Charles L. Raison

Introduction: Although psilocybin has shown promise for treating depression, responses vary considerably, with some individuals experiencing limiting improvement and even adverse effects. Research has largely relied on assessments conducted at discrete time points, providing limited insight into how post-psilocybin change unfolds in everyday life. The Dial-In study aims to characterize daily-life processes associated with differential responses to psilocybin, including factors associated with improvement or worsening following challenging dosing experiences. Methods and Analysis: Dial-In is a prospective, observational, multi-method longitudinal study embedded within a clinical trial administering 25 mg of psilocybin to up to 141 adults with major depressive disorder. Ambulatory assessments combine ecological momentary assessment (EMA) and voice diaries for 14 days pre- and post- dosing, and passive audio sampling via the Electronically Activated Recorder (EAR) for three four-day periods to characterize everyday affect, behavior, reflections, and social interactions. Outcomes include depressive symptoms, psychological well-being, and psychedelic-related adverse effects assessed through eight weeks post-dose. Analyses will examine whether affective sudden gains and losses, social support, interpersonal conflict, conversational focus, reflection and rigidity predict differential outcomes. Additional analyses will test whether these factors moderate associations between challenging dosing experiences and clinical outcomes. Ethics and Dissemination: The project was approved by WCG Institutional Review Board, with Emory University relying on WCG as the reviewing board. All participants provide written informed consent. Findings will be disseminated through peer-reviewed publications and scientific presentations.

We examined self-reported precipitants of mania, psychosis, and depression on Reddit using AI-assisted code development and automated coding, with blinded human validation. Analyses compared precipitants of mania (n = 337), psychosis (n = 339), and depression (n = 252). Generic stress and sleep disruption were common to mania and psychosis but rare in depression. Cannabis and trauma/abuse/assault were more frequently reported for psychosis, while antidepressants and positive activation/reward were more frequently reported for mania, and self-evaluative thought patterns and social isolation/rejection for depression. Automated and human coding showed strong agreement (κ = 0.82), supporting the feasibility of AI-assisted analysis of perceived psychiatric precipitants.

Persecutory and grandiose thinking (PGT) is evident in mental disorder, religion, and politics. This paper offers an interdisciplinary explanation of PGT with a focus on common causes, mechanisms, and functions. First, psychopathological and ideological variants of PGT are introduced and compared. Theories of stress-induced psychological and social change are invoked next to explain shifts towards PGT in individuals and groups. These include a Status Threat/Reward Model of psychopathological PGT and a relative deprivation theory of political violence. Potential functions and dysfunctions of PGT are considered next, with a focus on how persecutory and grandiose thinking may orient individuals towards mitigating social threats and gaining social rewards, respectively. Conditions for collective PGT are then explored, including systemic stress and exposure to redemptive ideological narratives. Finally, we consider how religious and political institutions regulate PGT.

This paper explores whether some religious and spiritual experiences (RSEs) associated with depression resemble hypomania/mania. Content analysis and phenomenological analysis were used to characterize first-person RSE reports associated with depression (N = 249). Findings reveal that some RSEs that follow depression are characterized by long-duration states (lasting days to weeks) of positive emotion, cognitive clarity, and a sense that the external environment is imbued with extra positive emotional and perceptual qualities (e.g., love, beauty, light, vividness). These long-duration positive states are not always preceded by discrete visionary or hallucinatory phenomena, suggesting that hypomanic/manic-like experiences, in addition to psychotic-like experiences, bear relevance to the study of RSEs. Some RSEs that resemble hypomania reportedly annihilate depression or prevent its recurrence. Other reports of recurrent RSEs associated with depression refer to mental health and social problems. Relational features of certain RSEs, such as experiences of unconditional love, acceptance, and support, may relate to better outcomes associated with RSEs relative to typical psychopathological experiences. This interpretation is consistent with the idea that RS traditions function in part, like psychotherapeutic traditions, to promote mental well-being and to protect against psychosocial dysfunction.

This paper examines first-person experiences of demons, devils, and Satan contained in the Alister Hardy RERC database of religious and spiritual experiences (RSEs). Word frequency analysis, content analysis, and phenomenological analysis are used to characterize the features of demonic experiences and how they relate to psychopathology and religious/cultural affiliations. Results show that demonic experiences are less common than positively valenced RSEs in the RERC database, and that they disproportionately reflect psychotic-like experiences and mental health difficulties. Personal experiences of demonic forces also appear to be related to dreams and parasomnias (e.g., sleep paralysis), while reference to the possession/exorcism of other persons is associated with Pentecostal/evangelical affiliation. Results suggest that personal experiences of demonic forces are more associated with mental health difficulties than with particular religious or cultural affiliations within the current sample.

Passive ambient audio sampling bears great potential for objectively measuring daily social activity and its association with wellbeing and health. However, detecting true conversations via human annotation is labor-intensive, and automatic labeling via audio signal processing has thus far only received proof-of-concept validation. Here, we conduct a comprehensive psychometric validation of a deep learning-based foreground speech detection algorithm for conversation activity detection (CAD) from ambient audio sampled with the Electronically Activated Recorder (EAR) method (Hebbar et al., 2021). We assess the CAD algorithm’s validity as an objective measure of conversation activity using four archival EAR datasets with human ground-truth conversation annotations (N = 566 participants, n = 167,539 audio recordings). Specifically, we evaluate, across the four samples, the degree to which the CAD algorithm converges with human-annotated conversation activity, yields temporal stability estimates of conversation activity, and replicates patterns of external correlates (with demographic, wellbeing, and personality measures) comparable to those derived from human ground-truth annotations. We further compare the distributional properties of conversation activity derived from the CAD algorithm and human ground-truth annotations and use this information for thresholding the algorithm’s continuous conversation activity estimates. Overall, the CAD algorithm evidences strong psychometric properties for estimating conversation activity across a range of participants and study characteristics, suggesting that it is suitable for at-scale deployment to objectively measure daily socializing from passively sampled ambient audio.

Despite being induced by a transient pharmacological exposure, psychedelic experiences can catalyze enduring psychological transformation, presenting a central challenge for understanding the mechanism of action of psychedelic medicines. To address this challenge, the Allostatic Reset Model (ARM) of psychedelic action is proposed, which conceptualizes psychedelic therapeutic effects as a staged, multi-system adaptive stress process unfolding across the following interacting domains: autonomic physiology, neurophysiology, epigenetics, psychological transformation, and narrative meaning-making. In this model, psychedelic administration initiates a perturbation of homeostasis characterized by acute sympathetic activation, psychological challenge, increased neural entropy, and destabilization of relevant neural and cognitive regularities. Subsequently, a coordinated compensatory response emerges, marked by parasympathetic engagement and heightened multi-system plasticity. During this concluding phase, psychological flexibility and integrative meaning-making parallel structural and functional recalibration across systems. We associate this sub-acute period of relative quiescence with the ‘after glow’ of a psychedelic experience, analogous to a ‘calm after a storm’. Epigenetic changes in the brain further facilitate durable biological change. ARM leverages cross-disciplinary frameworks, including hormesis, rebound, supercompensation, and the ‘Hero’s Journey’ archetype to furnish a new model of the therapeutic action of psychedelics integrating acute autonomic and psychological stress with a compensatory, adaptive multi-system regulatory response.

Schizophrenia and bipolar disorder are biologically related, but symptoms of schizophrenia disproportionately reflect a preoccupation with social threats, while symptoms of mania in bipolar disorder disproportionately reflect a preoccupation with social opportunities and rewards. This paper suggests that social defeat/low status and threats to status, well-being, or autonomy play a role in differentiating the developmental trajectories of schizophrenia and bipolar disorder. Evidence suggests that individual traits and environmental factors that plausibly contribute to low status and social threat are risk-factors for schizophrenia but not for bipolar disorder.

The serotonergic psychedelic psilocybin induces neural plasticity and profoundly alters consciousness. The benzodiazepine midazolam blunts neural plasticity and induces conscious sedation and amnesia at low doses. In our recent open label pilot study, we administered oral psilocybin (25 mg) along with intravenous midazolam at doses allowing a full psychedelic experience while blunting memory for the experience. We previously reported preliminary results from high density scalp electroencephalography (EEG) recorded during the dosing session. Here, we examined changes in EEG band power, normalized Lempel Ziv complexity (LZCn), and spectral exponent. We used linear mixed effects models that incorporated time and the subjective effects of midazolam and psilocybin, measured with the Observer’s Assessment of Arousal and Sedation (OAA/S) and selected items from the Altered States of Consciousness (ASC) questionnaire, respectively. At 15–30 min, when midazolam but not psilocybin was at its targeted effect site concentration, we observed increased beta power and decreased spectral exponent. As the subjective effects of psilocybin commenced and over the next six hours, we observed increased LZCn and spectral exponent and decreased broadband power, with the most prominent power reductions in the delta, theta, and alpha frequency bands. OAA/S improved model fits for alpha power while ASC improved model fits for LZCn and spectral exponent. While recognizing limitations inherent to the small sample size and variability in dosages of midazolam, these data are further evidence that the effects of psilocybin are maintained in the presence of midazolam, supporting its utility in mechanistic studies of psilocybin’s therapeutic activity.