Neural Mechanisms and Psychology of Psychedelic Ego Dissolution

This review (2022) investigates the neural mechanisms, 5HT2A receptor agonism at the top of the cortical hierarchy, that lead to ego dissolution and long-term neural plasticity. This study uses the hierarchical predictive coding framework to understand the neural mechanisms of consciousness (and psychedelics to test the model).

Abstract

“Neuroimaging studies of psychedelics have advanced our understanding of hierarchical brain organisation and the mechanisms underlying their subjective and therapeutic effects. The primary mechanism of action of classic psychedelics is binding to serotonergic 5HT2A receptors. Agonist activity at these receptors leads to neuromodulatory changes in synaptic efficacy that can have a profound effect on hierarchical message passing in the brain. Here, we review the cognitive and neuroimaging evidence for the effects of psychedelics; in particular, their influence on selfhood and subject-object boundaries—known as ego dissolution—surmised to underwrite their subjective and therapeutic effects. Agonist of 5HT2A receptors, located at the apex of the cortical hierarchy may have a particularly powerful effect on sentience and consciousness. These effects can endure well after the pharmacological half life, suggesting that psychedelics may have long-term effects on neural plasticity – that may play a role in their therapeutic efficacy. Psychologically, this may be accompanied by a surrender of ego resistance that increases the repertoire of perceptual hypotheses, including those that undergird selfhood. We consider the interaction between serotonergic neuromodulation and sentience through the lens of hierarchical predictive coding, which speaks to the value of psychedelics in understanding how we make sense of the world—and specific predictions about effective connectivity in cortical hierarchies that can be tested using functional neuroimaging.“

Authors: Devon Stoliker, Gary F. Egan, Karl J. Friston & Adeel Razi

Summary

ASSOCIATE EDITOR: ERIC BARKER

The significance statement is the first paragraph of the introduction. Advances in neuroscience have led to an increased understanding of the brain’s role in subjective experience, and the use of psychedelics to induce ego dissolution. Measures of subjective effects of psychedelics are discussed, as well as therapeutic outcomes. Ego resistance is an important factor in self-development. The authors describe the psychedelic effects of cannabis and other psychoactive drugs, and discuss the possible uses of these drugs in the medical field. K. Free Energy Principle and 5-HT2A Receptor Agonist Activity, L. Psychedelics Amplify Set and Setting, M. Brain Connectivity, N. Subcortical Connectivity is filtered by the thalamus, and the thalamus is responsible for the processing of sensory information in the brain. Midbrain Connectivity is important for proper brain function. The medial temporal lobe contains the amygdala, the parahippocampus, and the hippocampus, which are all important for memory and emotion. The retrosplenial cortex is composed of several parts, including the subcortical area and the insula. Connectivity within large-scale resting-state networks and prior beliefs are discussed. The Default Mode Network is also discussed in relation to mental health. The posterior cingulate cortex is connected to the medial prefrontal cortex. SalienceNetwork and Frontoparietal Control Network are two large-scale resting-state networks that are connected with each other. The self in networks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Methodological considerations are given for calculating the coordinated balance between anticorrelated networks.

I. Introduction

Psychedelics are drugs with origins in certain plants, animals, and fungi. They were first used in ancient cultural rituals to achieve altered states of consciousness and spiritual insight, and were later introduced into mainstream Western culture. The counterculture of the 1960s led to restrictions on psychedelic research by regulatory institutions, but interest in the neurobiological basis of psychosis continued, leading to studies in healthy adults before the turn of the millennium.

Psychedelic research was resumed in the United States in the new millennium, and has since produced clinically significant reductions in depression and anxiety where alternative treatments failed.

A. Advances in Neuroscience

Over the period of restricted psychedelic research, neuroscience advanced considerably. PET and fMRI were developed, and functional integration was proposed as a way to integrate distributed neuronal responses among functionally segregated regions.

Research shows that the metabolic consumption of the brain at rest requires 20% of the body’s energy, and that brain consumption during tasks increases this value a mere 5%. This led to the identification of multiple resting-state brain networks.

The reintroduction of psychedelics to scientific research offers new opportunities to use brain imaging to better understand the neural correlates of sentience and consciousness.

C. Subjective Effects of Psychedelics

Classic psychedelics are perception-altering drugs classified as entheogens, which induce effects related to empathy, such as emotional warmth and connectedness.

Classic psychedelics exist in natural sources and chemically synthesized forms. They are divided into three main chemical classes: indoleamines, phenylalkylamines, and semisynthetic ergolines. Psilocybin, the prodrug of psilocin, occurs naturally in magic mushrooms and has a long history of use in medicinal and religious cultural contexts. LSD, a semisynthetic psychedelic compound, has been of primary interest in modern psychedelic culture and research, though much recent attention has shifted to psilocybin. Psychedelic experiences have been characterized as mystical-type experiences and peak experiences, but no characterization subsumes and epitomizes the psychedelic experience more precisely than ego dissolution.

D. Ego Dissolution

Our theoretical treatment of ego dissolution reflects gestalt psychology, which views consciousness as an emergent whole.

Despite its high level of abstraction, ego dissolution has been suggested as a valid, measurable construct, and is tied to therapeutic outcomes.

Ego dissolution overlaps with other descriptions of psychedelic experience, such as mystical-type experiences or peak experiences, and remains somewhat confounded with other facets of the psychedelic experience. The onset of ego dissolution is thought to be a binary state, an all-or-nothing phenomenon, and is influenced by external stimuli, particularly music. The ensuing insights can result in lasting therapeutic effects and transformation of self-related beliefs.

E. Measures of Subjective Effects of Psychedelics

Acute subjective effects of psychedelics have been measured using the hallucinogen rating scale, the mystical experiences questionnaire, and the abnormal mental states questionnaire. The 5 dimensions of altered states of consciousness scale includes three primary dimensions: oceanic boundlessness, dread of ego dissolution, and visionary restructuralization. The ego dissolution inventory (EDI) is a more recent inventory that validates ego dissolution as an independent construct. It is perhaps the best characterization of the primary subjective effect of psychedelic drugs.

F. Psychedelic Subjective Experience and Therapeutic Outcomes

Interest in psychedelics has been renewed in part due to their tolerability, safety, and the provision of guidelines for safe administration. Some patients have shown significant improvement from as little as one or just a few psychedelic sessions.

Psychedelics produce a transformative experience that differs from traditional pharmacotherapy. This experience is integral to transformative therapeutic change, and it is reflected in the dependence of lasting therapeutic outcomes upon the spiritual or personally meaningful quality of ego dissolution, here read as mystical experiences.

G. Ego Resistance

The free energy principle (FEP) is a theory that explains the tendency of living organisms to minimize surprise. Psychedelics may dissolve recalcitrant beliefs by removing a hurdle and relaxing psychologic resistance.

Psychologic resistance may be fundamental to mental well-being and may be considered as the departure of the ego from the solved state, which manifests self-beliefs that provide a form of emotional catharsis in lieu of more authentic solutions.

If the beliefs are maladaptive, the experiences may lead to further experiences of resistance, producing incongruence, or dissonance, between the innate desire for positive emotional self-worth and the experiences.

Maladaptive beliefs fail to reduce experiences of resistance, and instead perpetuate dissonance, leading to the development of rigid, ingrained patterns of thinking. In more extreme cases, these unhelpful beliefs may develop into symptoms of psychopathological disorders.

Resistance to experience, including psychedelic ego dissolution, leads to dissonance and maladaptive beliefs. Psychedelics target this psychologic ego resistance and introduce a permissive flexibility in cognition that dissolves rigid patterns of thinking. From the perspective of FEP, psychedelics dissolve precise belief states. The optimal state of mind for psychedelic experiences is a state of openness, acceptance, and surrender, which is commensurate with the relaxation of precise beliefs and ego defenses.

H. Psychedelics and Meditation

Psychedelics and meditation share similar processes of dissolving the self and attaining insight, and both demonstrate the capacity to inspire insights leading to personal growth and improved well-being. Similarly, psychedelics may enhance meditation and spiritual practice. The phenomenological richness of the psychedelic experience is a prominent difference between psychedelics and meditation, and the effectiveness of meditation through nonjudgement and nonresistance may reflect an innate self-corrective tendencyofthemind towardthereductionofresistance to engender well-being.

I. Outline of the Review

Psychedelic studies using noninvasive brain imaging are surveyed with a special emphasis on how modeling and estimating brain connectivity may shed light on the neural mechanisms that underlie the psychedelic experience.

Psychedelics affect neurotransmitter receptors in the brain, and this affects the function of the thalamus, which filters information exchanged with the cortex. The medial temporal lobe is also involved in memory and emotion, and may share an association with ego dissolution and the therapeutic engagement of emotion. Resting-state brain connectivity across distinct networks is considered, and psychedelic effects may deconstruct belief constructs that play a role in our sense of identity and identification with the world.

J. Pharmacology, Plasticity, and Context

Psychedelics are characterized by agonist activity at the serotonin 5-hydroxytryptamine (2A) receptor, which is one of the earliest evolved neurotransmitter systems and innervates a diversity of receptors. The 5-HT2A receptor is expressed throughout the cortex and may mediate higher cognitive and integrative functions.

The 5-HT2A receptor is located on the apical dendrites of layer 5 pyramidal neurons, which are the primary output from cortical regions projecting to distal cortical and subcortical regions. It is also found on thalamocortical afferents projecting to the neocortex. Psychedelics only depolarize a small percentage of deep cortical cells; the majority do not. Only a small percentage of excitatory neurons express 5-HT2A receptors. LSD stimulates 5-HT2A receptors in GABAergic interneurons and 5-HT1A receptors in prefrontal pyramidal cells, which inhibit and disinhibit prefrontal pyramidal cell activity and show downstream effects on dopaminergic and glutamatergic systems.

Agonist Activity

Altered serotonin transmission has been linked to neuronal responses to unexpected or surprising events. The FEP provides a framework to understand responses to surprise – and the influence of psychedelics.

The minimization of free energy is understood in terms of minimizing prediction error, and psychedelics are thought to alter the sensitivity to prediction errors at various hierarchical levels in the cortical hierarchy by rebalancing the influence of sensory evidence and prior beliefs during belief updating.

Psychedelics increase neuronal entropy via modulation of 5-HT2AR neurotransmission, and this increased entropy is topographically organized, exhibiting increases in some brain regions and decreases in others under psychedelics. This increased plasticity is thought to be a key mechanism used to explain the therapeutic effects of psychedelics.

Under the FEP, psychopathology is usually interpreted in terms of false inference, and 5-HT2AR modulation under psychedelics is thought to relax overly precise prior precision and enable the revision of maladaptive priors through experience-dependent learning.

Psychedelics may target the substrate of high-order (Bayesian) beliefs, which is supported by the FEP. This account also explains the context sensitivity that individuals exhibit under psychedelics.

L. Psychedelics Amplify Set and Setting

Psychedelics can amplify exogenous influences of the setting and endogenous influences of attentional set, which can manifest opposing (emotional) responses. Under supportive environmental conditions, subjects typically respond well to even high psychedelic doses, but challenging experiences should be anticipated.

Unregulated use of psychedelics remains potentially hazardous. Users generally prepare both mindset and environmental settings before the dose intake.

Set and setting are crucial factors when explaining negative psychotomimetic and positive therapeutic reactions to psychedelics. Studies suggest that meditation training may reduce challenging experiences in the state of uncertainty accompanying ego dissolution and may offer a promising mode of preparation for therapeutic applications.

Despite modern screening practices, reports of adverse reactions to meditation exist. Psychedelics reduce vigilance and create impairment in memory tasks while paradoxically enhancing the vividness and recollection of autobiographical memories.

The mindset and setting at the outset of psychedelic experiences may predispose a subject to spiritual bypassing. Psychosocial preparation and integration programs that focus on the meaning and utility of the experience to personal development may be required.

Overinterpretation may be proportional to the clinical populations for whom psychedelics are recommended, and may also be increased when no therapeutic intent is determined prior to psychedelic use.

Evidence of contextual influences under psychedelics offers another research opportunity to explore neural plasticity and cognitive flexibility relating to 5-HT2AR agonist activity.

M. Brain Connectivity

Psychedelics may affect brain regions involved in associative functions related to sentience and perception, and may alter cortico-subcortical networks and limbic structures, which may account for aspects of the psychedelic subjective experience.

Dynamic causal modeling for resting-state fMRI showed that the thalamus is more connected to the posterior cingulate cortex under LSD and that this is consistent with a relaxation of prior precision in high levels of cortical hierarchies.

The medial temporal lobe (MTL) is connected to several cortical regions, including the anterior cingulate cortex (ACC), medial prefrontal cortex (mPFC), and parahippocampus (PHC). It is thought to play a role in memory and emotion, which may relate to the therapeutic effects of psychedelics.

The amygdala is involved in perception, emotion processing, and identifying emotionally salient stimuli. It comprises substructures with distinct functions and connectivity to various brain regions.

Whole AMG analyses indicate that top-down connectivity between the ventral ACC and AMG may play a role in mediating visual salience. This emotional processing circuitry may be sensitive to the effects of psychedelics.

AMG activation does not determine the emotional valence of subjective experiences, but rather the emotional salience of the experience. Psilocybin treatment may increase AMG activation, which may be associated with positive mood change.

The AMG is thought to have contradictory associations with behavioral outcomes. It appears to deactivate under acute psychedelic effects in response to negative emotional stimuli in supportive conditions, but increases in activation following clearance of the drug.

Understanding top-down connectivity may help disambiguate the changes in AMG relating to psychologic function and therapeutic outcomes. The visual-limbic-prefrontal network is involved in detecting visual threat cues, and psychedelics disrupt top-down connectivity.

Researchers found that individuals with borderline personality disorder showed hyper-AMG activation to emotional face tasks, suggesting that top-down connectivity between the prefrontal cortex and the AMG may be an important mechanism underlying previously reported therapeutic outcomes of emotional reconnection.

AMG and affect responses to negative faces were measured up to 1 month postpsilocybin in healthy participants. These results indicate that psychedelics can have enduring effects on neuroplasticity, lasting well beyond the half-life of psilocybin.

EEG recordings under psilocybin show decreased PHC oscillations, which are also observed in coherence between the ACC and PCC. These findings suggest that changes to cortical FC and the PHC contribute to the psychedelic experience.

The retrosplenial cortex supports self-location, navigation, visualization, autobiographical memory, future-oriented thinking, retrieval of memory, and self-orientation.

The rostral prefrontal cortex is involved in spatial orientation and representation of permanence, which may be affected by ego dissolution. Desynchronization of d-band oscillations was seen under psilocybin, which may facilitate insight-enhanced reprocessing of autobiographical memories.

The evidence relating hierarchical connectivity changes between subcortical limbic regions and the cortex under psychedelics is consistent across studies and may relate to ego dissolution and therapeutic effects. The role of the thalamus in ego dissolution and the cognitive aspects of psychedelic experiences is uncertain. Psychedelics may affect associative processes in the PHC, which may mediate therapeutic effects through routing of neuronal signals between limbic structures and the cortex.

Under psychedelics, subcortical areas are connected with higher cortical areas, which influences bottom-up projections from cortical regions.

The default mode network is a brain network that shows increased endogenous fluctuations when an individual is awake but not engaged in a task requiring attention. It is believed to emerge over the course of human evolution.

The free energy principle and associated Bayesian brain hypotheses rest on the notion that the brain embodies a hierarchical generative model of how sensations are generated, and that the DMN is situated at the top of the cortical hierarchy and may control bottom-up (prediction error) signals from lower levels of the hierarchy.

The Default Mode Network (DMN) is a system that regulates behavior by suppressing the free energy of subordinate structures, such as the limbic and paralimbic systems, and by directing attention inward, which manifests as self-oriented thoughts.

The DMN is rich in 5-HT2AR and may be involved in ego dissolution, which may involve the dissolution of self-related priors, which may in turn lead to a decrease in DMN connectivity and a corresponding increase in DMN receptivity to bottom-up influences.

Psychedelics may reduce ego resistance and play a permissive and foundational role in the updating of priors, which may help disarm maladaptive ego defenses and facilitate cognitive-emotional engagement, emotional reconnection, and a sense of being attuned with one’s emotions.

The importance of DMN connectivity in mental well-being is evidenced in psychopathology research, and decreases in DMN functional connectivity is related to reduced references to the past by subjects post-LSD in task-based studies, suggesting that psychedelics may relate to rumination.

Defense mechanisms may have evolved to mitigate psychosocial hazards and minimize surprise. However, these mechanisms also mark instability and suggest the difficulty of the ego to effectively estimate the value of immediate relative to temporally delayed action or gratification.

The Posterior Cingulate Cortex (PCC) is a cardinal structure associated with the self, and it absorbs around 20% more metabolic energy than most other brain regions. It is also a hub that routes and regulates neuronal message-passing throughout the brain.

The PCC is important in the preservation of ego, as demonstrated by decreased cerebral blood flow in the PCC and decreased a power in the PCC in association with ego dissolution induced by psilocybin.

The ventral PCC is thought to orient attention toward the self, whereas the dorsal PCC is involved in the dynamic coordination of attentional focus between internal and external thoughts.

The medial prefrontal cortex (mPFC) is implicated in executive cognitive functions, including memory and decision making, and integrates bottom-up internal and external information. It is also involved in emotional processing, as demonstrated by reduced reactivity of right mPFC and left AMG functional connectivity in response to fearful faces.

Research has identified reduced mPFC and PCC connectivity in meditators following training compared with control subjects, which suggests a potential synergy between psychedelic experiences and meditation practice.

Using psilocybin during a 5-day mindfulness retreat led to reduced mPFC-PCC connectivity that correlated with ego dissolution, and lasting therapeutic outcomes. Moreover, meditators in the psilocybin group were able to better modulate experiences of self-transcendence through their meditation.

A fMRI study found decreased connectivity between the PCC and mPFC in psilocybin users, but this was not supported by an effective connectivity analysis of the directed influence. Instead, the mPFC and PCC showed reduced self-connectivity, which may indicate self-related attention, contextual judgement, emotional regulation, and suppression of bottom-up signals.

The salience network is composed of the dorsal anterior cingulate cortex (dACC) and anterior insula, and it serves important roles in sentience and conscious awareness, including detecting and evaluating salient events, monitoring the environmental features relevant to goal-directed thinking, and coordinating attention between internal and external stimuli.

The anterior cingulate cortex (ACC) is a cortical midline hub region of the supplementary nucleus (SN) involved in cognitive control and is frequently highlighted in connection with psychedelic-induced altered states. It is also situated between emotional and cognitive domains, suggesting that it may bridge and mediate emotional responses.

The ACC is implicated in emotional responses, and the rostral ACC (rACC) subarea of the ACC is related to emotional expression and subjective scores on emotional subcategories of the 5D-ASC. The ACC also mediates the interaction between cognition and emotion that contributes to psychedelic afterglow effects and enhanced mindfulness capacities.

Despite its large size and differing functions, the ACC is not always reported in psychedelic literature. This may contribute to conflicting findings, such as increased ACC and MTL activity under psilocybin, or increased synchronization and entropy between the ACC and hippocampus under psilocybin.

The structural size of the ACC has been related to psychedelics, and this structural variation across volunteers may predict feelings of unity, bliss, spiritual experience, and insightfulness. Long-term ayahuasca users show structural increases of the ACC and reduced cortical thickness in the PCC.

The ACC and PCC structural differences align with evidence of the reliance of mindfulness capacity on SN control over the DMN, and SN control over the DMN is cited as a crucial component in cognitive health and performance.

The frontoparietal control network is an attention control network that encompasses the dorsolateral and anterior prefrontal cortices, inferior parietal lobes, AI, and ACC, and is associated with cognitive control and decision making, as well as access to conscious information.

Under psychedelics, the FPCN experiences decreased connectivity within the network and increased connectivity between networks, a pattern known as disintegration and desegregation. This pattern is mediated by neural gain modulation and speaks to the importance of connectivity in psychedelic experiences.

Psychedelic brain dynamics preserve new, complex forms of coherence and stability, including higher spatial and temporal variability.

Psychedelics alter brain connectivity across resting-state networks, which may influence consciousness and therapeutic outcomes. These changes may be related to the disintegration of the FPCN and relaxation of priors, which are thought to contribute to the cognitive aspects of ego dissolution.

Cortical oscillatory changes may be related to psychedelic experiences and therapeutic introspection, and decreased b-band activity in the FPCN may be a measure related to change and revision of the association between behavior and stimuli. However, FPCN connectivity changes are not always reported under psychedelics.

The Self in Networks is related to the minimal aspects of conscious self-awareness, such as physical boundaries, proprioception, interoception, and the experience of oneself being rooted in (sensory) motor processes. The Self in Networks is also related to ego dissolution.

DMN-SN connectivity is important in clinical and theoretical models of various mood disorders, and its change under LSD is associated with positive mood and arousal. However, its relationship to ego dissolution suggests that psychedelic influence on these networks may contribute to ego dissolution.

The coordinated balance between anticorrelated networks is an important feature of intrinsic brain networks supporting consciousness. The dorsal attention network (DAN) is responsible for orientation to behaviorally salient cues.

The SN mediates the anticorrelation of the DMN and DAN through dynamic mechanisms, and psilocybin reduces the anticorrelation between DMN-DAN connectivity deployment. This finding reinforces the suggestion that the DMN-DAN anticorrelation maybe crucial to the loss of boundaries between the subjective and objective world.

Evidence suggests that altered anticorrelations in the DMN and DAN may be involved in therapeutic outcomes following psychedelics, including enhanced mindfulness capacities, reduced reactivity, judgmental thinking and enhanced self-kindness.

Subcortical brain regions that evince anticorrelation under psychedelics have also been investigated. These findings may help determine the functional importance of brain anticorrelations in ego dissolution, therapeutic outcomes, and the consciousness of self.

There are many conflicting findings in psychedelic neuroscience. Ego dissolution is often associated with DMN hub regions under psychedelics, but brain-wide connectivity changes are also associated with ego dissolution and extend beyond the DMN under LSD.

Psychedelic-induced changes in connectivity are seen in nonpsychoactive studies without subjective effects, and a similar deactivation pattern is also elicited by anxiety and antidepressants. Therefore, it is important to note known confounds when trying to identify neural mechanisms.

Neuroimaging studies suggest that connectivity changes in the brain are associated with ego dissolution and other subjective effects of psychedelics. However, accurate modeling of psychedelic brain connectivity is encumbered by challenges.

Recent alternate methods for determining anatomical coordinates have also been proposed, involving probabilistic mapping to improve consensus and inferences. These strategies may produce different connectivity results when referring to the same regions.

Imaging and analytic approaches can advance the understanding of the mechanistic unfolding of processes after psychedelics, but standardization of image processing pipelines is essential to ensure accurate comparisons across neuroimaging studies.

We consider several issues related to the measurement of ego dissolution in imaging studies. These include the variability of ego dissolution across subjects, the issue of reliability of retrospective self-report measures, and the time at which imaging occurs.

To offset issues related to psychedelic peak effects, researchers may want to consider recording subject qualitative behavior reports and observing subject ego dissolution. They may also want to consider establishing a registry of subjects with high subjective effects for future imaging studies.

Psychedelics may temporarily exercise neuronal and behavioral flexibility, resulting in a state of disorder in the brain. Criticality characteristics have been used to understand the stable and coherent organization of brain dynamics under psychedelics.

A recent imaging study suggested that psilocybin reduces connectivity in associative regions and increases connectivity in sensory regions across subcortical and cortical areas, which may explain subjective sensory and self-related experiences under psychedelics.

Thalamic gating is controlled by glutamatergic cortico-striatal and cortico-thalamic pathways, and serotonergic and dopaminergic projections. Thalamic gating alters bottom-up flow of information, and may contribute to psychedelic perceptual alterations.

The brain uses sensory signals to make predictions about hidden states in the world, which are then tested against new sensory evidence in a cyclical process described variously as predictive coding, Bayesian filtering, or Bayesian belief updating.

The computational formulation of hierarchical predictive coding goes on to consider neuromodulation in the construction of predictions, and suggests that gain control (i.e., sensitivity) is a key player in selecting the most reliable or precise prediction errors for belief updating at higher hierarchical levels.

Psychedelics stimulate serotonergic 5-HT2A receptors in deep pyramidal cells, which are densely distributed in visual and associative areas of the cortical hierarchy, and are thought to be the cells-of-origin of descending predictions to subcortical systems or lower hierarchical levels.

Consistent connectivity findings across visual and associative areas can be framed within the hierarchical predictive coding framework, and can help explain the effect of pharmacological interventions at the synaptic level in terms of sentience and planning.

The relaxation of beliefs under psychedelics (REBUS) model describes a rebalancing of prior and sensory precision that enables new prior hypotheses and narratives to be engaged.

Neuroimaging findings show decreased within-network connectivity and altered oscillatory rhythms in regions of the cortex associated with psychedelic subjective and therapeutic effects. This may explain how serotonergic agonist activity can influence internalizing disorders.

The altered beliefs under psychedelics (ALBUS) model and related strengthened beliefs under psychedelics (SEBUS) model describe similar adaptations of the REBUS model, suggesting that the strength of a dose calibrates the flexibility or rigidity of prior beliefs. Psychedelics may flatten the energy landscape of prior beliefs, making it easier for higher-level beliefs to jump from one to another, and thereby enable new directions for thought patterns without a complete breakdown of cognition.

Psychedelics’ net-excitatory effect on layer 5 pyramidal neurons may strip down the precision of the hierarchical generative model’s priors of the world’s contents, causes, and contexts, resulting in a sense of heightened existential experience and primordial awareness.

The hierarchical generative model places boundaries on the physiologic states of living systems to support the behavior that ensures biologic survival. Belief updating supports adaptation by resolving mismatches in bottom-up prediction errors and top-down predictions.

Top-down disinhibition may factor into alternative models and enable the desegregation of connectivity, which may further extend the probability distribution and cognitive flexibility at the level of consciousness and sentience.

Psychedelics alter the generative model, which speaks to the role of serotonin and the layer 5 apical dendrites in the emergence of consciousness. Advances in psychedelic imaging analyses are uncovering more specific mechanisms underwriting connectivity changes proposed by unifying theories.

Future research may focus on the cytoarchitecture of the brain’s hub regions, the desegregation of FC from network pathways, and the increased sensitivity to intrinsic and extrinsic perturbations (i.e., environmental influences) under psychedelics.

Functional connectivity measures are blind to directed connectivity, but DCM can infer the directed causes of neuronal responses and can link synaptic level mechanisms described in hierarchical predictive coding formulation to the directed connectivity changes of region level neural substrates.

Separating subjective effects from therapeutic outcomes is a debate that can be informed by further neurobiological study. However, some research suggests that the biologic effects of psychedelics may be divorced from the subjective psychedelic experience while retaining therapeutic properties.

Preclinical research suggests that rats can achieve long-lasting antidepressant effects from a single administration of a psychedelic, and that the subjective experience of ego dissolution may be a marker predicting a successful therapeutic outcome.

The lowest doses in preclinical studies typically resemble the highest doses in clinical trials, but allometric scaling may account for differences in pharmacokinetics and pharmacodynamics among species.

A 15-year-old female individual who had previously suffered from 3 years of chronic depression accidentally consumed 10 times the standard dose of LSD (1200 mg). She reported no symptoms of depression for the next 13 years, and a separate case also found that chronic pain was alleviated following a massive overdose of LSD (550 times the standard dose).

Psychedelic therapeutic effects depend upon psychosocial contributions, but it is unlikely that the psychedelic aspect of psychedelics is superfluous, given the reported therapeutic experiences and outcomes, such as in the case of end-of-life psilocybin treatments. We still have much to learn about how experiences of ego dissolution influence long-term behavioral outcomes. However, palliative care experiences of unity suggest that ego dissolution is exceptionally meaningful and can provide personal meaning, closure, and peace for those facing end of life.

Research efforts to understand the relationship between subjective effects and therapeutic qualities are growing, although removing the psychedelic experience may reduce the efficacy of psychedelic therapy.

Future pharmacology studies will likely test this hypothesis and determine the limits of separating subjective experience from biologically induced therapeutic benefits. Neuroimaging research will also likely contribute to this line of inquiry.

Uncertainty exists whether ego dissolution involves a gradual onset or a binary (all or nothing) experience. PET investigation of plasma psilocin occupancy and the reported subjective intensity of experience support a gradual onset.

We propose that psychedelic altered object phenomena such as visual, temporal, and emotional alterations occur as a binary shift in the observer, whereas lower-level observed constructs encounter gradual dose-dependent changes, for example, in visual alterations.

Time-dependent connectivity mechanisms of ego dissolution may be helpful to answer the dose-response question, but require psychedelic-experienced participants and sequential time-dependent scanning and behavioral measures across high-dose onset.

A related controversy pertains to psychedelic doses adjusted by body weight. Further research is needed to determine the mechanisms controlling the relationship between dose and response, and to determine the predictors of dose-response relationships in psychedelic naive participants. Post-hoc analyses can help determine the dose-response relationship by determining the effectiveness of connectivity pathways between key brain regions and hierarchical strength between networks.

Measures administered after psychedelic ingestion are crucial to advancing research. These measures may be sensitive to discriminations between minimal and narrative aspects of the self, and may help determine network-dependent changes to consciousness under psychedelics.

Psychedelics may be better understood by comparing the connectivity changes observed across different classic psychedelics and a variety of other altered states of consciousness, including psychosis and meditation. However, the influence of context is more likely to be biased by negatively felt ego dissolution. Psychedelic experiences differ from experiences of psychosis in several key manners, including consent given prior to administration, targeted use of psychedelic experience, and temporary duration of the psychedelic experience. Moreover, preparing mindset may influence the organized coherence of dysregulated and disintegrated connectivity under psychedelics.

The benefits of integrating meditation in psychedelic study design are highlighted by evidence that the quality of psychedelic experiences may determine therapeutic outcomes. Neuroimaging protocols could be equipped with groups assigned to meditation programs to identify the connectivity differences based on meditation and psychedelic synergy.

e. Plasticity. Preclinical evidence shows that psychedelics leave the brain in a more plastic (i.e., malleable) state, and that serotonergic psychedelics stimulation of neural and glial cells may reduce inflammation and reduce oxidative stress and act as disease-modifying therapeutics in neurodegenerative disorders. Clinical research shows that brain-derived neurotrophic factor (BDNF) increases after administration of 200 mg of LSD compared with placebo, and that this dose goes above the ceiling of therapeutic ego dissolution.

Psychedelic-induced entropy may relate to lasting behavioral change, including behavioral flexibility in rats and increased openness, a personality trait connected to schizotypy and antithetical to ego resistance.

Plasticity is a measure of dynamic flexibility in brain networks, and it can be associated with positive adaptive behaviors such as learning and the desire for cognitive endeavors. However, beyond metastable ranges, elevated flexibility is a biomarker of schizophrenia and increased risk of psychosis.

Neuroimaging research shows that connectivity changes in the AMG and mPFC-PCC are associated with openness, suggesting that underlying neuroplastic mechanisms may account for lasting connectivity changes and behavioral outcomes. Future research can measure the influence of psychedelics on regional connectivity changes over time after administration, and how contextual determinants and psychologic support influence these changes. This research may also benefit nonclinical populations by enhancing social and cognitive skills, empathy, and creativity.

Psychedelic-induced neural plasticity is undirected and not inherently therapeutic, and the psychologic response to psychedelic effects is likely to mediate the therapeutic utility of psychedelic-induced plasticity. Psychedelic-reduced belief constructs may open the range of alternative hypotheses entertained by beliefs without guaranteeing a therapeutic direction.

II. Conclusions

The use of psychedelics to alter consciousness and manifest insight has existed in cultures around the world since antiquity. Their popularization in Western culture during the mid-20th century affected sociopolitical beliefs and led to legislation that cast shade over psychedelic research.

In the late 1970s, it was discovered that 5-HT2 receptors are involved in regulating responses to psychedelics. The 2A subtype is the primary target for psychedelic’s effects on consciousness. Understanding the effect of serotonergic activity on whole-brain connectivity poses significant challenges. However, the disintegration of the DMN and midline cortical connectivity – and their inhibitory function – and reduced thalamic gating may contribute to the loss of self experienced in ego dissolution. Neuroimaging experiments are required to address a range of questions probing the nature of psychedelics. These experiments will provide further empirical evidence for unifying frameworks.

Hierarchical predictive coding provides a biologically plausible computational model of sentience that explains serotonergic synaptic mechanism’s role in making sense of the world through top-down predictions and bottom-up prediction errors. Understanding the link between psychology and neurology is crucial to understanding how psychedelics work. This is why it is important to cultivate reduced ego resistance to the onset of psychedelics and to use integration programs to cement psychedelic insights into lasting well-being.

Psychedelics alter synaptic processes in the brain that are involved in consciousness and attention. Hierarchical predictive coding explains these changes and can be synthesized with dynamic causal modeling to help understand the neural mechanisms of consciousness and attention.

Through psychedelic alteration of serotonergic receptors, the hierarchical relationship between top-down associative processes and bottom-up sensations are collapsed, enabling bottom-up influences to update beliefs about interactions with the world. This updating of beliefs can lead to therapeutic insights leading to changes in patterns of thought and perspective.

The review suggests that ego dissolution is the shift in consciousness that manifests from an array of brain changes, primarily the disintegration of the self-related associative connectivity and desegregation of connectivity involved in space, time, and various other subjective effects.

The introduction of psychedelics to Western culture reflects a similar process of reidentification through challenge to the hierarchical authority of top-down beliefs from political leadership and bottom-up grassroots influences. This suggests a common effect of psychedelics across neurology and sociology, in which boundaries limiting perception are broken.