Brain substates induced by DMT relate to sympathetic output and meaningfulness of the experience.

N,N-Dimethyltryptamine (DMT) is a serotonergic psychedelic, known to rapidly induce short-lasting alterations in conscious experience, characterized by a profound and immersive sense of physical transcendence alongside rich and vivid auditory distortions and visual imagery. Multimodal neuroimaging data paired with dynamic analysis techniques offer a valuable approach for identifying unique signatures of brain activity - and linked autonomic physiology - naturally unfolding during the altered state of consciousness induced by DMT. We leveraged simultaneous fMRI and EKG data acquired in 14 healthy volunteers prior to, during, and after intravenous administration of DMT, and, separately, placebo. fMRI data was preprocessed to derive individual dynamic activity matrices, reflecting the similarity of brain activity in time, and community detection algorithms were applied on these matrices to identify brain activity substates; EKG data was used to derive continuous heart rate. We identified a brain substate occurring immediately after DMT injection, characterized by increased superior temporal lobe activity, and hippocampal and medial parietal deactivations under DMT. Results revealed that hippocampus and medial parietal cortex hypoactivity correlated with scores of meaningfulness of the experience. During this first post-injection substate, increased heart rate under DMT correlated negatively with the meaningfulness of the experience and positively with hippocampus/medial parietal deactivation. These results suggest a chain of influence linking sympathetic regulation to hippocampal and medial parietal deactivations under DMT, which combined, may contribute to positive mental health outcomes related to self-referential processing following psychedelic administration.

LSD-induced changes in the functional connectivity of distinct thalamic nuclei.

The role of the thalamus in mediating the effects of lysergic acid diethylamide (LSD) was recently proposed in a model of communication and corroborated by imaging studies. However, a detailed analysis of LSD effects on nuclei-resolved thalamocortical connectivity is still missing. Here, in a group of healthy volunteers, we evaluated whether LSD intake alters the thalamocortical coupling in a nucleus-specific manner. Structural and resting-state functional Magnetic Resonance Imaging (MRI) data were acquired in a placebo-controlled study on subjects exposed to acute LSD administration. Structural MRI was used to parcel the thalamus into its constituent nuclei based on individual anatomy. Nucleus-specific changes of resting-state functional MRI (rs-fMRI) connectivity were mapped using a seed-based approach. LSD intake selectively increased the thalamocortical functional connectivity (FC) of the ventral complex, pulvinar, and non-specific nuclei. Functional coupling was increased between these nuclei and sensory cortices that include the somatosensory and auditory networks. The ventral and pulvinar nuclei also exhibited increased FC with parts of the associative cortex that are dense in serotonin type 2A receptors. These areas are hyperactive and hyper-connected upon LSD intake. At subcortical levels, LSD increased the functional coupling among the thalamus's ventral, pulvinar, and non-specific nuclei, but decreased the striatal-thalamic connectivity. These findings unravel some LSD effects on the modulation of subcortical-cortical circuits and associated behavioral outputs.

Increased low-frequency brain responses to music after psilocybin therapy for depression.

BACKGROUND: Psychedelic-assisted psychotherapy with psilocybin is an emerging therapy with great promise for depression, and modern psychedelic therapy (PT) methods incorporate music as a key element. Music is an effective emotional/hedonic stimulus that could also be useful in assessing changes in emotional responsiveness following PT. METHODS: Brain responses to music were assessed before and after PT using functional Magnetic Resonance Imaging (fMRI) and ALFF (Amplitude of Low Frequency Fluctuations) analysis methods. Nineteen patients with treatment-resistant depression underwent two treatment sessions involving administration of psilocybin, with MRI data acquired one week prior and the day after completion of psilocybin dosing sessions. RESULTS: Comparison of music-listening and resting-state scans revealed significantly greater ALFF in bilateral superior temporal cortex for the post-treatment music scan, and in the right ventral occipital lobe for the post-treatment resting-state scan. ROI analyses of these clusters revealed a significant effect of treatment in the superior temporal lobe for the music scan only. Voxelwise comparison of treatment effects showed relative increases for the music scan in the bilateral superior temporal lobes and supramarginal gyrus, and relative decreases in the medial frontal lobes for the resting-state scan. ALFF in these music-related clusters was significantly correlated with intensity of subjective effects felt during the dosing sessions. LIMITATIONS: Open-label trial. Relatively small sample size. CONCLUSIONS: These data suggest an effect of PT on the brain's response to music, implying an elevated responsiveness to music after psilocybin therapy that was related to subjective drug effects felt during dosing.

Changes in music-evoked emotion and ventral striatal functional connectivity after psilocybin therapy for depression.

BACKGROUND: Music listening is a staple and valued component of psychedelic therapy, and previous work has shown that psychedelics can acutely enhance music-evoked emotion. AIMS: The present study sought to examine subjective responses to music before and after psilocybin therapy for treatment-resistant depression, while functional magnetic resonance imaging (fMRI) data was acquired. METHODS: Nineteen patients with treatment-resistant depression received a low oral dose (10 mg) of psilocybin, and a high dose (25 mg) 1 week later. fMRI was performed 1 week prior to the first dosing session and 1 day after the second. Two scans were conducted on each day: one with music and one without. Visual analogue scale ratings of music-evoked 'pleasure' plus ratings of other evoked emotions (21-item Geneva Emotional Music Scale) were completed after each scan. Given its role in musical reward, the nucleus accumbens (NAc) was chosen as region of interest for functional connectivity (FC) analyses. Effects of drug (vs placebo) and music (vs no music) on subjective and FC outcomes were assessed. Anhedonia symptoms were assessed pre- and post-treatment (Snaith-Hamilton Pleasure Scale). RESULTS: Results revealed a significant increase in music-evoked emotion following treatment with psilocybin that correlated with post-treatment reductions in anhedonia. A post-treatment reduction in NAc FC with areas resembling the default mode network was observed during music listening (vs no music). CONCLUSION: These results are consistent with current thinking on the role of psychedelics in enhancing music-evoked pleasure and provide some new insight into correlative brain mechanisms.

Psychedelics, Meditation, and Self-Consciousness.

In recent years, the scientific study of meditation and psychedelic drugs has seen remarkable developments. The increased focus on meditation in cognitive neuroscience has led to a cross-cultural classification of standard meditation styles validated by functional and structural neuroanatomical data. Meanwhile, the renaissance of psychedelic research has shed light on the neurophysiology of altered states of consciousness induced by classical psychedelics, such as psilocybin and LSD, whose effects are mainly mediated by agonism of serotonin receptors. Few attempts have been made at bridging these two domains of inquiry, despite intriguing evidence of overlap between the phenomenology and neurophysiology of meditation practice and psychedelic states. In particular, many contemplative traditions explicitly aim at dissolving the sense of self by eliciting altered states of consciousness through meditation, while classical psychedelics are known to produce significant disruptions of self-consciousness, a phenomenon known as drug-induced ego dissolution. In this article, we discuss available evidence regarding convergences and differences between phenomenological and neurophysiological data on meditation practice and psychedelic drug-induced states, with a particular emphasis on alterations of self-experience. While both meditation and psychedelics may disrupt self-consciousness and underlying neural processes, we emphasize that neither meditation nor psychedelic states can be conceived as simple, uniform categories. Moreover, we suggest that there are important phenomenological differences even between conscious states described as experiences of self-loss. As a result, we propose that self-consciousness may be best construed as a multidimensional construct, and that "self-loss," far from being an unequivocal phenomenon, can take several forms. Indeed, various aspects of self-consciousness, including narrative aspects linked to autobiographical memory, self-related thoughts and mental time travel, and embodied aspects rooted in multisensory processes, may be differently affected by psychedelics and meditation practices. Finally, we consider long-term outcomes of experiences of self-loss induced by meditation and psychedelics on individual traits and prosocial behavior. We call for caution regarding the problematic conflation of temporary states of self-loss with "selflessness" as a behavioral or social trait, although there is preliminary evidence that correlations between short-term experiences of self-loss and long-term trait alterations may exist.

Correction to: The hidden therapist: evidence for a central role of music in psychedelic therapy.

The article The hidden therapist: evidence for a central role of music in psychedelic therapy, written by Mendel Kaelen, Bruna Giribaldi, Jordan Raine, Lisa Evans, Christopher Timmerman, Natalie Rodriguez, Leor Roseman, Amanda Feilding, David Nutt, Robin Carhart-Harris, was originally published electronically on the publisher's internet portal.

The hidden therapist: evidence for a central role of music in psychedelic therapy.

RATIONALE: Recent studies have supported the safety and efficacy of psychedelic therapy for mood disorders and addiction. Music is considered an important component in the treatment model, but little empirical research has been done to examine the magnitude and nature of its therapeutic role. OBJECTIVES: The present study assessed the influence of music on the acute experience and clinical outcomes of psychedelic therapy. METHODS: Semi-structured interviews inquired about the different ways in which music influenced the experience of 19 patients undergoing psychedelic therapy with psilocybin for treatment-resistant depression. Interpretative phenomenological analysis was applied to the interview data to identify salient themes. In addition, ratings were given for each patient for the extent to which they expressed "liking," "resonance" (the music being experienced as "harmonious" with the emotional state of the listener), and "openness" (acceptance of the music-evoked experience). RESULTS: Analyses of the interviews revealed that the music had both "welcome" and "unwelcome" influences on patients' subjective experiences. Welcome influences included the evocation of personally meaningful and therapeutically useful emotion and mental imagery, a sense of guidance, openness, and the promotion of calm and a sense of safety. Conversely, unwelcome influences included the evocation of unpleasant emotion and imagery, a sense of being misguided and resistance. Correlation analyses showed that patients' experience of the music was associated with the occurrence of "mystical experiences" and "insightfulness." Crucially, the nature of the music experience was significantly predictive of reductions in depression 1 week after psilocybin, whereas general drug intensity was not. CONCLUSIONS: This study indicates that music plays a central therapeutic function in psychedelic therapy.

LSD modulates music-induced imagery via changes in parahippocampal connectivity.

Psychedelic drugs such as lysergic acid diethylamide (LSD) were used extensively in psychiatry in the past and their therapeutic potential is beginning to be re-examined today. Psychedelic psychotherapy typically involves a patient lying with their eyes-closed during peak drug effects, while listening to music and being supervised by trained psychotherapists. In this context, music is considered to be a key element in the therapeutic model; working in synergy with the drug to evoke therapeutically meaningful thoughts, emotions and imagery. The underlying mechanisms involved in this process have, however, never been formally investigated. Here we studied the interaction between LSD and music-listening on eyes-closed imagery by means of a placebo-controlled, functional magnetic resonance imaging (fMRI) study. Twelve healthy volunteers received intravenously administered LSD (75µg) and, on a separate occasion, placebo, before being scanned under eyes-closed resting conditions with and without music-listening. The parahippocampal cortex (PHC) has previously been linked with (1) music-evoked emotion, (2) the action of psychedelics, and (3) mental imagery. Imaging analyses therefore focused on changes in the connectivity profile of this particular structure. Results revealed increased PHC-visual cortex (VC) functional connectivity and PHC to VC information flow in the interaction between music and LSD. This latter result correlated positively with ratings of enhanced eyes-closed visual imagery, including imagery of an autobiographical nature. These findings suggest a plausible mechanism by which LSD works in combination with music listening to enhance certain subjective experiences that may be useful in a therapeutic context.