temporal lobe system (including hippocampus and parahippocampus) and the insula in music-evoked emotion. The medial temporal lobes are high-level unimodal association cortices, specialised in memory-formation, memoryactivation and context-dependent cognition (Lavenex and, and are considered to be important for top-down regulation of emotion. In turn, the insula is often activated to music-evoked emotion, and has been more described as a high-level association region involved in self-awareness and emotional -awareness.
HUMAN NEUROIMAGING OF MUSIC-EVOKED MENTAL IMAGERY
Mental imagery is defined as a perceptual experience, without the presence of an external perceptual stimuli. Neuroimaging studies suggest that mental imagery has overlapping, if not identical, neural mechanisms to the neural mechanisms underlying perception. With regard to the relationship between music and mental imagery, musical mental imagery has been studied in the context of music performance, but there exists a significant lack of knowledge into how music can evoke visual mental imagery. This is striking, since music's effect on mental imagery, and more broadly on spontaneous imagination, is popularly considered to be amongst music's major effects, and plays a central role in several music therapy modalities.
PRIMARY RESEARCH OBJECTIVES OF THIS THESIS
This introduction chapter provided an overview of the historical and modern scientific knowledge and psychotherapeutic perspectives on psychedelics and music. It highlighted how music plays a central role in the increasing numbers of clinical trials that implement and study psychedelic therapy, yet it demonstrated how little is known empirically on the function of music in this context. The reportedly profound effects of psychedelics on the subjective experience of music suggests that music may play an important therapeutic function, that demands empirical studies in order to advance the rapidly expanding scientific and psychotherapeutic community that works with psychedelics and music in combination. Furthermore, by studying the brain mechanisms underlying their combined effects on subjective experience, our understanding of how the brain processes music and complex subjective states may be significantly furthered. Example of this are the brain mechanisms underlying complex emotions associated with peak experiences, autobiographical experiences and visual mental imagery evoked by music. The primary research objectives of this thesis are (1) to study the acute effects of psychedelics and music in combination on brain function under LSD (2) to associate changes in music-evoked emotion and music-evoked mental imagery with changes in brain function under LSD, (3) to study the music-experience in psychedelic therapy with psilocybin and the relationship between music-experience and therapy outcomes. These objectives will be addressed via four separate studies, of which the hypothesis and methods will be discussed separately in more detail in each corresponding chapter: "The conclusion from all these considerations is that the most important step in the art of being, is everything that leads to and enhances our capacity for heightened awareness and, as far as the mind is concerned, for critical, questioning thinking" Erich Fromm
METHODOLOGY
This chapter serves to provide an introduction into the methods used in this research. It will briefly explain the background of functional magnetic resonance imaging (fMRI), and introduce the different fMRI data analysis methods used to measure changes in brain function (BOLD activity, functional connectivity and effective connectivity). Finally, it will introduce the selection of the psychological metrics used to study changes in musical experiences under LSD, including the Geneva Emotional Music Scale (GEMS) and Interpretative Phenomenological Analysis (IPA). The chapter will outline the study-designs that were used in the experiments in this thesis, but details will be provided seperatey for each separate experiment in the corresponding chapters.
A BRIEF INTRODUCTION TO FMRI RESEARCH
The emergence of fMRI in neuroscience research in the 1990s had a revolutionary impact in the field. It was the first time that neuroscientists were able to measure human brain activity non-invasively and in vivo in a relative high spatial resolution. MRI works by exploiting the behaviour of hydrogen (H) atoms in a strong magnetic field. The MRI machine applies a strong magnetic field, that aligns the hydrogen protons with the magnetic field. Subsequently, radio frequency energy is applied to the hydrogen protons in the brain using a gradient coil around the head, "exciting" the protons into a high-energy state and "flipping" the protons 90° from the magnetic field axis. After excitation, the hydrogen protons release radio frequency energy while returning to their "relaxed" baseline state. This release of radio frequency energy is measured by the MRI scanner, and underlies the generation of an image. The full 3D brain images are usually acquired one slice at a time, with each slice being a 2D image. To overcome this relatively slow process, gradient echo planar imaging (EPI) techniques were developed that allow a faster acquisition of sequences of images, by collecting multiple "echoes" from each radio frequency pulse, providing one full brain image each few seconds -depending on the MRI scanner & selected parameters. fMRI measures the blood oxygenation level-dependent (BOLD) signal, which is a surrogate or indirect signal for brain-activity. The BOLD signal reflects the oxygenation of blood in the brain, estimated via magnetization difference between oxyhaemoglobin and deoxyhaemoglobin. When brain areas have increased synaptic brain activity, these areas undergo an increased metabolic demand, which results in the proportion of oxyheamoglobin and deoxyhaemoglobin to be relatively reduced. Thus, the BOLD-signal correlates with brain activity, and hence, BOLD-increases are typically inferred as increases. There are several limitations using fMRI to study changes in brain function. One major limitation of measuring the BOLD signal, is that the signal changes occur much slower than real brain activity (up to 80Hz). Changes in blood flow show a slow peak (5 second from the beginning of the increase), a signal referred to as the haemodynamic response function (HRF), and thereby significantly limit the temporal resolution of the BOLD measure. Secondly, the BOLD-signal changes are non-absolute, making only relative fluctuations in BOLD signal within one scanning session utilisable. Thirdly, the analyses of the BOLD-signal need to take into account a significant amount of noise in the data (e.g. non-specific background noise or head-movement artefacts in the measured fMRI signal). And finally, one needs to be reminded, that despite the superior spatial resolution of fMRI when compared with other neuroimaging modalities, the BOLD-signal that is measured per 3-dimensional unit or voxel, still represents the mixed activity of approximately one million neurons. Nevertheless, advances in methodology have made fMRI a dominant paradigm for relating brain function to behaviour and cognition, and over the previous decennia, fMRI has provided important insights into the brain's functional organisation. For example, fMRI research has highlighted the functional specialisation of functionally segregated "modules" that are localised in distinct regions and networks of the brain, such as for example the auditory cortex being specialised into the processing of auditory information. Furthermore, fMRI research furthered our understanding of the functional organisation of the brain, and highlighted processing hierarchies. For example, auditory information received by the cochlea, is forwarded to areas in the brain stem and the thalamus that are specialised into the processing of sound, which then relays this information to the primary auditory cortex in ascending levels of specialisation, abstraction, and association. The auditory cortices, in turn, represent different regions specialised into processing different properties of the sound, including its pitch, loudness and timbre. This will then be forwarded, in parallel, to other areas that process the what (object recognition) and the where (localisation) of the sound, and link the sound with complex mental representations and emotional responses). The further in the processing hierarchy, the more abstracted and multi-modal the signal is processed. This is one example of how fMRI research has advanced the field, by moving the focus away from localising specialised brain functions, to studying how brain areas communicate with each other as part of a highly interconnected complex system of processing units -also known as functional integration. Understanding how the brain coordinates and integrates activity from separate specialised regions as a dynamic network, is one of the central challenges in neuroscience research today. The experimental methods representing these advances that were used in this research, will be the focus of the following sections.
DESIGNING FMRI EXPERIMENTS
The hypotheses that fMRI allows to address are determined by the design of the experiment. A general distinction can be made between stimulus-or task-based paradigms and restingstate or task-free paradigms. In a task-based paradigm, the aim to is to present a stimulus or a cognitive/behavioural task for a certain duration (a block or epoch) (e.g. an auditory tone for 5 seconds), and to contrast this with a control condition (e.g. silence for 5 seconds). Contrasting these two conditions will then allow to identify the brain regions that are more activated (sound > silence) or less activated (silence > sound) during the auditory tone. Taskbased paradigms, allow to investigate specific modes of perception and cognition (e.g. auditory processing and working memory). In contrast, task-free or resting-state paradigms are characterised by the absence of stimuli or tasks, and allow to investigate "resting-state" brain functioning, and the "spontaneous" cognition associated with this (e.g. self-referential thinking or day-dreaming). A baseline or "default mode" of resting brain function was discovered via observing consistent de-activations in a set of brain regions during tasks. This led to identification of resting state brain networks, and to important insights into the intrinsic functional organisation of the human brain. With regard to the fMRI experiments (study 2 and 3), the stimuli consisted of full music tracks, that were contrasted with a stimulus-free condition (resting-state) to study an effect of music. In addition, given the objective to assess how psychedelics alter the effects of music on the brain, the experiments consisted of two separate study days, where on one day placebo (saline) was administered, and on the other day the drug (LSD) resulting in a factorial design (i.e. two conditions (music vs no music), present within 2 conditons (LSD vs placebo). The order of the conditions was randomised, to control for possible order-effects. These criteria did not apply to study 1, which was placebo-controlled, but in fixed order, and study 2, wich was an open-label clinical trial (i.e. with no placebo condition). Detailed motivations behind these study designs, including the motivations behind the music selection, are provided in the respective chapters.
FMRI SCANNING AND DATA PRE-PROCESSING OF FMRI DATA
Neuroimaging was performed on a 3T GE HDx system. An initial 3D FSPGR anatomical scan was obtained in an axial orientation, with field of view = 256× 256× 192 and matrix = 256 × 256× 192 to yield 1-mm isotropic voxel resolution (TR/TE = 7.9/3.0 ms; inversion time = 450 ms; flip angle = 20°). This was used for registration and segmentation of functional images. Functional images were acquired using a gradient echo planer imaging sequence, TR/TE = 2000/35ms, field-of-view = 220mm, 64 × 64 acquisition matrix, parallel acceleration factor = 2, 90° flip angle. 35 oblique axial slices were acquired in an interleaved fashion, each 3.4mm thick with zero slice gap (3.4mm isotropic voxels). The precise length of each of the BOLD scans was 7 minutes and 20 seconds. fMRI scanning sessions usually acquire a high-resolution anatomical/structural (T1-weighted) image and a number of functional (T2-weighted) images. Both the structural and functional images undergo a sequence of pre-processing procedures. This is critical, in order to correct for motion-or scanner-related noise in the data and to be able to compare the functional scans across subjects. The methods used in this thesis aimed to reflect the most recent advances in pre-processing methods (such as for example methods for correcting for motionartefacts), in accord with the significant changes these guidelines underwent over recent years. The fMRI pre-processing programme was assembled from several different complementary imaging software packages: FMRIB Software Library (FSL), AFNI, Freesurferand Advanced Normalization Tools (ANTS)were used. More details of the utilised pre-processing procedures and the chosen parameters are provided in the methods section of each separate neuroimaging study (study 2 and 3), but in general, the following pre-processing procedures were included: 1) De-spiking (3dDespike, AFNI): removal of "spikes" in the time series, to correct for motion artefacts. 2) Re-allignment (3dvolreg, AFNI): registration (mapping) of each functional image to the functional image that is most similar to all other images within the same scanning session (per subject), to correct for motion artefacts. 3) Brain extraction (BET, FSL): removing of all non-brain tissue from the structural images, to aid subsequent image registration of functional images onto anatomical images. 4) Anatomical registration (rigid body registration using FSL's BBR, or Freesurfer's bbregister when done manually): registration of all functional images to anatomical image per subject. 5) Template registration (aka normalisation) (SyN), ANTS): Non-linear registration to 2mm MNI template brain to align all subject-level images to the same template image, allowing subsequent group level analyses. 6) Scrubbing: substituting TR's with high framewise displacement (FD), to correct for motion correction. 7) Spatial smoothing (FWHM) (3dBlurInMask, AFNI): convolution of the BOLD signal with a 5mm full-width gaussian kernel, to control for spatial inhomogeneity and for radio frequency noise within the scanner . 8) Temporal filtering: using a high-pass filtering at a cut-off frequency of 0.01 Hz to remove baseline signal drifts in the BOLD signal, to correct for scanner noise (drift) correction. 9) Nuisance regressors (9 in total) were added into subsequent data-analysis (General Linear Model, explained below) to correct for motion correction. These were six motion-related (3 translations, 3 rotations) and three anatomically-related (not smoothed).
THE GENERAL LINEAR MODEL
The general linear model (GLM) is a statistical linear model, consisting of explanatory variables that predict the response variable. In fMRI data analysis, the GLM typically implies a multiple linear regression, where the BOLD signal is the response variable (Y), described by a linear combination of multiple explanatory variables (X), which can be the time courses that describe the experimental design (e.g. presence or absence of auditory tone) and nuisanceor noise-variables (e.g. time courses for head-movement). This is written as: For each voxel, the GLM finds the weights (𝛽 i ) that minimize the residual variance (𝜀) between the predicted and observed BOLD signal. This informs a statistical map for explanatory variables of interest, that can be examined in isolation or can be contrasted with other variables (e.g. auditory tone A versus auditory tone B). This statistical map illustrates BOLD-activations or BOLD-deactivations on a subject level, but most fMRI studies aim to make inferences on group level (e.g. condition A compared to condition B). To do so, the estimates of the subject-level GLMs enter a group-level (high-level) analysis, which typically involves a t-test or ANOVA. This results in a group average, which can be contrasted between different conditions (e.g. LSD vs placebo).
MEASURING CHANGES IN BOLD ACTIVATION
The analysis employed in study 2 (chapter 4), will assess BOLD activity changes related to different aspects (acoustic features) of the music. This study follows a classical task-based design as described above, where multiple time courses, each describing a distinct feature in the music, will be added as regressors into one GLM (e.g. loudness, pitch, brightness, etc.). This allows the generation of a statistical map for each different acoustic feature, and thereby allows to assess what regions are involved in the processing each separate feature, and subsequently, to investigate the differences between drug and non-drug condition in processing these features.
MEASURING FUNCTIONAL INTEGRATION: FUNCTIONAL CONNECTIVITY
As was said in the beginning of this chapter, the field has witnessed a significant shift in focus from studying functional localisation to studying functional integration. Various ways of assessing functional integration in the human brain have been developed for analyses of fMRI data. The most commonly employed are measures of "functional connectivity", which refers to the statistical dependencies, or correlations, between time courses representing BOLD-signal variations from different voxels or regions. In the present study, functional connectivity has been measured by using "seed-based paradigms", where the BOLD signal time-course of one region of interest (ROI, the "seed") is extracted to correlate against each other voxel in the brain. The research presented here used two different seed-based methods of measuring functional connectivity: Standard seed-based functional connectivity: In seed-based functional connectivity analyses, the BOLD-signal timecourse from one region of interest (ROI), i.e. the "seed", is extracted and correlated against each other voxel in the brain. This allows the identification of other regions that show co-variation in activity with the seed region, and permits to assess the changes regions or networks of regions show in correlated activity, across different experimental conditions (e.g. comparing functional connectivity between LSD and placebo conditions). Psycho-physiological interaction analysis: In psychophysiological interactions (PPIs) analyses, a time course from one seed ROI is extracted, and then multiplied, element-by-element, with the task-regressor. This generates a "PPI regressor", that will correlate with the seed ROI time course during tasks, but anti-correlated with the seed ROI time-course during rest blocks. Therefore, when the PPI regressor is correlated against each voxel in the brain, taskspecific changes in functional connectivity can be revealed.
MEASURING FUNCTIONAL INTEGRATION: EFFECTIVE CONNECTIVITY
Correlations can however arise in various ways. For example, activity in two separate regions can correlate because they share a common input of the stimulus, or their activity correlates because activity in one region causes activity in another via excitatory forward connections. Measures for the latter are called "effective connectivity", i.e. the causal or directed information flow between separate brain regions. Measures for effective connectivity take into account the hierarchical organisation of the brain via differentiating between forward and backward connections, and hence give a more accurate depiction of the involved brain mechanisms. Effective connectivity can be assessed by different methods, including Granger Causality, Structural Equation Modelling and Dynamic Causal Modelling (DCM). In the present study, effective connectivity was assessed using DCM. Informed by standard DCM procedures, this was preceded by functional connectivity analyses to identify the network to interrogate with further hypothesis testing using DCM. Dynamic causal modelling: DCM is a biologically-informed modelling procedure that estimates the causal interactions (i.e. effective connectivity) between different pre-selected nodes of a network, and the changes in coupling strength between and within those nodes (extrinsic and intrinsic connections respectively) due to experimental manipulations. The basic architecture of a model is defined by structurally plausible and functionally-informed brain regions, whose connections are defined as either bilinear (i.e. information flow between regions) or non-linear (i.e. activity in one region modulating information flow between regions). Typically, experimental manipulations can directly affect activity in each node (as 'driving inputs') or alter the strength of coupling within or between nodes (as 'modulatory inputs'). In DCM, a series of plausible models, representing competing hypotheses, are specified. Each model corresponds to a hypothesis about how observed changes in BOLD signal were caused by changes in neural activity in each network node. The different models can vary in terms of the position of driving and modulatory inputs. DCM uses a biophysical model of the hemodynamic response to predict the underling neuronal activity -and the underlying (changes in) connectivity -from the observed BOLD signal. Model estimation, or inversion, returns conditional estimates for the changes in connectivity and scores the model in terms of its accuracy and complexity. Following model estimation, Bayesian Model Selection (BMS) is used to compare different models to identify the model with the greatest evidence -i.e. the model that offers the best explanation of the data. This model can be selected to assess coupling parameters post-hoc, to characterize the size and direction of the changes in connection strength caused by the experimental manipulations. Coupling parameters quantify the strength of the coupling in terms of the rate (in Hz) at which a response is caused in a given region, and modulation is expressed as either an increase or decrease in this coupling measure.
METHODS FOR QUALITATIVE RESEARCH
This thesis also aims to investigate changes in the subjective experience of music under a psychedelic. In particular, the objective is to assess changes in music-evoked emotion and music-induced imagery, to associate these effects with measured changes in brain function in the neuroimaging studies, and to study the music-experience during psychedelic therapy. The methods employed to do so, include questionnaires, visual analogue scales (VAS) and qualitative analysis of interview data. Visual Analogue Scales and questionnaires: Visual analogue scales (VAS) for questions that assess the subjective experience of music were implemented. Examples of such questions are "how emotionally affected were you by the music?" (study 1), or "did you experience simple eyes-closed imagery?" (study 2), and responses to these questions are scored on a VAS scale ranging from 0 to 100, with respective anchors to indicate the qualitative meaning of the value. Comparing average ratings between conditions, allows to assess difference in subjective experience between drug and non-drug states, and the change-scores (drug>nondrug) allows correlation-analyses that associate changes in subjective experience with changes in brain function (e.g. correlating increases in ratings for mental imagery versus changes in effective connectivity (study 3)). There have been several psychological metrics developed to assess music-evoked emotion. A classic approach utilises a 2-dimensional model that differentiates between arousal (activating versus relaxing), and valence (positive emotions versus negative emotions). The critique on this metric is that it does not acknowledge the complexity inherent in musicevoked emotion: music-evoked emotions are argued to often be a mixture of basic emotions. For example, feelings of nostalgia include feelings of sadness (negative valence) and joy (positive valence). Some argued that those complex or aesthetic emotions are what makes the scientific study of music-evoked emotions in particular significant, and questionnaires have been developed that address this, such as the Geneva Emotional Music Scale (GEMS). This study uses the GEMS, which has been derived from a sequence of studies, starting with qualitative studies, towards large-sample rating studies, that used factor-analyses to validate distinct dimensions or factors of music-evoked emotion. Phenomenological analysis. The objective of study 4 was to deepen our understanding of the subjective experience and therapeutic function of music in psychedelic-assisted psychotherapy. Understanding patient-experiences in a naturalistic setting was an important motivation for this objective, given other expriments in this thesis concerned effects of psychedelics and music on healthy voltuneers, and within a context that is strikingly different from the therapeutic application (i.e. fMRI scanner vs quiet room with supportive therapists and music listening). To accomplish this objective, like in any other experiment, the study design determines the the conclusions that can be drawn. Science, in simplest terms, is a practice of advancing an emperical understanding of reality by finding meaningful patterns in data, in order to, in the words of physicist David Deutsch, "test new theories that seem to show promise of explaining things better than the prevailing ones do". To find meaningful patterns, many research designs are hypotesis-driven, in which the experiments are designed as such so that inferences can be made regarding specific, isolated variables of interest. A caveat with hypothesis-driven approaches is that hypohteses are per definition bounded by the limitations of current knowledge. Designing experiments with prior expectations, therefore, runs the risk of biasing and thereby excluding alternative, better explanations. This is especially problematic, when chartering unknown terrorities, such as the case in this thesis. Data-driven research approaches, on the other hand, allowing inferences to be told by the "data itself" (Shih, 2016), on the assumption that when prior beliefs are absent there is a greater possibility of insight into a phenomenon "where nobody had looked before". For study 4, we haven implemented a qualitative (semi) data-driven approach, called interpretative phenomenological analysis (IPA). This approach was chosen to analyse interviews with patients about their experience with the music during psychedelic therapy psilocybin, after their therapy session. The interviews consisted of open questions (for example: "Did the music influence your experience? And if so: in what ways?", to allow patients to share, using their own words and interpretations, unbiased by the researcher's hypotheses, whether or not, and how the music influenced their subjective experience. IPA is an approach increasingly used in healthcare research, and is considered in particular appropriate when ascertaining and unveiling the complexity behind patients' subjective experiences. Details on the methods and implementation of this analysis will be provided in the corresponding chapter (Chapter 6). The rather profound effects of classic psychedelics on emotion that early researchers in the 1950s and 1960s observed, was one of the primary motivations for their therapeutic use. It was believed that by dismantling usual control-mechanisms, or "ego defences", psychedelics enhance emotional therapeutic processes.
OVERVIEW OF SOFTWARE USED FOR DATA-ANALYSES
Like was detailed in the introduction chapter, psychedelics were found to produce a diverse spectrum of subjective experience, and music was introduced as a means to promote the occurrence of those types of experiences that were believed to have most therapeutic significance. These included peak experiences as well as autobiographical experiences. Music became a key component in psychedelic therapy sessions, and is still used in modern psychedelic therapy studies. Psychedelics under music-listening conditions are shown to reliably facilitate peak experiences, and those experiences are correlated with sustained positive changes in behaviour, personality, and clinical outcomes. To study the contribution of music in facilitating these types of experiences, a basic question must first be addressed: is music-evoked emotion intensified under psychedelics? This first study sought to test the hypothesis that music-evoked emotion is enhanced under the classic psychedelic drug LSD. Secondly, to probe more specific aspects of participants' emotional experiences during music listening, the Geneva Emotional Music Scale (GEMS-9) was implemented. The GEMS was developed to measure a range of emotional experiences during music listening and has been considered in particular useful to assess complex or "aesthetic" emotions, such as feelings of "transcendence", "wonder" and "nostalgia". The study predicted that the emotional response to music is higher under LSD, and that specifically emotions related to peak experiences ("transcendence" and "wonder") would be enhanced.
RECRUITMENT AND SCREENING OF PARTICIPANTS
All study participants were recruited via word of mouth and gave written informed consent before participating in the study. Prior to study enrolment, all participants were screened in a clinical research centre at the Hammersmith hospital campus of Imperial College London (the Wellcome Trust Clinical Research Facility, WTCRF). This screening consisted of recording of demographic information and medical history, as well as a physical examination (electrocardiogram (ECG), routine blood tests and blood pressure measurement), and a psychiatric assessment. All participants gave full disclosure of their drug taking histories. Participants and were properly briefed on the study and the potential drug effects. Key exclusion criteria were: <21 years of age, personal history of diagnosed psychiatric illness, immediate family history of a psychotic disorder, an absence of previous experience with a classic psychedelic (E.g. LSD, mescaline, psilocybin/magic mushrooms or DMT/ayahuasca), having experienced a persistent adverse reaction after psychedelic drug use, pregnancy, problematic alcohol use (i.e. > 40 units consumed per week), or a medically significant condition rendering the volunteer unsuitable for the study.
DRUG DOSING AND SETTING
One thousand µg of LSD freebase (certified 99.4% purity) was reconstituted with 10ml saline and sterile filtered, yielding a 100µg:1ml sterile solution. Since a primary motivation of the study was to determine a safe and appropriate dose of LSD for a subsequent neuroimaging study, the dosage of LSD varied among participants, i.e. one received 40µg, two 50µg, six 70µg and one 80µg. For each administration, the appropriate amount of LSD solution (E.g. 0.7ml = 70µg) was transferred to a 10ml syringe and made up to 10ml with saline. The 10ml solution was then infused intravenously over a three-minute period, followed by a 60 second infusion ("flush") with 10ml saline. The experiments were performed at the WTCRF at the Hammersmith Hospital. All experiments took place in a clinical room, consisting of a hospital bed, physiological monitoring equipment and en suite bathroom facilities. Since psychedelics have the potential to induce psychological distress, the clinical conditions of the room were adapted to promote feelings of comfort and safety, i.e. the lighting was dimmed and the room was decorated with soft furnishings. The setting was identical for all study days.
EXPERIMENT OVERVIEW AND PROCEDURES
Participants were carefully prepared for the drug experience at screening and the study was conducted in accordance with guidelines for the safe management of psychedelic drug sessions. This included psychoeducation on the subjective effects of LSD, introductions to the research-team that will be present, and an outline on how the experiment days are structured. After screening, eligible participants attended two study days, with at least five days in between. Participants were told they would receive LSD on one of these two occasions but were not told in which order. Thus, participants were blind to the condition (i.e. drug or placebo), however the researchers were not. Placebo (10ml saline) was always administered on the first day. This single-lind fixed order design was chosen to 1) avoid potential carry-over effects (E.g. residual psychological effects) of LSD into the next session, given evidence psychedelics can occasion changes in berhaviour and persionality up to months after the experience, and also 2) given experiences with psychedelics can be profound, having the placebo session first was argued to build interpersonal rapport, prior the drug session. Aware of the trade-offs of this design choice, the limitations are acknowledged and discussed in the discussion section. Volunteers arrived at the research centre between 10:00am and 11:00am on testing days, were briefed about the study procedure, gave a urine test for drugs of abuse and pregnancy (where relevant) and carried out a breathalyser test for recent alcohol use. A cannula was inserted into a vein in the antecubital fossa by a medical doctor and secured. Subsequently, volunteers were encouraged to close their eyes and relax in a reclined position before a 10ml solution of saline alone (placebo) or containing LSD was intravenously infused over a period of 3 minutes. Blood pressure was measured prior to dosing (baseline), 45 minutes after dosing and at the end of the study day (prior to discharge). Heart-rate was recorded at regular intervals, together with self-ratings of the subjective intensity of the drug effects on a scale of zero ("no effects") to ten ("extremely intense effects"). These measurements were taken every 1-5 minutes during the first 45 minutes post-infusion, and then continued in intervals of approximately 30-45 minutes until the end of the experiment. During the initial 45 minutes post-infusion, participants were encouraged to relax with their eyes closed and maintain a supine position while listening to music by the ambient music artists "Stars of The Lid". This music was only played during the initial 45 minutes, and not during the subsequent psychological testing. Participants reported first noticing subjective drug effects between 5 to 15 minutes postdosing, and these approached peak intensity between 45 to 90 minutes post-dosing. The duration of a subsequent plateau of drug effects varied among individuals but was generally maintained for approximately three hours post-dosing. Psychological tests were performed within this time-frame. Five music tracks were played to each participant during each session at the following time points post-dosing (minutes: mean, SD): 44 ± 17 (Track 1), 101 ± 25 (Track 2), 139 ± 33 (Track 3 and 4) and 250 ± 53. The time in between the tracks, participants either spent relaxing or performing tasks that were part of separate experiments and therefore not reported here. Once the subjective effects of LSD had sufficiently subsided participants completed a 29-item questionnaire enquiring about the drug's subjective effects. Following this, the study psychiatrist assessed the participant's suitability for discharge. Participants remained in the research centre for an average of six hours post-infusion.
STIMULUS SELECTION AND TASK DESIGN
Two playlists were compiled (A and B), each containing five different music tracks. One version was heard on the first study day and the other on the second, with the order of the playlists counterbalanced across participants. The emotional potency of the two lists was balanced based on pre-study ratings from a separate sample (n=10). Pre-ratings were provided for 16 instrumental music tracks of the classical, neo-classical, ambient and newage genres using the GEMS-9. In addition, the tracks were also rated for general liking and familiarity. It was from the subsequent ratings that 10 tracks were selected for the study. Specifically, tracks were chosen that produced highest liking and lowest familiarity, and a two-tailed paired t-test confirmed no significant differences between the playlists on liking, familiarity and GEMS-9 scores. The final five tracks selected for each playlist consisted of neoclassical and ambient music composed by the following four contemporary musicians: Greg Haines, Ólafur Arnalds, Arve Henriksen and Brian McBride (see table.1). Each music track and all rating scales were presented via Psychopy presentation software. Before listening to a music track, participants were instructed to close their eyes and relax. Music was played via high-quality stereo headphones (Beyerdynamic DT990 Pro) and participants were allowed to adjust the volume via remote volume control. When the music ended, a pre-recorded voice instructed them to open their eyes. They were then presented with the question "how emotionally affected were you by the music?" Participants gave ratings via a continuous visual analogue scale from 0 ("not at all") to 100 ("very much"). Following this, a digitalized and shortened version of the full GEMS, the GEMS-9, was presented. A particularly important instruction given prior to completing the questionnaire was that participants should rate how he or she personally felt in response to the music, and not what he or she thought the music was trying to communicate to them or how he or she felt in general. The GEMS-9 consists of 9 items or categories of emotion, with sub-items presented in brackets: wonder (filled with wonder, dazzled, moved), transcendence (fascinated, overwhelmed, feelings of transcendence and spirituality), power (strong, triumphant, energetic), tenderness (tender, affectionate, in love), nostalgia (nostalgic, dreamy, melancholic), peacefulness (serene, calm, soothed), joyful activation (joyful, amused, bouncy), sadness (sad, sorrowful), tension (tense, agitated, nervous). Each item was scored from 0 to 4: 0 = "not at all", 1 = "somewhat", 2 = "moderately", 3 = "quite a lot", and 4 = "very much".
DATA ANALYSIS
All statistical tests were performed in Statistical Package for the Social Sciences (SPSS) for Windows, Version 21.0. Scores for the question "how emotionally affected were you by the music?" for each stimulus were averaged for each subject per condition. A paired two-tailed t-test was performed to test for significant difference between conditions. Since the 5 possible ratings for the GEMS-9 were ascribed a relevant number (e.g. 0 = "not at all", 1 = "somewhat") and the resultant data was normally distributed, two-tailed paired t-tests were used to analyse between-condition differences. Subsequent false discovery rate (FDR) control was used to correct for multiple comparisons. Finally, a Pearson's correlational analysis was performed to evaluate a hypothesised relationship between the peak intensity of LSD's subjective effects and the intensity of emotional arousal in response to music under LSD (i.e. the average score for all music stimuli to the question "how emotionally affected were you by the music?") as well as the relationship between peak drug intensity and increases in the GEMS-9 item "transcendence".
PHYSIOLOGICAL EFFECTS OF LSD
Measurements of blood pressure and heart rate under placebo and LSD are displayed in table 3.2. Systolic blood pressure was slightly elevated under LSD relative to baseline and placebo but these changes were not statistically significant after correcting for multiple comparisons.
SUBJECTIVE EFFECTS OF LSD
Subjective drug effects were first noticed between 5 to 15 minutes post-LSD and approached peak intensity between 45 to 90 minutes post-dosing. Drug effects maintained a subsequent plateau for approximately three hours, and showed a gradual decline in the following hours. These results suggest that compared with oral administration of LSD, intravenous administration produces a quicker onset, and (slightly) shorter lasting experience. LSD produced diverse subjective effects (see Figure.1). The five VAS items that were scored highest under LSD were (in descending order) were "my thoughts wandered freely", "my imagination was extremely vivid", "I felt amazing", "things looked strange" and "I felt an inner warmth".
EFFECTS OF LSD ON MUSIC-EVOKED EMOTION
The average scores for all music stimuli to the question "how emotionally affected were you by the music?" were significantly higher for the LSD condition (0.71 ± 0.14) than for placebo (0.51 ± 0.18), t = 3.559, df = 9, p = 0.006 (see Figure.2). Significant increases were observed in the GEMS for the items "wonder" (p=0.027), "transcendence" (p=0.027), "power" (p=0.027) and "tenderness" (p=0.027) (reported p-values are FDR adjusted, see Figure.3).
EFFECTS OF LSD ON MUSIC LIKING
The average scores for "liking" the music showed a trend-level significant increase under LSD (0.80 ± 0.14) compared to placebo (0.71 ± 0.06), df = 9, p = 0.06. A Pearson correlation test revealed a significant positive correlation between "liking" of the music and VAS ratings on the question "how emotionally affected were you by the music?" (R = 0.68, p <0.001, n = 100) (see Figure.4). A significant positive relationship was found between ratings of the intensity of LSD's effects and emotional arousal to music (r = 0.79, n = 10, p = 0.01), as well as between the former and increases in the GEMS-9 factor "transcendence" (r = 0.79, n = 10, p = 0.01). Participants gave significantly higher ratings under LSD than placebo, t = 3.559, df = 9, p = 0.006. Figure.3 Geneva Emotional Music Scale (GEMS). Mean plus standard error values for the GEMS-9 scores for the complete playlist per condition. Scores were significantly higher for the LSD condition than placebo for the items "wonder" (p=0.027), "transcendence" (p=0.027), "power" (p=0.027) and "tenderness" (p=0.027). Reported P-values are FDR adjusted. * = p < 0.05 after FDR correction for multiple comparisons.
DISCUSSION
This study assessed changes in music-evoked emotion under LSD. The primary hypothesis that music-evoked emotions are intensified under LSD was supported, as was the more specific hypothesis that music-evoked emotions related to peak experiences showed an increase under LSD. Ratings for the Geneva Emotional Music Scale (GEMS) were significantly higher under LSD for the emotions "wonder" (i.e. filled with wonder, dazzled, moved), "transcendence" (i.e. fascinated, overwhelmed, feelings of transcendence and spirituality), "tenderness" (i.e. tender, affectionate, in love) and "power" (i.e. strong, triumphant, energetic). Ratings for drug intensity correlated positively with ratings for emotional arousal to music, as well as with music-evoked feelings of "transcendence". In addition, the study also showed a trend increase for ratings of music-liking under LSD, and a positive correlation between music-liking and the emotional-response to music.
IMPLICATIONS FOR PSYCHEDELIC THERAPY
These findings reinforce the assumption that normal musical influences are intensified under psychedelic drugs, and that this effect may be harnessed for therapeutic objectives. Typically, the conditions in which psychedelic therapy sessions are performed, are intended to promote a state of enhanced "introspection", where music constitutes the only external stimulus: Individuals lie supine in a relaxed position, close their eyes or wear eye-shades, and listen to a music for the duration of the drug-effects (5-8 hours). Under these conditions, peak experiences can be reliably facilitated, and the occurance of these experiences has been correlated with sustained improvements in well-being, increases openness, and improved therapy outcomes. Emotions of transcendence and wonder are considered core constituents of peak-and spiritual experiences. Thus, the ability of music to evoke these emotions, and of LSD to facilitate an enhancement of these music-evoked emotions, suggests that their combination may contribute to the occurrence of peak experiences. If peak experiences are associated with the sustained therapeutic effects of psychedelic therapy, and if the likelihood of their occurrence can be increased by music, then this would support the view that music is a valuable component within psychedelic therapy.
STUDY LIMITATIONS AND FUTURE DIRECTIONS
This experiment had several important limitations that need to be addressed. First, LSD has been found to enhance suggestibility, and such an effect may have influenced the present findings. Participants were not informed of our hypotheses, but it would not have been difficult for them to have inferred them from the experimental procedures. Participants' ratings for the question "how emotionally affected were you by the music", may have been higher to reinforce their own expectations or to confirm (their perception of) the researchers'. In addition, the discernible subjective effects of LSD make it difficult, if not impossible, to maintain study blind, and may have compounded any of such biases. Therefore, measures to reduce expectation or increase uncertainty about the experimental aims could be introduced in future studies. For example, variable doses of LSD and a larger sample size would allow to examine dose-dependent effects of the present findings. In addition, physiological measures for emotional arousal could also be introduced, such as the measure of "chills" via changes in galvanic skin response, which have previously been related to emotional arousal to music. Secondly, an active control would strengthen the blinding of the conditions in individuals who are naïve to subjective effects of psychedelics. For example, Griffith et al () utilised methyl-phenidate as an active placebo condition, and found some participants to be "fooled" by the condition. In addition, alternative pharmacological conditions could serve to probe into mechanistic hypotheses. For example, if the effects of psychedelics are instantiated via serotonin 2A receptor activation, co-administration with a selective serotonin 2A receptor antagonist would be predicted to significantly diminish the effects of the psychedelic on music-evoked emotion. This hypothesis is supported by a body of animal research suggesting an important role for serotonin 2A receptor activation in emotion regulation and emotion-guided behaviour. Another limitation of the experiment is that it did not have a balanced order, i.e. all participants received placebo on the first visit, and LSD on the second visit. Randomising or at least balancing the order of the LSD and placebo sessions be worth incorporating into the design of future studies to control for potential effects of order. However, it is unlikely that order contributed significantly to the present outcomes, given that the music playlists were balanced across participants and days, and order effects are typically sensitive to elements like learning and habituation. However, it may be argued that by the second visit in this experiment, participants may have been more familiar with the study procedure and study environment, and that this could have positively influenced their ability to be emotionally affected, thereby introducing a bias towards a positive finding. One other major limitation of this experiment concerns its ability (or lack thereof) to differentiate between the effect of drug and the effect of music. The experiment did not assess emotion pre-and post-music, but assessed the magnitude of being emotional affected by the music after listening. Without pre-and post-music ratings implemented within a factorial design, this experiment cannot exclude the possibility that the findings are driven by a general drug effect rather than a specific effect of music in combination with drug. The positive correlation between drug effects intensity and increased feelings of "transcendence" to music could be construed as supportive of this alternative interpretation. Alternatively, however, stronger drug effects may have simply enhanced a true music x LSD interaction. In defence of the present findings, both the ratings for "How emotionally affected were you by the music?", as the ratings for GEMS-9, explicitly requested that the participant rate how the music made them feel and not how they felt in general or what they thought the music was intending to convey. While no formal statistical tests for an interaction between drug and music on emotion was performed, the questions were intentionally constructed to enquire about the effect of music on emotion. This does allow to interpret the findings as differences in music-evoked emotion between the two conditions. Nevertheless, to investigate an interaction between drug and music on emotion, a factorial design will need to be performed, since the absence of such a design in the present study prevents a formal rejecting of the hypothesis that the results were driven by a general drug effect. Other limitations of the study design that future studies can address include studying the route of drug-administration, and identifying advantages of IV over oral administration. The assumption that a fixed-order design (with drug on the first), prevents possible "residual" psychological effects on the second study day, must be tested. Also, it is important to emphasise that this was a pilot study with a small sample size. Future studies with larger sample sizes, could address the dose-response relationship of LSD by including sufficient numbers of participant within different dose-groups. Moreover, only one female was recruited, all participants were psychedelic-experienced and only a selection of music styles were included. Inferences on the present results can therefore not be generalised beyond the music styles used in the present study and neither can they be easily generalised to larger populations. Future studies could assess the importance of specific genres or styles of music and the effect of individual music taste in determining outcomes in response to psychedelics.
CONCLUSIONS
The results of this experiment provide tentative support for the hypothesis that psychedelics enhance music-evoked emotion, yet more extensive studies are required to confirm and extend the inferences that have been discussed here. Specifically, more studies are warranted to probe into the relation between drug-effect and music-effect on subjective experience, as well as studies that test the importance of music as a component in psychedelic therapy, and studies that investigate how psychedelics enhance the emotional response to music via their effect on brain activity. These will be the objectives of the subsequent experiments. The quote that opens this chapter is provides a glimpse into how profound the subjective experience of music can be under a psychedelic. Similar reports are not difficult to find, and the widespread historical use of psychedelics and music by humans, may very well be related to their capacity to evoke such deeply idiosyncratic experiences. The potential of music on its own to evoke "complex" emotions, such as feelings of wonder and self-transcendence, as opposed to merely "simple" or "basic" emotions such as fear and pleasure, has been argued to yield an important tool for studying the neural correlates of human emotions. Music allows a relatively reliable activation of complex emotions under experimental conditions, such as feelings of nostalgiaor intense emotional experiences. Psychedelic drugs are shown to reliably facilitate emotionally intense peak experiences under music-listening conditions, and the findings reported in the previous chapter (study 1) indicated that music may play an important function in facilitating these experiences. Studying the brain mechanisms of musiclistening under psychedelics will help to understand how they interact on subjective experience, what their therapeutic potential may be when used in combination, and to provide empirical insights on how music may be best implemented in psychedelic therapy sessions. Studying music brings unique experimental challenges and opportunities, because music is a highly dynamic and multi-dimensional stimulus. Music consists of distinct acoustic features, such as pitch, loudness, tempo, rhythm and timbre, and neuroimaging studies with music have highlighted a hierarchy of processes; ascending from the cochlear, the auditory system processes increasingly complex acoustic features that are subsequently integrated via multi-modal and higher-order cortical regions that furnish the experience with mnemonic and affective properties. Several neuroimaging studies have used controlled auditory experiments to study acoustic features in isolation, however, recent studies advocate the use of more naturalistic paradigms in which participants listen to real, extended pieces of music. These naturalistic conditions, increase the ecological validity and obtain a more comprehensive description of the brain mechanisms involved in processing the complexity inherent in real musical stimuli and the complex emotionality they can evoke, such as those emotions that are associated with peak experiences. Psychedelics activate the serotonin 2A receptor, and produce an altered state of consciousness that is characterised by marked reductions in functional coupling within high-level brain networks, and simultaneous increased cross-talk between low-level areas. This "collapse" of the usual processing hierarchy, is thought to be a core mechanism underlying their subjective effects. This study intends to investigate the changes in brain processing of distinct acoustic features in under naturalistic music-listening conditions under LSD. The primary aim of this study was to identify what specific features of music are most sensitive to modulation by LSD, and how this relates to the changes in musicevoked emotions under LSD. More broadly, this experiment can offer insight into the brain's processing of complex naturalistic stimuli accompanying this network collapse under psychedelics.
PARTICIPANTS
Twenty participants (16 males and 4 females) were recruited for the study after successful screening and written informed consent. Screening consisted of physical and mental health assessments. Physical health assessments included electrocardiogram (ECG), routine blood tests, disclosure of full medical history and urine test for recent drug use and pregnancy. Mental health assessment consisted of psychiatrics interview. All participants provided full disclosure of their drug use history. Exclusion criteria included: being younger than 21 years of age, having a personal history of diagnosed psychiatric illness, having an immediate family history of a psychotic disorder, having used illicit drugs within 6 weeks of the first scanning day, having experienced a persistent adverse reaction to a psychedelic drug, pregnancy, problematic alcohol-use (i.e. > 40 units consumed per week), and having a medical condition rendering them unsuitable for the study. All participants were required to have at least one previous experience with a classic psychedelic drug (E.g. LSD, mescaline, psilocybin or dimethyltryptamine (DMT)). One participant did not complete the MRI scans due anxiety and three participants were excluded from analyses due to technical problems with the sound delivery. This resulted in including the data of 16 participants (13 males, 3 female) in the data-analysis; with preserved counterbalanced experimental design.
STIMULI
Two excerpts (A and B) from two songs by musician's Robert Rich & Lisa Moskow were selected for the study (form the album yearning). The stimuli were both 7 minutes and 20 seconds long and were balanced in their acoustic properties, and rich in timbre, but not in rhythm (see table 4.1). Pre-study assessments using GEMS in a separate group confirmed balance for their emotional potency (n=10). To reduce interference of fMRI scanning noise with the music experience, volume-maximization and broadband compression was carried out using Ableton live 9 software. Each participant listened to both stimuli, in a balanced order across conditions. The selective choice for calm ambient music for this study, was motivated by a study from, who performed a regression analysis on pooled data from 261 healthy volunteers, showing that under the influence of psilocybin, neuroimaging, together with trait "emotional excitability", are strong predictors for anxiety. That ambient music can compensate for this, however, is an assumption. Trade-offs of genreselection for this study, and implications for future studies, will be provided in more detail in the discussion section.
EXPERIMENT OVERVIEW AND PROCEDURES
All participants attended two study days that were separated by at least 14 days. LSD was received on one of the study days, and placebo (saline) on the other. The condition-order was balanced across participants, and the participants, but not the researchers, were blind to the condition-order (i.e. the study was a single-blind within-subject design). All participants received 75 µg of LSD intravenously, via a 10ml solution infused over a two-minute period via an inserted cannula. Administration was always followed by an acclimatization period of approximately 60 min, in which participants were encouraged to relax. Drug effects were noticed between 5 to 15 min post-dosing, approached peak intensity between 60 to 90 min post-dosing, and maintained peak intensity for approximately four hours post-dosing. BOLD fMRI scanning was performed during peak drug intensity, starting approximately 120 minutes post-dosing, and lasted for approximately 60 minutes. Once the subjective effects of LSD had sufficiently subsided, the study psychiatrist assessed the participant's suitability for discharge. Each fMRI scanning session involved three eyes-closed resting state scans, each lasting seven minutes and twenty seconds. The music-listening scan (220 TRs, 7.3 min) always occurred after the first resting state (no music) scan and before a final resting-state scan (no music). Prior to each scan, participants were instructed via a display screen to close their eyes and relax. The music itself was triggered by the first TR, and listened to via MR compatible headphones (MR Confon). Music volume was adjusted to a personal level that was "loud, but not unpleasant" and maintained for both condition.
QUALITATIVE MEASUREMENTS
The intensity of different types of music-evoked emotion was assessed via the 25-item Geneva emotional music scale (GEMS), and was administered under placebo and under LSD immediately after fMRI scanning was completed. The GEMS assesses music-evoked or "personally felt" emotion, and not the perception of musical emotion in the music. The 25 items were averaged into nine distinct factors of emotions: wonder, transcendence, power, tenderness, nostalgia, peacefulness, joyful activation, sadness, and tension. A paired t-test was performed to compare ratings between conditions (LSD versus placebo) for each emotion. Non-parametric permutation testing (10,000 permutations, twotailed) was carried out to correct for multiple comparisons.
ACOUSTIC FEATURE EXTRACTION
Acoustic features from excerpt A and B were extracted separately using the Music Information Retrieval (MIR) toolbox (version 1.6.1) (Lartillot and, implemented in MATLAB. Selection of acoustic features was informed by, who identified 25 features that broadly capture the dynamics of the timbral, tonal and rhythmic properties present in the music stimuli. From the original 25 features we excluded fluctuation entropy and fluctuation centroid because they have not been studied in the literature and did not carry any valid perceptual meaningpersonal communication). The 23 acoustic features used in our analyses were categorized in short-term features and long-term features (for an overview see Table.2). The short-term features were extracted with a sliding window of 25 ms, with 50% overlap between each segment while for the computation of the long-term features a longer sliding window of 3 s was employed, with 33% overlap between each segment (following the approach in. Subsequently, principle component analysis (PCA) on the acoustic features (combined for excerpt A and B) was performed to (1) identify acoustic properties that are present in both excerpts and (2) to reduce the number of regressors that entered the general linear model (GLM) for fMRI analyses. To prepare the acoustic features for the PCA, we first resampled short and long-term features to the same sampling rate of 1 s. We then rescaled (between 0 and 1) those acoustic features separately that were computed by different MIR toolbox functions (i.e., measured on different scales) whilst rescaling acoustic features combined that were computed by the same MIR toolbox function (i.e., measured on the same scale as the case for the 10 sub-band flux features) in order to preserve their covariance structure. The resulting time courses for excerpt A and B were then concatenated, to undergo the PCA. We performed varimax rotation on the first eight principal components (PCs) that explained over 90% of the variance (see Figure.2 for rotated PCs and their respective loadings). In order to validate that the first eight PCs explained the two excerpts equally well (i.e., that
SHORT-TERM FEATURES
Zero crossing rate, spectral centroid, high energy-low energy ratio, spectral spread, spectral roll-off, spectral entropy, spectral flatness (Wiener entropy), roughness, RMS energy, spectral flux, and Sub-Band Flux (10 coefficients).
LONG-TERM FEATURES
Pulse clarity, fluctuation centroid, fluctuation entropy, mode and key clarity. The fMRI pre-processing pipeline was assembled from four complementary imaging software packages . Specifically, FMRIB Software Library (FSL), AFNI, Freesurferand Advanced Normalization Tools (ANTS)were used. The following pre-processing stages were performed: 1) de-spiking (3dDespike, AFNI); 2) motion correction (3dvolreg, AFNI) by registering each volume to the volume most similar, in the least squares sense, to all others (in-house code); 3) brain extraction (BET, FSL); Specifically, the anatomical nuisance regressors were: I) ventricles (Freesurfer, eroded in 2mm space), II) draining veins (DV) (FSL's CSF minus Freesurfer's Ventricles, eroded in 1mm space) and III) white matter (WM) (FSL's WM minus Freesurfer's subcortical grey matter (GM) structures, eroded in 2mm space). In order to cut the fMRI data and nuisance regressors to the same length as the PC time courses, we removed the first 5 TRs.
FMRI DATA ANALYSIS
We applied standard FSL FEAT GLM to determine the effect of PC time courses on BOLD activation. All eight PC time courses were entered as regressors of interest into subject-level GLMs in addition to their temporal derivatives and all nine nuisance regressors (resulting in 27 regressors in total). We then analysed the fMRI data with respect to eight contrasts (one contrast for each PC). The resulting individual subject-level contrasts were then entered into a high-level (mixed-effects) cluster-corrected FEAT analysis (FLAME 1+2) to obtain the paired t-test contrasts of LSD > Placebo and Placebo < LSD. In order to model out any potential effect of the order in which subjects listened to the different music excerpts under the different conditions, respectively, we included an interaction term in the higher-level FEAT as a regressor of no interest. We repeated the high-level analysis without the interaction term and obtained nearly identical results (not reported). All final group-level images were thresholded using a cluster correction threshold of Z > 2.3 and a cluster significance threshold of p = 0.05. Group-level images were visualized on an average surface brain using MRIcron.
ROI SELECTION AND EXTRACTION FOR CORRELATION ANALYSES
Regions of interest (ROI) analysis was constrained to the group-level contrast LSD>Placebo for timbral complexity (i.e., PC3, see Results). ROI selection was based on previous literature and encompassed structures that have been commonly identified for music-evoked emotion (striatum, precuneus and insula), auditory perception (planum temporale and right IFG)and the subjective effects of psychedelics (precuneus and insula). ROIs were created by first selecting corresponding binarized structural areas from the Harvard-Oxford atlas (using a probability threshold of 10%) and then multiplying these with the group-level results to guarantee anatomical and functional specificity of the ROIs. Note that only the largest consecutive cluster of voxels were considered within each ROI. This procedure led to nine ROIs: right planum temporale, left planum temporale, right precuneus, right putamen, left putamen, right caudate, left caudate, right inferior frontal gyrus and right anterior insula (see table.3). The mean parameter estimates within each ROI were extracted for each participant, and Spearman's rank correlation tests were used to relate the changes in parameter estimates (LSD > Placebo) with changes in GEMS-ratings for musicevoked emotions for the factors wonder and transcendence (LSD > Placebo). Non-parametric permutation testing (10,000 permutations, one-tailed) was carried out to correct for multiple comparisons (9 ROIs x 2 GEMS scales).
PSYCHOPHYSIOLOGICAL INTERACTION ANALYSIS
In order to assess timbral-specific changes in functional connectivity for the brain regions that showed a significant relationship with music-evoked feelings of wonder (i.e., precuneus and right inferior frontal gyrus, see Results), we conducted two separate psychophysiological interaction (PPI) analyses. For this, we first extracted subject-specific time courses from those ROIs and then applied standard FSL FEAT GLM. In addition to regressors that were included in the initial fMRI analysis (eight PC time courses, their temporal derivatives and nine nuisance regressors), we included the ROI timecourse (physiological regressor) and the PPI regressor that consisted of the element-wise multiplication of the physiological regressor with the timecourse encoding timbral complexity (psychological regressor, i.e. PC 3). The resulting individual subject-level contrasts were then entered into the same higher-level (mixed-effect) cluster-corrected FEAT analysis as described above (with an interaction term to model out the effect of "group").
ACOUSTIC FEATURE EXTRACTION
For acoustic feature selection and extraction, an approach similar to that described inwas used. From the two musical excerpts used in the present study we extracted 23 acoustic features capturing tonal, rhythmical, and timbral properties that subsequently underwent a principle component analysis (PCA) to reduce the dimensionality of the data. The first eight principal components that together explained more than 90% of the variance were selected, and qualitatively were similar with the components identified in previous, independent studies. The consistency of the identified components across musical genres (tango, classic and pop, as well as ambient music here) supports their reliability for representing fundamental acoustic properties in music. Importantly, perceptual validation and labelling for similar components has been demonstrated. In the present study, a similar/comparable labelling for the principle components was therefore adopted (PCs) (Figure.1). In fact, when quantitatively comparing our PC's with the PC's from Alluri et al.
EFFECTS OF LSD ON MUSIC-EVOKED BRAIN ACTIVITY
The BOLD changes under LSD appeared particularly pronounced to timbral complexity, and within brain networks commonly identified for music perception and emotion. ROI selection for connectivity analyses described below (paragraph 4.3.4) where therefore constrained to this contrast (see table 4.3 for ROI's). For insight into the effects of LSD and on timbral-complexity induced BOLD changes, parameter estimates from these ROI's for timbral complexity were plotted for placebo and LSD separately (see figure.4)
EFFECTS OF LSD ON MUSIC-EVOKED EMOTION
Alongside investigating changes in music-evoked brain activity under LSD, our study aimed to assess the effects of LSD on music-evoked emotions. We measured nine different musicevoked emotions using the Geneva Emotional Music Scale (GEMS) that was completed by each participant after listening to music in each condition. Paired t-tests on the GEMS scales revealed that, compared to placebo, music-evoked emotions were
CORRELATION ANALYSES BETWEEN MUSIC-EVOKED BRAIN ACTIVITY AND EMOTION
Having established that psychedelics intensify the emotional experience with music, we subsequently focused exploring the interactions between peak experience emotions (as captured by the GEMS scales wonder and transcendenceand associated increases in music-evoked brain activity. We therefore conducted correlation analyses (Spearman's rank) between changes in music-evoked peak emotions (LSD > Placebo) and music-evoked BOLD activity (LSD > Placebo) for nine regions of interest (ROIs). This correlation analysis was constrained to the contrast for timbral complexity (i.e., PC3) as related BOLD changes were most pronounced and occurred in brain networks commonly identified for music perception and emotion. ROI selection was based on previous literature and encompassed structures that have been commonly identified for music-evoked emotion (striatum, precuneus and insula), auditory perception (planum temporale and right IFG)and the subjective effects of psychedelics (precuneus and insula). See table 4.3 for the coordinates and size of each ROI. We found significant positive correlations between changes in music-evoked feelings of wonder and music-evoked BOLD activation to timbral complexity within the precuneus (r = 0.67, p = .034) as well as within the right inferior frontal gyrus (r = 0.65, p = .045) (see Figure.6). In addition, we found trend-level positive correlations between changes in feelings of transcendence and the right inferior frontal gyrus (r = 0.61, p = .066). P-values reported were corrected for multiple comparisons using one-sided permutation testing with α set to .05.
EFFECTS OF LSD AND MUSIC ON FUNCTIONAL CONNECTIVITY
The relationship between feelings of wonder and music-evoked activation to timbral complexity in the precuneus and the right IFG informed subsequent PPI analyses with the aim to gain insights into underlying music-specific changes in functional connectivity under LSD. Two separate PPI analyses were conducted, using either precuneus or right IFG as seed ROI, in order to identify brain areas for which the activation time course during the LSD condition were more (increased) or less (decreased) coupled with the seed regions depending on the level of timbral complexity in the music. Under LSD, we found significantly increased coupling of the precuneus with the right superior frontal gyrus (SFG) for passages when the music exhibited high timbral complexity. In addition, we found significantly decreased coupling of the precuneus with the right IFG as well as the right auditory cortex under LSD when timbral complexity in the music increased. No significant timbral-specific changes in functional connectivity were found for the right IFG as seed (Figure.7).
EFFECTS OF HEAD MOTION
In order to investigate the effect of motion on our results, frame-wise displacement (FD) was investigated between the drug and placebo condition as well as conducted correlation analyses between changes in FD (LSD>placebo) and extracted parameter estimates from the nine ROIs. The mean ± SD FD for placebo and LSD were 0.091 ± 0.037 and 0.174 ±0.1, respectively, which was found to be statistically significant using a paired t-test (t (15) = -3.28, p=0.005). However, no significant correlations (Spearman's rank) was found between changes in FD (LSD>Placebo) and changes in music-evoked BOLD activity for the contrast here are uncorrected for multiple comparisons. In addition, to control for an effect of FD on timbral complecity-evoked brain-activity, average FD for stimulus A and stimulus B were correlated with respective time-courses for timbral complexity, and no significant correlations were detected (r=0.11, p=0.09, df=25 (stimulus A); r=0.12, p=0.07, df=215 (stimulus B)).
DISCUSSION
This study investigated the effects of LSD on the brain's processing of distinct acoustic features in music, and the relationship of these effects to changes in music-evoked emotion Timbre, or tone colour, refers to the properties of the sound distinct for pitch or loudness. Timbral complexity, in turn, corresponds to the complexity in the shape and the spread of music's spectral distribution. Thus, timbral complexity, can be treated as an index for the complexity in the shape of power spectrum of the sound signal. Spectral properties of sound are initially processed by the planum temporale, a central "computational hub" within the auditory cortex that segregates incoming spectral signals into distinct spectrotemporal patterns). Subsequent information exchange with higher cortical regions such as the IFG, is thought to facilitate the linking of the perceived spectrotemporal patterns with learned representations and associations. The auditory cortex and IFG are anatomicallyand functionallywellconnected, and considered an important pathway for the perception of auditory objects, musical melody, musical harmony, musical syntax, and the encoding of musical expectationas well as musical imagination. Damage and abnormal functioning in the auditory-IFG network has been linked to impaired music perceptionand auditory hallucinations. The findings of the present study indicate that LSD has major effects on the way's the brain processes music's timbre properties, and it seems plausible that this effect relates to changes in auditory perception under psychedelics that are often reported (such as in the opening quote of this chapter), but this remains yet to be determined experimentally. This experiment focussed on relating changes in brain function to changes in music-evoked emotion under LSD. Apart from a key role in music perception, converging evidence describes the IFG's involvement in the evaluation of emotional valence in acoustic information more generally. Happy emotional vocalisations produce increased IFG activity compared to angry vocalisations) -an effect that has been observed as early as 7-months in human infants. Brain damage and experimentally disrupting brain activity in the IFG using transcranial magentic stimulation (TMS), is linked with impairments in identifying vocal emotion. The IFG processes emotionally salient information from different sensory modalities, and has been more generally conceptualised as being part of a cognitive control networkthat redistributes attentional resources for emotionally salient information. Paying attention to the emotional valence of visualand auditorystimuli is associated with increases in IFG activity, and emotionally salient information can produce marked attentional biases. Increased right IFG activation to music's timbral complexity under LSD, and the positive corelation with music-evoked 'peak' emotion, may therefore indicate increased allocation of attentional resources for emotional information processed within the auditory-IFG circuitry. This view, that the auditory-IFG network may play an important role in LSD's effects on musical information processing, was further supported from the findings of the functional connectivity analyses. The PPI analysis revealed a significant decoupling between the right precuneus and the right auditory cortex and right IFG under LSD, in interaction with timbral complexity. The precuneus is a highly connected hub region that plays an important role in self-referential cognition) and emotionregulation, and shows desynchronized activity under psychedelics. This disorganising effect of psychedelics on precuneus activity has been associated with "ego-dissolution", characterised by increased emotional liability. Although the precuneus is activated to music-evoked emotion, the region shows poor anatomicaland resting state functional connectivitywith auditory regions. The precuneus is however anatomically and functionally well-connected with frontal regions such as the IFG and SFG, and is thought to provide top-down control to these (hierarchically subordinate) brain regions. As such, decreased precuneus-auditory/IFG coupling under LSD may reflect a reduced regulatory influence of the precuneus over emotion processing in the auditory/IFG network, and this may facilitate an intensified (or disinhibited) emotional response to music. Finally, LSD also produced marked increases in BOLD activation to timbral complexity in the striatum and in the insula; regions that have been consistently associated with music-evoked emotion. The striatum has been implicated in brain mechanisms underlying music-evoked pleasure, likely via the encoding of auditory expectation and reward in interaction with auditory cortices. The insula is a high-level hub region that is thought to facilitate emotional awareness, the attribution of emotional meaning to music, sound and human voice, and the subjective effects of classic psychedelics. Interestingly, the present study did not find a relationship between music-evoked feelings of wonder and transcendence, and the striatum. An implication of this could be that the striatum is predominantly concerned with the processing of "simple" affective states characterised by pleasure, whereas more complex emotional states, such as feelings of wonder and transcendence, may require more complex cognition, and thus more complex cortical mechanisms to facilitate them. The selective positive correlation between increased feelings of wonder and BOLD signal changes in higher-level brain regions such the IFG and precuneus support this idea. Taken together, these observations suggest that LSD alters the dynamic interplay between the analysis of "low-level" spectral properties in the music, and the subsequent "high-level" regulation and processing of the emotional associations. The precuneus, the IFG and the insula may play a particular important role in facilitating music-evoked peak emotion, given previous literature implicating their involvement in the processing of emotional awarenessand "complex" music-evoked emotion. A disintegration or weakening of the mechanisms that normally regulate emotion, may be a fundamental mechanism via which strong emotional experiences with music can be facilitated under psychedelics. Discussing the possible brain mechanisms will be the focus of the subsequent paragraph.
POSSIBLE BRAIN MECHANISMS
Classic psychedelics such as LSD stimulate serotonin 2A receptors, which are primarily expressed on deep layer V pyramidal cells. Upon activation of these receptors, the cells' membranes depolarize, reducing the neuron's threshold for firing. Hyper-activation of the serotonin 2A receptor underlies desynchronised activity within high-level brain networks, leading to impaired top-down control and an increased information exchange between brain modules that are usually more strictly functionally segregated. Deep layer V pyramidal cells encode learned mental representations or "predictions" that are matched with incoming sensory stimuli in a top-down fashion, and over-activation of the serotonin 2A receptor system by psychedelics is reasoned to produce a disorganised or "entropic" quality of brain activity, manifesting as a more variegated quality of consciousness. The high density of serotonin 2A receptors within the precuneus, insula and the planum temporalesuggests that psychedelics alter auditory information processing at different stages of the processing hierarchy. Since the planum temporale is functionally specialised in classifying distinct spectrotemporal patterns, the particularly pronounced BOLD increases under LSD to "timbral complexity" in this region may reflect an increased activation of intrinsic deep-pyramidal neurons that encode (predictions for) music's spectral properties. Such an effect may result in dramatic alterations in the processing and perception of auditory spectral information (i.e. timbral complexity) in music, and thereby indirectly lead to an intensification of the emotional meanings that are conveyed through timbre. Alternative to this hypothesis that holds LSD changes timbre-perception, is the view that increased activity in planum temporale may be consequential of an increased input from topdown projecting deep layer V pyramidal cells, originating from the IFG and insula and encoding emotional valence of timbre, i.e. an increased IFG/insula to planum temporale effective connectivity. Effective connectivity has not been assessed in this study, but doing so would aid testing such mechanistic hypotheses of LSD's effects on timbreprocessing. Finally, one other possible brain mechanism at play could be that the decoupling of the auditory/IFG circuitry from the precuneus propagates an unregulated activation of timbre-emotion associations. The absence of this top-down control, would hence produce an intensified (disinhibited) emotional response to the emotions conveyed through music.
THE SIGNIFICANCE OF TIMBRE
An important question is why did LSD have such a marked effect specifically on the brain's processing of music's timbral complexity? One explanation may be found in the significance of timbre in acoustic communication across species. Timbre is used across species to communicate salient information such as the presence of predators or the fitness of potential mates, and the perception of timbre is argued to have underwent high evolutionary selection pressure. Timbre's capacity to convey emotion is shown cross-culturally, to do so independently from other acoustic features, and timbre-perception is present in very early infancy before the perception of other acoustic features develop, such as tempo and musical mode, and long before the acquisition of verbal language (Dalla. The infants' ability to memorise and recognize their mother's voice as early as at 2 days after birth has been argued to be due the infant's innate tuning to timbral properties common to speech and music. Timbre has been conceptualised to function like an interface, that connects distinctive spectral features within sound with meaningful emotional associations. The findings of this study suggest that LSD targets this interface, "tuning" the brain to non-verbal, or even pre-verbal, acoustic properties that carry important emotional information.
EFFECTS OF LSD ON THE BRAIN'S PROCESSING OF OTHER ACOUSTIC FEATURES
The previous discussion centred around the changes observed for timbral-complexity, because these changes were most pronounced and appeared to be localised in networks commonly associated with music-perception and music-evoked emotion. However, there were other findings that must be mentioned. Increased thalamus and decreased IFG activation was observed under LSD in response to "fullness", i.e. simply the loudness of the sound. Loudness reflects a less complex acoustic property (occupying a single dimension, i.e. amplitude of the signal), and has previously been associated with a preferential activation of lower auditory regions. Significant BOLD signal changes were also observed in occipital cortices for various acoustic features, an area rich in serotonin 2A receptors and significantly functionally altered under LSD alone.
IMPLICATIONS FOR PSYCHEDELIC THERAPY
The present study supports the usefulness of music in facilitating peak experience, which are associated with positive therapy outcomes. The findings also suggest that knowledge on how timbre conveys emotion, may be a particular fruitful avenue to inform music-selection for psychedelic therapy.
STUDY LIMITATIONS AND FUTURE DIRECTIONS
The study focussed on LSD's effects on the neurophysiological processing of acoustic properties in music, but did not included perceptual measures for these features. Future studies may address questions such as "is timbre perceived differently?", and "are certain acoustic features experienced more differently than other features?". Studies assessing these questions will be in particular important for our understanding of how psychedelics alter the perception of music, how this relates to changes in music-evoked emotion, and more broadly, in how understand and use music in psychedelic herapy. Another study limitation was that only a single musical genre was used. The music used was rich in timbre, but low in tempo. The music choice may therefore have resulted in a selective reflection of LSD's effect on timbral features in music, since it can be hypothesised that other brain networks will be engaged when, for example, more rhythmic music is used. However, the component for which LSD showed most pronounced neurophysiological changes (i.e. "timbral complexity"), was not the component that explained most of the variance within the music (i.e. being the third component), supporting the validity of the method in identifying brain changes to distinct and diverse musical features within a naturalist music listening experience.
CONCLUSIONS
The present study revealed altered brain activity and connectivity to acoustic features in music under LSD. Most pronounced changes were observed for the component timbral complexity, representing the complexity of the music's spectral distribution, and these occurred in brain networks previously identified for music-perception and music-evoked emotion. These changes showed a correlation with enhanced music-evoked feelings of wonder under LSD. The findings suggest music can be utilised in psychedelic therapy to facilitate peak experiences, and provided insights into the brain processes underlying music perception and peak emotion under naturalistic listening conditions. "The reactions music evokes are not feelings, but they are the images, He wrote: "It was particularly remarkable how every acoustic perception, such as the sound of a door handle or a passing automobile, became transformed into optical perceptions. Every sound generated a vividly changing image, with its own consistent form and colour."This experience was also the first experience with LSD in modern history, and it already captured a feature of psychedelics' subjective effects that became a great fascination for scientists, artists and therapists: the combined effects of music and psychedelics on visual mental imagery. Since the inception of psychedelic therapy, it is thought that music acts synergistically with the drug to stimulate the imagination in idiosyncratic and powerful ways: to evoke mental images, memories and thoughts that are highly vivid and have significant personal meaning. The focus of study 2 was on the effects of LSD on music-evoked emotion, yet it was striking to us how frequently participants elaborated on the ways music influenced their "extremely vivid" eyes-closed mental imagery, such as in this remark on the music-experience: "The imagery was quite strong. And I felt quite present in the imagery. In the beginning, I felt like I was in a ditch, a muddy ditch, then, like a sort of faded vision or photograph, I felt like I was on a rock, a version of a planet, and I was revolving around it and I then flew into space. And then I had clear images of my daughter, and this was very moving. There was a sense of mortality, and the music kind of forced me to have a larger perspective. I saw specific images, and with strong emotions."
AND ANOTHER PARTICIPANT RECALLED:
"There were lots of memories of home, and lots of memories and thoughts of my own family. […] It was like the soundtrack of a film, a little trailer of a film." The main aim of this study was to investigate this phenomenon empirically, by studying brain mechanisms underlying the effects of LSD and music on mental imagery. Of particular interest to the neuro-scientific study of mental imagery is the parahippocampal cortex (PHC). The PHC is an important hub within the medial temporal lobe (MTL) system, and plays a role in constructing mental imageryand autobiographical memory recall. Damage to the PHC can result in visual deficits, whereas direct stimulation of the PHC can produce visual hallucinations of scenes, vivid autobiographical memoriesand dream-like states, accompanied by enhanced coupling between the PHC and the visual cortex (VC). Importantly, PHC activity is modulated by music and psychedelics separately. The PHC receives direct projections from the auditory cortex, and shows increased activity during music-evoked emotion) and music-evoked personal memories. The PHC expresses serotonin 2A receptors, and altered PHC functioning under psychedelics has been observed using fMR, depth EEG) and PET. Furthermore, attenuation of the subjective and behavioural effects of LSD were observed after resection of the MTLs in humans) and chimpanzees, suggesting a role for the MTL in facilitating subjective effects of psychedelics. These insights motivated the hypothesis that LSD in combination with music modulates PHC functional connectivity to enhance mental imagery. This hypothesis was tested using functional magnetic resonance imaging (fMRI) and a balanced-order, placebo-controlled design, with healthy participants. Measures for changes in PHC functional connectivity informed a subsequent Dynamic Causal modelling (DCM) analysis that assessed how an interaction effect between music and LSD modulates the direction of information flow between the PHC and the VC (i.e. effective connectivity). Participants completed ratings of eye-closed visual imagery and spontaneous recall autobiographical memories to assess subjective effects, which were correlated with changes in effective connectivity.
APPROVALS
This study was approved by the National Research Ethics Service (NRES) committee London -West London and was conducted in accordance with the revised declaration of Helsinki (), the International Committee on Harmonisation Good Clinical Practice guidelines and National Health Service (NHS) Research Governance Framework. Imperial College London sponsored the research which was conducted under a Home Office license for research with schedule I drugs.
PARTICIPANTS
Twenty participants (16 males and 4 females) were recruited, carefully screened for physical and mental health and provided written informed consent before participation. The screening for physical health included electrocardiogram (ECG), routine blood tests, and urine test for recent drug use and pregnancy. A psychiatric assessment was conducted and participants provided full disclosure of their drug use history. Key exclusion criteria included: being younger than 21 years of age, having a personal history of diagnosed psychiatric illness, an immediate family history of a psychotic disorder, an absence of previous experience with a classic psychedelic drug (E.g. LSD, mescaline, psilocybin or dimethyltryptamine (DMT), drug use within 6 weeks of the first scanning day, a persistent adverse reaction to a psychedelic drug, pregnancy, problematic alcohol-use (i.e. > 40 units consumed per week), and/or a medically significant condition rendering them unsuitable for the study.
EXPERIMENT OVERVIEW AND PROCEDURES
Screening took place at Imperial's clinical research facility at the Hammersmith hospital campus. All study days were performed at Cardiff University Brain Research Imaging Centre (CUBRIC). Eligible participants attended two study days that were separated by at least 14 days. LSD was received on one of the study days, and placebo on the other. The order of receipt of LSD was balanced across participants, and they were kept blind to this order but the researchers were not. On scanning days, volunteers arrived at the study centre at 8:00 am, were given a detailed brief about the study day schedule, gave a urine test for recent drug-use and pregnancy, and carried out a breathalyser test for recent alcohol-use. A cannula was inserted into a vein in the antecubital fossa by a medical doctor and secured. Participants were encouraged to close their eyes and relax in a reclined position while the drug was administered. All participants received 75 µg of LSD, administered intravenously via a 10 ml solution infused over a two minute period, followed by an infusion of saline. Dosing was followed by an acclimatization period of approximately 60 minutes, in which (for at least some of the time) participants were encouraged to relax and lie with their eyes closed inside a mock MRI scanner. This functioned to prepare the participants for the subsequent (potentially anxiogenic) MRI scanning experience. Participants reported noticing subjective drug effects between 5 to 15 minutes post-dosing, and these approached peak intensity between 60 to 90 minutes post-dosing. The duration of a subsequent plateau of drug effects varied among individuals but was generally maintained for approximately four hours post-dosing. BOLD MRI scanning started approximately 120 minutes post-dosing, and lasted for approximately 60 minutes. This included a structural scan, arterial spin labelling (ASL) fMRI, and BOLD fMRI. After the MRI scanning, magnetoencephalography (MEG) scanning was performed but these findings will be reported elsewhere. Once the subjective effects of LSD had sufficiently subsided, the study psychiatrist assessed the participant's suitability for discharge.
FMRI STUDY DESIGN
Each fMRI scanning session involved three eyes-closed resting state scans, each lasting seven minutes. After each scan (7 minutes and 20 seconds), visual analogue scale (VAS) ratings were performed in the scanner via a response-box after each scanning block (no music, music, no music). The music-listening scan always occurred after the first resting state (no music) scan and before a final resting-state scan (no music). The music itself was triggered by the first TR, and listened to via MRI compatible headphones (MR Confon). Two long excerpts (A and B, each 7 minutes and 20 seconds in duration) were selected from the album Yearning, by musicians Robert Rich and Lisa Moskow. Pre-study assessments confirmed the two excerpts to be balanced for their emotional potency. Each participant listened to both stimuli, in a balanced order across conditions. Volume-maximization and broadband compression was carried out using Ableton live 9 software. Prior to each scan, participants were instructed via a display screen to close their eyes and relax. Prior to the music scan, the music volume was adjusted to a level that was "as loud as possible, without being unpleasant" and then maintained for each condition. When the music ended, participants were instructed to open their eyes and rate the degree of simple mental visual imagery (i.e. "with my eyes closed I saw colours or geometric patterns") and complex mental visual imagery (i.e. "with my eyes closed I saw complex hallucinations") they experienced. Complex imagery was defined for the participants prior the scanning as the seeing of concrete objects, landscapes or entities (E.g. plants, buildings, people or animals). Items were completed on a continuous visual analogue scale from 0 ("not at all") to 20 ("extremely intense"). Soon after the MRI scanning session was complete, participants rated some further VAS items that assessed their subjective experience during scanning. The VAS item "I saw scenes from my past" was selected for special consideration because of personal memory recollection being consistently associated with PHC functioning, as well as a prior hypothesis inspired by previous findings) that this would be modulated by the experimental conditions.
FMRI SCANNING AND DATA PRE-PROCESSING
All imaging was performed on a 3T GE HDx system. Thirty five oblique axial slices were acquired in an interleaved fashion, each 3.4mm thick with zero slice gap (3.4mm isotropic voxels). The precise length of each of the BOLD scans was 7:20 minutes. Pre-processing utilised a combination of AFNI, FSL, Freesurferand ANTS. After brain extraction (Freesurfer), anatomical images were segmented into their three underlying tissue types: cerebrospinal fluid (CSF), grey matter (GM) and white matter (WM) (fast, FSL) and registered to a 2mm MNI152 template using affine (ANTS), followed by non-linear transformation (SyN, ANTS). Anatomical images also underwent segmentation to define subcortical structures (Freesurfer). Participants in this study were from the same experiment as study 2, but due differences in the measures used in the separate studies, different inclusion criteria were used for dataanalyses (connectivity measures here versus BOLD activition in study 2). One participant was excluded from analyses because of early termination of the scanning due to him reporting significant anxiety during the LSD session. Three participants were excluded from analyses due to technical problems with the sound delivery and four more subjects were discarded from the group analyses due to excessive head movement. This leaves a total of twelve participants that entered the group analyses. Principally, motion was measured using framewise displacement (FD). The criterion for exclusion for excessive head movement was subjects displaying higher than 15% scrubbed volumes when the scrubbing between-condition differences in the post-scanner questionnaire item "I saw scenes from my past".
SEED-BASED FUNCTIONAL CONNECTIVITY ANALYSIS
A bilateral PHC region of interest (ROI) was acquired from the Harvard anatomical atlas tool and used to extract PHC time series for each subject. To begin with, a general linear model (GLM) was used (FEAT, FSL) to model whole brain resting state functional connectivity with the PHC seed, with correction for autocorrelations (FILM, FSL) for each run separately. Next, a fixed-effects model was used to compare music versus non-music runs for each subject, for LSD and placebo separately. Finally, these drug effects (LSD versus placebo) were fed into a higher-level mixed effects model (FLAME1, FSL) to calculate the modulation of the effects of music by LSD on PHC functional connectivity across the brain (cluster correction threshold z > 2.3, p < 0.05).
DYNAMIC CAUSAL MODELLING: BACKGROUND AND IMPLEMENTATION
Dynamic Causal Modelling (DCM, as implemented in SPM12b) was used to estimate changes in effective connectivity. DCM is a biologically-informed modelling procedure that estimates the causal interactions (i.e. effective connectivity) between different pre-selected nodes of a network, and the changes in coupling strength between and within those nodes (extrinsic and intrinsic connections respectively) due to experimental manipulations. The basic architecture of a model is defined by structurally plausible and functionallyinformed brain regions, whose connections are defined as either bilinear (i.e. information flow between regions) or non-linear (i.e. activity in one region modulating information flow between regions). Typically, experimental manipulations can directly affect activity in each node (as 'driving inputs') or alter the strength of coupling within or between nodes (as 'modulatory inputs'). In the present study, all six scans were concatenated in the following order: placebo nomusic (NM), placebo music (M), placebo NM, LSD NM, LSD M, LSD NM. The measured BOLD time-series for the DCM were extracted as the first principal eigenvalue from a bilateral PHC and VC mask (The PHC mask was defined by Harvard-Oxford atlas, and the VC mask was defined by results of the PHC functional connectivity analysis, i.e. the occipital cluster), and adjusted for the effects of interest (i.e. main effect of music, main effect of drug, and an interaction effect -described below). Between-node connections were defined as bilinear meaning that information flow could be modulated in either direction. Three experimental inputs entered the model as modulatory inputs: a main drug effect, a main music effect, and an interaction effect of music and drug (0.5 -1 0.5 -0.5 1 -0.5). Due to the resting-state conditions of the scanning, activity in the nodes was driven by stochastic (i.e. spontaneous) fluctuations.
DYNAMIC CAUSAL MODELLING: BAYESIAN MODEL SELECTION
In DCM, a series of plausible models, representing competing hypotheses, are specified. Each model corresponds to a hypothesis about how observed changes in BOLD signal were caused by changes in neural activity in each network node. The different models can vary in terms of the position of driving and modulatory inputs. DCM uses a biophysical model of the hemodynamic response to predict the underling neuronal activity -and the underlying (changes in) connectivity -from the observed BOLD signal. Model estimation, or inversion, returns conditional estimates for the changes in connectivity and scores the model in terms of its accuracy and complexity (using a Free Energy bound on log model evidence). Bayesian Model Selection (BMS) is used to compare different models to identify the model with the greatest evidence -i.e. the model that offers the best explanation of the data. In the present study, one "full model" was specified, with all three experimental inputs modulating all extrinsic and intrinsic connections. Following inversion of this full model, a post hoc Bayesian model optimisation scheme was used to identify the model structure with the greatest model evidence (i.e. lowest free energy). This approach provides an efficient scheme for scoring large numbers of competing models. Optimal model structure is usually determined by computing Bayes factors, as an approximation of the model evidence. A Bayes factor of 20 corresponds to a belief of 95% in the statement that a particular hypothesis (i.e. the proposed model) is true, and therefore a p value of 0.05. A Bayes factor higher than 150 corresponds to a belief of 99% in the hypothesis, and equates a p-value smaller than 0.01. A Bayes factor higher than 95 is therefore considered as strong evidence for the proposed model. After model selection, coupling parameters are analysed post-hoc to characterize the size and direction of the changes in connection strength caused by the experimental manipulations. Coupling parameters quantify the strength of the coupling in terms of the rate (in Hz) at which a response is caused in a given region, and modulation is expressed as either an increase or decrease in this coupling measure.
CORRELATION ANALYSES BETWEEN CHANGES IN EFFECTIVE CONNECTIVITY AND SUBJECTIVE EFFECTS
Following model selection, the hypothesis was tested that the magnitude of the modulation in effective connectivity by the music x drug interaction would explain the observed variance in participants' subjective responses to the music under LSD. More specifically, we asked whether the size of the interaction effect as estimated by the DCM, correlated with the magnitude of the enhancement of: 1) eyes-closed imagery and 2) visions of one's past ("I saw scenes from my past"). A spearman's correlation was used due the non-parametric nature of the data.
PARTICIPANTS
The data from twelve participants were found suitable for data-analysis (2 female, mean age = 33±9 years, range 22-47 years). All had at least one previous experience with a classic psychedelic drug. Mean estimated lifetime LSD-use was 12 ± 15 (range = 0 -40). Selfestimates of other drug-use were as follows (mean ± SD, range): weekly alcohol units = 8 ± 8, 0-28; daily cigarettes = 0; lifetime cannabis uses = 686 ± 625, 30-2000; lifetime MDMA uses = 20± 18, 2-50; lifetime psilocybin/magic mushroom uses = 10 ± 9, 1-35; lifetime ayahuasca/DMT uses = 14 ± 21, 0-50; lifetime ketamine uses = 3 ± 6, 0-20; lifetime cocaine uses = 6 ± 8, 0-20; lifetime amphetamine uses = 6 ± 11, 0-35; lifetime heroin uses = 1 ± 3, 0-10.
SUBJECTIVE EFFECTS AS MEASURED BY IN-SCANNER RATINGS
A paired t-test revealed a significant increase in personal memory recollection under LSD (t = 1.9, df = 19, p = 0.04). For simple visual imagery, a two-way ANOVA revealed a significant drug effect (F = 42.2, df = 18, p < 0.001) but no significant effects were found for music (F = 1.7, df = 18, p = 0.2) or the interaction between music and LSD (F = 1.1, df = 18, p = 0.3). For complex visual imagery, a two-way ANOVA revealed a significant drug effect (F = 24.7, df = 18, p < 0.001), a trend level effect of music (F = 10.0, df = 18, p = 0.09), but again, no significant interaction effect for music x LSD (F = 1.8, df = 18, p = 0.5). Positive (enhanced) drug effects on simple and complex visual imagery survived multiple comparisons, using Bonferroni adjusted alpha levels of .025 per test (0.05/2) (see Figure.1).
FUNCTIONAL CONNECTIVITY
Seed-based functional connectivity analysis of the bilateral PHC showed a positive interaction between music and LSD for the contrast LSD (music versus no music) versus placebo (music versus no music), with increased coupling between the PHC and two main clusters: One being the bilateral visual cortex and the other being the left inferior frontal gyrus and insula. No decreases in PHC functional connectivity were observed for this contrast. All effect reported are cluster-corrected, Z>2.3. (see Figure.2, for the reader's insight, other contrasts are displayed too).
EFFECTIVE CONNECTIVITY
Post-hoc model optimisation determined the optimal model structure. The optimal model had a Bayes factor 344 higher than the 2nd best model. This equates, in a frequentist statistical approach, to a p-value much smaller than 0.01, and is therefore considered as very strong evidence for the model. The optimal model features a main effect of drug and music modulating the intrinsic connections of both nodes, and an interaction effect modulating the connection from the PHC to the VC. Group averages for the posterior estimates are -0.41±0.05 Hz for drug effect on PHC, -0.42±0.06 Hz for music effect on PHC, -0.38±0.06 Hz for drug effect on VC, and -0.40±0.06 Hz for music effect on VC. The group average of the posterior estimate for the interaction effect is 0.02±0.04 Hz (see Figure.3)
CORRELATIONS BETWEEN CHANGES IN EFFECTIVE CONNECTIVITY AND SUBJECTIVE EFFECTS
A significant positive correlation was found between the interaction effect of LSD and music on PHC to VC effective connectivity, and increases in the in-scanner ratings for complex visual imagery (Spearman's ρ =0.71, with p=0.01, and Pearson r = 0.65, with p = 0.03). A trend-level positive correlation was found between the interaction effect of LSD and music on PHC to VC, and the post-scanner questionnaire item "I saw scenes from my past" (Spearman ρ =0.67, with p=0.02, and Pearson r = 0.69, with p =0.01). These tests were conducted using Bonferroni adjusted alpha levels of .0167 per test (0.05/3) (see Figure.4). Figure.1 | Scanner-ratings for mental imagery. For simple visual imagery, a two-way ANOVA revealed a significant drug effect (F = 42.2, df = 18, p < 0.001) but no significant effects were found for music (F = 1.7, df = 18, p = 0.2) or the interaction between music and LSD (F = 1.1, df = 18, p = 0.3). For complex visual imagery, a two-way ANOVA revealed a significant drug effect (F = 24.7, df = 18, p < 0.001), a trend level effect of music (F = 10.0, df = 18, p = 0.09), but no significant interaction effect between music and LSD (F = 1.8, df = 18, p = 0.5). Drug effects on simple and complex imagery survived multiple comparisons, using Bonferroni adjusted alpha levels of .025 per test (0.05/2).
DISCUSSION
This study assessed neurophysiological changes associated with music-induced mental imagery under LSD. The results demonstrated increased functional connectivity of the parahippocampus (PHC) with the left inferior frontal gyrus (IFG), the left insula and the visual cortex (VC) during music listening under LSD. By using dynamic causal modelling (DCM), a positive modulation of effective connectivity (i.e. the direction of information flow) was found from the PHC to VC, by an interaction between the LSD and music. Furthermore, we found that the magnitude of this modulation correlated with increased ratings for eyesclosed complex visual imagery and personal memory recall. These results are consistent with the converging view that the PHC-VC pathway serves as an important network for the (re)construction of mental images. The PHC is implicated in imagining scenes, episodic personal memory recollectionand music-evoked personal memories. The PHC and VC are structurallyand functionallyconnected, and increased effective connectivity from the PHC to the VC has previously been associated with the construction of imagined visual scenes. Of particular significance for the present findings, are studies in which the PHC was directly stimulated or damaged. Direct stimulation of the PHC has been found to produce hallucinations of complex visual scenesand recall of autobiographical memories. Furthermore,demonstrated that upon direct stimulation of the PHC, a strengthening of PHC-VC coupling occurred only when such visual experiences were reported. Damage to the PHC can result in visual impairments, visual hallucinations, and hippocampal damage has been associated to an impaired ability to imagine autobiographical past and futureAltogether, these studies provide a body of evidence that implicate the PHC-VC network as an important mechanistic pathway for the construction of mental visual images, whether this imagery is real (i.e. personal memories) or imaginary. And consistent with this view, the present findings suggest that psychedelics and music influence mental imagery by modulation of PHC-to-VC effective connectivity. Possible underlying mechanisms via which psychedelics and music may cause this modulatory influence will be proposed in the following section.
POSSIBLE BRAIN MECHANISMS
The PHC can be subdivided into the perirhinal cortex, the postrhinal cortex and the entorhinal cortex. The entorhinal cortex shows prominent bidirectional connectivity with the visual cortex, and receives direct input from the auditory cortex. The PHC can be conceptualised as a central "hub", an important relay station, that receives and integrates input from dispersed functionally specialised brain areas. The majority of axonal projection that the entorhinal cortex receives from the auditory cortex terminate on deep layer V pyramidal neurons. These neurons express serotonin 2A receptors, and provide intra-hippocampal forward projections as well as backward projections to the visual cortex. Because LSD increases excitability of deep layer V pyramidal neurons via serotonin 2A receptor activation, this leads to the prediction that under LSD the backward PHC-to-VC projections are more likely to fire in response to input from the auditory cortex. In light of these studies, the findings of this study may indicate that under LSD, backward PHC-to-VC projecting pyramidal neurons in the PHC become abnormally engaged in response to music. An interesting analogy can be found in epileptic seizures, where abnormal activity of backward projecting pyramidal neurons within the MTL are hypothesised to be responsible for the seizures, and the entorhinal cortex is found to be in particular susceptible for epileptic seizuresvia recurrent signalling of layer V pyramidal neurons. MTL epilepsy shares phenomenological characteristics with the psychedelic-induced states (e.g., spontaneous personal memory recollection). Most importantly, these experiences can be experimentally induced by increasing coupling between the PHC and the visual cortex. A complementary brain mechanism can be formulated in light of the psychedelics' effects on brain networks that control PHC activity. The PHC possesses high baseline connectivity with high-level cortical regions that make-up the so-called default-mode network (DMN). Under normal conditions, top-down inhibitory control over PHC activity is provided by projections from the precuneus, the posterior cingulate cortex (PCC), the retrosplenial cortex (RSC) and the medial prefrontal cortex (mPFC), that terminate on inhibitory interneurons within the PHC. Human PET studies have shown that the RSC, PCC and mPFC express notably high levels of serotonin 2A receptors, and psychedelics are found to have a dysregulating effect on activity within these regions as shown with fMRIand EEG. This dysregulation effect likely compromises the ability of these regions to maintain top-down control over the PHC, and subsequently, may increase responsiveness of the PHC to stimuli that normally engage it, such as music. In support of this view is the finding that reductions in functional connectivity between the PHC and the RSC are observed after both psilocybin and LSD. This naturally leads to the question how this could explain the vivid mental images people experience under LSD and music. What is it that the PHC-to-VC pathway does to produce such subjective experiences when modulated by the LSDxMusic interaction? Information flow from the PHC to the VC has been associated with to the encoding of learned representations, or top-down (prior) "predictions", for complex mental scenes (Aguirre and D. The experience of perceiving complex scenes in the absence of visual input may therefore be the result of an enhanced gain on circuits that normally confer complex, top-down information about (a potential) visual scene. The present experiment showed that the modulation of PHC-to-VC effective connectivity by the combination of LSD and music, was associated with an enhancement in eyes-closed visual imagery. This association was however only present for the item assessing complex visual imagery item (i.e. concrete visual features, such as objects, entities and scenes), and not for the item that assessed simple visual imagery (i.e. low-level visual features such as colours and patterns). This lends indirect support for the view that LSD and music facilitate complex mental imagery via an abnormal engagement of backward projecting pyramidal neurons in the PHC that encode learned representations or "predictions" of complex visual imagery.
IMPLICATIONS FOR PSYCHEDELIC THERAPY
Music alone is an effective medium for stimulating the imagination, and these effects of music are typically exploited in the context of conventional forms of music therapy. The present experiment supports the hypothesis that under psychedelics, music-induced imagery is intensified. This suggests that psychedelics can be utilised to allow an enhanced engagement with mental images music on subjective experience. The findings of the present study help to elucidate the mechanisms by which music and psychedelics can do this in healthy volunteers. Further research is required to test the therapeutic value of enhanced mental imagery in the context of psychedelic therapy.
STUDY LIMITATIONS AND FUTURE DIRECTIONS
This experiment represented several limitations. First, no significant interaction effect was found between LSD and music on in-scanner subjective ratings for visual imagery, whereas connectivity analyses did show a significant interaction effect on PHC-VC coupling. Since enhanced PHC-VC coupling via the interaction between LSD and music correlated with complex visual imagery, this may be explained by small sample size and variance between individuals in their subjective responses to LSD and music. In addition, appraisal of the music may have played a role too: some participants may have disliked the genre of music or may not have been engaged with it for other reasons, such as being distracted by the considerable noise emitted by the MRI machinery. Only one style of music was used in this experiment, and therefore the results may not be generalised to the experience of other music's. For example, the music used in this study did not contain clear rhythmicity, whereas some studies indicate effects of repetitive drumming on mental imagery. A study could be designed that incorporates more than one genre of music (E.g. emotionally relaxing music versus emotionally intensifying or arousing music). Finally, the study group represented psychedelic-experienced users with no history of mental health issues. The present results can therefore not be extrapolated to a patient population, in which the combination of music and psychedelics is thought to be especially important for psychedelic therapy. Subsequent work is needed to further our understanding of how music and psychedelics interact and how this may be useful for psychedelic-assisted therapy.
CONCLUSIONS
The present study revealed a positive interaction between LSD and music on PHC functional and PHC-VC effective connectivity. More specifically, a modulation of PHC to VC effective connectivity was observed that correlated positively with eyes-closed visual imagery, and particularly imagery of a complex and autobiographical nature. These results extend our understanding of circuitry involved in mental visual imagery and suggest candidate brain mechanisms for how LSD and music can work in concert to facilitate mental imagery. The study supports the view that psychedelics influence the experience of music, however, a large amount of work is required to further our understanding of psychedelic therapy and the roles of music. "The listener does not find a simple reflection of his or her own expectancies. The music forms the listener's experience, and in its unique negotiation of the tension between striving and grief, it creates knowledge of something that has been formerly unknown, something that asks to be integrated in the mind of the hearer" The capacity of psychedelics to facilitate intense emotionality and autobiographical salient experiences was a primary motivation for their therapeutic use in the 1950s and 1960s. Music was soon introduced within the therapeutic framework as a way to non-verbally guide patient's experiences into therapeutically meaningful directions. Although modern psychedelic therapy sessions typically involve a 'hands-off' approach on behalf of the therapists, music is still widely used, and considered to be a valuable therapeutic tool. During the drug sessions, patients are typically encouraged to focus their attention inwards, while lying down in a relaxing position and listening to music. It is believed that in this way, music can facilitate experiences that have most therapeutic value, such as psychedelic peak experiences or autobiographical experiences. The views behind this procedure were described in detail in the introduction chapter (chapter 1), and in subsequent chapters, data was presented that demonstrated that musicevoked emotion and music-evoked mental imagery are significantly modulated by LSD (chapters 3, 4 and 5). Although these studies support the hypothesis that the subjective response to music is intensified under psychedelics, these studies were performed in a population of healthy volunteers, and only used a short duration of music-listening and limited music styles. At present, there is no empirical data available on the experience of music under therapeutic conditions, and on the therapeutic functions that music may serve in this context. This present study aimed to address this matter, by investigating the different ways music influences the subjective experience of patients undergoing psychedelic therapy with psilocybin for depression. This study used psilocybin, and not LSD, given most clinical evidence for safety and efficacy is for psilocybin, and psilocybin has a favourable half-life compared to LSD (which last longer). In addition, the study aimed to assess how the music- Because music-evoked emotion (study 1 and 2) and music-induced mental imagery (study 3) are significantly modulated under psychedelics, and because both musicand psychedelicscan facilitate peak experiences, the influence of music on patient's experiences and on therapy outcomes was predicted to be substantial. These findings will be discussed in light of previous work, including a discussion on possible therapeutic mechanisms of music in psychedelic therapy, and on how the findings inform strategies for the use of music in psychedelic therapy sessions.
PARTICIPANTS
Inclusion criteria for the study were moderate to severe major depression, as determined by the 21-item Hamilton Depression Rating scale (HAM-D), with absence of improvements despite at least two different pharmaceutical antidepressant treatments for a minimum of 6 weeks within the current depressive episode. Exclusion criteria included current or previously diagnosed psychotic disorder, diagnoses of psychotic disorders in immediate family members, a medically significant condition rendering the patient unsuitability for the study, history of suicide attempts that required hospitalisation, history of mania, having a blood or needle phobia, pregnancy, and current drug or alcohol dependence.
EXPERIMENT OVERVIEW AND PROCEDURES
Psilocybin was synthesised and obtained from THC-Pharm (Frankfurt, Germany), and formulated into 5mg capsules of psilocybin, by Guy's and St Thomas' Hospital's Pharmacy Manufacturing Unit (London, UK). Screening consisted of evaluating the patient's current and past physical and mental health. Patient-rated scales for the severity of depressive symptoms were completed during the screening visit and served as baseline measures. These included the 16-item Quick Inventory of Depressive Symptoms (QIDS) and Beck Depression Inventory (BDI). Written informed consent was given, and by the end of the screening, eligible patients met with the two therapists that would support them through the remainder of the trials. A subsequent visit functioned as preparation for the session. This included conversations with the therapists about the patient's personal history, expectations for the sessions and education about the effects of psilocybin. The patient also had an opportunity to listen to samples of session music while wearing eye-shades, as a simulation-experience in preparation for their first session. The preparation visit lasted approximately 4 hours in total. Following the preparation session, patients received two different dosages of psilocybin on two separate subsequent occasions, each separated by one week. In the first session, all patients received an oral dose of 10 mg psilocybin. This lower dose was intended to function like a "taster", a preparation for the higher dose administered one week later.
THERAPEUTIC SETTING
Considering the importance of the therapy setting, all sessions took place in a specially designed therapy room within the Clinical Research Facility at Imperial College London. All unnecessary medical equipment was either removed or hidden, light quality was adjusted using Philips hue lamps. Drapes, cushions, plants, art paintings and artefacts were introduced to engender a cosy and comfortable climate. After receiving psilocybin, patients were encouraged to relax in a reclined position on the bed and wear eye-shades. Two therapists were present on either side of the bed, and checked-in with the patient every 30-60 minutes, to obtain insight into how the patient's subjective experience was unfolding, and to determine whether psychological support might be needed. Calming ambient music was played on entrance, but the session playlist (see appendix, chapter 8.3) was started upon ingestion of psilocybin. Patients had the option to listen to the music via high quality in-ear headphones (Sennheiser IE 800) or via a high fidelity standing stereo-speaker (Meridian DSP3200). Both headphones and speakers received the same audio signal, which allowed the music be played in synchrony and continuously through both channels. This set-up was considered helpful for: 1) providing a sense of continuation of the experience in case the headphones were pulled off or muted while the music was still playing. 2) helping the therapists have insight into the patient's experience, as well as how the patient responds to particular parts of the music. 3) allowing the music to be perceived not only via the ears, but also bodily and more spatially.
MUSIC SELECTION
The central purpose of the use of music in the present therapeutic study was consistent with that of early psychedelic-therapy studies, i.e. to facilitate personally meaningful experiences. In order to achieve this, researchers often emphasised the importance of adapting the music to individual patient's changing therapeutic needs, as their therapeutic experience unfolds dynamically. For the present study, however, a standardized playlist was used to control for music as a potential confounding variable. Therefore, all patients were intended to listen to the same music playlist. In (rare) cases where the music selection was strongly disliked by the patient in the first session, or a strong preference was expressed to only listen to classical music, the music playlist used by John Hopkins was used, which includes music originally suggested by Bonny and Pahnke. Several of the musical works originally included in playlists for psychedelic-therapyare very familiar today. Examples include: "Samuel Barber -Adagio for strings" and "Beethoven -Piano Concerto 5". Such high familiarity may reduce the opportunity for patients to have a new experience with the music, unfettered by prior associations. In addition, a strong emphasis on music with "Christian religious" content may not be appropriate for individuals that are either non-religious or practice a different religion. Therefore, a music playlist was designed for the present study, containing predominantly contemporary music such as the ambient-, neo-classical-, modern classical-, jazz-and diverse ethnic-music styles. The intention with this music selection was to transcend religious boundaries, and to support spiritual peak experiences within a secular framework. In addition, a part of the music-selection was tailored to the condition treated (i.e. depression), via a selection of music that reflected sentiments of sadness and grief, yet simultaneously, in the song's dynamical narrative, reflected themes of hope, change, beauty and personal empowerment. Music with such emotional sentiments was only played during peak drug intensity, on the assumption that this music would then reflect autobiographical and therapeutically significant content, and thereby increase the person's therapeutic engagement in the experience.
PLAYLIST DESIGN
The design of the music-playlist was informed by) and the LSD psychotherapist and author Stanislav Grof, who defined different phases in psychedelic therapy sessions, where each phase is associated with a distinguishable set of psychological needs the music can serve. These phases are, in chronological order: "pre-onset", "onset", "building towards peak", "peak", "re-entry" and "return". In the present study, the durations of the phases were adjusted to the shorter duration of psilocybin's effects, compared with LSD. Furthermore, "onset" and "building towards peak", were grouped together as "ascent", and "re-entry" was named "descent".
THE STRUCTURED INTERVIEW
The structured interview was always conducted one week after the final session, by the same researcher, apart from on one occasion. The interview consisted of four open questions: 1) "Did the music influence your experience? And if so: in what ways?", 2) "Can you comment on how the different styles of music influenced your experience? And which music did you prefer?", 3) "Were there any aspects in the music that in particular influenced your experience positively?", and 4) "Were there any aspects in the music that in particular influenced your experience negatively?". Additional questions were sometimes asked to clarify patient's responses if the interviewer felt the need to do so.
THEORETICAL APPROACH OF INTERVIEW DATA-ANALYSIS
Interpretative phenomenological analysis (IPA) was chosen to analyse the interviews. IPA is an approach increasingly used in healthcare researchthat examines the meanings particular experiences hold to people. It is particularly appropriate for ascertaining the complexity (i.e. the quality and phenomenology of experience) behind patients' subjective experience of music during the therapeutic sessions, and has previously been used to investigate the benefits of music therapy interventions in cancer care settings6.2.9 Interview data analysis: Coding Interviews were transcribed verbatim and checked for accuracy. All coding was done by at least two researchers, to increase inter-rater reliability. A step-by-step analysis of the data was followed. All transcripts were read through twice before carrying out the analysis. During the third reading, any phrases considered as especially pertinent in terms of how the music influenced the patient's subjective experience, were highlighted and coded into initial interpretations. At this stage, some text was assigned to more than one code when more than one interpretation could be made, and queries about the meaning of what was being said were recorded in a separate column. This process was repeated for four further transcripts. Key words, phrases and initial interpretations from the first four completed transcripts were then comprehensively explored, leading to the creation of themes in a separate column. These themes were then used as guidelines for subsequent transcripts. As new themes emerged from these subsequent transcripts, all data were iteratively scrutinised and the list of themes refined. Throughout the process of analysis, codes were examined and discussed among the authors to decide which themes were the most accurate reflections of participants' experiences. Following further discussion between authors, a final master list of themes emerged. The final stage of analysis involved the organisation of the list of themes into a more concise list of overarching, superordinate "clusters" or domains representing the patient experience of music, each of which contained a number of subsidiary themes. After all transcripts were coded into themes and clusters, the presence of each unique theme and cluster across all patients' responses was calculated. This lead to a percentage index describing the frequency to which the themes and clusters were present within the total study population.
RATINGS FOR MUSIC-EXPERIENCE
Three predictors for therapy-response were hypothesized: 1) "liking", referring to the degree to which the music styles and the music quality were liked, 2) "resonance", referring to the degree to which the music matched with or was "harmonious" with the intrinsic emotional state of the patient, and 3) "openness", referring to the degree in which the patient was open to, or accepting of the music-evoked experience. Four researchers that were blinded to patient identifiers and treatment outcomes rated these variables for all 19 patients based on their interview transcripts. Ratings were done via a visual analogue scale, with five anchors presented. For the "liking", the question was formulated as "To what extent did the patient like or dislike the music?", with the following anchors on the response scale: "0 = strong disliking", "25 = major disliking, some liking", "50 = mixed disliking and liking", "75 = major liking, some disliking", "100 = major liking". For "resonance", the question was formulated as "To what extent was the music in resonance with the patient's subjective experience?", with the following anchors on the response scale: "0 = strong dissonance", "25 = major dissonance, some resonance", "50 = mixed resonance and dissonance", "75 = major resonance, some dissonance", and "100 = strong resonance". And finally, for the third, the question was formulated as "To what extent was the patient accepting of or open to the music-evoked experience?", with the following anchors on the response scale: "0= strong resistance", "25 = major resistance, some openness", "50 = mixed resistance and openness", "75 = major openness, some resistance" and "100 = strong openness". A total of twenty participants were enrolled in the trial, including 14 males and 6 females, with an average age of 44.1 ±11 years. Ethicities included 15 white, 3 black, 1 asian, and 1 hispanic. 11 were unemployed. Average years of depression was 17.7 ±8.5, and average severity of depressive symptoms was 19 ±2.7 on QIDS-16, 35 ±7.4, 23.9 ±5.4. The average number of different medications used in the past was 4.6 ±2.6, and 17 out of 20 underwent psychotherapy in the past. 18 had higher education. Weekly alcohol use in units was 3.7 ±6.5, and previous (life-time) use of psilocybin was 0.7 ±1.1. For more details on demographics see. Analayses of the interview resulted in the identification of four separate groups, that include clusters of related themes. These groups were: 1) "Welcomed influences", including all influences of music on subjective experience that were described as welcomed, wanted, accepted or appreciated (Figure.1)), were identified in 18 out of 19 patients (95% of total); 2) "Unwelcomed influences", including all experienced influences of music that were described as unwelcomed, unwanted, unacceptable or unappreciated (Figure.1)), were identified in 10 out of 19 patients (53% of total); 3) "Appreciated music styles and playlist features", including all aspects related to music genres, styles, and playlist design, that were appreciated or liked, (Figure.2), and were identified in all 19 patients (100% of total) ; 4) "Unappreciated music styles and playlist design", including all aspects of music genres, styles and playlist design that were not appreciated or were disliked (Figure.2), were identified in 11 out of 19 patients (58% of total). Here, the term "music styles" refers broadly to the instrumentation, compositional-, genre-and acoustic-features of the music. The term "playlist design" refers to all aspects related to the selection and structuring of the music into the full music playlist. The figures displaying the four groups (Figures 6.1 and 6.2) include the clusters present in more than 30% of the respective group, and the themes present in more than 30% of the respective cluster. All patient's quotes of themes present in each of these groups and clusters, are displayed in separate tables (Table. It is important to emphasise that the identification of a theme in a patient's experience, and subsequently the including of that theme in counting its presence in the total population, does not allow us to make any statements on the duration that this theme was present in the patient's total experience. E.g. one patient may have experienced a sense of irritation in response to one particular song, and therefore the theme "irritation" under the cluster "intensification" in the group "unwelcomed influences" is present. But this does not imply that the patient experienced persistent feeling of irritation during his or her experience. In addition, the measure also only allows the capturing of spontaneous mentioning and elaborations on the subjective experience of the music, as opposed to the questions targeting (and biasing) specific facets of the patient's experience. in more than 30% of all participants, and per cluster the themes that were present in more than 30% of the cluster. The numbers below the group-, cluster-or theme-name, refers to the total number of patients that referred to this. The size of the circle is proportional to the percentage of patients referring to the group, cluster or theme.
WELCOMED INFLUENCES: INTENSIFICATION
The most prominent cluster in the group "welcomed influences", including 17 out of 19 patients (88% of total), refers to themes that describe an "intensification" of the subjective experience by the music. Within this cluster, themes that describe an "intensification of emotion" were identified in 15 out of 17 (82% of cluster), including descriptions of music enhancing or changing emotions. Importantly, the emotion-evoking effects that were welcomed, showed diverse emotional valence, and included descriptions of the music facilitating "happiness" or strong "ecstatic" experiences, as well experiences of the music intensifying "tearfulness". Themes describing an "intensification of imagination" were identified in 9 out of 17 (53% of cluster). This included statements of the music evoking vivid and complex mental imagery, and of the concrete imagery related to specific aspects of the music. Such as for example the ethnic "Indian" style of the music being associated with "seeing an Indian temple". 8 out of 17 patients (47% of cluster), mentioned a "general intensification" effect of the music, without specifically referring to this being an intensification of emotionality, imagery or others. Other themes, present below 30% in the cluster "intensification", include effects of music on "personal thoughts or memories" (2/17, 12% of cluster), music facilitating a "sense of transcendence" (2/17, 12% of cluster) and music enhancing "ego-dissolution" (2/17, 12% of cluster) (Figure.1). See Table.1 for a listing of all themes present in the cluster "intensification". "the visuals … [The music] kind of opens up your imagination in a way, your imagination is much easier to picture. One of the songs created imagery of a "wooden bannister" that had a shape, it had a texture and a material, with some water and marbles with rainbows in it. I could picture it really clearly." Imagination "[the music and the experience] was a symbiotic kind of thing." General intensification "That piece of music was probably the peak of positivity, it was almost like a subdued kind of ecstasy, you know, it was so amazing. It was such a beautiful feeling." "It changed the sort of imagery in my head, it didn't make it any better or worse, but it had a definite impact" Imagination "It felt like everything added towards the experience rather than took away" General intensification "The music evoked a lot of emotions." Emotionality "I had a sort of ecstatic experience." "That seemed to be the point at which I was kind of carried away, in this ecstatic rapture."
EMOTIONALITY (ECSTASY)
"Clearly the music enhanced the emotional experience." Emotionality "I suppose church-type music, I think was responsible for enhancing the religious experience."
EMOTIONALITY (SPIRITUALITY)
"My experience seemed sometimes to coincide with the lightness of the music into the light place and the darkness of the music to the dark." Emotionality "There was a specific moment when I felt as though I was being given birth to the universe, and I semi-recall there was this sort of crescendo of music at that point, that was a very strong point in the journey for me." Imagination, Sense of transcendence "When I was born into the universe, you know, everything dropped away apart from these slight tethers that were holding me back, and I was into the vastness of the universe, and that could have been when the music stopped, because I remember at that particular point looking at this immense void in front of me."
SENSE OF TRANSCENDENCE
"The music did affect [the experience]." General intensification "The music just made it more emotional." Emotionality "Yeah, it definitely served the function of helping emotions flow." Emotionality
WELCOMED INFLUENCES: GUIDANCE
The second most prominent cluster of welcomed influences, includes themes that depict the music as a source of "guidance". This cluster was mentioned by 15 out of 19 patients (79% of total). Within this cluster, statements that the music provided a "sense of being on a journey" were identified in 11 out of 15 (73% of cluster). This included descriptions of the music being experienced as a "vehicle" that "transports" or "carries" the listener forward, providing a sensation of "traveling" to different psychological "places". Themes describing the music as a source for psychological "support" were identified in 11 out of 15 (73% of cluster). This includes various statements of the music providing a sense of "grounding", "help" and "reassurance". Descriptions of the music being in tune with, or in "resonance" with the person's intrinsic emotional state were identified in 6 out of 15 (40% of cluster). Rather than describing the music as evoking emotion, this theme is defined by statements of the music being experienced as "fitting", "following" or "matching" present emotional states. Finally, 5 out of 15 of patients (33% of cluster) referred to the music as providing a "sense of continuity and direction", this included statements of music providing a sense of connection between different parts in the experience, making the experience feel "driven" by the music and "flowing" into a certain direction (Figure.1). See Table.2 for a listing of all themes present in the cluster "guidance". Table.2 | Welcomed influences: Guidance. A list of all the themes and respective quotes by patients, that were present in the cluster "guidance". # Quote Theme 1 "I think that it was comforting, knowing that the music was there, because it was there the whole period, the music was always in the background, so in in a way it grounded me." Sense of being on a journey "I feel the music in large part drove a lot of the experience." Sense of continuity and direction "I did feel as if I was being held" Sense of support "[The music] took my thinking and my experience to uncomfortable places, but I was kind of reassured in the experience." Sense of support "There was something there that meant that, you know, 'I'm going to take you on a ride here, but I promise I won't abandon you. It's just going to be tough, and you know, you're going through the grinder here, but you won't be left in pieces.' That seemed to be what the music was saying to me."
SENSE
Sense of support, sense of being on a journey "The music took you to the places you needed to be." Sense of support, sense of being on a journey "It felt we had a profound relationship, between my heartbeat and the beat of the music." Resonance "It felt like the music picked you up and carried you to the next part, and the next piece, and it was the vehicle that moved you." Sense of being on a journey, Sense of continuity and direction "There was a point and I didn't want music anymore, I didn't want anything but I definitely think the music sort of transported there to where you should be"
SENSE OF BEING TRANSPORTED
"It felt like it all fitted the experience" Resonance "That seemed to be the point at which I was kind of carried away, in this ecstatic rapture." Sense of being on a journey "I was able to just put the headphones on and the mask on, and really enjoy it." Sense of support "The music definitely assisted me." Sense of support 18 "The music both took me to very beautiful places and to incredibly dark places." Sense of being on a journey "My experience seemed sometimes to coincide with the lightness of the music into the light place and the darkness of the music to the dark." Resonance "I went to a very dark place." Sense of being on a journey "It was a woman's voice, it was a sort of operatic voice, and first it was beautiful because, you know, I was following it and it took me to a beautiful place." Sense of being on a journey 19 "Yeah, it definitely served the function of helping emotions flow." Sense of support
WELCOMED INFLUENCES: CALMING
10 out of 19 patients (53% of total) described calming effects of the music. From this cluster, 9 out 10 (90% of cluster) described "general calming" effects, whereas 5 out of 10 patients (50% of cluster) described the music as providing "mental calming" effects, including sensations of peacefulness and of the music calming and "slowing the mind". 1 out of 10 (10% of cluster) described the music to help feel more physically relaxed. Calming effects of music often referred to ambient music by Brian Eno, Harold Budd and Stars of the lid. See table 2 for a listing of all themes present in more than 30% of the cluster "guidance" (Figure.1). See Table.3 for a listing of all themes present in the cluster "calming". "There was a piece that was quite calming, so that was very positive." General calming
WELCOMED INFLUENCES: OPENNESS TO MUSIC-EVOKED EXPERIENCE
7 out of 19 patients (37% of total) made statements about their own attitude of openness towards the influences of the music, and in addition, about the effects of music on their attitude of openness. From this cluster, 6 out of 7 (86% of cluster), referred to the "importance" and the "purpose" of being open to "challenging experience" evoked by the music, and that this felt like an important part of the therapeutic process. This included statements of accepting being deeply emotionally moved by the music, and the music helping to "face" or "connect with" the listener's "unresolved" inner conflicts. 4 out of 7 (57% of cluster) described that some music specifically helped to enhance their attitude of openness, such as statements that "the music opened [him/her] up" or that because of the music was "well-chosen", the listener "felt open to it all" (Figure.1). See Table.4 for a listing of all themes present in the cluster "openness to music-evoked experience". Openness to challenging experience feels therapeutic 16 "There was a point and I didn't want music anymore, I didn't want anything, but I definitely think the music sort of transported there to where you should be" Openness to challenging experience feels therapeutic
UNWELCOMED INFLUENCES: INTENSIFICATION
The most prominent cluster, including 5 out of 10 patients (50% of cluster), described music to "intensify" emotions they did not want to feel, such as increased "fearfulness", "sadness" or "fear". In addition, 5 out of 10 (50% of cluster) said made statements about the music creating a sense of "discomfort", including "unpleasant" or "uncomfortable" experiences, and 4 out of 10 (40% of cluster) described "irritation" as a consequence of the music. In less than 30% of the cluster, the music was described as bringing mental imagery, thoughts or memories that were unwelcomed, a sense of puzzlement, inner conflict, and tension, or a "dark atmosphere". This cluster of unwelcomed "intensification" influences, forms a contrast with the cluster of themes describing intensification as a welcomed influence (Figure.1 and Table.1). See Table.5 for a listing of all themes present in the cluster unwelcomed "intensification". "With a higher tempo everything feels a bit more tense." Tension 15 "I wanted to explore a certain experience or vision, but the music changed that. I was experiencing these geometric shapes which were seeming to construct themselves into something that I was beginning to understand, but then the music interrupted that and changed it and I was slightly annoyed by that." Irritation "The piano pieces, irritated me. It was like little needles." Irritation, Discomfort "The piano playing was irritating, because I found it quite amateurish." Irritation 17 "There was some sort of Indian-style music, I think I found it a bit creepy at the time." Emotionality (fear)
SECTION
"Made me a bit more emotional, more vulnerable." Emotionality "A bit annoying" irritation "What I was experiencing at the time, it was you know, unpleasant" Discomfort "Made me feel 'uurgh'" Irritation "Some of [the music] was uncomfortable." Discomfort 6.3.6 Unwelcomed influences: Resistance to music-evoked experience 9 out of 19 patients (47% of total) described feelings of "resistance to the music-evoked experience". This includes statements of "not liking" or "not wanting" the subjective effects of the music. This cluster of unwelcomed influences contrasts the cluster of themes describing an "openness to music-evoked experience", as a welcomed influence (see Table.4 and Figure.1). See Table.6 for a full list of all themes in the cluster "intensification". Table.6 | Unwelcomed influences: resistance to music-evoked experience. A list of all the themes and respective quotes by patients, that were present in the cluster "resistance to music-evoked experience".
" MUSIC FACILITATES RESISTANCE
"There was resistance, massively, to everything, every sort of sensory input I had a fearful response. I was afraid to open my eyes, I was afraid to do anything, I was afraid that this sort of music was the last thing I'd ever hear."
MUSIC FACILITATES RESISTANCE
"But I listen to a lot of similar kind of music on my own, so obviously, it does move me, whether or not I admit that, it does shape my emotions and my 6 out of 19 (32% of total) made statements about the music providing a sense of "misguidance", this cluster primarily includes descriptions of the music being a "mismatch" or being incongruent with the unfolding subjective experience. This cluster, named "dissonance", was present in 4 out of 6 (67% of cluster), and forms a contrast with the welcome influence "resonance", when the music was experienced as harmonious, or a good match, with the subjective experience. Other themes of misguidance, present in less than 30%, include descriptions of the "music feeling intrusive", the music being "unable to positively influence a challenging experience", the music giving a "sense of being manipulated", the music giving a "sense of unmet potential", or the music giving a sense of "foreboding", as if something "bad" was going to happen. This cluster of unwelcomed influence contrasts the cluster of themes describing a sense of "supportive" and "helpful" guidance, as a welcomed influence (see Table.2 and Figure.1). See Table.7 for a full list of all themes in the cluster "misguidance". present in more than 30% of the cluster. The numbers below the group-, cluster-or theme-name, refers to the total number of patients that referred to this. The size of the circle is proportional to the percentage of patients referring to the group, cluster or theme.
APPRECIATED MUSIC STYLES AND PLAYLIST FEATURES: MUSIC STYLES
All 19 patients referred to some music styles within the music playlist that they especially appreciated (Figure.2). Most frequent were positive statements about "ethnic or cultural music", present in 8 out of 19 patients (42% of cluster), such as "Indian", "Spanish" or "African" music styles (e.g.. Positive statements about music with human voice were mentioned by 7 out of 19 patients (37% of cluster). Importantly, this refers to vocal music either without lyrics or music with lyrics in a foreign language (e.g. The Journey by Ludivoco Enaudi, and Enya's sumiregusa). One other music style that was frequently appreciated by 7 out of 19 (37% of cluster), was neo-classical music (e.g. Max Richter or Olafur Arnalds) or classical music (e.g. Henryk Gorecki or Arvo Part). Apart from these styles, the appreciated music styles showed a noticeable diversity. In less than 30%, positive statements were directed to "music with crescendo" (5 out of 19, 26% of total), "powerful music" (4 out of 19, 21% of total), and only 1 to 2 out of 19 made explicit statements about their appreciation for specific instruments, such as violin, guitar, piano, or "music with a solid drone". See table.8 for a full listing of all themes referring to music styles that were explicitly appreciated. "I think the one that I liked the most was the one in the beginning, sort of filmlike music?" Cinematic music "There was some sort of activity going on and a suspense, and I did like that one." Cinematic music "There was activity going on and at the same time some feeling of expected, which you would see in film, a soundtrack." Cinematic music 3 "At the end where there were more words, which was pretty good. I respect that maybe in the beginning I wouldn't have appreciated that as much, when the drug was at its most intense." Vocal music "There was an "African" song, where, I think they're singing about "our father" or something? And it was just a whole bunch of voices most of the time in the song, which was pretty good."
ETHNIC OR CULTURAL MUSIC (AFRICAN)
"There was one that just built up, [Greg Haines -Azure] was one example where in the beginning it just sounds like someone is just hitting sh*t randomly in his music room and then it all comes together in the end and blows your mind." [interviewer: were there any ones that you had a particular preference for?] "Yeah, the classical pieces." Classical or neoclassical music "There were some [that I preferred], a man's voice. The experience changed when there was a voice, from when it was just music." Vocal music (male) "I heard the beginning of one of my favourite pieces of music. Beethoven's Emperor Piano Concerto, the second movement." "There was a specific moment when I felt as though I was being given birth to the universe, and I semi-recall there was this sort of crescendo of music at that point, that was a very strong point in the journey for me." Music with crescendo "The Mexican song I thought was quite good." Ethnic or cultural 6.3.9 Appreciated music styles and playlist features: Playlist design 17 out of 19 patients (89% of total) made statements reflecting appreciation for the design of the playlist (Figure.2). Most prominent were positive descriptions of the "music selection", described by 12 out of 17 patients (71% of cluster), including descriptions of the music "working well" or being "well-selected". Secondly, 9 out of 17 patients (53% of cluster), provided positive descriptions on the way the music was structured into the full playlist. This theme, named "music order", is defined by statements of the "structure" and the "ordering" of the music playlist, "aligned" well with the drug-effects. The third most prominent theme, present in 6 out of 17 (35%), corresponds to the "music presence", meaning the mere presence of the music itself. This includes descriptions from the music being present as "helpful", to statements that it couldn't be imaginable doing the sessions without it and that the music presence felt "necessary". Finally, other themes include appreciation for "calming music" to be played mainly during "onset", "ascent" and "return" phases, whereas more emotive music (i.e. "sentimental" or "cinematic" music) to be better reserved for late in the "ascent" phase and during "peak" phase. See Table.9 for a full listing of all themes describing playlist design features that were appreciated. "I think that that it was comforting, knowing that the music was there." Music presence "Variations in the degree of the music and the intensity of it. Some of it was more mellow, some of it more forceful." Variety "[The music] was structured in line with the way the effects of the drug were." Music order "I think that the music, because it was so varied I think it did kind of make you think a bit." Variety 2 "I think the one that I liked the most was the one in the beginning, sort of filmlike music?" Cinematic music in ascent-phase "I could see that there was a great effort to put the music together in a way that it followed the experience as it was meant to be. These responses reflected different degrees of the individual's disliking of the music, and were highly diverse, making no theme present in more than 30% of this cluster (Figure.
).
Some examples of themes in this cluster refer to "music with lyrics", "vocal music", "piano music" "classical or neo-classical music" and "cheesy music". Often, "vocal music" and "cheesy music" referred to one particular song played during the final "return" phase by Buffy Saint Mary, up where we belong. See Table.10 for a list of all themes present in the cluster of un-appreciated music styles. 6 out of 19 patients (32% of total) referred to aspects of the playlist design that were not appreciated. In 2 out of 6 (33% of cluster), a clear disliking of the "music selection" was present, and a preference for "own music selection" was expressed (Figure.2). See Table.11 for a complete list of all themes present in the cluster of un-appreciated playlist design features.
INTER-RATING RELIABILITY AND DISCRIMINATIVE VALIDITY OF MUSIC-EXPERIENCE VARIABLES
Pearson correlation tests between the scores of all researchers (n=4) who rated the three music-experience variables (liking, resonance and openness), demonstrated good inter-rater reliability (average r = 0.6 ±0.1, from total of 18 correlations). Pearson correlation tests between the three music-experience variables showed significant correlations (r = 0.9, r=0.96, and r=0.91). Drug intensity did not correlate with any of the music-experience variables.
DISCUSSION
This study reported marked effects of music on the subjective experiences of patients with major depression who underwent psychedelic therapy with psilocybin. Phenomenological analysis revealed several prominent influences of the music that were welcomed, including an intensification of emotions and of mental imagery, calming effects, and the music providing a sense of guidance. The music-experience was selectively associated with the occurrence of peak experience and insightfulness. The music-experience also predicted reductions in depression after psilocybin, whereas drug-intensity did not. Together, these findings suggest that music has a major influence on patient's experiences in psychedelic therapy, and that music may play an important function in facilitating positive therapy outcomes.
MUSIC-EXPERIENCE
From all the themes identified, patients most frequently reported that emotions and mental imagery were intensified by music under psilocybin, and the study thereby complements the previous studies included in this thesis that demonstrated a modulatory influence of LSD on music-evoked emotion (study 1 and study 2) and music-induced imagery (study 3) in healthy volunteers. By focussing on detailing the phenomenology, the present study also provides new insights into other aspects of the music-experience. In addition to influencing emotion and mental imagery, the music was also often described as providing a sense of guidance within the experience, including feeling personally supported by the music (with the music serving to "ground" and "help" the listener), the music being "resonant" with the individual's intrinsic emotional state (the music being in tune or a good match with inner feelings), and the music bringing the sensation of being guided on a journey. In these scenarios, the music was frequently referred to as a "vehicle" that "carried" and "transported" the listener to different parts in their mind, rich with personally meaningful emotionality and imagery. In contrast to the sense of (welcomed) guidance by the music, were descriptions of the music providing a sense of (unwelcomed) misguidance. In these situations, the music was typically described as being "dissonant" with the patient's intrinsic emotional state: The music was perceived as being "out of tune", "misplaced", or as a "mismatch" with their inner emotions and thoughts. One example of the experience of misguidance by the music can be found in the response by patient #16: "The light music at one point took me to a place where I thought I was safe, and it became unsafe, and the music was playing a trick with me, you know, sort of giving me a false sense of security. I can remember thinking "this is beautiful music, why am I going to this dark place?" It didn't line up with what had gone on before. I just felt as I was being manipulated, being duped almost. The music lured me to this beautiful place, and then things started to become dark even with this beautiful music still playing." An important observation is that effects of the music that were welcomed, sometimes included emotions such as increased grieving or tearfulness. This attitude of openness towards "negative" music-evoked emotions, was frequently described as an important therapeutic aspect, to bring to expression and to find resolution in unresolved inner conflicts. These experiences were grouped under the theme "openness to challenging experience feels therapeutic", and one example of this attitude of openness towards the music can be found in the responses from patient #9: "I can even view the negative moments as positive in a way because they served a purpose. The purpose was to sort of let me face the darkness, and my demons, I guess. It was beautiful at times, but also… yeah, the darker moments really helped to reflect on and connect with your unresolved shadows." Contrasting such an attitude of openness, is an attitude of resistance to the intensifying effects of the music. This experience was characterised by not wanting the music or its effects, and was named "resistance to intensification". An example of this is described by patient #5, who stated: "I worried that I let [the music] shape this sort of melancholy. There was resistance, massively, to everything, every sort of sensory input, I had a fearful response. I was afraid to open my eyes, I was afraid to do anything, I was afraid that this sort of music was the last thing I'd ever hear." When taking these findings together, a diverse and mixed picture emerges of welcomed and unwelcomed influences of the music on patient's subjective experiences. Welcomed influences were characterised by often intense and personally meaningful emotionality and imagery, a sense of guidance by the music, calming effects, and an attitude of openness to the music-experience. On the other hand, unwelcomed effects of music were characterised by unwanted emotionality and imagery, feelings of discomfort and irritation, a sense of misguidance by the music, and an attitude of resistance to the music-experience. These findings suggest that in order for the music to act therapeutically, it may require a sufficient degree of resonance with the individual's intrinsic feeling state, and a sufficient degree of openness or receptivity to the resulting intensification effects. This hypothesis will be further discussed in paragraphs 6.4.4 and 6.4.5.
MUSIC STYLES AND PLAYLIST DESIGN
The present study did also shed light on the experience of different musical styles and the design of the music playlist. The choice of the music and the design of the music playlist was overall well-appreciated, with the most frequently appreciated musical genres being ethnic-, vocal-and (neo-) classical music. Appreciation was also expressed for the design of the playlist, in particular for the calming music to be primarily present during the early (pre-onset and early ascent) and the final (return) phases, and of the more emotive music to be reserved for the peak phase. This provides indirect support for previous frameworks, to structure the music according to its emotional intensity into different phases of drugexperience. Strong disliking of the music-selection was rare (patient #6), but when this did occur it proved insightful into the role of music-selection: Typically, disliking of the music seemed to be associated with either a "diminishment" of the drug-experience, with unpleasant feelings (such as discomfort and irritation), and with an attitude of resistance, characterised by an attempting to distance oneself from the music, such as detailed in the following excerpt: "The music blocked my experience and feelings. A sense of irritation, frustration, and sense of lowering mood. The majority of the songs were not my kind of music, I can't sit with that music … I have to leave the room. I was sort of feeling bad, because I wanted to work with it. I sensed the potential for a really profound experience. I couldn't meet that potential with music that I felt was quite mediocre. To me it didn't feel real, so I felt quite torn. (#6) In study1, a positive relationship between the liking of the music and the emotional response to music was shown, and such an association has been reported by other studies too. The present data does therefore suggest that the music style may require a sufficient degree of appreciation in order for meaningful emotionality to be evoked by the music, and thereby for the therapeutic process to be supported by the music. This hypothesis will be discussed further in the subsequent paragraph.
MUSIC-EXPERIENCE PREDICTS EXPERIENCE AND THERAPY OUTCOMES
As outlined above, this study found noticeable polarities in the music-experience, such as the music being either liked or disliked, the music being either resonant or dissonant with the patient's experience, and the patient being either open or resistant to the influence of the music. These three variables (liking, resonance and openness) positively predicted the extent to which patients reported having peak experiences (defined as the experience of unity, blissful emotionality and spirituality). In addition, resonance and openness, but not liking, predicted the extent to which people reported experiencing insightfulness (defined by having inventive ideas, feelings of profoundness, insights and the experience of vivid personal memories or mental images). Drug-intensity, on the other hand, also correlated with other aspects of the psilocybin-experience, such as impaired cognition and audio-visual perception changes. The finding that the music-experience variables were selectively associated with peak experience and insightfulness, but not with other subjective experiences under psilocybin, supports the original motivations to include music in psychedelic-therapy, i.e. to promote the occurrence of personally meaningful experiences (such as peak experiences or autobiographical experiences). Modern studies have confirmed that psilocybin can reliably facilitate peak experiences, and these experiences have been associated with sustained positive changes in behaviour and personality, and with positive therapeutic outcomes (Garcia-Romeu,. Although all these studies incorporated music-listening in combination with psilocybin, this is the first study to demonstrate that the experience of music is related to the occurrence of peak experiences. A positive relationship was found between the music-experience and reductions in depression one week after the psilocybin-experience. Importantly, reductions in depression were not related to the intensity of the drug-effects, and only to the music-experience variables liking, resonance and openness. This finding provides tentative support for the hypothesis that it is not merely the drug effects in isolation, but an interaction between the drug and the music that promotes therapeutic experiences and positive therapeutic outcomes. Due the prominence of music-listening in psychedelic therapy, understanding the therapeutic function of music in psychedelic therapy may be fundamental in maximising therapeutic efficacy.
POSSIBLE THERAPEUTIC MECHANISMS OF MUSIC IN PSYCHEDELIC THERAPY
A principal effect of psychedelics is that they temporarily impair brain mechanisms that usually regulate emotion, and this could underlie the enhanced emotional responsiveness to stimuli reported here and elsewhere. Importantly, the emotional experiences to music in this study were not only described as more intense than usual, but as a "release" of meaningful psychological content (ex: autobiographical memories and deep tearfulness). The belief that accepting and moving through challenging emotions is important for psychotherapeutic change is central to many psychotherapeutic models, and has empirical support). In psychedelic therapy, the function of psychedelics may be to bring about a quick relinquishment of psychological control (i.e. ego-dissolution), thereby allowing a fuller (i.e. less inhibited) expression of emotionality. The music, in turn, may play the important function of activating emotionality, thoughts and memories that are most personally significant, thereby guiding the patient's experience into directions that are most therapeutically salient. The key difference between psychedelic therapy and other psychotherapies, may be the capacity of psychedelics and music to facilitate such emotional "breakthrough" experiences more quickly and with deeper emotional intensity. It may be specifically the interaction between the psychological state induced by psychedelics and music, that facilitated the acute and sustained changes in mood and behaviour reported in in this trialand several other studies6.4.5 Implications for psychedelic therapy The findings in this study show similarities with the therapeutic guidelines for music as it was developed by Helen Bonny and colleagues working with LSD in the 1960s, who referred to the therapeutic influence of music as being of "profound significance". Bonny also emphasised the care needed in selecting the right music and playing the music at the right moments. The present study showed that when the music is dissonant (out of tune) with the experience, this was related to reduced therapy outcomes, whereas when the music was more resonant (in tune) with the patient's intrinsic feelings, this was predictive of better therapy outcomes. This finding provides support for the view that adapting the music to patient's individual and highly dynamic experiences under psychedelics may be critical to provide adequate therapeutic support. It also suggests a considerable responsibility on behalf of the therapists to use music appropriately, and the present study has provided some insight into how therapists may best do so to optimise psychedelic therapy sessions. First, the musical style may require a sufficient degree of appreciation. Liking of music is usually defined as a mixture of genre-appreciation and aesthetic judgements, and this factor may be an important pre-requisite for music to evoke meaningful emotionality. In addition, some musical styles and acoustic properties may be more suitable for the state of consciousness induced by psychedelics, than others, although this has not been studied yet. Secondly, when the music is liked, the music may still require an appropriate attunement to the inner emotional state of the patient. By being in resonance with the present emotional state of the patient, the music can enable him or her to better explore and express personal narratives more easily and deeply. In contrast, when music is dissonant, this may "block" such progress or may even become counter-therapeutic. Thirdly, the patient's attitude requires a sufficient degree of openness to the music-evoked experience. This openness may include not only a state of surrender, but also a pro-active focus and engagement together with the minimization of intellectualisation. This hypothetical framework holds that if these three requirements are met (style liking, music's resonance and openness to music), an expression of meaningful therapeutic content could occur, often characterized by the sense of being on a personal journey, with a spontaneous and often intense emergence of personally meaningful imagery, thoughts and emotionality. If any of these pre-requisites is not met adequately, the patient is likely to distance him or herself from the music and the experience, and a rejection of meaningful therapeutic content could occur, characterised by feelings of discomfort, or the absence personally meaningful imagery, thoughts and emotionality (i.e. the absence of the sense of being on a journey). Resolving any such resistance in these scenarios may be the responsibility of the therapist, such as ensuring music styles are sufficiently liked, via thoughtful music-selection, and ensuring the appropriate attunement of the music to the patient's unfolding experience, via thoughtful playlist-design and adaptation of the music when needed. In other scenario's, the music-evoked experience may be rich with therapeutically meaningful content, yet the experience may be highly unpleasant or in other ways emotionally challenging. In these scenarios, feelings of resistance may be due the patient wanting the experience to be different, and this may be resolved by the therapist's reassurance of their safety, and providing therapeutic support to explore these challenging feeling states. In this framework, resistance can be regarded as an important indicator of music's failure to act therapeutically, and the type of intervention needed to restore music's therapeutic function may be determined by one central question the therapist may need to clarify, i.e. what is the source of resistance? Is it due a disliking of music style, or due a dissonance of the music with the individual's experience, or due a resistance to therapeutically meaningful content?
LIMITATIONS AND FUTURE DIRECTIONS
This study has a number of limitations. First of all, the data was acquired without a placebocondition, making inferences about the effects of psilocybin on the experience of music problematic. Secondly, the main body of data used for this study was qualitative in nature. Therefore, the experiment did not allow studying the magnitude of the observed effects of music. It should therefore be emphasised that the primary objective of this study was to provide a patient-perspective on the influence of music. We hope that the theoretical framework this provided, inspires testable hypotheses for future studies, and that it assists Furthermore, to advance the therapeutic use of music, a significant body of work is required to establish baseline measures that predict music-experiences during psychedelic therapy sessions. Such predictive measures can range from personality traits (e.g. openness to experience, absorption or suggestibility), to measures for music preferences at baseline. Furthermore, research that focusses on identifying reliably indicators for positive (welcomed/supportive) and negative (unwelcomed/unsupportive) influences of music on the therapeutic processes during psychedelic therapy sessions, may be highly significant for the development of psychedelic therapy, and the tools used during psychedelic therapy. These could range from simple physiological measures, such as heart-rate, body movement, and breathing patterns, or more complex measures such as facial affect-coding, vocal-affect coding, and EEG-signatures, that could inform therapists in on-the-fly adaptation of musicselection, or inform playlist generation algorithms.
CONCLUSIONS
Music was described as having a substantial influence on the therapeutic experience with psilocybin. The music-experience was predictive for peak experiences and insightfulness during the sessions, and reductions in depression after the sessions. This suggests that music may play a fundamental role in facilitating therapeutic change in psychedelic therapy. The findings support the usefulness of music in psychedelic therapy, but more research is warranted to better understand the therapeutic effects of music, including how music-use can be optimised for different types of psychotherapeutic experiences, as well as to investigate the specific therapeutic mechanisms. "We should long ago have become angels had we been capable of paying attention to the experience of art, and allowing ourselves to be changed in accordance with the ideals it expresses" Andrey Tarkovsky 7.1 Summary of qualitative findings
EFFECTS OF PSYCHEDELICS ON MUSIC-EVOKED EMOTION
Study 1 (Chapter 3) reported that healthy participants were significantly more "emotionally affected" by music under LSD than under placebo. In addition, both study 1 (Chapter 3) and study 2 (Chapter 4) reported on the implementation of the Geneva Emotional Music Scale (GEMS) to assess the effects of LSD on different types of music-evoked emotions. In both of these studies, the GEMS showed significant higher ratings under LSD for the music-evoked emotions "wonder" (filled with wonder, dazzled, moved), "transcendence" (fascinated, overwhelmed, feelings of transcendence and spirituality), "tenderness" (tender, affectionate, in love) and "power" (strong, triumphant, energetic). In addition to these types of emotions, chapter 3 also showed a significant increase under LSD for the emotions "nostalgia" (nostalgic, dreamy, melancholic), "peacefulness" (serene, calm, soothed), and "joyful activation" (joyful, amused, bouncy). Both studies reported no significant increases in musicevoked emotions of negative valence ("sadness" (sad, sorrowful) or "tension" (tense, agitated, nervous)). The findings reported in study 4 (Chapter 6) supplemented these findings by showing that the most frequently mentioned influence of music on subjective experience during psychedelic therapy sessions with psilocybin, was an "intensification of emotion", and that in the therapeutic context this applied to both positive emotions and negative emotions (e.g. tearfulness).
EFFECTS OF PSYCHEDELICS ON MUSIC-EVOKED MENTAL IMAGERY
In study 3 (Chapter 5), the neurophysiological correlates underlying LSD and music's combined effects on mental imagery were examined via rating scales during and after the neuroimaging procedures. During scanning, changes in eyes-closed mental imagery were assessed via ratings for simple visual imagery (i.e. colours and patterns) and complex visual imagery (i.e. concrete objects, landscapes or beings). Subsequently, the effect of LSD, of music, and of their interaction between the two, were assessed separately via a repeated measures ANOVA. Ratings for simple hallucinations were found to be increased under LSD, but no increase was found as an effect of music or as an effect of the interaction between music and LSD. Ratings for complex visual imagery were also found to be increased under LSD, and a trend level significant increase in complex visual imagery was found as an effect of music, but no significant interaction effect was found between LSD and music. In addition, after fMRI scanning the participants completed a survey about their subjective experience inside the scanner, and a significant increase was found under LSD for the item that rated the spontaneous recollection of autobiographical memories: "I saw scenes from my past". These findings suggest that psychedelics do increase mental imagery, and that music may selectively modulate "complex" mental imagery, and not "simple" mental imagery. The qualitative analysis reported in study 4 (Chapter 6) showed that "intensification of the imagination" was one of the most prominently mentioned influences of music during psychedelic therapy with psilocybin for depression, which included descriptions of the music influencing the content of the mental imagery, as well as descriptions of the music making mental imagery more vivid. Study 4 (Chapter 6) also reported that the music-experience was associated with a factor called insightfulness, which was defined by having inventive ideas, feelings of profoundness, insights, as well as the experience of vivid personal memories or mental images.
PHENOMENOLOGY OF THE MUSIC-EXPERIENCE DURING PSYCHEDELIC THERAPY
Study 4 (Chapter 6) reported in detail on phenomenological themes presented in patient's descriptions of their subjective experience of the music while under the influence of psilocybin. The study showed that patients experienced "welcomed" and "unwelcomed" influences of the music, each including several prominent clusters of themes. The most frequently described welcomed influences of the music included an "intensification" of emotion and imagination, calming effects of the music, and of the music providing a sense of guidance. This sense of guidance included a sense of personal support, a sense of being "carried away" or "being transported on a journey", and a sense that the music was resonant or in tune with the patient's intrinsic emotional state. In addition, a recurrent theme included descriptions that an attitude of openness to the music-evoked experience felt like an important therapeutic element, and also that music itself can help facilitate such an attitude of openness to the music-experience. In contrast, the most frequently described unwelcomed influences of the music were an intensification of (undesirable) or a diminishing of (desirable) emotions and imagery, and the music facilitating feelings of resistance (i.e. the opposite of openness) or a "sense of misguidance" (i.e. the opposite of "sense of guidance"). This sense of misguidance most often included the sense that the music was dissonant or not in tune with the present internal emotional state of the patient (i.e. the opposite of resonance). Study 4 (Chapter 6) also reported on appreciated and un-appreciated music styles, showing that the most appreciated musical styles included ethnic music, neo-classical-and classical music, vocal music (non-lyrical), followed by ambient music. The liking and disliking of the music styles showed a remarkable diversity, but one compositional feature in the music that was found to be in particular appreciated was music with a build-up or "crescendo" or, contrastingly, music that helped to feel calm and secure. Music that was most disliked included music with lyrics, and music with high pitched sounds. The music-evoked experiences were often described as personally meaningful. The degree to which patients described a resonance of the music with their underlying emotional state, as well as the degree to which patients described an attitude of openness to music-evoked experience, and a liking of the musical styles -these three variables were found to significantly predict the occurrence of 'peak experiences'. Resonance and openness, but not liking, were associated with experiences of insightfulness. All three variables predicted clinical improvements one week after psilocybin, whereas drug-intensity did not. These findings suggest important therapeutic functions of music during psychedelic therapy, which are discussed in more detail in section 7.4.
THE EFFECTS OF LSD ON THE BRAIN'S PROCESSING OF MUSICAL FEATURES
The fMRI study reported in study 2 (Chapter 4) investigated the effects of LSD on the brain's processing of distinct acoustic features of music under naturalistic listening condition in healthy volunteers. The study revealed widespread BOLD activity changes under LSD in cortical and subcortical areas to different acoustic features in the music, including music's fullness, brightness, timbral complexity, and others. Considered the most meaningful of these findings were the BOLD signal increases that were observed under LSD for the component timbral complexity. Not only because these changes were particularly marked, but also because these changes were localised to brain networks commonly identified for musicperception and music-evoked emotion. These include the bilateral auditory cortices, including the superior temporal gyrus (STG) and the planum temporale, right inferior frontal gyrus (IFG, also known as broca's area), right insula, precuneus, bilateral striatum and supplementary motor area (SMA). The significant BOLD increases under LSD in the planum temporale and in the IFG to timbral complexity were suggested to be of particular significance for understanding how LSD affects the brain's processing of acoustic features. Timbral complexity refers to the spread and the spikiness (hence, complexity) of the powerspectrum of auditory information. The planum temporale is argued to be specialised in analysing these spectral properties in sound by segregating them into distinct spectrotemporal patterns. Subsequently, the planum temporale (together with other auditory cortices such as the superior temporal gyrus (STG)) forms a circuit of information exchange with the IFG. This circuitry is found to be important for auditory perception and music perception. In addition, the psychophysiological interaction (PPI) analysis demonstrated a significant decoupling of the precuneus from this circuitry (i.e. the right auditory and IFG) to the timbral complexity. Together, these findings suggest that a major effect of LSD is to change the brain's processing of music's timbral or spectrotemporal content via modulating a neural circuit encompassing the planum temporale, the STG and the IFG, and by functionally decoupling this circuit from the precuneus.
NEURAL CORRELATES OF LSD AND MUSIC-EVOKED EMOTION
Following the neurophysiological measures in study 2 (Chapter 4), the changes in musicevoked BOLD activation were related to changes in music-evoked emotion measured by the GEMS via correlation analyses. These analyses were performed between increases in musicevoked emotions "wonder" and "transcendence" (LSD > Placebo) and increases in musicevoked BOLD activation to timbral complexity (LSD > Placebo) for nine regions of interest (ROIs). Only changes in music-evoked feelings of "wonder" and "transcendence" were included in this analysis, because these are typically associated with peak experiences. Psychedelic peak experiences occurring under musiclistening conditions have been related to enduring positive behaviour changeand therapeutic outcomes. The nine ROI's were pre-defined based on their implication in musicperception, music-evoked emotion and the effects of psychedelics, by previous literature and by their increased activation to timbral complexity under LSD in the present study. These included right and left planum temporale, precuneus, the striatum (right and left putamen, right and left caudate), right IFG, and right anterior insula. Significant positive correlations were found between increased music-evoked feelings of wonder and music-evoked BOLD activation to timbral complexity within the precuneus and within the right IFG. A trend-level positive correlation was detected between increased music-evoked feelings of transcendence and the right IFG. Despite previous literature that associates the striatal system with music-evoked emotion, and the significant bilateral increases in BOLD activation observed in the striatum to timbral complexity under LSD, none of these striatal regions were associated with increased music-evoked emotions of wonder and transcendence. Instead, the findings suggest that music-evoked emotions of wonder and transcendence are enhanced to music's timbre properties under LSD via functional changes occurring in high-level association cortices (IFG and precuneus). A body of previous research has implicated the IFG in evaluating emotional valence in music and speech, and the syntactical analysis of auditory information. Timbre is an important acoustic feature for conveying emotionality in voice and music, and the present study suggests that LSD increases the emotional response to music via modulating the way brain networks process the timbre of music.. These deep-layer V pyramidal neurons provide predictions via backward projections to subordinate (hierarchically lower) brain regions. Serotonin 2A receptor activation by LSD increases the firing-likelihood of the deep pyramidal neurons, arguably leads to an uncoordinated or an "entropic" activation of the predictions encoded by these neurons. A state of "hyper-activation" of prior predictions has previously been argued to lead to a "perceptual inference in the absence of sensory evidence". Studies have linked deficient predictive coding in the auditory cortex with auditory hallucinationsand musical hallucinations. The planum temporale is considered an important computational hub to segregate complex spectrotemporal information, and altered functioning of the planum temporale has been related changes in auditory perception. The marked BOLD increases under LSD observed in the planum temporale to music's timbral complexity may therefore indicate increased activation of deeppyramidal neurons that encode predictions for the music's spectrotemporal (timbral) information. Although the present study did not formally address effects of LSD on acoustic perception, increased activation of deep pyramidal neurons in the planum temporale to timbral complexity under LSD may yield significant changes in auditory perception and this may be one route via which psychedelics alter the subjective experience of music (from altered perception to altered emotionality). Serotonin 2A receptors are densely expressed within the insula and the IFG, and overstimulation of the deep-pyramidal neurons expressing serotonin 2A receptors in these regions could result in the auditory cortex (planum temporale and STG) to receive increased top-down predictions from these higher regions. There is evidence for a selective role of timbre features to convey emotion, and for the insula and IFG playing a key role in detecting emotional valence in sound, and more generally in processing and regulating emotions. The marked BOLD activation to timbral complexity in a network encompassing the auditory cortex, the IFG and the insula, may therefore reflect a "hyper-associative" matching of the brain's emotional interpretations (predictions) with activated acoustic representations. that such an effect may have dramatic consequences when the brain is subsequently exposed to emotionally salient stimuli, such as music. The model outlined in this paragraph, aimed to provide a mechanistic explanation for the intensified subjective experience of music under psychedelics, but more research is warranted to test these hypotheses empirically. How these findings and these hypotheses can inform an empirical framework for their therapeutic use will be the focus of the subsequent paragraph.
IMPLICATIONS FOR PSYCHEDELIC THERAPY
As was reviewed in the introduction chapter of this thesis (Chapter 1), one major motivation for introducing music in psychedelic therapy in the 1950s and 1960s was its purposed capacity to modulate emotionality and mental imagery, as well as its capacity to provide a sense of calm, direction and continuity within the experience (. The findings presented in this research are to author's knowledge the first to provide empirical support for these motivations within a modern scientific framework, and to ground the therapeutic work within a neurobiological understanding. This section will summarise some of the central implications that these findings have for psychedelic therapy: The possible therapeutic functions and mechanisms of psychedelics and music in combination, and how music may best be used during psychedelic therapy sessions. Its aim is to provide a theoretical framework of which it is hoped it will help to better understand and employ the therapeutic actions of music in psychedelic therapy.
POSSIBLE THERAPEUTIC FUNCTIONS OF MUSIC
There are several important observations with regard to the possible therapeutic functions of music in psychedelic therapy. First, a growing body of evidence associates peak experiences during psychedelic therapy with positive therapy outcomes (Garcia-Romeu,. One motivation to introduce music in psychedelic therapy was its capacity to facilitate peak experiences, and the present findings support this. The findings reported in chapter 3 and 4 suggest music may help facilitate peak experiences by evoking emotions that are typically associated with peak experiences, such as feelings of wonder and transcendence. Furthermore, chapter 6 showed that from the diverse subjective experiences patients can report under psilocybin (ranging from increased emotionality, audio-visual effects, to anxiety and cognitive impairments), the music-experience was selectively predictive for peak experiences (feelings of union, bliss, and spirituality) and insightfulness (having innovative ideas, a sense of profoundness, and experiencing vivid personal memories). This is important, as it indicates that music can be effective in engendering specific emotionally charged experiences that hold particular therapeutic meaning and potential value, and that music may thereby play an important role in driving positive therapeutic outcomes in psychedelic therapy. The finding in chapter 6 that it is not the mere intensity of the drug-effects, but the quality of the music-experience that is predictive for positive therapy outcomes, provides further support for this view. Secondly, early researchers reported that LSD has "the astonishing quality" to re-activate patient's "repressed emotional attitudes", and that "frequently whole sequences unroll before the patient's eyes as though they had been stored on microfilm". One important motivation to introduce music in psychedelic therapy was to promote a "deeper involvement" with these autobiographical processes, and the findings of this thesis support this motivation too. The findings presented in chapter 4 indicated that psychedelics and music modulate mental imagery, by revealing a relationship between enhanced PHCàVC information flow in healthy volunteers, and enhanced complex mental imagery (i.e. concrete objects, beings or landscapes) and autobiographical. Interestingly, this association was only found for complex visual imagery, and not for simple visual imagery. Accordingly, in chapter 6, the musicexperience during psychedelic therapy sessions was predictive for insightfulness, a factor that included loadings from items capturing the experience of vivid personal memories, but not simple mental imagery (audio-visual synaesthesia or elementary imagery). Together these findings suggest that one other function could be to shift the focus within the eyes-closed visual experience, towards imagery that is particularly autobiographically "insightful", and hence particularly therapeutically meaningful. Finally, for many patients, music was found to be helpful in providing states of calm, comfort, and security. Related to this are the feelings of guidance attributed to the music, such as feeling personal helped by the music, and the music being grounding and reassuring. These securing/calming effects were found to be particularly appreciated in situations where apprehensions were present, such as prior to the onset of drug-effects, or when mental calm and "clarity" was required, such as after emotionally intense periods. These findings suggest that one other function of music may be to provide a sense of calm, security & guidance -a function that may form an important contrast with the previously described evocative (i.e. intensifying) influences of music. The findings in these studies show a remarkable congruency with theoretical frameworks and patient-experiences of "introspective" forms of music therapy, where music is utilised as the means to provide an experience -emotionally and mentally-that is thought to help the listener to examine and change the relationships with themselves. This includes using music to evoke intense emotional experiences, as well as a way to provide a "holding environment", that feels "safe and secure" to express and experience new aspects of oneself. Anxiety-and tension-reducing effects of music are widely reported in literature and utilised across different health care disciplines. Taking these findings together, it can be concluded that music can modulate subjective experience in psychedelic therapy in profound and functional ways, and that the therapeutic functions of music in this context may be generally classified into two distinct categories: 1) A directive/suggestive function, characterised by the music being arousing/activating (emotionally, bodily and mentally), and the listener becoming fully immersed into the music-experience (E.g. the music furthering ego-dissolution). Directive music may be seen as to provide non-verbal "suggestions" that the listener can personally identify with and follow. Once surrendered to the perceived suggestions of the music (i.e. open to the music-evoked experience), the experience unfolds as a "journey", rich with personally meaningful thoughts, emotionality and imagery. This function may be especially important to facilitate an expression or "release" of (previously) previously suppressed psychological content and emotionality. Music styles that may be particularly suitable for this function are emotive or cinematic music styles, such as for example (neo)classical music and ethnic music styles. 2) A non-directive/non-suggestive function, characterised by the music being calming (emotionally, bodily and mentally), and the listener becoming more relaxed and present in the here and now. This function may be especially important to facilitate a sense of security, that subsequently facilitates an attitude of openness to the experience, as well as to create an environment that allows contemplation and interaction, with oneself or with the therapist (i.e. the music furthering ego-(re)integration). Music styles that may be particularly suitable for this function are ambient or other "non-musical" styles that focus on creating an acoustic ambience, a climate, rather than to a dynamic musical experience that demands attention. In the words of the ambient music pioneer Brian Eno: "Ambient music is intended to induce calm and a space to think. Ambient music must be able to accommodate many levels of listening attention without enforcing one in particular; it must be as ignorable as it is interesting." -Technically speaking, one may argue that here is not such a phenomenon as nondirective/non-suggestive music, since any stimulus will have a capacity to trigger emotionalmental associations, and hence induce psycho-behavioural changes in the listener. Nonsuggestive music may indeed, in reality, be suggestive of for example calmness and security. Yet, how the two functions differ, is in the "coerciveness" of the suggestion. Where nondirective/non-suggestive music can be "as ignorable as it is interesting", directive/suggestive music can be seen as more or less un-ignorable, and does not give "space to think", but instead requires a full surrender to the direction or suggestion that the listener perceives in the music.
POSSIBLE THERAPEUTIC MECHANISMS OF PSYCHEDELICS AND MUSIC
The presented research did not directly study therapeutic mechanisms of psychedelics and music, but provided important clues as to how and why psychedelics and music may act therapeutically in combination. Indeed, the two-fold functions of music as defined above raise the question why such musical experiences would be therapeutic. One key finding of this research, is that the music-experience seems to be substantially intensified under psychedelics, and that this can evoke meaningful, but also sometimes challenging emotional experiences. An open and interactive attitude towards these music-evoked experiences was frequently described as being important in finding therapeutic resolution, and "openness" to the music-evoked experience correlated with reductions in depression. This section aims to consolidate these findings into a theoretical framework, based on neuroscience and psychotherapeutic thinking, that proposes the therapeutic mechanisms via which psychedelics and music possibly work together. An important function of the brain is to maintain homeostasis (i.e. balance), and to acquire learned representations (i.e. predictions) that guide this process effectively. Throughout life, the many learned representations are assembled into a complex inner working model, that functions (to introduce a simplifying analogy) like an innerroadmap: it determines how information is processed, what it means, it informs behaviour, and produces a coherent sense of self or identity. The main purpose of this inner roadmap, is to help the self survive and thrive in a highly complex and always-changing world. Yet, it can also be this inner roadmap, or the use of it, that is the source of psychological suffering, and which individuals seek to change when seeking help in psychotherapy. Subsequently, it is goal of all psychotherapies "to influence the client in such a way") so that new aspects of oneself and new ways of experiencing oneself are discovered and re-assembled into a new self-concept, an updated roadmap. Deeply feeling and expressing challenging emotions is argued to be important for psychotherapeutic change, and this aim is central to many psychotherapeutic models. Some research has indicated that the patient's level of experiencing emotions (i.e. its "depth") during therapy sessions, is predictive for positive therapy outcomes. Psychedelics temporarily disorganise the brain's functional hierarchy, and this dissolving of the usual roadmap (i.e. ego-dissolution) has been argued to underlie the intensified subjective response to music under psychedelics (summarized in paragraph 7.7.2). In line with many earlier researchers, these findings suggest that a central therapeutic function of psychedelics is to provide a rapid relinquishment of emotional control, so that emotions can be aroused and expressed to a fuller extent. This effect of psychedelics, however, is considered unspecific, leading to a wide spectrum of possible subjective experiences. In the absence of the usual roadmap, music in this context may play the important role of a "road-navigator", guiding the experience (either in directive or non-directive ways (see paragraph 7.4.1)) into territories beyond the usual road-map (beyond the usual boundaries of the self), to remember or experience new aspects of oneself that are most therapeutically significant (characterised by the qualities of autobiographical-and/or peak experience (see paragraph 1.4.1 and paragraph 7.4.1)). Subsequently, newly acquired self-representations (new routes or guidelines) can be assembled into an updated working model (an updated inner-roadmap)-or, as the pioneering humanistic psychologist Carl Rogers formulated, an altered self-concept: "To perceive a new aspect of oneself is the first step toward changing the concept of oneself. The new element is, in an understanding atmosphere, owned and assimilated into a now altered self-concept. This is the basis, in my estimation, of the behaviour changes that come about as a result of psychotherapy, Once the self-concept changes, the behaviour changes to match the freshly perceived self"
THE UNIQUE THERAPEUTIC VALUE OF MUSIC
Compared with other psychotherapy modalities, psychedelic therapy is unique in its capacity to facilitate rapid and sustained therapeutic changes. The promising effectiveness of psychedelic therapy may be due its focus on providing a deeply felt and personally meaningful experience, rather than conventional mental health treatments, that tend to focus on changing cognition, behaviour, or neurochemistry (see Chapter 1.6). Experiences are the basis for implicit learning, and implicit learning is the foundation for any behavioural change. The studies in this thesis indicated that music can help engender implicit-learning experiences that may be particularly therapeutic significant. There may indeed be other means than music to facilitate meaningful experiences, and more generally, to fulfil the therapeutic objections discussed above; but the unique value of music in this context may be 1) its capacity to convey emotional experiences that are dynamic (time-based), and 2) do so without the use of words. The significance of this can be conceptualised through the process of "affect attunement" -a term formalised by the developmental psychologist Daniel N. Stern. Stern argued that the very first interpersonal world of human experience, that of the infant interacting with his or her mother, is in essence a musical relationship. Affect attunement refers to the matching of the mother's non-verbal expressions (the changes in intensity and tonality of her voice), with the infant's behaviour. Affect attunement does not imply the providing of perfect mirror-image of the infant's experience, but the providing of a reflection in a different modality (i.e. sound), of the dynamic contours of the infant's internal feeling-states. According to Stern "for the infant, the music comes before the lyrics", and "the entire flow of maternal social behaviors can be likened to a symphony, in which the musical elements are her changing facial expressions, vocalizations, movements, and touches"). Affect attunement is believed to guide the awareness of the infant to the subjective basis underlying his or her own behaviour, while maintaining a sense of being securely held and "contained" by the caregiver. Mother-infant interactions are present cross-culturally, and are argued to promote emotional learning. In psychedelic therapy, the therapeutic actions of music may resemble the process of mother-infant affect attunement. Here, music can be seen as a non-verbal (or even preverbal) language, that provides an attunement to dynamic internal feeling states of the listener, thereby facilitating emotional learning experiences, while simultaneously providing a sense of being securely held and supported. By dramatically enhancing the usual subjective response to music, psychedelics may create a unique therapeutic opportunity for the musicexperience to become deeply experiential (i.e. the listener becomes fully immersed in the music). Importantly, the musical (non-verbal) language is entirely process-based, as opposed to content-based (example: movies). This may be particularly important, as music can thereby can reflect and activate intrinsic feeling states (i.e. the processes conveyed by the music), while allowing the specific autobiographical content to be spontaneously associated with the music by the mind of the listener. As the classical composer Richard Wagner eloquently formulated: "What music expresses, is eternal, infinite and ideal: it does not express the passion, love, or longing of such-and-such an individual on such-and-such an occasion, but passion, love or longing in itself, and this it presents in that unlimited variety of motivations, which is the exclusive and particular characteristic of music, foreign and inexpressible to any other language". -Richard Wagner, quoted by Anthony Storr in Music and the Mind7.4.4 Implications for using music in psychedelic therapy The findings suggest several implications for therapists working with music in the context of psychedelic therapy. The ability of music to evoke meaningful therapeutic experiences was discussed as a mixed function of (1) the patients' liking of the music styles, (2) the music being in resonance or in tune with the patient's dynamic feeling states, and (3) an attitude of openness on behalf of the patient to the resulting music-evoked experience. Resistance was suggested to be an important indicator of the patient rejecting the music, and thereby hindering therapeutic progress. Here, resistance was defined as a distancing of the music and its influences, and was often characterised by an intellectualisation of the experience, by feelings of discomfort, irritation, fear, and a by general sense of the experience being diminished or blocked by the music. This experience can be seen as the opposite of the often-reported music-evoked sense of being on a journey (characterised by the dispensing of intellectualisation), which was associated with a welcomed music-experience. The findings do suggest that resistance should not be merely understood as an inability of the patient to open up, but that it could occur for different reasons, and hence require different interventions: 1) The music may be rejected because the experience it evokes is challenging, yet the experience may hold therapeutic significance (e.g. the music may remind the listener of a deceased loved-one, and the resulting emotions may feel too overpowering). 2) The music may be rejected because of a disliking of the music style (e.g. a lack of personal connection with the music style, or finding the music aesthetically abrasive). 3) The music may be dissonant (out of tune / a mismatch) with the patient's internal feeling states (e.g. the individual undergoing a deep sensation of grief, and the music being joyful). An attitude of openness to the music-evoked experience could be optimised via adequate preparation prior to the therapy session. This would include an encouragement of full immersion into the experience, and a curious and interactive engagement with the experience even in situations when it becomes challenging. The aid of music-listening exercises prior to therapy sessions have as yet not been explored, yet may be an effective way to prepare a mind-set conducive to immersion. Such exercises might also provide the therapist with some idea of music styles that may work best for the individual patient. Dialogue may determine the right response to resistance as it arises during a session. When it occurs in relation to therapeutically meaningful psychological material, a constructive relationship with the experience can be increased via a reassurance and reminder of safety and personal support, an encouragement to explore the experience interactively. In contrast, when the music is rejected due disliking of the music styles, and or when the music is dissonant with the patients underlying emotional state, the therapist may need to take action. Analogous to usual client-centred dialogues in psychotherapy, where the therapist listens attentively and reflects back to the patient his or her observations in a dynamic and interactive fashion, so it may be necessary for the therapists to ensure that the music is adequately "attuned" to the patient's dynamically unfolding experience and psychotherapeutic needs. Liking of the music may be an important primary pre-requisite for the individual to be able to relate personally and respond emotionally to the music. This liking may not only reflect the individual's aesthetic judgements, but could also refer to the suitability of the music styles to the conscious state induced by psychedelics. Needless to say, this area requires significant more research. When the music is dissonant with the patient's emotional state, a change in the music may be required. This would include a better matching of the music's emotional and dynamic characteristics to the patient's present internal emotional state, on the assumption that this would help him or her experience these feelings more deeply, and that this experience would lead to meaningful therapeutic processing. For example, feelings of grief, can be matched with music that symbolises this process of grief. The capacity of music to not merely convey tonic emotional states, but also emotional dynamics (e.g. with nadirs, crescendo and breakthrough) may help develop a constructive and meaningful experience. To continue this example, the subsequent development of the resonant music is not merely reflecting a state of grief, but a dynamic process that can carry the engaged listener through a deeply felt emotional release, towards subsequent constructive resolution.
IMPLICATIONS FOR PSYCHEDELIC THERAPY: SUMMARY
The findings of this research suggest that psychedelics and music interact on subjective experience to provide a unique opportunity for experiential learning. A hypothetical framework was described in which psychedelics function to dissolve the usual psychological control mechanisms, thereby facilitating a substantial intensification of the subjective experience of the music. Music here has been suggested to have a two-fold function, one being directive/suggestive (activating), and the other being non-direct/non-suggestive (calming). The musical experience, in turn, has been argued to act therapeutically when the music is sufficiently attuned to (in resonance with) the patient's intrinsic dynamic feeling states, in order to facilitate a fuller emotional expression of these feeling states. When fully experientially immersed in the music, and when openly and interactively engaged with this experience, music can facilitate personally meaningful experiences (autobiographical experience and peak experiences), via which new self-concepts can be acquired that can form the basis for sustained positive therapeutic changes.
STUDY LIMITATIONS AND FUTURE DIRECTIONS
The research findings present several limitations and opportunities for future research (see paragraphs) First, despite the GEMS being designed and formulated to specifically assess music-evoked emotions, the experimental design of the studies reported in study 1 (Chapter 3) and study 2 (Chapter 4) did not allow us to separate drug-effects from music-effects on emotion. For example, LSD may have produced sensations of "transcendence" alone, without the music, and increased ratings of music-evoked transcendence under LSD and music-listening may therefore be influenced by this. Future studies are warranted that better enable a separation between music-and drug-conditions to deepen our understanding of their interactive effects on emotion. Secondly, although such design was implemented for the study assessment of LSD's and music's effects on mental imagery, reported in study 3 (Chapter 5), only a trend-level effect of music was observed for enhanced "complex" visual imagery. Mental imagery was however significantly enhanced by LSD alone. It may be that music influences a certain component of mental imagery, and as such, more specific measures may be needed to detect those changes, such as for example measures that not only assess vividness of the visual imagery, but also the content or the visual imagery. The absence of finding a significant music effect or a significant interactioneffect of music and LSD on visual mental imagery, may also be due a significant variance within the study population and the study population being small. This explanation is supported by the correlation-analyses in study 3 (Chapter 5), showing individuals with increased PHCàVC information flow reporting increased mental imagery, while other individuals reported decreased PHCàVC information and decreased mental imagery under LSD in response to music. Using a similar line of reasoning, the study reported in study 2 (Chapter 4) showed a positive correlation between music-specific changes in brain-activity (i.e. to timbral complexity) and music-evoked emotion (wonder and transcendence). One may argue that if an effect on emotion was primarily due to LSD alone, a neurobiological measure highly specific to a feature within the music (i.e timbral complexity) would not be expected to correlate with changes in music-evoked emotion. Finally, the qualitative findings discussed in study 4 (Chapter 6) provided insight into patientexperiences, but the lack of placebo condition emphasises the care needed in drawing strong inferences. The study should be valued for its exploratory nature, and its discussion, including the suggested possible therapeutic functions of music, must be viewed as speculative. The study provides directions for future studies where these hypotheses can be tested directly, and under placebo-controlled conditions. Examples of future studies that can test these hypotheses via better controlled experiments, are studies that assess the predictive value of liking of the music, resonance of the music, and openness to the music for subjective experience and therapy outcomes. Self-rating-scales can be implemented for the general experience of the playlist, or better, for specific genres of music. Such a study would have capacity to identify separate factors within the music-experience, and could help identify aspects of the music-experience (e.g. optimisation of music's resonance via an adaptive approach) may yield better therapy outcomes. Other important facets invite further investigation are the role of an individuals' music-listening history (individuals' usual music taste) in determining the music-experience under a psychedelic, and the relative contribution to music to the therapeutic experience and outcome compared to other factors in therapy sessions, such as for example interpersonal factors or the design of the physical environment in which the experience takes place. Furthermore, studies can aim to better understand the interactions between mind-set (mood and attitudes) and personality-traits (ex: trait absorption, openness, suggestively) with the subjective experience of music under psilocybin. Research that focusses on identifying reliably indicators for positive (welcomed/supportive) and negative (unwelcomed/unsupportive) influences of music on the therapeutic processes during psychedelic therapy sessions, may be highly significant for the development of psychedelic therapy, and the tools used during psychedelic therapy. These could range from physiological measures, such as heart-rate, body movement, and breathing patterns, or more complex measures such as facial affect-coding, vocal-affect coding, and brain mechanisms (EEG-signatures), that could yield technologist that can assist therapists in on-the-fly adaptation of music-selection to maximise music's attunement to the individual's therapeutic needs, or inform playlist generation algorithms. It must be emphasised that these studies were amongst the first to assess the combined effects of music and psychedelics on subjective experience and on brain function. The findings therefore naturally necessitate their replication in future independent studies. For example, the choice of music may have significantly influenced the present findings, and future studies that use different or a multitude of musical genres, may be utilised to control for this. Additionally, although the majority of individuals in the neuroimaging study and the clinical study reported a "liking" of the music, no measures were implemented to assess music taste or attitudes to music-listening beforehand, and these variables could have influenced the presented the results too.
Study Details
- Study Typeindividual
- Populationhumans
- Characteristicsliterature review
- Journal
- Compound