Serotonin 2A Receptor Signaling Underlies LSDinduced Alteration of the Neural Response to Dynamic Changes in Music, Frederick S. Barrett et al., 2018

Serotonin 2A Receptor Signaling Underlies LSD-induced Alteration of the Neural Response to Dynamic Changes in Music

Frederick S. Barrett, Katrin H. Preller, Marcus Herdener, Petr Janata and Franz X. Vollenweider

Cerebral Cortex, November 2018, 28, 3939–3950.

doi : 10.1093/cercor/bhx257



Classic psychedelic drugs (serotonin 2A, or 5HT2A, receptor agonists) have notable effects on music listening. In the current report, blood oxygen level-dependent (BOLD) signal was collected during music listening in 25 healthy adults after administration of placebo, lysergic acid diethylamide (LSD), and LSD pretreated with the 5HT2A antagonist ketanserin, to investigate the role of 5HT2A receptor signaling in the neural response to the time-varying tonal structure of music. Tonality-tracking analysis of BOLD data revealed that 5HT2A receptor signaling alters the neural response to music in brain regions supporting basic and higher-level musical and auditory processing, and areas involved in memory, emotion, and self-referential processing. This suggests a critical role of 5HT2A receptor signaling in supporting the neural tracking of dynamic tonal structure in music, as well as in supporting the associated increases in emotionality, connectedness, and meaningfulness in response to music that are commonly observed after the administration of LSD and other psychedelics. Together, these findings inform the neuropsychopharmacology of music perception and cognition, meaningful music listening experiences, and altered perception of music during psychedelic experiences.

Key words : functional magnetic resonance imaging (fMRI), music information retrieval, psychedelics, tonality


Classic psychedelics, including psilocybin, lysergic acid diethylamide (LSD), and dimethyltryptamine (DMT), are potent compounds that have their primary receptor mechanism of action at serotonin 2A (5HT2A) receptor sites (Nichols 2016). 5HT2A receptors are widely distributed throughout the neocortex (Andree et al. 1998). Accordingly, psychedelic drugs, including psilocybin (Griffiths et al. 2011; Studerus et al. 2011), DMT (Strassman et al. 1994; Riba et al. 2003), and LSD (Schmid et al. 2015; Carhart-Harris et al. 2016a), have substantial effects on perception, cognition, and emotional experience (reviewed in Preller and Vollenweider 2016). Psychedelic drugs also have notable effects on the perception of music. This is not surprising, as 5HT2A signaling has been shown to alter neuronal responses to auditory stimuli from the cochlear nucleus (Tang and Trussell 2015) along the precortical primary auditory sensory pathway (Hurley 2006; Hurley and Sullivan 2012) through to primary auditory cortex (Luo et al. 2016; Riga et al. 2016).

Psychedelics, however, do not simply alter the perception of sensory stimuli such as music. LSD has been shown to increase positive mood during music listening (Kaelen et al. 2015) as well as music-induced imagery and communication of related brain regions (Kaelen et al. 2016). LSD has also been shown to increase the personal relevance of both meaningless and meaningful music, and alter functioning of brain areas involved in processing the meaningfulness of stimuli (Preller et al. 2017). This follows from the neurobiology, as the neural response to music involves both the primary auditory pathway and a wide range of domain-general brain networks including those involved in memory, emotions, self-referential processing, and visualization (Peretz and Zatorre 2005; Janata 2009; Koelsch 2014). Many of these brain regions densely express 5HT2A receptors and show marked alterations in activity and/or connectivity during the acute effects of psychedelics (Carhart-Harris et al. 2016b). Thus, there is extensive neurobiological overlap in the brain regions that are impacted by psychedelics and the brain regions that may be recruited during music listening.

Research and clinical methods have taken advantage of altered experience of music during psychedelic experiences. Music has played a key role in the conduct of psychedelic therapy and research for many decades, with the expectation that supportive music may facilitate a meaningful experience (Chwelos et al. 1959; Bonny and Pahnke 1972). Current best practices for safe conduct of a psychedelic session include the use of music, with the goal of providing psychological support (Johnson, Richards, Griffiths 2008).

Neurochemical effects of music listening on stress, immunity, and social affiliation have been demonstrated (reviewed by Chanda and Levitin 2013), and music listening has specifically been shown to lead to dopamine release and drive reward circuitry (Salimpoor et al. 2011). While these effects of music on neurochemical processes are important, there are very few empirical studies (Preller et al. 2017) that have investigated effects in the opposite direction; namely, the more general role of neuropharmacology in supporting or altering music perception and cognition. There is evidence suggesting commonalities among pieces of music that are optimally supportive during peak experiences with psychedelics, supporting the notion that there are structural principles to the relationship between music listening and psychedelic experiences (Barrett et al. 2017). These principles may have emerged from a shared neuropharmacological basis of psychedelic experience and music perception and cognition.

Music is a complex stimulus that varies in time in a number of dimensions that range from lower-level acoustic features (such as loudness, frequency spectra, or simple tonal features such as pitch height) to higher-level cognitive schema that represent relationships between events that define rhythm, meter, and tonality. Tonality refers to the system in Western tonal music of major and minor keys, in which notes and chords change over time and fulfill or violate expectancies to create a sense of tension and resolution. Tonality has been well-defined as an important cognitive schema for shaping expectations during music listening (Toiviainen and Krumhansl 2003; Huron 2006; Collins et al. 2014).

Change over time in the tonal center of a musical selection (i.e., which key is implied by the music at a given time) can be collectively described and computationally modeled as changes in the pattern of activation on a toroidal surface (Krumhansl and Kessler 1982; Janata et al. 2002; Janata 2005; Collins et al. 2014; Toiviainen and Krumhansl 2003). The toroidal surface model was initially derived from multidimensional scaling analysis of subjective ratings of the perceptual “fit” of probe tones after a tonal center was established in each of 24 major and minor keys, where distance between tonal centers on the 4-dimensional surface of a torus directly reflects perceptual distance (the inverse of perceptual “fit”) between notes, chords, and keys (Krumhansl and Kessler 1982). The model was shown to reflect not only the perception of tonal distance when listening to musical stimuli, but also the organization of tonal structure as understood in music theory (Krumhansl 1990). Thus, modeling tonal space on a toroidal surface simultaneously represents concepts in music theory, cognitive psychology, and the pitch statistics of western music (Janata 2005).

The tonal center of a piece of music at any given point in time can be computationally derived by integrating the tonal information in that piece of music over a window of time preceding the point of interest, and this tonal center can subsequently be reflected on a torus (Janata et al. 2002; Janata 2005). As the melodies and harmonies of a piece of music unfold in time, the sense of tonal center of that piece of music also unfolds in time. Change over time in tonal center can be calculated using a sliding window, and across a piece of music, a timecourse of change in tonal center can be calculated and reflected on a torus. This time-varying pattern of information on the torus thus represents the dynamic tonal structure of a piece of music. The rate of change in that timecourse is determined by both the stability of the distributions of tonal information in the music as well as the duration of the sliding window over which one integrates the tonal information (Janata 2007; Collins et al. 2014). Using spherical harmonic analysis, this timecourse of toroidal (4-dimensional) representation can be decomposed into a series of 34 spatially orthogonal patterns with associated weight vectors, and these weight vectors can be entered into a design matrix that can be used to regress fMRI blood oxygen level-dependent (BOLD) activity that was measured while an individual was listening to a piece of music (Janata 2005). This analysis approach has been applied previously, and spherical harmonic regressors describing the change in tonal center over time were shown to explain variance in brain activity measured while volunteers listened to melodies that moved systematically through all 24 major and minor keys in tonal space (Janata et al. 2002). Change in tonal center (and toroidal space) has been associated with variance in BOLD signal in different domain-general brain regions depending on the psychological context of the music listening experience, such as the experience of music-evoked nostalgia (Barrett and Janata 2016) and autobiographical memories (Janata 2009). This type of stimulus/brain coupling has been labeled “tonality-tracking” (TT) (Janata et al. 2002; Barrett and Janata 2016; Janata 2009).

The current report applies TT analysis of BOLD signal collected while participants listened to both personally meaningful and nonmeaningful music after the administration of placebo, LSD, and LSD pretreated with the 5HT2A antagonist ketanserin, to investigate the role of 5HT2A receptor signaling in the neural response to the time-varying tonal structure of music.