This theory-building paper proposes the ALBUS (Altered Beliefs Under Psychedelics) model as an extension of the REBUS hypothesis, suggesting that 5-HT2A receptor activation can lead to both relaxation (REBUS) and strengthening (SEBUS) of beliefs depending on dosage and context. The authors draw parallels between psychedelic states and lucid dreaming, focusing on mechanisms of conscious perception, dreaming, and memory.
How is it that psychedelics so profoundly impact brain and mind? According to the model of Relaxed Beliefs Under Psychedelics (REBUS), 5-HT2a agonism is thought to help relax prior expectations, thus making room for new perspectives and patterns. Here, we introduce an alternative (but largely compatible) perspective, proposing that REBUS effects may primarily correspond to a particular (but potentially pivotal) regime of very high levels of 5-HT2a receptor agonism. Depending on both a variety of contextual factors and the specific neural systems being considered, we suggest opposite effects may also occur in which synchronous neural activity becomes more powerful, with accompanying Strengthened Beliefs Under Psychedelics (SEBUS) effects. Such SEBUS effects are consistent with the enhanced meaning-making observed in psychedelic therapy (e.g. psychological insight and the noetic quality of mystical experiences), with the imposition of prior expectations on perception (e.g. hallucinations and pareidolia), and with the delusional thinking that sometimes occurs during psychedelic experiences (e.g. apophenia, paranoia, engendering of inaccurate interpretations of events, and potentially false memories). With Altered Beliefs Under Psychedelics (ALBUS), we propose that the manifestation of SEBUS vs. REBUS effects may vary across the dose-response curve of 5-HT2a signaling. While we explore a diverse range of sometimes complex models, our basic idea is fundamentally simple: psychedelic experiences can be understood as kinds of waking dream states of varying degrees of lucidity, with similar underlying mechanisms. We further demonstrate the utility of ALBUS by providing neurophenomenological models of psychedelics focusing on mechanisms of conscious perceptual synthesis, dreaming, and episodic memory and mental simulation.
Papers cited by this study that are also in Blossom
Amada, N., Shane, J. · Journal of Humanistic Psychology (2022)
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Brouwer, A., Carhart-Harris, R. L. · Journal of Psychopharmacology (2020)
Carhart-Harris, R. L. · Neuropharmacology (2018)
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Earlier theorising about how classical psychedelics act on brain and mind has converged around predictive-processing accounts such as the Relaxed Beliefs Under Psychedelics (REBUS) model, which links 5-HT2a receptor agonism to a relaxation of high‑level priors and therefore greater influence of bottom‑up sensory evidence. At the same time, many phenomenological features of psychedelic experience—enhanced meaning, vivid imagery, pareidolia, hallucinations and sometimes delusional interpretations—are more naturally framed as cases in which prior expectations exert stronger influence over perception and cognition. Safron and colleagues situate these tensions within the broader “psychedelic renaissance” and argue that more nuanced, multiscale models are required if clinical translation and basic science are to proceed reliably. This paper introduces Altered Beliefs Under Psychedelics (ALBUS), a unifying conceptual framework that integrates REBUS with a complementary hypothesis termed Strengthened Beliefs Under Psychedelics (SEBUS). The authors propose that both relaxation and strengthening of beliefs can occur under 5-HT2a agonism depending on dose, neural subsystem, and contextual factors (including ‘‘set and setting’’), and they develop neurophenomenological and mechanistic models linking cortical microcircuits, oscillatory dynamics, hippocampal/entorhinal systems and modes of conscious perception to these opposing effects. ALBUS is presented as a hypothesis-generating synthesis that aims to explain a wide range of psychedelic phenomena—from waking dreaming and mystical noeticity to hallucinations and therapeutic insight—and to motivate specific empirical tests.
This is a theoretical and integrative paper rather than an empirical study. The authors synthesise prior empirical findings, computational theories (notably hierarchical predictive processing), neurophysiological observations concerning cortical microcircuits and oscillations, and phenomenological reports of psychedelic experiences to construct ALBUS. Visual and schematic models (figures and tables described in the text) are used to map hypothesised relationships between 5-HT2a agonism, activity of layer 5 pyramidal neurons and layer 2/3 interneurons, oscillatory bands (theta, alpha, beta, gamma), and the hierarchical levels at which beliefs are represented. Safron and colleagues develop neurophenomenological scenarios for perception, imagination (dream‑like imagery) and episodic memory/mental simulation, and they articulate six cognitive regimes corresponding to increasing levels of 5-HT2a stimulation (‘‘Unaltered’’ through ‘‘Extreme dose’’). Where relevant, they draw on animal paradigms (e.g. the head‑twitch response) and human neuroimaging/electrophysiology literature to motivate hypotheses, and they explicitly note gaps in the empirical record. The paper outlines testable predictions and experimental paradigms that could adjudicate REBUS versus SEBUS tendencies, including carefully titrated perceptual‑illusion tasks, layer‑specific imaging (high‑field fMRI or multimodal approaches), electrophysiological assays of hippocampal sharp‑wave ripples and dose‑response studies across multiple modalities and contexts.
The manuscript does not present new empirical data; its primary outputs are theoretical claims, mechanistic hypotheses and a set of testable predictions. Key propositions are: - ALBUS integrates two complementary processes: SEBUS (strengthening of certain priors or attractor states) and REBUS (relaxation or desynchronisation of high‑level priors). These processes may co‑occur or predominate under different conditions rather than being mutually exclusive. - At the microcircuit level, increased excitability of layer 5 pyramidal neurons (via 5-HT2a agonism) can lead either to loss of synchrony (the REBUS mechanism) or to enhanced synchrony and stronger intermediate‑level priors (the SEBUS mechanism), depending on stimulation regime and circuit context. Modulation of layer 2/3 inhibitory interneurons is also hypothesised to influence the gain on ascending prediction errors and thereby shield or expose priors to sensory evidence. - Oscillatory dynamics are used as mechanistic markers: SEBUS is associated with strengthened beta/alpha complexes at intermediate hierarchical levels (producing heightened vividness and meaning‑laden imagery), whereas REBUS involves disrupted large‑scale coherence (reduced alpha power and potential ego‑disintegration). Suppression of gamma power in primary sensory cortex under 5-HT2a agonism is cited as consistent with reduced bottom‑up prediction‑error signalling. - The authors propose an inverted‑U relation between dose (or 5-HT2a engagement) and cognitive stability: low‑to‑moderate stimulation may elevate vividness and imaginative capacity without catastrophic disruption (microdose/threshold regimes), moderate‑to‑high doses produce complex admixtures of SEBUS and REBUS effects (typical psychedelic phenomenology), and extreme stimulation can collapse coherent self‑models leading to profound ego‑dissolution. - At the systems level, ALBUS emphasises hippocampal/entorhinal system (H/E‑S) roles in orchestrating streams of consciousness, with hypotheses that 5-HT2a agonism affects sharp‑wave ripples and remapping processes relevant to episodic memory, planning and the temporal chunking of experience. - Clinically relevant predictions include (i) potential utility of low‑level 5-HT2a agonism (microdosing) to elevate conscious vividness without wholesale belief relaxation—suggesting exploratory use in conditions such as anhedonia, autism spectrum features, Alzheimer’s and disorders of consciousness—and (ii) caution about administering classic psychedelics to individuals at risk for psychosis. The authors stress these are speculative and require empirical testing. - Finally, the paper lists concrete experimental approaches to discriminate SEBUS versus REBUS effects, including titrated illusion susceptibility tasks and layer‑specific neuroimaging; it also notes an absence of robust dose‑response datasets in current animal paradigms and human studies.
Safron and colleagues interpret ALBUS as offering a useful ‘‘lingua franca’’ linking Bayesian cognitive science, machine learning and neurophenomenology to account for the heterogeneous effects of classical psychedelics. They argue that integrating SEBUS and REBUS mechanisms permits more precise, context‑sensitive statements about what a given psychedelic at a given dose in a given setting is likely to do, rather than blanket claims that psychedelics uniformly relax or expand consciousness. The authors emphasise the causal complexity inherent in the framework: SEBUS phenomena can arise directly from circuit‑level strengthening of priors or indirectly as consequences of REBUS‑type desynchronisation at higher levels (and vice versa). They outline how these looping causal cascades complicate inference—observing a given phenomenology (for example, increased illusion susceptibility) does not immediately identify a single underlying mechanism without dose‑ and level‑specific experiments. Limitations are acknowledged explicitly. The paper is largely conceptual and rests on incomplete empirical coverage: reliable, systematic dose‑response data for 5‑HT2a signalling across microcircuits, layers and large‑scale networks are scarce, and many claims invoke animal paradigms (such as the head‑twitch response) that do not map cleanly onto subjective human phenomena. The authors also recognise uncertainties about the detailed contributions of specific oscillatory bands and interneuron subtypes, as well as the extent to which models of hippocampal remapping can be translated to high‑level cognitive and phenomenological descriptions. Finally, they caution against overgeneralising clinical implications and call for targeted empirical work—for example, psychophysical tasks, layer‑resolved imaging and electrophysiology—to adjudicate competing predictions. In positioning their contribution relative to prior work, the authors do not abandon REBUS but propose it be complemented by SEBUS and other process theories (e.g. thalamic gating, claustrum involvement) within an ALBUS framework. They suggest that such pluralism can enhance the explanatory and predictive power of psychedelic neuroscience while generating concrete, falsifiable hypotheses.
The authors conclude that alterations of belief dynamics under psychedelics are best modelled as context‑dependent admixtures of strengthened and relaxed priors rather than as a single uniform process. They argue that low‑to‑moderate 5-HT2a agonism may often produce SEBUS effects (heightened vividness and strengthened intermediate‑level priors), whereas moderate‑to‑high levels are likely to generate complex combinations of SEBUS and REBUS, and extreme levels can disrupt coherent self‑models. To move ALBUS from theory to empiricism, Safron and colleagues propose several priority research directions: (i) systematic investigation of how differing levels of 5‑HT2a agonism affect which priors are strengthened or relaxed across hierarchical levels; (ii) testing whether agonism of L2/3 interneurons reduces sensory gain (mimicking sensory‑deprivation effects) and thereby promotes unconstrained imaginings; (iii) layer‑specific neuroimaging (high‑field fMRI or multimodal approaches) to estimate relative strengths of predictions and prediction errors across cortical depths; (iv) pursuit of individual‑level alignment between neural measures and subjective reports to realise neurophenomenological goals; and (v) comprehensive psychophysical studies of perceptual and cognitive illusions with titrated susceptibility thresholds to determine whether priors are raised or lowered at various doses. The paper closes by calling for substantial further empirical work and funding to characterise relaxed, strengthened and generally altered beliefs under psychedelics and related conscious states.
ntroduction understanding, access to and acceptance of psychedelics continues to grow as legal barriers are relaxed in different parts of the he evolving "psychedelic renaissance" has the potential to radiworld. In light of these potentially radical changes for science and ally alter society, possibly in ways we are only beginning to undersociety, it is essential that we have detailed and accurate modtand. Psychedelics, especially under supels of these powerful compounds for this potential psychedelic ortive conditions, have been associated with profound (potenrevolution to live up to its promise and avoid undesirable ially life-changing) personal transformations at rates seldom clinical settings et outcomes. bserved in. The potency Perhaps unsurprisingly, attempts at trying to understand f psychedelics necessitates precise and comprehensive models mechanisms of psychedelic action have led to the development f their action to optimize therapeutic potential and mitigate of a variety of (seemingly incompatible) models. The recently dverse outcomes. Such models should capture the full spectrum f neurological and phenomenological effects of these substances, proposed model of Relaxed Beliefs Under Psychedelics (REBUS) panning recreational and clinical contexts. Given the diversity of attempts to understand psychedelic activity as involving a relaxxperiences that can arise from psychedelic use, this task is inher-ation of high-level priors, which in addition to altering selfntly challenging. Alongside these efforts for furthering scientific representations, also alters constraints on the space of possible In contrast, earlier models described psychedelics as "non-specific amplifiers" of experience or as "consciousness expanding". Inspired by both REBUS and the ways in which psychedelics can engender more intense-and potentially more compelling and/or meaningful)-conscious states, we here introduce a complementary model involving Strengthened Beliefs Under Psychedelics (SEBUS). The enhanced meaning-making in psychedelic therapy may be the most striking realization of SEBUS effects, but other examples may be found in the perceptual illusions and cognitive delusions that occur under these altered states of consciousness. The more intense realization of one's life priorities, potentially more insightful perspectives on personal challenges-be it existential orientation toward a cancer diagnosis, self-persecutory thoughts in depression, or the battle of competing motivations underlying addictions-seem to suggest some kind of belief strengthening is involved. A solely REBUS-focused account pharmacologically might better describe a dissociative or anesthetic effect, rather than the clinically significant induction of meaningful experiences and insights observed with psychedelic therapy. Our alternative model would suggest an opposite underlying mechanism whereby beliefs (e.g. access and responsiveness to personal meanings) may be transiently strengthened by psychedelic activity. Along these lines, pareidolia, the propensity to discern meaningful visual patterns in random noise, is a phenomenon consistently observed with psychedelic use-with overlapping neural correlates and associations with creativity)-and could be explained by transient belief strengthening. Psychedelic-related apophenia, or the potentially misleading perception of meaningfulness), could also be elegantly accounted for with models involving strengthened beliefs. Perhaps most compellingly, we believe strengthened beliefs provide the most parsimonious account of core aspects of psychedelic phenomenology in being able to account for both hallucinations and delusions in terms of experience being more heavily impacted by prior expectations, rather than present observations. One of our main goals for this manuscript is attempting to bring together different aspects of major theories to create a "minimum unifying model"of the effects of psychedelics on brain and mind, wherein insights from diverse perspectives may be integrated, and the differences between them adjudicated. We refer to this unifying framework as Altered Beliefs Under Psychedelics (ALBUS), with the operative term "altered" being meant to capture the capacity for psychedelics to either strengthen or relax beliefs at different levels of representational hierarchies. Key to the activity of psychedelic drugs is their action in the brain as 5-HT2a agonists. It is through consideration of the potential effects of this agonism across different doses and neural systems that we believe both strengthened and relaxed beliefs may (and must) be accounted for in a single framework. In addition to describing the core features of ALBUS and its implications, we will also explore how such understandings may illuminate fundamental mechanisms of mind, human nature, and potentially even selfhood and consciousness in all their various manifestations. In proposing ALBUS, we suggest a fruitful consensus and generative conversation can be realized by focusing on ways in which particular beliefs-whether in terms of perceptual synthesisor personal meanings-are either strengthened or weakened in different combinations based on multiple factors, including various (i) substances, (ii) doses, and (iii) "sets andsettings". That is, it is not only the case that we ought to expect both directly and indirectly strengthened and relaxed beliefs at different hierarchical levels (so allowing for both REBUS and SEBUS effects to occur), but we ought to expect further complexities in the ways these admixtures of belief strengthening and relaxation vary as a function of numerous factors that may vary not just across individuals, but even within individuals across contexts, including across the time-course of individual psychedelic sessions (with lower pharmacological levels being present at the ascending and descending limbs of high-dose sessions). As such, regardless of whether or not an ALBUS framework is accepted as a unifying model, we hope to show why it is necessary for us to take caution in ever making blanket statements about psychedelics. That is, rather than saying "psychedelics do X," we would do better to say, "this psychedelic at this range of doses tends to do X, Y, and Z in A, B, and C contexts." This is not just a matter of pedantry, but reflects the kind of precision we need if we are to proceed with the care required for discussing and studying these powerful (and so both promising and perilous) transformative agents. We begin by providing a brief overview of how 5-HT2a receptor agonism may lead to either strengthened or relaxed beliefs (Fig.). Next, we discuss how connecting models of predictive processing to psychedelic phenomenology requires a more thorough account of the nature of conscious perception (Fig.). We further consider how various kinds of sense-driven and imaginative experiences are suggested by different models of psychedelic action (Fig.). We then go on to extend these neurophenomenological models to "thought," operationally defined as sequences of mental actions, experienced as a "stream of consciousness" (Fig.). Finally, we discuss some of the complexities and future directions of our proposal for both basic and clinical research.. In brief, REBUS suggests that psychedelics alter hierarchical predictive processing (HPP) mechanisms in ways that flatten free energy landscapes, or the differential attracting forces associated with various (Bayesian) beliefs, so promoting flexibility in inference and learning. Algorithmically speaking, this would correspond to reduced "precision-weighting" over top-down prior expectations-functionally understood as reduced filtering of perception and cognition via attentional selection)-so allowing bottom-up prediction errors to have a greater influence on inference and learning. Or perhaps with fewer assumptions, one may consider REBUS effects to arise whenever minds are altered in ways that disrupt typical belief dynamics, with a potentially useful analogy being found in visualizing a physical mechanism having different functioning when deployed under atypical conditions. Such relaxations of beliefs and enhanced capacity for updating may help explain why psychedelics appear to have transdiagnostic relevance across a broad range of conditions, which may be expected because flexibility is almost synonymous with an essential capacity for FigureSEBUS and REBUS effects in Hierarchical Predictive Processing (HPP). The left image depicts mechanisms of inference and updating in cortical hierarchies, considered before the administration of 5-HT2a agonists. Dark purple rectangles indicate higher levels of cortical hierarchies (e.g. transmodal cortices and associated networks), encoding more abstract high-level beliefs regarding sources of prior expectations over the causal structure of the world (including oneself and others). Light purple circles indicate deep pyramidal neurons (layer 5), thought to encode predictions (or priors) via their ability to form large-scale synchronous complexes, partially due to the ability of these units to form re-entrant loops with the thalamus. Red shading indicates rhythmic complexes of synchronized neuronal activity forming at beta frequencies (∼13-30 Hz), where these probabilistic beliefs are propagated down cortical hierarchies toward primary sensory modalities, indicated by red arrows, where degree of thickness corresponds to relative strengths for these prior expectations. White circles indicate superficial pyramidal neurons (L2/3), corresponding to expectancy violations, providing a bottom-up flow of prediction errors (generated at faster gamma frequencies; gray shading) as the only information passed up cortical hierarchies in predictive coding. The confidence associated with these prediction errors is known as "precision weighting," indicated by thickness of black arrows. Ascending prediction errors are depicted as thinner grey arrows when they are attenuated by descending predictions. A REBUS effect (bottom right) would involve a weakening of priors (indicated by smaller beta complexes with thinner red arrows), so allowing more sensory observations to reach deeper portions of the brain as prediction errors fail to be suppressed (indicated by more numerous gray-shaded regions and somewhat thicker grey arrows). A SEBUS effect (top right), in contrast, would involve a strengthening of priors (indicated by larger beta complexes with thicker red arrows), which are depicted as being more effective at suppressing ascending prediction errors (indicated by thinner grey arrows). An additional SEBUS effect is depicted in terms of thinner arrows for all prediction errors, which could be functionally understood as a kind of default reduction in precision weighting and shielding (or reduced updating) from sense data. This attenuation of the gain on sensory observations may be functionally understood as providing prior expectations with greater (or stronger) influence on inferences and updating. In this way, psychedelics may not only involve strengthened prior expectations, but such beliefs may be given further strength/precision by being less likely to be contradicted by inconsistent sense data. all complex adaptive systems: open-ended evolution.
The foundational premise of REBUS is that 5-HT2a agonism promotes excessive excitability in "deep" pyramidal cells-i.e. layer 5 cortical neurons, as opposed to "superficial" layers (L2/3) associated with bottom-up prediction errors (Fig.)-which are thought to encode top-down "beliefs" based on our prior expectations, with this effect being especially pronounced with respect to higher levels of cortical hierarchies. According to REBUS, 5-HT2a agonism of deep pyramidal neurons causes overly excited ensembles to fail to synchronize, so resulting in the implicit relaxation of high-level priors, making it more likely that nervous systems will be updated by unsuppressed ascending prediction errors from the external world. This removal of topdown priors then affords a greater latitude for bottom-up sensory evidence to drive belief updating throughout the hierarchy. Here, we propose an alternative account of the effects of psychedelics that is in many ways compatible with REBUS, albeit Downloaded fromby guest on 15 February 2025 . Smaller and faster beta oscillatory complexes are depicted as sometimes nested within larger and more slowly synchronizing beta rhythms, so enabling hierarchical modeling of more complex events evolving across multiple spatiotemporal scales. Blue shading indicates even larger and more slowly unfolding alpha rhythms (∼8-12 Hz), providing yet another level of hierarchical depth for deep temporal world modeling (including with respect to self-processes). The left-most panel depicts modeling via fast and small beta complexes, with entailed representations constituting lower-level features such as vibratory patterns for hearing, somatosensation, and fine-grained visual information. The middle panel depicts this information being brought together into more complex compositions, including object information as modeled by each modality. However, these entailed objects are not intended to indicate conscious experiences, which are reserved for the rightmost panel in which modalities can be coherently integrated via egocentric reference frames (i.e. seeing one's hand reaching out to grab an apple from the branch of a tree). Seefor more details on the neural and computational bases of phenomenal (and access) consciousness with some important differences. In what follows, we introduce a unified model of ALBUS in which 5-HT2a agonism also involves SEBUS effects (Figs 1-3), particularly at intermediate levels of abstraction associated with conscious experience. By intermediate-level beliefs, we mean to indicate that SEBUS effects may primarily be observed at levels that are both hierarchically higher to and also more abstract than those that would be found closer to primary modalities where sense data is first processed. However, these beliefs are "intermediate" in that they may be thought of as lower in the predictive processing hierarchy, relative to more abstract "representations"as might be associated with/by the hippocampal/entorhinal system (H/E-S). In other words, perhaps intuitively for some, we suggest 5-HT2a agonism will tend to increase the overall intensity of phenomenal consciousness (e.g. with respect to the vividness and/or detail of experience). This increase in the overall intensity of perception (and imagination) may potentially occur along most of the full dose-response curve for psychedelics under both typical and altered conditions. We propose that this intensification of experience may be crucial for understanding (i) what "manifests" in which ways under psychedelics and (ii) what is likely to be acted upon and learned while under potentially intensely altered states. SEBUS effects may provide the most straightforward account of folk psychological descriptions of psychedelics as "mind manifesting" and "consciousness elevating." That is, we propose that 5-HT2a agonism may allow information to become more consciously accessible by strengthening the activity of particular neuronal ensembles. Perhaps more compellingly, strengthened beliefs-and as we will suggest later, potentially a shielding of these novel imaginings from conflicting sense data-evoke widely held impressions that psychedelic experiences can be similar to "waking dreams" and "transient psychosis". The complexity of cortical information flows clearly cannot be reduced to either 5-HT2a-mediated SEBUS or REBUS effects. Indeed, psychedelic alterations of working memory capacity may be accounted for by mechanisms that are independent of 5-HT2a receptors. Nonetheless, ALBUS (critically) supports a REBUS-like approach in suggesting that attempting to model the impacts of 5-HT2a signaling on predictive processing may be useful for attempting to model the complex effects of psychedelics on brain and mind. We propose that SEBUS effects are strongly suggested by the nonveridical nature of hallucinations, as well as pareidolia, both of which may be straightforwardly understood as strong prior expectations overwhelming sensory evidence. A strictly REBUS-involving account, in contrast, would suggest more veridical perception from increased driving of dynamics by raw sensory input from the world, with less influence from prior expectations. Further support for SEBUS effects may be found in similarities between psychedelic phenomenology and the varieties of images created with "Deep Dream"-style techniques. With these technologies, specific units in neural networks are made to exert particularly strong top-down influences in the process of generating likely patterns of inputs, resulting in generated stimuli becoming predominated by representations of corresponding features (e.g. superimposing fractal or insect-like forms onto visual fields in unusual combinations). This would be FigureREBUS, SEBUS, and ALBUS effects on brain and mind. These images depict how neurological and phenomenological processes might be altered with different levels of 5-HT2a agonism under different theoretical assumptions. Panels on the top indicate perception-grounded sensation, which is always necessarily experienced from a first-person point of view due to locations of sensors on the body. Panels on the bottom indicate imaginative perception (or dreaming) generated from memory decoupled from sensation, organized according to a third-person perspective. The extent of shaded complexes of rhythmic neural activity is meant to indicate degrees of coherent integration associated with various frequency bands. Sensation is characterized by alpha and beta complexes that extend further down toward primary modalities to indicate information flows being constrained by sense data to a greater degree. For imagination, alpha and beta complexes are hypothesized to be centered in deeper portions of the brain, so realizing imaginative processing as the unfolding of consciousness with reduced tethering by information from the external world an instance of strengthening, rather than weakening the beliefs entailed by particular units in artificial neural networks; we suggest not dissimilar principles may be at play in biological neural networks when high levels of 5-HT2a agonism drive increased activity from L5 pyramidal neurons. The increased subjective vividness and detail of experience with psychedelics would seem to suggest increased precision for sensory observations (i.e. more influence from prediction errors). However, models of consciousness centered on HPP suggest that perception and imagination are entailed by predictions, rather than sensory prediction errors. Individuals may feel like they are seeing more details of the world as it is-which could be the case, depending on many factors-when in reality they may actually be experiencing their expectations more vividly, but less accurately. Observations of similar effects in the domain of cognition-cf. the "noetic" quality of mystical experiences-suggest that SEBUS effects may parsimoniously apply to belief dynamics at multiple levels of abstraction. We believe that SEBUS effects are further suggested by findings in which gamma power-thought to encode prediction errorsfrom the primary visual cortex is inhibited with 5-HT2a agonism, as well as by associations between hallucinations and sensory deprivation (cf. Charles Bonnet syndrome or anomalous perceptual experiences sometimes reported with isolation tanks). To the extent that stimulating L2/3 interneurons contributes to imaginings that are more vivid and potentially less constrained, more detailed characterization of the mechanisms and phenomenology of sensory attenuation experiences may be a valuable line of inquiry (cf. "dark meditation retreats," the opening of critical plasticity windows with sensory deprivation. Connections between psychedelics and mental imagery have been compellingly explored in recent work by, shows even more extended sequences with even greater vividness, detail, and absorption, with the beginnings of more creative associations (e.g. imagining (and possibly remembering) an apple pie). (d) The fourth set of rows (Medium dose) shows the beginnings of psychedelic phenomenology as normally understood, with the number of theta cycles (and cognitive operations) in each sequence beginning to lessen due to reduced coherence. Imaginings become increasingly creative and closer to perception in vividness, which here shows an additional mnemonic association (i.e. one's mother in relation to apple pie) that might not otherwise be accessible under less altered conditions. (e) The fifth set of rows (Heroic dose) shows further truncated sequences with even more intense psychedelic phenomenology, near-complete blurring of imagination and reality, and altered selfhood. (f) The sixth set of rows (Extreme dose) shows radically altered cognition involving the visualization of archetypal images (i.e. core priors) and a near-complete breakdown of the processes by which coherent metacognition and objectified selfhood are made possible which are highly compatible with the current proposal in emphasizing the nature of such experiences as ranging from dream-like to hyper-real, oftentimes in seemingly paradoxical combinations. ALBUS should not be taken to suggest a simple account of either strengthened or relaxed beliefs associated with different levels of 5-HT2a agonism. Rather, we should expect different combinations of SEBUS and REBUS effects based on a variety of factors including the consideration of particular neural systems, substances, doses, sets, and settings. There may also be broad trends with respect to things like the availability of high-level schemas, the intensity with which goals are imagined (or consciously represented), and perhaps also with respect to the degree to which these intermediate and higher-order attracting states are updated by sense data. In terms of canonical microcircuits for HPP, we suggest the following hypotheses for the effects of altered 5-HT2a signaling: (i) Low-to-moderate levels of stimulation of L5 excitatory pyramidal neurons may be more likely to strengthen (SEBUS)-rather than weaken (REBUS)-complexes of synchronous activity to which these neuronal populations contribute via oscillations from thalamocortical loops. Such amplification would have the effect of strengthening entailed beliefs, functionally understood as implicit and sometimes explicit Bayesian prior expectations, or "predictions" with respect to HPP. (ii) Moderate-to-high levels of stimulation of L5 neurons may produce direct belief strengthening at intermediate levels of cortical hierarchies corresponding to conscious perceptual synthesis, or indirectly via higher-level belief-relaxation (e.g. from reduced suppression or unusual patterns of attention secondary to REBUS effects), or by inducing novel biophysical regimes that diverge from past shaping by experiential histories (e.g. thinking/attending differently because things feel different). (iii) Low-to-moderate levels of stimulation of L2/3 inhibitory interneurons)-which are presently not included in REBUS models-may also suppress ascending sensory prediction errors, so decreasing their influence on updating prior expectations. This could have the effect of further shielding (possibly strengthened) beliefs from disruption by inconsistent evidence (cf. hallucinations from sensory deprivation). In sum, we propose that low-to-moderate doses of psychedelics may often have impacts that are the opposite of what REBUS Downloaded fromby guest on 15 February 2025 models might suggest and may predominantly result in direct SEBUS effects, with perhaps indirect forms of belief-relaxation being generated as a function of expectations. We further suggest that moderate-to-high doses of psychedelics may produce complex admixtures of both direct and indirectly realized SEBUS and REBUS effects. The observation of the dosage-related effects described earlier (and further) would be invaluable for helping to determine the soundness of the ALBUS framework. Unfortunately, as will be discussed in greater detail later, most animal studies capable of addressing these questions tend to use a "head twitch" paradigm (de la Fuente, in which animals are provided with increasing doses until they exhibit behavior patterns considered to be indicative of psychedelic-like states. While the absence of such evidence is a limitation of the present discussion, we also believe that one of the primary sources of added value from ALBUS is motivating the collection of new datasets, and in this case experiments capable of reliably characterizing the functional characteristics of the full dose-response curve of 5-HT2a receptors. Overall, we propose that explaining the effects of compounds such as 5-HT2a agonists and other psychedelics may require a combination of SEBUS and REBUS models for understanding ALBUS. SEBUS-involving models may be necessary to sufficiently account for both the therapeutic and "psychotomimetic" effects of psychedelics. We suggest that strengthened-belief models may provide the most parsimonious explanation for how delusions and hallucinations are generated-and why these phenomena tend to show strong correlations-under both the temporarily altered states of psychedelics as well as in more enduring psychotic states). As we hope to demonstrate with the detailed neurophenomenological models presented here (Figs 2-4), we believe a more sophisticated analysis of cognition is required to adequately characterize ways in which beliefs may be altered under psychedelics. We believe ALBUS can provide a "minimum unifying model" for understanding psychedelics (Wiese 2020), with various combinations of SEBUS and REBUS effects at varying hierarchical levels providing a potentially sufficient conceptual lexicon for describing how belief dynamics may be altered under different circumstances. That is, we do not intend on supplanting theories that exist or will be developed in the future, but instead are proposing candidate mechanisms and principles by which other models can more readily be compared and synergistically integrated with one another. While the ALBUS model may be questioned, one of our main goals is to demonstrate how we may meaningfully specify computational descriptions for nervous systems using the language of probability theory and machine learning, with minds understood as evolving ecosystems of beliefs/predictions (that may be either strengthened or relaxed in myriad ways) for valuedriven agents. In this manuscript, we specifically focus ALBUS on classic psychedelics, whose effects are substantially (but not completely) mediated by 5-HT2a receptors. However, in what follows, we hope to show that the study of psychedelics within the ALBUS framework has broader implications for understanding varieties of conscious (and unconscious) experiences, including phenomena such as psychopathological conditions, various meditative states, and even the nature of dreaming. Any adequate attempt at unification requires considering the precise conditions under which people tend to utilize psychedelics, including with respect to repeated uses. This is especially important in light of the fact that complex behaviors usually require learning as part of their contextualization, especially with respect to interventions whose primary purpose often involves attempting to induce altered states in the service of forming altered traits). Other frameworks have been provided along these lines, such as recently proposed models of psychopathology based on the "canalization" of belief landscapes. However, we would also suggest that such models will neither be complete nor accurate if they fail to adequately account for ways in which both (direct and indirect) belief strengthening and relaxation play out in (and through) our minds.
Explaining alterations of perception under psychedelics may require models that go beyond the simplicity and elegance of HPP as usually understood in terms of a singular algorithm for Bayesian inference. Toward this end, we are required to consider models of the processes that generate different kinds of subjective experiences and their qualities: i.e. phenomenal consciousness. Without this kind of detailed understanding, we will likely fail to achieve sufficiently constrained hypothesis spaces for reliability for both scientific theorizing and clinical interventions.proposes that a multiscale nested hierarchy over posterior cortices affords phenomenal consciousness, partially by virtue of the scope of alpha-band rhythms. More specifically, these 8-12 Hz oscillations are suggested to afford neuronal synchronization at the spatiotemporal scales required to integrate multiple sensory modalities, and further organize this information according to egocentric reference frames for the sake of both informing and being informed by action-perception cycles on the timescales over which they evolve. Please note: we are not suggesting that we are in possession of a complete account of the neural bases of phenomenal consciousness. For example, it remains unclear whether these distributed rhythmic attractors themselves constitute the physical and computational substrates that generate experience (itself), or something more like an essential-but potentially without consciousness on its own-passive sampling from the environment (cf. carrier waves and multiresolution wavelet analysis). Fortunately, these unsolved technical questions do not impact the core claims made in the present manuscript, and we instead hope that psychedelics may provide valuable data for disambiguating between models of consciousness (cf. neural correlates of 5-MeoDMT experiences and "cessation" events with advanced Jhana meditators). In Fig., a visuospatial sketchpad-and "mind's eye," or "Cartesian theater" (Safron 2021b)-is depicted as centered on posterior medial cortices, which have been demonstrated to constitute major sources of alpha synchronization, implicated in generating both visual imagery and awareness, and as potentially essential for coherently translating between egocentric and allocentric perspectival reference frames. While not depicted, an additional source of conscious experience may be found in lateral parietal cortices in terms of somatospatial processing, which may couple with visuospatial modalities in complex ways that would influence things like awareness of embodied selfhood, coherent tracking of causal sequences, and senses of ownership for actions). If such couplings are disrupted, this could potentially contribute to the generation of a variety of anomalous inferences ranging from hallucinated external voices to the perception of nonexistent entities. Such perceptions of other agents are sometimes reported with psychedelic experiences, and we believe an ALBUS perspective may be able to provide a mechanistic (and naturalistic) account of some of the processes that might contribute to their generation. Our emphasis on the importance of the preconditions for establishing coherent perspectival reference frames may be crucially important for understanding psychedelics, especially considering the centrality of constructs such as "ego dissolution" or the ways in which mystic/awe experiences may both further and be furthered by various forms of self-decentering and disinhibiting self/cognitive-control processes. While further work is needed to support our suggested progression from predictive processing to coherent perceptual synthesis, we believe there are good reasons to understand nervous systems in terms of workspace-like architectures for multimodal inference). However, our primary goal here is to provide serviceable (and hopefully useful and accurate) "placeholder" models that provide the basis for the models of sophisticated cognition described later. Figuredescribes a progression of information being integrated into increasingly large and encompassing (but more slowly evolving) complexes of synchronous neural activity. An apple, for example, is consciously experienced if multiple sensory hierarchies combine their complementary sources of information to synergistically facilitate inference via cross-modal priors. These inferential capacities may be further enhanced if organized by egocentric perspectival reference frames, which may be required for sufficiently coherent experiences such that we can be made aware of and report on them, or perhaps may be necessary for any consciousness to be generated whatsoever. Across scales, neuronal synchronization is assumed to enable "communication through coherence", computationally understood as the establishment of joint beliefs from whatever information is capable of being exchanged on the timescales of formation for these metastable attracting states). An inverse relationship between the size and speed of rhythms is depicted, which may be a necessary consequence of the differential challenges of creating coherent oscillatory modes for networks of varying sizes.
Among the many aspects of phenomenology to be accounted for by an adequate account of psychedelics, we believe two key components of ways in which experience may be altered include the qualities of imagination and perception, as well as ways in which self-consciousness is shaped by tendencies and capacities for adopting egocentric and/or allocentric perspectives on oneself. With potential relevance to both spirituality and clinical practice, nondual awareness and dissociative (and potentially pathological) states associated with psychedelics and meditative experiences may involve a breakdown of such processes of selfobjectification. The contributions of posterior medial cortices to alpha power are notable in that this region has been shown to contribute to the establishment of coherent egocentric perspectival reference frames). Reducing coherence in signaling from these regions could have the effect of destabilizing egocentricity for selfhood on multiple levels, potentially contributing to the attenuation of more extended self-processes while preserving sufficiently coherent models of bodily states for maintaining some degree of conscious perception. Speculatively, such a partially dissociated state could allow for elevated absorption with respect to both imagination and perception, potentially achieved by forcing individuals to focus their perceptions and imaginings on "the now". The strength of rhythmic complexes of neural activity is suggested to reflect the strength of beliefs, some subset of which correspond to conscious subjective experiences. We further propose a model focusing on rhythmic complexes over posterior lobes as potential realizers of phenomenal consciousness, understood as the iterative estimation of likely sensory states, conditioned on a causal world model. Figuredescribes REBUS and SEBUS effects in the contexts of imagination (or dreaming) and perception. While imagination can involve either first-or third-person reference frames, only thirdperson perspectives are depicted to indicate their necessity for constructing objectified selfhood and reflexive meta-aware selfconsciousness (i.e. moving from an experiencing "I" to a Jamesian "me"). The second column in Fig.depicts what might be observed under smaller psychedelic doses with strictly REBUS effects (i.e. relaxed beliefs) with all beliefs being relaxed, depicted as less extensive alpha and beta complexes. The expected subjective effects from such modifications are depicted as including greater sensory details from perception, but with less perceptual vividness. Discrepancies between these predictions with actual subjective reports indicate that the REBUS model on its own may not be adequate for accounting for psychedelic experience. If all priors were relaxed for cortical generative models, then we would expect this to also apply to intermediate hierarchical levels at which perceptual synthesis and sensorimotor-grounded cognition may be realized). The third column in Fig.indicates what might be observed under smaller doses with strictly SEBUS effects (i.e. strengthened beliefs)-which could be the case for low-to-moderate levels of 5-HT2a agonism. This is subjectively depicted as including greater perceptual vividness, and details being more likely to match the expectations of potentially richer and more unusual imaginings, with the beginnings of psychedelic phenomenology in the form of fractal patterns and quasi-synesthetic percepts. Synesthetic phenomenology, however, does not appear to be well suited to disambiguate between models of psychedelic action, since such perceptual alterations could be explained either by SEBUS effects as strengthened cross-modal priors or in terms of REBUS effects where (nonstrengthened) priors are afforded greater cross-modal communicative capacity (when normal high-level beliefs are relaxed). The fourth column of Fig.indicates an admixture of REBUS and SEBUS effects (i.e. ALBUS), involving both strengthened beta and relaxed alpha synchrony, subjectively depicted as entailing both greater perceptual vividness and more intense psychedelic phenomenology, including the beginning of altered self-models. The fifth column indicates REBUS/SEBUS effects under extreme levels of 5-HT2a agonism, including the breakdown of organization of experience according to coherent self-models. Such highly altered states could be understood as a kind of "ego death" as Downloaded fromby guest on 15 February 2025 sometimes described by "psychonauts", and which is normally only reported by meditative adepts, with naturally occurring mystical experiences, or in individuals suffering from severe forms of psychosis (cf. disconnection hypothesis of schizophrenia). Our core claim is that mechanisms of predictive processing suggest that primarily SEBUS effects should be expected with lower levels of 5-HT2a agonism, and also that REBUS effects are unlikely to be observed in isolation without the concomitant strengthening of perceptual beliefs. We have considered situations in which one might observe both directly and indirectly strengthened and relaxed beliefs in different combinations as a potential explanation for different varieties of psychedelic alterations. We have further suggested that psychedelic states could be understood as being similar to waking dreams with varying degrees of lucidity. Tableprovides an overview of how the potential alterations of neural dynamics depicted in Fig.could explain different modes of waking and dreaming cognition, potentially (but not necessarily) involving endogenous psychedelic mechanisms. That is, we are suggesting that SEBUS-and REBUS-like effects could be useful for describing different states of consciousness, even without the administration of psychedelic compounds.
ALBUS highlights potential (both direct and indirect) alterations of hippocampal/entorhinal system (H/E-S) functioning as one of the primary explanatory mechanisms for understanding the effects of psychedelics. This emphasis is not arbitrary but is rather motivated by a growing consensus that H/E-S functions may be the key to understanding sophisticated cognitive processes such as episodic memory and imagination/planning, and even capacities for "mental time-travel" and autobiographical selfhood. It has been suggested that most (and perhaps all) highlevel cognition may be productively understood in terms of the problem of an autonomous system/agent/robot simultaneously attempting to locate itself and construct maps of environments within which it attempts to achieve (or forage for) valued goals. If this is indeed a profitable direction of travel for cognitive science and brain-inspired artificial intelligence, then it should no less apply to understanding psychedelic experiences. However, the complexity of the H/E-S is also daunting, with many details remaining unclear. To what extent do different psychedelic states involve alterations in the granularity with which space is organized according to hexagonal grids/tilings? To what extent do psychedelics alter the extent to which obstacles and goals distort these spaces, with what functional significances (e.g. Lilliputian phenomena from atypical modes of body mapping?)? While such unanswered questions suggest it may be premature to try to add further unknowns in investigating such complex phenomena, we propose that the opposite may be the case: by altering minds so profoundly, to what extent can psychedelics provide a "telescope for the mind" in providing edge cases and "exceptions that prove the rule" with respect to the normative functioning of core cognitive/affective systems? While this interpretation of hippocampal remapping is admittedly speculative, we believe it is also well supported by numerous computational models. With respect to psychedelics, we believe there may be an important interpretation of sharp-wave ripple events as indicating an attempt at (re)positioning organisms within the spatial reference frames used to situate themselves in environments within which they pursue valued goals. Some support for the centrality of the H/E-S for psychedelic cognition may be found in recent work in which reduced sharp-wave ripples correlated with reduced performance with respect to the ability of schizophrenic patients to coherently navigate through "semantic spaces". The models depicted in this section, if found to be accurate, would provide a powerful basis for understanding the effects of psychedelics on cognition. Some theoretical support for these models may be found by considering the H/E-S as a kind of energybased contrastive learner, with potential functional mappings onto machine learning architectures such as spectral graph nets). Theoretically, we may even find ourselves understanding these operations in terms of well-defined cognitive cycles with clear interpretations of different phenomena (e.g. interactions between hippocampal theta precession and more globally distributed synchronous dynamics across the brain). The details of the models presented here are necessarily preliminary, given our current state of understanding, but we believe they point to the potential and importance of trying to depict the unfolding of streams of experience with respect to their various aspects/qualities, as well as the ways these phenomena might vary both between and within individuals. Figuredescribes six different hypothetical regimes of cognition-organized with respect to levels of 5-HT2a-receptor stimulation-expected with various psychedelic interventions or similar endogenously generated states: "Unaltered," "Microdose," "Threshold dose," "Medium dose," "Heroic dose," and "Extreme dose." For each regime of cognition (with potential correspondences with different levels of 5-HT2a agonism and other psychedelic mechanisms), two episodes of ∼1-3 s in duration are shown as sequences of imaginative and perceptual states, with the second episode meant to indicate a stream of experience generated subsequent to termination of the first one. Depictions of the brain and associated experiences involve the model of phenomenal consciousness (and its alterations) from Fig.but are expanded to include orchestration by theta rhythms (yellow shading) from the H/E-S. Figuredepicts an inverted-U-shaped functionwith respect to the extent of the impact of increasing doses on the stability of cognition across time. This prediction is tentative in that there is at present little available evidence supporting nonlinear dose-response curves with respect to behavior or cognition. However, the potential for qualitatively different regimes may be suggested by enhanced attention with low (but not high) doses of lysergic acid diethylamide (LSD)) and impaired attention being observed with high-dose psilocybin). Some indirect speculative support for nonlinear dose-response effects could potentially also be found with respect to subjective time dilationa hallmark of flow states characterized by absorbed attention)-being most strongly observed for 10 μg (relative to 5 and 20 μg) doses of LSD. Further (admittedly both indirect and speculative) convergent support for qualitatively different effects may also be found in creativity enhancements being more reliably associated with lower doses of LSD. "Cognitive maps" in the hippocampus are depicted underneath each brain in Figureas embedded in hexagonal tiling of space, through which potential future trajectories through possible locations are indicated as green-shaded hexagons, with present-estimated trajectories indicated by red Table. Tentative mechanistic accounts of states of consciousness and their potential relations to SEBUS-and REBUS-like effects (without necessarily involving 5-HT2a receptors).. Anterior hippocampal maps show multiple routes through space, which are selected at each moment (darkest green) based on the expected value of choosing that route. Posterior maps, in contrast, show a single route through space, corresponding to the perceived path taken and encoded in memory, with the most intense red shading indicating estimates for the present moment of experience, and with this activity gradually fading across subsequent time steps. Notably, while these trajectories are most commonly understood with respect to navigation through physical space, it is increasingly suspected that this core system for localization and mapping was repurposed for the sake of high-level cognition as navigation through generalized space, including for conceptual spaces. Below these maps, within each theta cycle, two frames of experience are depicted as unfolding at alpha frequencies. While the generation of particular experiential frames may be influenced by counterfactual imagination and memory as orchestrated by the hippocampus, particular moments of experience could be a function of either imagination or perception depending on numerous factors (e.g. degree of driving inputs from the senses). The number of theta cycles in each row indicates tilings of (generalized) space along which trajectories may be planned and recorded in memory, which are shown as variable length sequences due to different levels of 5-HT2a agonism. These chunked sequences could be understood as Edelman's "remembered present" or James' "specious present," wherein "the now" has inherent temporal thickness as past moments both contextualize and are recontextualized by future moments of experience.
Two sequences (Episodes 1 and 2) are depicted for each level of dosing, where different cognitive regimes involve varying degrees of coherence (and potentially conscious access/remembering) maintained across time when separated by hippocampal resetting/remapping events. The precise extent of these trajectories through mental spaces may be influenced by "circuit-level" functional properties such as degrees of neuromodulation (Ul, with both 5-HT1a and 5-HT2a receptor agonism being capable of inhibiting the sharp-wave ripple events indicative of hippocampally mediated memory consolidation and activation of distributed cortical ensembles. Tentatively, inspired by models from machine learning, we suggest these suppressed ripples might also be accompanied by suppressed remapping of physical and conceptual spaces, which when refreshed, may afford different modes of sense-making with alternative sets of potential actions. Additionally, hippocampal remapping could potentially occur via surpassing thresholds for cumulative prediction error, such as might be expected as uncertainty builds with respect to the ability of a given set of behavioral policies to be effectively realized through enaction (and where this uncertainty would be likely to increase under highly altered conditions). 5-HT2a agonism may impact the extent of these predictive and remembered "task" sets both by inhibiting hippocampal resetting mechanisms directly, as well as by altering the coherence of streams of experience, so influencing degrees of overall accompanying prediction error, so influencing the likelihood of error-driven remapping. If the models described in Fig.were found to be usefully accurate depictions of the unfolding of the stream of consciousness and associated cognitive processes, then ALBUS may represent the first unified paradigm for understanding psychedelic phenomena and varieties of conscious experiences more generally. That is, while this may seem like an excessively bold claim, we believe the progression of regimes described in Fig.could potentially not only apply to different levels of 5-HT2a agonism, but could also be used to model various clinical conditions (cf. the "psychotomimetic paradigm"), the progression from sleeping to waking and back again, degrees of lucidity within dreams, or other progressions such as cognitive development and decline (e.g. Lewy body dementia and "terminal lucidity").
The ALBUS framework is intended to provide a common basis for integrating models and associated findings from other paradigms, whether emphasizing relaxed beliefs, opening attentional and perceptual thalamic filters, or altering cortical processing by disrupted coupling with integrative structures such as the claustrum. Apart from REBUS, other accounts of psychedelic action have tended to remain uncommitted in describing effects on the levels of computational functions and their potential algorithmic realizations. ALBUS suggests that Bayesian cognitive science and machine learning could provide a kind of "lingua franca" for shared (and potentially synergistic) sense-making across different theories. Our goal is not a definitive exhaustive account of psychedelic and related experiences, but to facilitate productive conversations across perspectives that have nonoverlapping strengths and weaknesses (and thereby potential for inferential synergy). Below we will consider some additional complexities and hypotheses before concluding with open questions and directions for future work.
REBUS emphasizes L5 pyramidal neurons, suggesting that increased excitability from 5-HT2a agonism results in asynchronous activation modes, and thereby relaxed beliefs through attenuated coherence. This suggestion provides a potentially sufficient account for reduced alpha power and ego dissolution associated with psychedelic states. In a similar spirit to this paradoxical reduction in coherent signaling via excessive excitation, the inhibitory-interneuron mechanism described earlier as a source of SEBUS effects may be challenged. That is, increasing the excitability of superficial interneurons may not necessarily inhibit ascending prediction errors in those layers, but could potentially have the opposite result via indirect disinhibitory dynamics. Detailed neurophysiological investigations with lower levels of 5-HT2a agonism will be helpful for gaining clarity on these issues. Perceptual illusions could be illustrative in terms of distinguishing between REBUS and SEBUS effects. Susceptibility to these misleading percepts is well explained by HPP in terms of perception understood as probabilistic inference. If our perception corresponds to our best guess for causes of sensory observations, given past experience, then these guesses can sometimes be mistaken. That is, minds are capable of being tricked in such ways because perception is structured according to prior expectations from (interpretations of) past sensory experiences. According to a purely REBUS-involving model, relaxation of these priors should raise illusion-susceptibility thresholds, so making us more resistant to going down these perceptual garden paths. According to a SEBUS model, however, the thresholds for illusory perception may be lowered, so making us even more likely to misperceive. Based on the mechanistic considerations described earlier, we suggest SEBUS effects are likely to predominate with low-to-moderate levels of 5-HT2a agonism (Figsand), and with some combination of SEBUS and REBUS effects at higher levels of stimulation for those pathways. Thus, we might expect either increased or decreased illusion susceptibility with, respectively, lower or higher doses of psychedelics. REBUS emphasizes the high concentrations of 5-HT2a receptors for deeper portions of generative models, suggesting that intermediate hierarchical levels associated with conscious perception could become strengthened as they are released from predictive suppression from hierarchically higher areas. This would be an example in which SEBUS phenomena are generated as an indirect consequence of REBUS effects. The inclusion of such looping causal cascades may make it difficult to establish whether SEBUS effects can occur independently of being driven by 5-HT2a stimulation that results in REBUS effects. Observing increased susceptibility for illusions involving low-level perceptual features with lower psychedelic doses could potentially provide evidence for the independent functional significances of SEBUS mechanisms. Such beliefs may be less likely to be influenced by highlevel expectations, and it is also unclear that we should expect excitation-induced desynchronization described by REBUS with low-to-moderate levels of 5-HT2a agonism. Yet another example of a complex relationship between strengthened and weakened beliefs was proposed by, where predictions form so readily that they are less likely to adequately explain incoming sense data, thereby generating increased prediction errors, and so result in more uncertain-or entropic)-belief landscapes. Under such a state of elevated uncertainty, hallucinations and other psychedelic phenomena are suggested to result as anomalous predictions attempt to explain incoming sense data, potentially involving a compensatory upregulation of high-level priors. In this view, SEBUS effects produce a greater diversity of less well-fitted beliefs-as opposed to larger joint beliefs-which indirectly produce REBUS effects via conflicting predictions at hierarchically higher levels. SEBUS effects (e.g. hallucinations) may also arise indirectly if relaxed beliefs at upper levels of cortical hierarchies reduce suppression of prediction errors at lower and intermediate levels of organization, so resulting in net disinhibition (Figsand). In this view, SEBUS effects would be the indirect result of REBUS effects. Causal complexity could become even greater if we consider various forms of conscious and self-referential processing. For example, low-to-moderate doses of 5-HT2a agonism could generate strictly SEBUS effects at the level of cortical microcircuitry (Fig.), yet produce multiple kinds of REBUS effects in overall belief dynamics such as the following: (i) Qualitative differences in processing resulting in individuals approaching experience atypically, so "relaxing" typical assumptions. (ii) Expectations of particular modes of cognition that deviate from typical priors causing such experiences to become more likely (cf. placebo and nocebo effects). (iii) Explicit expectation of REBUS-like effects producing patterns of cognition characterized by enhanced open-mindedness and creativity. In these ways, while we believe the account of predictive processing described by REBUS may require additional details to account for the full range of psychedelic phenomena, we want to emphasize that we are not suggesting this theory should be abandoned in favor of SEBUS models. Rather, we suggest the way forward will involve combining both SEBUS and REBUS phenomena (including their potential inter-relations), as well as additional neural process theories, into a broader framework that considers the diversity of ALBUS.
SEBUS effects may help account for observations of "psychotomimetic" properties for psychedelic phenomenology, for which overly strong priors represent a face-valid model of multiple aspects of schizophrenia (e.g. hallucinations and delusions)). Yet, REBUS effects may provide a more useful account of psychosis involving disruption of deep beliefs, including with respect to the integrative properties of self-related processing. Carhart-Harris et al. () note the similarities between their suggested mechanisms for psychedelic states and the excessive prediction errors that may represent a partial diathesis for autism. However, they go on to argue against this connection based on differences between dynamics unfolding on state and trait levels. While considerations of time scales over which relevant psychological phenomena evolve are surely important, it is nonetheless notable that there are clear dissimilarities between psychedelic and autistic phenomenology, as well as similarities between psychedelic and psychotic states. SEBUS-like processes may be required to reconcile differences between the altered states suggested by strictly REBUS-based models and particular traits of autism. It has been suggested that autism spectrum disorders may reflect one pole of a cognitive spectrum with schizophrenia on the opposing end. In this domain and others (Table), SEBUS/REBUS mechanisms may be important in suggesting which interventions might be most helpful in which circumstances. For example, by attenuating sensory prediction errors and increasing the ability to form high-level inferences-potentially including the kinds underlying different aspects of social cognition)-low-to-moderate doses of 5-HT2a agonists could potentially provide a valuable treatment for autism. Furthermore, a purely REBUS-based model might (perhaps questionably) suggest 5-HT2a agonists as beneficial in some cases of psychosis by attenuating overly strong beliefs). Yet a SEBUS-involving model, in contrast, would suggest that classic psychedelics may be strongly contraindicated for anyone at risk for psychosis-with potential exceptions from specific targeted interventions-and would further point to potential benefits from 5-HT2a antagonism for treating psychotic states. Please note: our hypotheses concerning the clinical implications of ALBUS are not meant to constitute a definitive statement of recommendations, with research being needed to inform interventions. As described earlier, the study of visual illusions with varying susceptibility thresholds could potentially provide valuable data on these matters. While resistance to visual illusions has been discussed with both psychedelics) and schizophrenia, this association might be more reliable Downloaded fromby guest on 15 February 2025 with respect to autism. Hypothetically, we might expect schizophrenia to be particularly strongly associated with resistance to illusions at early-or mid-stages if it is of a variety that has overlapping diatheses with autism), or at late stages where breakdown of global integration may be observed (e.g. via NMDA-receptor auto-immunity). However, we might also potentially expect prodromal individuals and relatives of schizophrenic patients to show the opposite pattern of heightened illusion susceptibility, potentially consistent with findings regarding predisposing factors for pareidolia and apophenia. To the extent that such inter-and intra-individual differences in predictive processing and cognitive spectrums apply, the kinds of models described in Figs 3 and 4 could provide valuable means of characterizing these sources of human variation. Thus, we might be able to adjudicate between mechanistic models based on SEBUS or REBUS effects, as well as their combinations (ALBUS) by assessing the extent to which visual illusion thresholds are raised or lowered with 5-HT2a agonists, with potentially notable differences across various kinds of minds.
Altered beliefs under classic psychedelics could result in overcoming barriers to breaking typical frames and engaging in nontraditional divergent thinking, so allowing novel streams of imagination to be considered. This kind of "out of the box" (or frame) creative thinking can be thought of as driving minds into otherwise uncharted territories of hypothesis spaces. In looking for systems potentially required for enabling robust patterns of counterfactual processing, the default mode network (DMN) may provide this kind of dynamo for creativity and imagination. By constituting a source of strong internally coherent predictions, the DMN may be capable of temporarily absorbing and then releasing free energy via the shaping of perception and driving of action, perhaps especially when coupled to salience networks). However, while the DMN is likely essential for constructing things (or processes) like autobiographical selfhood, its effective connectivity with the salience network and neuromodulatory nuclei of the brainstem is likely essential for understanding how dynamics may be orchestrated according to estimates of value based on past experiences. The connectomic properties of the DMN suggest this core network is ideally suited to serve these functions (in collaboration with other intrinsic functional networks) by virtue of having high centrality, and so high potential for integrating information and exerting control). The DMN is further located distally from primary modalities and is thereby capable of supporting dynamics more decoupled from immediate sensorimotor engagements. Furthermore, the DMN is likely to support some of the most stable inferences available to embodied embedded persons, with major nodes contributing to egocentric perspective, integrated memory, and even the foundations of selfhood and intersubjective modeling. While the precise roles of the DMN may be debated, this kind of trading-off of prediction error across neural systems may be involved in not only the unusual imaginings associated with creativity, but also agentic control, which necessarily involves prediction error generation due to the counterfactual status of yet-to-be-achieved goals. In this way, every intentional action is inherently creative in bringing desired states into being through holding onto prior expectations as a kind of sustained imagination. This is a clear case in which SEBUS effects are relevant and would recast the functional significance of (low-to-moderate) levels of 5-HT2a signaling as crucially involving strengthened beliefs for imaginative planning and goal-oriented cognition more generally. Perhaps this relates to the reported efficacy of the older model of "psycholytic therapy" in which talk therapy during experiences prompted by moderate psychedelic doses (in contrast to higher doses in "psychedelic therapy" in which there is minimal therapeutic interaction during the experience itself) is leveraged toward therapeutic change. The strengthening of DMN-mediated counterfactual imaginings with psychedelics is consistent with recent work involving LSD, in which dynamic causal modeling established increased effective connectivity from posterior portions of the DMN to associated thalamic nuclei. While recent work has identified additional complexities using similar methods, these sorts of findings provide intriguing support for a SEBUS-involving account of enhanced creative capacity (and potentially agency) via more vivid imaginings. In these ways, both SEBUS and REBUS effects may be observed in various ways at different levels of organization, including intermediate levels of hierarchical abstraction for which conscious experience may be realized as a stream of sensorimotor predictions. However, even if SEBUS effects may be required for explaining some aspects of psychedelic phenomenology, REBUS-informed models may be essential for capturing other aspects of personal experience and clinically relevant outcomes (Tables), such as the increased open-mindedness associated with psychedelic-use. In this way, an adequate account of the ways in which psychedelics alter brain and mind likely needs to be expanded into an ALBUS framework capable of integrating across both SEBUS and REBUS phenomena.
While SEBUS and REBUS effects may converge with moderateto-high levels of 5-HT2a agonism, we might expect qualitatively different effects with low-to-moderate doses. Under regimes characteristic of microdosing or threshold experiences (Figsand), consciousness may be elevated without substantially altering typical belief dynamics. In these ways, microdosing may provide a promising and overlooked therapeutic intervention for depression (e.g. anhedonia), autism, Alzheimer's disease, and disorders of consciousness. In contrast to a purely REBUS-focused model, a SEBUS-involving ALBUS perspective makes different predictions for the potential utility of various psychedelic interventions for these debilitating conditions, for which advances in treatment could have impacts on public health that may be difficult to overstate. We suggest the following lines of inquiry are likely to be informative for testing ALBUS: (i) Do lower and higher levels of 5-HT2a agonism have different effects on the extent to which particular priorsand at which levels of organization under which circumstances?-are either strengthened or relaxed in HPP? (ii) To what extent (and under which circumstances) could agonizing L2/3 inhibitory interneurons result in reduced gain on observations (cf. sensory deprivation), so contributing to more intense and/or less constrained imaginings? (iii) Can high-field strength fMRI (or multiple imaging modalities with complementary resolution in spatial and temporal domains) of psychedelic experiences allow for testing hypotheses regarding the relative strength of predictions and prediction errors from respective superficial or deep cortical layers)? (iv) With respect to such models, could sufficiently reliable estimates of individual-level data be obtained for alignment with subjective reports, so helping to realize some of the hopes of "neurophenomenology")? (v) Perhaps the most straightforward approach to investigating when we might expect SEBUS/REBUS phenomena would be the systematic study of perceptual illusions whose susceptibility thresholds have been titrated such that the relative strength of priors can be ascertained. This work could be conducted with a wide range of illusory percepts at multiple hierarchical levels in different modalities, in multiple combinations. Such work can include not only perception but also cognitive tasks such as thresholds of categorization. While this would be a nontrivial research program, it may also be one of the most effective ways of characterizing underlying mechanisms and would also have the advantage of helping us to be more precise in specifying which particular beliefs are suggested to be either strengthened or weakened in which contexts. Finally, in Tablesandwe provide a list of potential ways in which an emphasis on SEBUS and/or REBUS effects may suggest different use cases for psychedelics and explanations for commonly reported psychedelic phenomena. While these speculations are tentatively suggested, we believe they help to illustrate what might be at stake in obtaining more detailed models of psychedelic action, and also point to additional testable hypotheses. Given the immense potential of these powerful compounds for both clinical and basic science, we believe substantial further work and funding is warranted to explore the conditions under which we might expect relaxed, strengthened, and more generally altered beliefs under psychedelics and other varieties of conscious experiences.
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Papers in Blossom that reference this study
Stoliker, D., Preller, K. H., Novelli, L. et al. · Molecular Psychiatry (2024)
Sadibolova, R., Murray-Lawson, C., Family, N. et al. · Biorxiv (2023)
Aqil, M., Roseman, L. · Neuropharmacology (2022)
Stoliker, D., Egan, G. F., Friston, K. J. et al. · Pharmacological Reviews (2022)
Hipólito, I., Mago, J., Rosas, F. E. et al. · Psyarxiv (2022)
Stoliker, D., Novelli, L., Vollenweider, F. X. et al. · MedRvix (2021)