Social and Affective Mechanisms of Psychedelics: From Acute Dynamics to Long-Term Adaptation

Psychedelics represent a unique class of psychoactive substances capable of profoundly influencing consciousness, perception, and mood. Importantly, a growing number of recent studies have demonstrated that psychedelics exhibit promising therapeutic efficacy across various mental health disorders. Relatedly, we have witnessed a substantial rise in the naturalistic (non-clinical) use of these substances, often driven by the intent of self-medication. However, the fact that the real-world impact of psychedelics is shaped by complex, context-dependent factors that cannot be replicated in controlled laboratory settings creates a critical knowledge gap, which can be addressed only by naturalistic studies.

In both clinical and naturalistic settings psychedelic-induced therapeutic breakthroughs are often attributed to profound alterations in social connection, affective states, and self-awareness. Therefore, the proposed symposium will present recent research exploring mechanisms of psychedelic action in the domains of affective and social neuroscience. The particular focus will be on the translational perspective, bridging the gap between studies in animal models and human participants, experimental and cross-sectional approaches, as well as on linking acute neural dynamics with long-term effects. Considering the complex nature of the research problem, a broad range of methodological approaches will be presented, including rodent behavioral assays utilizing ultrasonic vocalizations, clinical outcome measures, and multimodal neuroimaging (EEG, fMRI) in naturalistic users.

Specifically, first, we will discuss how the bodily ‘self’ serves as a foundation for social connection and how ketamine and psilocybin modulate boundaries between self and other in the context of touch and grief. Second, we will present preclinical insights into the anti-addictive potential of classical psychedelics, elucidating how they modulate social reward processing and affective states in rats. Third, we will consider the distinct physiological footprints of different compounds, contrasting the acute neural dynamics of psilocybin and ketamine with the intense "somatic catharsis" observed in the naturalistic use of 5-MeO-DMT. Finally, we will explore the controversial topic of how acute effects translate into long-term neuroadaptations in naturalistic psychedelic users. We will contrast fMRI evidence of altered emotional reactivity in experienced users with null findings from resting-state EEG, thereby challenging the assumption of persistent, global network reorganization.

The symposium will thus present state-of-the-art research on the mechanisms of psychedelic action and discuss the challenges related to integrating findings from controlled laboratory settings with the complexity of naturalistic use.

Center for Social and Affective Neuroscience, Linköping University, Sweden 

Touch is fundamental to the development and maintenance of a coherent bodily self, emerging from early experiences of both self-touch and caregiver contact. This sense of bodily self remains deeply interwoven with our capacity for social connection and mental health throughout life. In this talk, I will present findings from my randomized, double-blind, placebo-controlled fMRI study investigating how ketamine, an anesthetic and dissociative substance considered a non-classical psychedelic, alters self-other distinction in the context of affective touch. Ketamine administration led to dissociative experiences, reduced interoceptive awareness, and diminished neural differentiation between self- and other-touch in a temporoparietal region. These findings illuminate the neural mechanisms by which psychedelic substances might cause ego-dissolution and increased feelings of connectedness. In addition, I will introduce my new study on the use of psilocybin for prolonged grief disorder, where I will investigate whether psilocybin can support the adaptation to the loss experience by re-establishing the sense of self.

Laboratory of Spatial Memory, Nencki Institute of Experimental Biology, Warsaw, Poland

This work provides insight into the anti-addictive potential of classical psychedelics through preclinical assessment of their effects on affective states in rats. The utilized protocol combined social isolation periods with group encounters, during which animal behavior was recorded using a behavioral observation system. Additionally, ultrasonic vocalizations (USVs) were collected as quantitative indices of emotional valence and arousal. Psychedelic compounds were administered following isolation periods to assess their ability to modulate positive emotional responses associated with rewarding social contact. By integrating high-resolution behavioral measures with USV-based affective readouts across both sexes and accounting for individual differences, this study aimed to identify psychedelic doses that modulate reward processing through changes in affective components and to elucidate the role of individual and social context in the heterogeneous effects observed across different classical psychedelics.

National Institute of Mental Health, Klecany, Czech Republic; Third Faculty of Medicine, Charles University Prague, Prague, Czech Republic

Psychedelics are recognized for their potential to induce fast-acting, long-lasting changes in cognition and psychological well-being, captivating both psychonauts and therapeutic researchers. This talk presents a triadic view of these compounds, contrasting data from controlled and naturalistic settings. First, we analyze the acute, time-resolved neural dynamics (EEG) of a single psilocybin dose in healthy subjects, providing high-resolution insight into the compound's immediate neurophysiological footprint. Second, we transition to the clinical sphere, comparing baseline versus post-treatment (Day 1) neural and clinical outcomes of both psilocybin and ketamine in patients with Treatment-Resistant Depression (TRD). This contrast illuminates the distinct sustained effects of these fast-acting agents. Finally, we explore the naturalistic use of Mebufotenine (5-MeO-DMT) via intramuscular administration. We present data on its acute time-resolved dynamics (ECG and EEG), emphasizing how its physiological and experiential profile is markedly different from psilocybin. Mebufotenine is often associated with intense somatic release: a bodily cathartic experience that is central to spiritual/underground practice yet remains largely unaddressed in clinical trials. We will discuss whether we can distinctly characterize this somatic release within the measured physiological dynamics, underscoring the necessity of integrating naturalistic insights with clinical data.

Centre for Brain Research, Jagiellonian University, Cracow, Poland; Doctoral School in the Social Sciences, Jagiellonian University, Cracow, Poland

Contemporary neuroscience proposes that acute neurophysiological changes during psychedelic administration translate to lasting reorganization of brain networks. However, critical gaps remain in understanding whether these effects persist in naturalistic users. We conducted a multi-level EEG investigation comparing experienced psychedelic users (N = 57) with matched non-users (N = 49). We assessed oscillatory power, neural signal complexity, and source-localized effective connectivity between the Default Mode, Salience, and Central Executive networks during drug-free resting-state. Contrary to predictions derived from acute studies, connectivity analyses revealed no significant group differences, while oscillatory power results were inconclusive, yielding no clear evidence for the spectral alterations predicted by acute administration models. Interestingly, users demonstrated reduced rather than increased neural complexity. These predominantly null findings in ecologically valid samples challenge the assumption that psychedelic use leads to persistent, large-scale neurobiological changes observable in resting-state EEG. The discrepancy between controlled laboratory...

Classic psychedelics profoundly influence emotional states, eliciting intense acute emotional experiences followed by subtle, sustained changes in emotional reactivity lasting up to several weeks. However, it remains unclear whether naturalistic psychedelic use similarly modulates emotional reactivity. To address this, our preregistered, cross-sectional fMRI study compared experienced psychedelic users (≥10 lifetime experiences; N = 33) with a matched group of non-users (N = 34) on behavioral and neural responses to emotional facial expressions. Psychedelic users demonstrated faster and more accurate recognition of angry facial expressions, suggesting reduced interference from threat-related stimuli. Whole-brain fMRI analyses revealed diminished neural responses to anger in limbic and salience network regions, coupled with enhanced responses to happiness in parietal and sensorimotor areas, consistent with prior clinical findings. Additionally, users showed increased precuneus activation in response to fearful facial expressions. Region-of-interest analyses further indicated reduced differentiation of emotional categories in two default mode network regions—the frontal medial cortex and parahippocampal gyrus. Our study provides a nuanced view of neurofunctional alterations in emotional processing associated with naturalistic psychedelic use, advancing our understanding of its potential long-term effects.

Chairman: Paweł Orłowski