This theory-building paper (2020) introduces the 'pivotal mental state', a hyper-plastic state (as reaction to chronic and acute stress -; or incited by psychedelics) which can mediate psychological transformation.
“This paper introduces a new construct, the ‘pivotal mental state’, which is defined as a hyper-plastic state aiding rapid and deep learning that can mediate psychological transformation. We believe this new construct bears relevance to a broad range of psychological and psychiatric phenomena. We argue that pivotal mental states serve an important evolutionary function, that is, to aid psychological transformation when actual or perceived environmental pressures demand this. We cite evidence that chronic stress and neurotic traits are primers for a pivotal mental state, whereas acute stress can be a trigger. Inspired by research with serotonin 2A receptor agonist psychedelics, we highlight how activity at this particular receptor can robustly and reliably induce pivotal mental states, but we argue that the capacity for pivotal mental states is an inherent property of the human brain itself. Moreover, we hypothesize that serotonergic psychedelics hijack a system that has evolved to mediate rapid and deep learning when its need is sensed. We cite a breadth of evidences linking stress via a variety of inducers, with an upregulated serotonin 2A receptor system (e.g. upregulated availability of and/or binding to the receptor) and acute stress with 5-HT release, which we argue can activate this primed system to induce a pivotal mental state. The pivotal mental state model is multi-level, linking a specific molecular gateway (increased serotonin 2A receptor signaling) with the inception of a hyper-plastic brain and mind state, enhanced rate of associative learning and the potential mediation of a psychological transformation.
Brouwer and colleagues frame ‘‘quantum change’’ or rapid, enduring psychological transformations as phenomena that have been described in psychology and philosophy but poorly specified in neurobiological terms. They argue that past work has focused on outcomes (for example spiritual conversion versus psychotic breakdown) rather than on the transient states that mediate such changes. Drawing together literature on stress, psychosis, spirituality and psychedelic drug effects, the paper proposes a new construct — the pivotal mental state (PiMS) — intended to capture a processual, multi-level state of mind and brain that can precipitate large psychological shifts. The paper sets out to define PiMSs operationally, to review evidence for their distal and proximal causes, to identify a plausible molecular gateway (the serotonin 2A receptor, 5-HT2AR), and to integrate phenomenology, pharmacology and systems-level neurobiology. Brouwer and colleagues emphasise that PiMSs are outcome-agnostic: the same mediating state can lead to beneficial or harmful long-term changes depending on context, predisposition and subsequent integration work. They also propose that understanding PiMSs can inform therapeutic approaches — notably psychedelic-assisted therapy — as well as other culturally embedded practices that intentionally induce intense mental states.
Papers cited by this study that are also in Blossom
Alamia, A., Timmermann, C., Carhart-Harris, R. L. · eLife (2020)
Argento, E., Strathdee, S. A., Tupper, K. et al. · BMJ Open (2017)
Barrett, F. S., Bradstreet, M. P., Leoutsakos, J. M. S. et al. · Journal of Psychopharmacology (2016)
Barrett, F. S., Doss, M. K., Sepeda, N. D. et al. · Scientific Reports (2020)
This paper is a theoretical, narrative review and integrative synthesis rather than an empirical study or systematic review. Brouwer and colleagues assemble evidence from diverse sources including human psychopharmacology, functional neuroimaging, animal models, receptor pharmacology, clinical phenomenology (psychosis, PTSD, near-death experiences), historical and cross-cultural descriptions of ascetic and ritual practices, and preliminary clinical trials of psychedelic-assisted therapy. The logic of the paper is conceptual: identify a candidate mediating state (PiMS), set out its defining criteria, and marshal converging lines of evidence that stressors and 5-HT2AR signalling can produce such states. The authors do not report a formal search strategy, inclusion/exclusion criteria or systematic risk-of-bias assessment. Instead, they discuss representative empirical findings (for example antagonist pre‑treatment studies with psychedelics, imaging correlates, animal studies of receptor expression, and clinical observations) to illustrate mechanistic links. Where numerical or procedural detail is lacking in the extracted text, it is because the paper emphasises conceptual integration over new data collection or meta-analytic methods.
The review yields a set of synthesis findings rather than new experimental results. Brouwer and colleagues first propose a working definition of PiMSs as transient, intense hyper-plastic mind–brain states with three key properties: (a) elevated cortical plasticity; (b) an enhanced rate of associative learning (including extinction learning); and (c) a particular capacity to mediate rapid, major and potentially enduring psychological transformation. A central empirical claim is that many PiMSs are primed and triggered by stress. The authors review evidence that multiple forms of stress — cognitive (e.g. perceived uncontrollability, neuroticism, depression), social (isolation, social defeat, migration, minority status), and physiological (sleep deprivation, starvation, hypoxia/hypercapnia, pain, inflammation) — are associated with upregulation of 5-HT2AR expression or with increased serotonin release. Animal and human studies are cited to show time-dependent and region-specific changes in 5-HT2AR expression following chronic stressors and that social isolation or maternal separation can potentiate behavioural responses to 5-HT2AR agonists. Classic serotonergic psychedelics (LSD, psilocybin, DMT, DOI, ayahuasca) are presented as a prototypical, experimentally reliable route to PiMSs because they act as direct 5-HT2AR agonists. The review summarises supporting pharmacological evidence: antagonist pre‑treatment attenuates psychedelic subjective effects, and subjective intensity correlates with 5-HT2AR occupancy. Psychedelics produce phenomenological features consistent with PiMSs — ego‑dissolution, altered perception, enhanced associative learning, emotional lability and ‘‘mystical-type’’ experiences — and can increase neuroplasticity markers such as BDNF in animal models. At the systems level, acute psychedelic states are associated with decreased functional modularity and increased global connectivity in brain networks, elevated brain signal complexity/entropy, and changes in default‑mode and control network integrity. These network-level effects are proposed to reflect a relaxation of high‑level priors (predictive models), consistent with the REBUS model (Relaxed Beliefs Under pSychedelics), which posits that reduced precision of top‑down expectations permits bottom‑up information to revise high‑level beliefs. The authors document that outcomes of PiMSs diverge widely and are strongly context-dependent. Positive, integrated contexts (for example deliberate set and setting, therapeutic support, community frameworks) are linked with beneficial long-term changes and ‘‘emotional breakthrough’’ predicts therapeutic gains in psychedelic therapy. Conversely, unprepared or adverse contexts, combined with genetic or developmental vulnerabilities, can steer a PiMS towards maladaptive outcomes such as psychosis or PTSD. The review also highlights cultural and intentional induction methods (asceticism, fasting, breathwork, ritual isolation) that plausibly engage the same physiology. Finally, Brouwer and colleagues outline therapeutic implications: PiMS‑focused interventions (most prominently psychedelic therapy) may offer a transdiagnostic route to recalibrating over-weighted internal models across a range of psychiatric conditions. They caution about risks (iatrogenesis, destabilisation of protective yet pathological beliefs) and draw attention to how routine 5-HT2AR antagonism via common psychiatric medications could suppress PiMS occurrence and thereby influence natural recovery dynamics.
Brouwer and colleagues interpret their synthesis to argue that PiMSs represent an evolutionarily conserved adaptive mechanism for radical psychological recalibration in the face of existential threat or intolerable chronic stress. They propose that 5-HT2AR signalling functions as a molecular gateway into a hyper‑plastic, high‑learning state that permits deep revision of high‑level beliefs or priors. In this view, PiMSs are neither inherently therapeutic nor pathogenic; the surrounding biopsychosocial context and individual predispositions determine whether the pivot yields ‘‘re‑birth’’ and growth or persistent pathology such as psychosis. The authors position psychedelic drug research as especially informative because classic psychedelics reliably induce the hypothesised PiMS signature across phenomenological, molecular and systems‑level measures. They draw links between the REBUS predictive‑processing account and clinical approaches that aim to increase psychological flexibility, for example Acceptance and Commitment Therapy, suggesting potential synergy between psychotherapeutic framing and PiMS‑inducing interventions. Key limitations acknowledged by the authors include the narrative (non‑systematic) nature of the review, potential confirmation bias in selecting supporting evidence, and gaps in direct validation of the PiMS construct across candidate states beyond psychedelics and psychosis. They also note unresolved complexities: stress can both facilitate plasticity and damage specific neural substrates, time‑dependent receptor regulation may produce opposite findings in cross‑sectional versus longitudinal studies, and multiple neurotransmitter systems (noradrenaline, glutamate, dopamine, endocannabinoid, opioids) likely modulate PiMS phenomenology and outcomes. For future work the authors call for empirical validation of PiMSs: experiments that induce stressors known to upregulate 5-HT2AR (for example sleep deprivation, hypercapnia) combined with receptor challenge (antagonist pretreatment), multimodal imaging (EEG, PET, fMRI) and careful phenomenological assessment. They also recommend research to define discriminant validity (what PiMS is not), to test boundary conditions (when state becomes protracted phase), and to refine clinical safety procedures that privilege optimal contextual framing, screening for vulnerability and integration support to minimise iatrogenic risk.
Brouwer and colleagues conclude that a coherent body of converging evidence supports the concept of pivotal mental states: transient, intense hyper‑plastic periods of mind and brain with high potential to catalyse rapid and lasting psychological change. They highlight increased 5-HT2AR signalling as a plausible molecular gateway for many PiMSs and treat classic psychedelics as a prototypical, experimentally tractable PiMS inducer. The paper closes by emphasising that PiMSs are outcome‑agnostic and that maximising beneficial outcomes requires careful attention to context, screening and integration. The authors suggest that developing humanistic, supportive contexts for constructive transformation and pursuing empirical validation of the PiMS construct are important next steps for research and clinical practice.
One way of explaining quantum change experiences is that they represent a kairos, a turning point in the life journey where major change simply must occur because the person in unable or unwilling to continue in his or her present course. It is a point of desperation, a breaking point where 'something has to give' -and it does.Psychological transformation (defined here as rapid, marked and enduring psychological change, where 'psychological' refers to perception, cognition and action or behaviour) has been the focus of previous psychological and philosophical textsas well as influential therapeutic programmes, but it has received surprisingly little formal scientific investigation and past definitions have been vague. This paper aims to rectify this by proposing a multi-level, biologically informed, context-dependent and process-based approach to the phenomenon. Advancing previous work, we introduce a potentially useful new construct, the pivotal mental state (PiMS). Focusing on psychological transformation as a process is a simple but important aspect of our approach that enables us to offer a potential explanation for how transformative experiences (experiences mediating psychological transformation) can manifest into extremely divergent outcomes, such as positively life-changing spiritual breakthrough versus descent into a potentially life-long psychotic illness. More concretely, we propose that however divergent the nature of the transformations themselves, many can be traced to somewhat consistent triggering conditions, with chronic stress being a primer and acute stress a trigger. In what follows, we highlight striking similarities in the conditions of induction, neuropharmacology, neurobiology and psychology of transformative experiences. We demonstrate that these similarities are most compelling when one focuses on the states preceding and mediating psychological transformations, but become obscured when one selectively attends to the products of the transformations themselves. In the same way that traumatic experiences can trigger posttraumatic stress disorder (PTSD) or post-traumatic growth, we hypothesize that intense periods of psychological crisis can serve to kindle conditions for major, potentially lasting, psychological change, pivotable either towards illness or wellness (Figure). This process will later be linked to the phenomenon of bifurcation as described in dynamical systems theory. PiMSs share many parallels with so-called broad definition of PiMSs is that they are transient, intense hyper-plastic mind and brain states, with exceptional potential for mediating psychological transformation. We sharpen this definition by suggesting three key identifying criteria: (a) elevated cortical plasticity, (b) an enhanced rate of associative learning and (c) a unique capacity to mediate psychological transformation. The study of the nature and causes of PiMSs and their close association with psychological transformation is a central focus of this review. Our approach is multi level and integrative, addressing the neurobiology, pharmacology and physiology of PiMSs as well as their psychology. In keeping with popular contemporary psychological perspectivesas well as the biopsychosocial approach to mental health, we are mindful of the essential role played by context in shaping the quality and influence of PiMSs. It is our view that the principle of qualifying the longer-term impact of PiMSs by the context(s) or 'relational frames'in which they arise subside and potentially recur is vital for resolving the wellness versus pathology paradox, namely whether positive or negative changes in mental health follow from a PiMS. Unlike past literature on quantum change, our PiMSs model does not favour positive outcomes over negative, speaking to an essential context and relational dependency, where context refers to both biological (e.g. polygenic) predisposition as well as the individual's immediate and remote environmental context. Thus, the term 'context' is used here in an extended biopsychosocial and temporal way (Figure). If we are correct that context plays a key role in shaping the outcome of a PiMS, an important implication is that contextual factors need to be treated with special attention and therapeutic care (where possible) if an individual's psychological wellbeing is to be safeguarded, whenever a PiMS arises or seems imminent. This said, we recognize that certain emergent PiMSs -such as manic psychotic states -may, however, be particularly difficult to manage via the manipulation of current environmental context alone, particularly during the active PiMS itself. Thus, we do not advocate for environmental contextual management as an exclusive therapeutic strategy and neither do we argue against pharmacological intervention. Figure 2. Schematic that acknowledges the breadth of timescales over which contextual factors can influence one's current state. The boundaries between the three timeframes are arbitrary but one may think of 'past' in terms of, for example, an enriched versus adverse childhood or any past trauma but it can also include what is inherited (i.e. genetically encoded). The 'recent' past might include such things as a recent relationship breakdown or a bereavement, ongoing cultural or social crisis, or recent success or cause for celebration. What is happening in one's immediate environment (i.e. 'now') might be easier to observe, describe and manipulate but is not necessarily the most potent influencer of one's present state. This schematic is intended to acknowledge the temporal range of contextual influences that can impinge on the quality and outcome of a pivotal mental state (PiMS).and social defeatall appear to upregulate 5-HT2AR expression, particularly in the cerebral cortex; see also Table), which is well known to be massively expanded in humans. Social isolation and defeat also reliably sensitize behavioural responses to 5-HT2AR agonists; see also Table). The role of stress and the 5-HT2AR system has been the focus of two recent review papers. Supplementing these findings, direct agonism of the 5-HT2AR via psychedelic drugs can sometimes induce psychological states exhibiting phenomena that mimic those seen in extreme stress states, for example, enhanced associative learning and a significant capacity for mediating psychological transformation, as can occur via traumatic encounters. Psychedelics have also been shown to increase the release of stress hormones. We highlight how certain natural inducers of stress such as social isolation, starvation, atypical breathing, sleep deprivation, extreme body temperature and pain can be intentionally manipulated for the purposes of personal and/or spiritual development, presumably by promoting endogenous psychedelic-like signaling and we review several cross-cultural, historical and modern examples of such manipulation. In keeping with principles of bidirectional translation, research with psychedelic ('mind-manifesting') drugs can inspire research into the pharmacology and phenomenology of endogenously occurring PiMSs, which, in turn, helps inspire hypotheses on the function of 5-HT2AR signaling, including how it relates to mental illness and its treatment, such as via psychedelic therapy, plus other methods of manipulating PiMSs for psychotherapeutic ends. All classic serotonergic psychedelic drugs have direct agonist properties at the 5-HT2AR, and the key role this particular receptor plays in mediating their signature behavioural effects is supported by: (a) affinity-by-potency relationships in animals and humans; (b) a plethora of antagonist pre-treatment studies (e.g.; and (c) evidence of a 5-HT2AR occupancy by subjective effects relationship. A wealth of evidence now exists that, via their action at the 5-HT2AR, psychedelics, at relevant dose ranges, reliably trigger conditions conducive to psychological transformation. Thus, identifying the 5-HT2AR as a key trigger site for inducing PiMSs, we propose that psychedelics hijack the same neurochemical mechanisms that are engaged during, and likely exist for, situations where a hyper-plastic state and associated psychological change is felt as needed. Developing an understanding of endogenously occurring PiMSs can thus shed light on the evolutionary function of brain 5-HT2AR, as well as the action of psychedelics themselves. We propose that the mechanisms underlying PiMSs have evolved to aid rapid and deep learning in situations of perceived or actual existential threat or crisis for the ultimate purpose of catalyzing psychological change when (perceived) circumstances demand this. Somewhat consistent ideas have been expressed in the past, and more recently in two separate reviews (e.g., but are more fully developed here. We conclude this article by restating the principle that although PiMSs may be associated with major psychological change, the quality of such change is neither consistent nor predetermined. We propose that the surrounding context and relational frame in which a given PiMS occurs is a vital determinant of how it manifests. Thus, we end this paper by discussing how engineering of optimal contextual frames (as far as this is possible), including not just the containing environment for the PiMS itself but also prior intentions and integration work after the eventcan enable PiMS-related psychotherapy to be delivered most safely and effectively. We focus on psychedelic therapy as a prototypical PiMSfocused intervention but there are other relevant examples. Indeed, PiMS-focused therapeutic work can be viewed as a more fundamental therapeutic approach than psychedelic therapy, with the latter merely representing one (particularly potent) example. We believe that a growing appreciation of PiMSs could inspire a healthy pivot in mental healthcare and research, more firmly towards the biopsychosocial model. Psychedelic therapy, and the PiMS-based model more generally, are quintessentially 'biopsychosocial'as they recognize how social, psychological and biological factors interact in bidirectional, synergistic ways to determine health and illness. The PiMS model purports to explain how biopsychosocial synergies can be harnessed for the delivery of improved mental healthcare. Such improvements are needed if the significant burden of mental illness is to be properly addressed. Elevating an awareness of PiMSs as key states of mind and brain, with a heightened potential for mediating lasting change, may have implications for the scientific study of a range of PiMSs-related approaches, such as 'breathwork', meditationand accelerated psychotherapies, which should serve to develop their shared validity. Before beginning our detailed review of relevant literature pertaining to the PiMSs construct, it feels necessary to flag some of its complications early on. For example, it is an implication of the 'outcome agnosticism' of the PiMS model that these states be capable of fomenting iatrogenic outcomes, that is, a worsening or triggering of psychopathology, if the surrounding context is negative, for example, as is often the case in the aetiology of psychosisand perhaps even more plainly, PTSD. This matter is highly relevant to inappropriate and/or unsupported psychedelic drug use, as well as malpractice in any kind of paediatric, pastoral or healthcare sector where individuals exhibiting elevated brain plasticity are implicated. A wealth of evidence from psychedelic drug, child psychology and mental health research can be cited to highlight the importance of contextual factors, such as: (a) preparedness, (b) intentions and expectations, (c) inter-personal trust/therapeutic alliance, (d) community support and (e) other forms of psychological integration, for safeguarding against harm and enhancing positive therapeutic outcomes. We also wish to recognize the stabilizing influence that certain implicit assumptions can have on one's mental state, even if they are symptomatic of mental illness. One should therefore be mindful of potential risks entailed by destabilizing such beliefs, either via the direct action of psychedelic drugs or other means; seefor a relevant discussion paper. Delusional beliefs are a good example of psychologically stabilizing, but plainly pathological, beliefs. However, we also highlight evidence supporting a role for destabilization as mechanism of therapeutic change. Themes of psychological flexibilityand experiential acceptanceare also relevant here. Relatedly, the position that PiMSs are ripe mediators of psychological transformation, whether towards pathology or away from it, could be viewed as unjustly dismissive or neglectful of the important contribution made by factors such as polygenic predispositionand early life adversityin shaping mental health. Such apparent neglect is not intentional, and indeed we consider the highlighted factors part of the overall contextual/relational frame shaping the onset and outcome of a PiMS, where context is a phenomenon that stretches over a broad timescale (Figure). Although the recent and current context surrounding a PiMS might be easier to manipulate in favour of positive outcomes, more remote contextual factors such as polygenic predisposition or childhood trauma could still be accounted for, for example, a high polygenic risk for psychotic symptoms might contraindicate psychedelic therapy and thus be used to inform screening for such therapy. A fork in the road or river analogy is often used to reflect a bifurcation process, namely a 'cross-roads', where the trajectory of a system can rapidly destabilise and complexify at a point of bifurcation. In the schematic below (Figure), the analogy is used in relation to the PiMS. Contextual factors can be viewed as biasing currents in the river influencing particular outcomes, in the same way that cambers or slopes bias outcomes along a solid path. Briefly, bifurcation theory describes the occurrence of sudden changes in the trajectory of a system. Typically, energy introduced into a system causes the destabilization of a previously dominant trajectory or state (e.g. represented by the single path that precedes the fork). The critical destabilization creates new potential states or trajectories that the system can enter or follow. For simplicity, 'wellness' and 'illness' are presented here as discrete binary states but we recognize that this is an oversimplification and that mixed features are also possible, for example symptoms consistent with post-traumatic stress and growth can co-exist or 'flip-flop' after a traumatic episode, and similarly, mixed euphoric and dysphoric states can occur in manic psychoses. The unifying principle, however, is that change, whatever its nature, is more likely after such pivotal events.
Throughout this paper we argue that PiMS can mediate divergent outcomes that strongly depend on the surrounding context in which they arise. Here we apply this principle to a classic controversy in psychology and psychiatry: namely, the relationship between spiritual experiences and psychosis. It has long been noted that certain spiritual and early and acute psychotic experiences exhibit similar features such as anomalous self-experience, magical thinking and perceptual aberrations. All three phenomena are reliably induced by 5-HT2AR agonist psychedelics, thus implying their relationship to a more fundamental state -the 5-HT2ARR-mediated PiMS. According to the model presented here, the framing of psychosis as pathological and spiritual experience as psychologically beneficial, obscures their common relationship to the PiMS. Indeed, a negative or positive outcome is the paramount criterion for distinguishing between mystical and psychotic experience, respectively). Moreover, scales used to measure trait schizotypy and spirituality also contain items relating to social and emotional Figure. Use of the 'fork in the river analogy' to communicate the nature and effect of pivotal mental states (PiMSs). The boat, named '5-HT2A', represents the molecular gateway leading to the occurrence of a PiMS, that is, entry into a hyper-plastic state in which the likelihood of major psychological change is enhanced, and the nature of that change is especially context dependent. The fork in the road reflects a bifurcation and thus can be expected to fall under the principles of bifurcation theory more generally; the details of this are beyond the scope of this article. adjustment, behaviour and appearance, which capture divergent responses to ego-disturbance, perceptual aberration and magical thinking. It is our view that certain psychoses and spiritual or religious conversions share a common heritage in the PiMS. We also argue that this connection is often overlooked because of a tendency to selectively focus on outcomes rather than the processes that lead up to them (Figure). The mediational states themselves are often relatively brief and intense, but they can also be more protracted. We describe them as 'pivotal' based on the principle that a consistent root state can mediate strongly divergent outcomes, such as spiritual or religious epiphany or conversion versus the acquisition of a psychotic delusion. The Oxford definition of a pivot (as a noun) is a central point or person from which a mechanism turns or oscillatesand the adjective 'pivotal' is defined as '[a thing] of crucial importance in relation to the development or success of something else'. We therefore use the adjective here in reference to the principal properties and function of PiMSs, that is, a heightened ability to mediate major psychological change. We propose that a focus on the root state preceding a given outcome should reveal the presence of the defining properties of PiMSs. In this paper, we use a recent definition of stress as 'the body's multi-system response to any challenge that overwhelms, or is judged likely to overwhelm, selective homeostatic response mechanisms'. The cited paper is a useful reference for reviewing alternative definitions. Discussing different definitions of stress is beyond the remit of the present paper but it is relevant to note that most definitions appear to agree that stress is a multi-level response to an apparent threat to an organism's present state. This consistent definition of stress is useful, as it acknowledges how stress can engage adaptive mechanismssuch as heightened plasticity -that is, the quality of being more shapeable. Appreciating the link between stress and adaptability can help us understand the etiological and evolutionary function of PiMSs. As we show below, stress is a particularly robust and reliable primer, trigger and potentiator of PiMSs. Stress is typically construed of and felt as an aversive phenomenon and recognizing this can help us understand why naturally arising PiMSs often lead to negative outcomes (Figure). For example, if a PiMS is not expected and the experience is protracted, then the net effect of this is likely to be distressing. Adverse conditions are, almost by definition, stressful and classic examples such as unintentional social isolation, urban-environment-related stress, poor socioeconomic status and childhood adversity are likely to mediate and/or potentiate PiMS, and have all been significantly linked with psychotic disorders. In contrast, spiritual experiences appear to be more likely to arise in positive environmental contexts, such as in nature. The bidirectional and often mutually reinforcing relationship between belief and affect is reflected in emotionally antithetical experiences of self-dissolution in spiritual versus psychotic experiences. In severe and enduring psychosis, self-fragmentationis often felt as invasive and torturous, whereas sensations of 'mystical union' or 'inter-connectedness'appear to lie at the heart of positive experiences of ego-dissolution in naturally occurringand psychedelic-induced spiritual experiences. Seefor another detailed comparison of mystical and psychotic experience. We are mindful, however, that manic episodes can also have a euphoric quality and thus, euphoric states are not therapeutic themselves. Increased emotional tone is a common feature of PiMSs that likely plays an important role in modulating their immediate nature and longer-term impact. Recent work with psychedelics has revealed that 'emotional breakthrough' is an important and distinct mediator of long-term positive outcomes after psychedelic therapy. Relatedly, feelings of 'awe' in nature have been found to mediate improvements in wellbeing via nature exposure. The active suppression of emotion is associated with the nature and severity of symptomatology in psychosis and PTSDand the duration of negative affect (but not its intensity) has been found to predict negative long-term outcomes after psychedelic drug use. A logical explanation for the impact of intense emotion on long-term psychological outcomes from PiMSs is that the felt emotion modulates the nature of associations made during the pivotal state and intensifies their influence, allowing for beliefs and perspectives to be affected. In predictive processing terms, emotion can be thought of as prediction error modulating the 'precision' (inverse variance) of 'posteriors' or 'priors' (probability distributions in the Bayesian sense, i.e. the expected likelihood of a set of possibilities). Expressed in a way to serve readers' intuition: at a high hierarchical level, the precision of a prior relates to one's confidence in a given perspective or belief. If the the implication is that this may not have been an inevitability and measures can be taken to either shepherd the pivotal mental state (PiMS) in a particular direction or even seek to avoid it altogether, for example, in cases where there are polygenic vulnerabilities. affective tone of a PiMS is positive and intense, this may drive a 'de-weighting' or relaxation of a negatively held belief. For example, a negative (cognitive) bias characterizing a depressive disorderwould be felt less confidently if it were relaxed. However, if the affective tone accompanying a PiMS is intense, negative and unresolved, this may contribute to an instilling and/or reinforcement of negative beliefs -it would add precision to the (negative) belief. See Carhart-Harris (2019) for a discussion of related themes. Increased emotional tone coupled with hyper-plasticity and enhanced associative learning is a potent mix for moderating or reinforcing deeply held beliefs and perspectives. Symbolic associations may become increasingly oriented to one's underlying emotional state, encouraging the formation of 'affect-laden' worldviews. Indeed, if emotion is intensified during a PiMS but its valence is unpredictable, it may explain how a consistent root state can mediate extremely divergent outcomes. The intensity, duration, psychological preparedness and degree of psychological resolution may all contribute to the nature and influence of emotion on the quality and impact of a PiMS. Negative affect predominates in schizophrenic psychosis and is associated with delusions of persecutionand general cognitive disorganization. Conversely, positive affect predominates in western conceptions of spiritual experienceas well as psychedelic drug experiences, all of which usually feature some degree of positive context. Manic states could be seen as a challenge to this rule, however. Relatedly, we recognise that persecutory and grandiose thinking and associated negative and positive mood states are not mutually exclusive and can exist in parallel and/or interchangeably, as exemplified by apocalyptic and religious delusionsand manic psychoses. Perceptions of interconnectedness and self-transcendence in manic states bear resemblance to the phenomenological qualities of spiritual states, including those induced by psychedelics (e.g. see. Manic states are often triggered by stressful events and culminate in chronic psychotic disorders. Comorbidity of bipolar, schizophrenia and schizoaffective disorders reflects a shared polygenic vulnerability to psychotic symptomsand possibly, by extension, PiMSs. Context is rarely, if ever, either entirely 'positive' or 'negative' and the same is true for how it is received, that is, context is inherently relational and subjective. Moreover, we recognize the paradox that highly positively valanced mood states, for example euphoric states in manic psychoses or a psychedelic drug experience, do not naturally imply positive long-term outcomes for mental health. The phenomenon of 'spiritual bypassing' is relevant in this regard. For example, the zealous promotion of self/ego transcendence in the absence of Figure. The upper process is perhaps the most typical scenario for a naturally occurring pivotal mental state (PiMS) but also the worst possible scenario as far as long-term mental health is concerned. It is the scenario that, we believe, most often accompanies the development of a psychosis. The lower process can be described as 'outcome agnostic' in the sense that the quality of the PiMS itself and its subsequent impact on mental health is contingent on the surrounding context and relational frame into which is arises. If the recent, current and post-PiMS context can be shaped favourably, then one can expect the longer-term impact of the PiMS to be favourable also. However, more remote contextual factors (e.g. polygenic make-up or a history of trauma) are, understandably, harder to manipulate and may, on occasion, merely signal that a PiMS could be especially risky, for example, in terms of its outcomes. This said, it is entirely plausible that naturally occurring PiMS can yield favourable psychological outcomes. subsequent psychological integration could be regarded as a (subtly) negative, or at least 'imperfect', context. Psychotic episodes and spiritual experiences are both commonly preceded by a dissatisfaction with reality and one's place within it;). In the prodrome to psychosis (i.e. a pre-psychotic period that precedes a conspicuous psychotic episode) an individual's presentation may often resemble that of a depressive phenotype. Indeed, an individual entering a PiMS (whether interpreted as psychotic, spiritual, both or neither) may perceive their world as unreal, thus spurring belief in a 'meaningful' but concealed other reality: 149-155). One should be mindful how transition into a psychotic episode or spiritual experience can be construed as a 'manic defence', that is, an escapist 'flight from reality'. See againon the topic of 'spiritual bypassing'. In longer prodromal states, a loss of interest in key activities and pursuits (e.g. education and vocation) and pleasures (e.g. food, sex, social interactions) can coexist with an emerging interest in supernatural paranormal, religious and ritual domains. Thoughts may begin to feel unrelated to the self and emotionally distant. Individuals may find themselves examining their thoughts and behaviours from a third-person perspective, as aware yet dissociated subjects. A dissociation of subjective awareness from one's body and/or thoughts evokes common religious/spiritual notions of the incorporeal soul, 'true-self' (Ātman) and 'no-self' (Anātman)as well as the related notions of 'non-dual awareness'and the 'unitive experience'. Many religious traditions place value on understanding the nature of the self, its relationship to the world and its transformation. One potentially relevant theme here is 'salvation', which, outside of theological contexts, has been defined as a 'preservation from destruction or failure' and 'deliverance from danger or difficulty'. Thus, the 'salvific' and/or adaptive function of extraordinary personal experiences has historically been framed in a religious way and religion may function to ease human suffering via other plausible mechanisms. For example, rituals may mitigate anxiety and facilitate healingand absolutist religious beliefs may protect against a basal existential uncertainty. Thus, religion and non-denominational spirituality (whether secular or otherwise) offer potentially useful frameworks/belief systems from which to positively frame experiences that in other contexts might be readily construed as pathological.
Serotonin is an endogenous monoamine found throughout the body, particularly in the gastrointestinal system, lungsand, to a lesser extent, the central nervous system. Despite its more modest prevalence in the brain, serotonin neurotransmission is known to play an important modulatory role in several key aspects of mind and behaviour, including brain development, mood, cognitionand sleep. Serotonin is a particularly complex neuromodulator, with a broad range of receptor subtypes (i.e. at least 14 different subtypes have been identified to date, some of which have opposing functions on activation). Previous attempts at a unifying model of the function of brain serotonin have tended to focus on its role in moderating anxiety statesas well as impulsivity/impatience and aggression. The most reliable inducers of 5-HT release appear to be stress, painand uncertainty, see Table. Thus, it has been proposed that serotonin's 'serenic' effects, particularly via non-5-HT2AR (i.e. most notably postsynaptic 5-HT1A receptors in stress circuitry), may be a perceived as an adaptive response to adversity, for example, aiding a type of resilience one might call 'fortitude', 'passive coping' or an enhanced ability to endure adversity and thus, 'get by'. However, meeting stress with an intention to merely endure may not be an optimal long-term strategy. For example, efforts to suppress and thereby avoid, stress may not be conducive to the revision of (potentially problematic) internal models, such as those linked to cognitive biases in depression, for example. Thus, it seems reasonable to ask: does there not exist an alternative adaptive mechanism, sufficiently different to the stress avoidance/mitigation strategy just described, perhaps one that becomes triggered when adverse conditions surpass a critical threshold of severity and/or chronicitysuch that mere endurance is not enough? It has been proposed before that a principal function of the serotonin 2A receptor subtype is to induce a state of cortical hyper-plasticity conducive to major adaptive change. The present paper extends this previous work to highlight how chronic stress primes the serotonin (2A receptor) system for the elicitation of a PiMS: a hyper-plastic state in which prior assumptions are relaxed, enabling an enhanced sensitivity to potential new information, consistent with rapid and deep learning. In psychosis, this process may result in the maladaptive formation of delusional beliefs that nevertheless help make sense of a frightening world. In spiritual experiences, individuals may report sudden moments of clarity and insight (e.g. epiphanies) servicing positive self-development and renewed perspective (C'De. Highly consistent themes can be found in reports of post-traumatic growth after recovery from psychosis and other severe conditions, neardeath experiencesand in cases of clinical breakthrough with psychedelic therapy. See also. Addressing the following questions can help us develop our hypotheses on the role of stress and the 5-HT2AR in PiMSs: 1. Are certain stressors linked with the occurrence of states meeting the definition of a PiMS (e.g. incipient psychosis or spiritual experience)? 2. What types of stress and stressors appear to upregulate the 5-HT2AR system most robustly and reliably? 3. Does increased 5-HT2AR activity facilitate psychotic or spiritual states or traits? 4. Are 5-HT2AR-induced PiMSs associated with major psychological change or transformation? These questions will be addressed in the following sections, starting with an examination of various stressors that facilitate self-transformation and upregulate 5-HT2AR signaling.
A perceived lack or loss of control is a well-known cause of stressand a potential transdiagnostic factor in a variety of mental illnesses. Perceived uncontrollability of thoughts correlates with intensification of pathology in obsessive compulsive disorder (OCD) and schizophrenia. In general, negative thoughts are more likely to be misattributed to sources other than the self, reflecting less felt ownership. Abnormal meta-cognition ('thinking about thinking') is a characteristic of psychosisand schizotypal individuals are also significantly more likely to show abnormal metacognition. The schizotypal mind may relieve (or reward) itself by hypothetically solving matters of uncertainty via escape into fantasy or delusion, akin to the relief served by compulsive rituals in OCD. A similar function may be served by ritual in religion. Indeed, the over-weighting of priors (excessive 'precision', or inverse variance, synonymous with excessive confidence), particularly in response to perceived uncertainty and loss of control, may be a transdiagnostic feature of psychological suffering, namely the proposed (defensive) function of many symptoms of psychopathology may be to mitigate uncertainty through the over-weighting of beliefs and/or excessive reinforcement of certain specific behaviours. Neuroticism and depression, indicative of chronic cognitive stress, regularly precede and coexist with psychotic disordersand depression and despair also often precede religious experiences. Most studies suggest that chronic stress upregulates 5-HT2AR binding and expressionalthough seeand the 5-HT2AR is implicated in physiological and behavioural responses to chronic stress in humansand animal models; although see. Various studies show upregulated 5-HT2AR transcript and protein expression in neuroticismand depression; although see, particularly in relationship to dysfunctional attitudesand suicide. Given the close association between depression and PiMSrelated outcomes (i.e. spiritual and psychotic experiences), it is natural to surmise that cognitive-stress-induced upregulation of 5-HT2AR expression may be an important biology x environment interaction through which both spiritual and psychotic experiences manifest via a subsequent increase in 5-HT2AR activation. Consistent with the PiMS model, baseline neuroticism is associated with elevated cortical 5-HT2AR expression, predicts thought disturbance, blackout and challenging experiences under psychedelics; although see) and yet may be reduced after psychedelic therapy, presumably because of positive contextual manipulation during the acute hyper-plastic state, as well as afterwards. In relation to naturally occurring PiMSs, both uncontrollable stressand punishmentare associated with 5-HT release. Psychological trauma predisposes certain individuals towards dissociation, hallucination and other psychotic-like features. There exists an especially high comorbidity between psychotic and PTSD symptoms. The 5-HT2AR may mediate altered mind and brain functioning in relation to traumatic events. Consistently, 5-HT2AR variants have been associated with PTSD, symptom severity in PTSD, and the degree of default mode network connectivity amongst people with PTSD, a network implicated in the action of psychedelicsthat is rich in 5-HT2AR. Animal models implicate the 5-HT2AR in anxietyand anxiety following exposure to trauma. Indeed, traumatic experiences are likely to meet all three of the key criteria for a PiMS.
Social stress and other relevant factors such as urban stress, ethnic minority status, migration, childhood trauma, poor cognitive aptitude and drug abuse all contribute to a sense of social defeat and have been linked with schizophrenia. Social defeat is a phenomenon relative to one's immediate social surroundings and expectations for the future, that is, one's specific relational frame. Social stress has also been linked with higher rates of religious engagement. Loss of close social connections and social isolation have been linked with cognitive-perceptual abnormalities such as a hallucinated sensed presence, and loneliness has also been linked with facets of magical thinking such as anthropomorphization, which is a feature of religious belief. Perceived social disconnection, social isolation and social withdrawal regularly precede psychotic and spiritual experiencesand solitary confinement, conceived initially as a method of spiritual rehabilitation, often leads to perceptual distortions, hallucinations, cognitive deficits and paranoia. It is also worth highlighting that the classic 5-HT2AR agonist psychedelics quite reliably induce experiences of vivid sensed presence (e.g.as well as magical thinking more broadly. In preclinical modelling studies, 5-HT2AR antagonism impairs acquisition of conditioned defeatand suppresses hyperthermic response to social defeat, whereas agonist administration into the basolateral amygdala increases acquisition of conditioned defeat. Acute social defeat increases 5-HT levels, and region-specific increases in 5-HT2AR expression have been found in chronically subordinate animals. Acute social defeat has not been shown to upregulate 5-HT2AR expressionor produce phenotypes indicative of 5-HT2AR sensitization, such as that seen after recurring defeat. These observations are consistent with the present model, which acknowledges that the positive relationship between various stressors and 5-HT2AR upregulation is dependent on the chronicity and severity of that stress. Maternal separation stress in rodents potentiates the effects of 5-HT2AR agonists, and 5-HT2AR antagonists reduce maternal separation-induced anxiety, aggression and bradycardia. Preliminary evidence also suggests that maternal separation upregulates 5-HT2ARsand 5-HT2AR mRNA expression; although see. Isolation rearing likewise seems to upregulate 5-HT2AR expressionand potentiate the effects of 5-HT2AR agonists. Pre-pulse inhibition deficits displayed by isolation-reared animals are reduced by 5-HT2AR antagonismThe effects of isolation housing on 5-HT2AR expression is inconclusive and time variable, e.g., one study found that 5-HT2AR expression is decreased at 4 weekswhereas others found increases at 6 and 12 weeks, while another found decreased 5-HT2AR mRNA expression at 6 weeks. More evidence is needed to clarify these time-dependent relationships and how they relate to 5-HT2AR mRNA versus protein expression. The effects of isolation on 5-HT2AR sensitization appears more straightforward, with isolation housing in mature animals potentiating 5-HT2AR agonist-induced wet dog shakesand head twitch.
Chronic inflammation, excitotoxicity, hypoxia, metabolic dysfunction, starvation, sleep deprivation and pain are all physiological processes linked to stress. Brain inflammation and excitotoxicity are putative risk factors for psychosis and likely contribute to neurodevelopmental abnormalities (e.g. reduced grey matter volume) in schizophrenia. Various studies show that 5-HT2AR activation has neuroprotective and antiinflammatory effectsand inflammation is a common feature of stress-related disordersincluding psychosis. The general neuroprotective and anti-inflammatory functions of the 5-HT2AR may explain why this receptor is upregulated by and mediates responses to so many stressors (Figure) and lends additional support to its candidacy as a therapeutic target. Hypoxia (oxygen deficiency) may be particularly relevant, as respiratory complications are associated with increased rates of psychosis. Hypoxia is also implicated in near-death experiences (NDEs), 'runners' high', high-altitude-induced psychosis, panic attacksand spiritual practices and experiences. Hypercapnia (increased CO 2 in the bloodstream) may mediate the psychedelic-like effects of naturally occurring hypoxic conditions. Indeed, there is a history of CO 2 'carbogen' therapythat overlaps in some regards with psychedelic therapy, such as with an emphasis on the induction of cathartic experiences. Hypoxia upregulates cortical 5-HT2ARs) and the 5-HT2AR agonist psychedelic N,N-Dimethyltryptamine (DMT) exerts neuroprotective effects in cells exposed to hypoxic conditions, leading scholars to suggest endogenous DMT may be released as an adaptive response to physiological stress (da Silva. A recent study observed increased DMT levels in rat visual cortex following cardiac arrest, a finding that supports the hypothesized role of endogenous DMT in NDEs. The specificity of this release needs to be considered, however, given that concentrations of 5-HT and other neurotransmitters are also massively increased during asphyxiation, cardiac arrest and hypercapnia and may compete with DMT at the 5-HT2AR. Stimulation of the 5-HT2AR may also precipitate psychotic symptoms during panic attacks, which often involve a physiological disturbance (e.g. hypercapnia) coupled with cognitive misinterpretation. Preliminary evidence suggests the 5-HT2AR mediates CO 2 -induced arousal, a popular model of panic attack, as well as anxiety responses to corticotrophin-releasing factor receptor 1 stimulation. That CO 2 inhalation can induce panic or pleasant psychedelic-like experiences, with activation of 5-HT2ARs likely playing a role, is supportive of the PiMS model, including its emphasis on the context dependency of outcomes. Metabolic dysfunction and starvation are associated with psychotic phenotypes. Chronic tryptophan depletion (3 weeks) selectively increases cortical 5-HT2AR binding. Fasting also increases serotonin-induced intracellular calcium cation concentration, a proposed correlate of 5-HT2AR function in the brain, as stimulation of 5-HT2ARs induces intracellular calcium release. Increases in cortical brain-derived neurotrophic factor (BDNF), as well as the antidepressant and anti-inflammatory effects of fasting, are consistent with the effects of 5-HT2AR activation. Acute fasting and intermittent religious fasting have been shown to increase 5-HT levels and metabolism; although seewhereas longer-term tryptophan depletion or starvation may decrease 5-HT levels. Agonists and antagonists of the 5-HT2AR reliably decrease and increase feeding, respectively (see
There is some evidence of increased 5-HT2AR expression in overweight individuals; although seeand reduced 5-HT2AR expression in anorexia nervosa (AN). That patients recovered from AN continue to display reduced 5-HT2AR expressionmight be interpreted as suggesting that decreased 5-HT2AR expression is an inherited trait marker of AN, but we suggest a compensatory long-term downregulation of 5-HT2ARs in AN could also occur in response to chronic overactivation of 5-HT2ARs associated with restricted feeding. Enduring but state-specific decreases in 5-HT2AR expression, as well as epigenetic modifications of the 5-HT2AR, have been observed in schizophrenia; see below. Sleep deprivation can serve as a model of psychosis and the relationship between sleep deprivation/disorders and psychosis is well established. Sleep deprivation is associated with a rapid upregulation of 5-HT2AR expression in rodentsand increased cortical 5-HT2AR binding in humans. Antagonists and agonists of the 5-HT2AR promote sleep and wakefulness, respectively (seefor review), and both increases and decreases in 5-HT levels following sleep deprivation have been observed (seefor review), although increased 5-HT levels may be more likely if combined with malnourishment. Severe and chronic pain and pain-processing abnormalities are associated with psychosis. The function of 5-HT2AR is involved in nociception and antinociceptive response in peripheral tissue, spine and brain in ways that are too nuanced for generalizations or coverage here. Acute pain quite reliably increases 5-HT release (seefor review of serotonin modulation of pain) and increased 5-HT2AR binding in various cortical areas is associated with tonic pain ratings in humans. The 5-HT2AR also plays a role in body temperature regulation, with agonists reliably increasing core body temperatureand antagonists blocking this effect. Antagonism of the 5-HT2AR also reduces body temperatureand blocks hyperthermic response to social defeat. Some evidence suggests that exposure to heat or cold increases 5-HT levels), but other studies found no relationship between temperature manipulations and brain 5-HT levels. We are not aware of any direct evidence showing that body temperature manipulation influences 5-HT2AR activity, but given the intentional manipulation of body temperature in spiritual and therapeutic practice (see below), there are logical reasons to suspect there may be a relationship. Preliminary evidence suggests that decreased brain pH is an endophenotype for schizophrenia and bipolar disorders (see. Acidosis (low pH) could be caused by hypercapnia due to respiratory complications, high altitude, breathing techniques, as well as ketoacidosis associated with starvation, metabolic dysregulation and alcoholism. It has been proposed that brainstem and midbrain 5-HT neurons act as chemoreceptors sensitive to extracellular pH, potentially explaining how homeostatic imbalance caused by stress might generally engage the serotonergic system and elicit psychedelic-like subjective effects via heightened 5-HT2AR agonism. Experimentally exploring this relationship, for example by testing the capacity of a 5-HT2AR antagonist to block the effects of putative CO 2 -induced psychedelic-like experience, would be a relevant and potentially fruitful future research avenue for the PiMS hypothesis. The link between stress and psychosis is well established and consistent with the 'diathesis-stress' model of psychopathology in which pre-existing vulnerabilities (diathesis = predisposition) combine with stress to catalyse transition into illness. The causal link between stress and spiritual experience may be less obvious -but it is, in fact, supported by a wealth of evidence -as we shall see more clearly in the next section. In summary, a large variety of chronic and acute intense stressors upregulate and activate the 5-HT2AR and are associated with PiMS-relevant phenomena.
Is it possible that humans have intuited how to hijack or 'hack' their own physiology for the purpose of self-development? Asceticism, or the withdrawal from sensory stimulation and dedication to a simple but disciplined lifestyle, has an ancient history of association with altered states of consciousness. Our perspective is that self-manipulated and intended 'stress' leading to increased 5-HT2AR signaling and associated PiMSs is a relevant candidate mechanism here. Various evidence supporting this view is provided below. Intentional social isolation, often in nature, is associated with spiritual and transformative experiences. Many religious narratives report that religious exemplars (e.g. Moses, Jesus, Mohammed, Siddhartha, Lao Tzu) sought extreme solitude -often in conjunction with the discovery of their benchmark philosophies. With regard to cognitive stressors, meditation on sin, guilt, death and suffering play a role in the spiritual exercises of various religious traditions. Celibacy is another ascetic practicethat may create tension and stress. Fasting, or extreme moderation of food intake, is a common religious practice. Bouts of extreme fasting, such as those reportedly undertaken by Jesus in the wilderness or Prince Siddhartha (the 'Buddha') before enlightenment, often precede important spiritual or religious revelations. Spiritual 'athletes' practice sleep restriction, promote night-time and/or early morning spiritual exercises, and in extreme cases, physically disable themselves from lying down. Endurance activities, such as the epic kaihōgyō (1000 marathons in 1000 days) or sun dance, are sometimes used for spiritual development, as is self-inflicted bodily pain and self-mortification. Manipulations of respiration and body temperature, as evidenced by yogic breathingand the Native American sweat lodge, also play roles in spiritual practices and ceremonies. Modern therapeutic techniques such as breathworkand whole-body hyperthermiacontinue to reinforce the idea that physiological stress or dysregulation can lead to meaningful changes in mental states and have been found to interface with the serotonin system. The cross-cultural and recurring practice of asceticism cannot be explained as a purely culturally contingent phenomenon. As reviewed byand noted by, 'shamans' (or their cultural equivalents), in various societies, engage in ascetic practices such as social isolation, food, sleep and sex restriction. Combining multiple ascetic practices with meditation, prayer or ritual and a background of stress may (perhaps inadvertently) create ideal synergistic conditions for the natural upregulation of 5-HT2AR signalingand thus, the emergence of a PiMS. A crucial distinction between ascetic practices and unintentional counterparts, such as social exclusion or involuntary celibacy, is that the ascetic retains a sense of control over the stressors and a willingness towards self-transformation. Although some ascetics may be predisposed towards harm avoidance in the domains of social interaction or sexual relationships, for example, a positive estimation of this behaviour m0ay be protective against the derogatory and persecutory evaluations so integral to psychosis. This raises the important question of whether ascetic behaviour directly drives the occurrence of PiMSs, or whether the onset of PiMS biases a person towards social withdrawal, celibacy, starvation, as well as other behaviours associated with asceticism. As is often the case with such 'chicken and egg' type questions, the dilemma may be solved by invoking bidirectional causality. While acknowledging the relevant causal pathways may operate bidirectionally and be mutually reinforcing, additional evidence for ascetic-like behaviour being causative of PiMSs is provided by secular uses of stress to induce altered states. For example, militaries regularly subject new recruits to psychosocial and physiological stressors in efforts to break down and reform the individual into a community-minded soldier. It is also debated whether various forms of torture involving sleep deprivation, social isolation and pain may render an individual more suggestible to the planting and/or imprinting of new/false beliefs and memories. Indeed, it seems logical, given the already cited associations between stress and the 5-HT2AR, that such torture techniques would elevate brain plasticity via upregulation and activation of 5-HT2ARs. It is therefore relevant and noteworthy that a significant history exists of combining torture, coercion and interrogation techniques with the administration of psychedelic drugs such as LSD, which are known to promote suggestibility. Returning to the question at the beginning of this section, there are good reasons to surmise that, at some given period in our evolutionary development, a perhaps universal intuition arose amongst humans that physiological manipulation can induce hyper-plastic mind and brain states; a realization that has since been exploited throughout the ages for purposes of selfdevelopment and spiritual or religious growth. In the next section, we will begin to address in more detail some candidate physiological and neuropharmacological processes that are likely to serve an important causal and/or mediational role in the induction of PiMSs. Given the special reliability with which they can induce PiMSs, we focus on the action of psychedelic drugs.
As discussed earlier, certain psychotic states (e.g. early and acute psychosis) are considered important examples of naturally occurring PiMSs. The psychotomimetic (psychosis-mimicking) effects of classic 5-HT2AR agonist psychedelics have been well documented. Importantly, psychedelics are felt to be useful models of incipient psychotic states that may be more likely to display psychedelic-like phenomena, such as changes in perception, cognition and ego functioning. Conversely, established psychotic disorders such as schizophrenia are more likely to feature characteristics of rigid cognition such as fixed delusions. Selective 5-HT2AR antagonism attenuates the main characteristic subjective effects of LSD, psilocybin and ayahuascaand the intensity of psychedelic states is reliably predicted by 5-HT2AR occupancy. Beyond the hypothesized involvement of the 5-HT2AR in the induction of psychotic states, it is generally thought that dopaminergic (DA) dysregulation serves as a 'final common pathway' underlying chronic psychoses. In support of this notion, tolerance to sustained 5-HT2AR agonism develops quickly) and more selective 5-HT2AR antagonists lacking any appreciable DA antagonism properties have not proven to be efficacious antipsychotics. However, some evidence does suggest that 5-HT2AR binding and blockade may contribute to the superior efficacy of atypical antipsychotics (particularly clozapine) in attenuating positive and negative symptoms. Pimavanserin, a selective 5-HT2AR inverse agonist, has been licensed for psychotic symptoms in relation to Parkinson's disease psychosis, with some additional evidence of efficacy for psychotic symptoms in Alzheimer's diseaseand schizophrenic psychoses unresponsive to clozapine. It has also been demonstrated that, via antagonism of the 5-HT2AR, clozapine ameliorates the psychotomimetic effects of N-methyl-D-aspartate receptor (NMDAR) antagonism in animal models. Similar findings have also been observed with risperidone (which has appreciable 5-HT2AR antagonist properties) and ketamine (an NMDAR antagonist) in humans; seefor a critique of NMDAR antagonist drug models of psychosis. Serotonin 2A antagonism has less marked effects on cognition than 5-HT2AR agonism but there is some evidence it can impair learningand promote compulsive behaviouras well as sleep. Thus, it is possible that some of the therapeutic effects of 5-HT2AR antagonist antipsychotics may be due to a generic negative action on learning-related cognition and wakefulness. Given the central thesis of this paper, the deployment of 5-HT2AR antagonists early in the etiology of a psychotic disorder may conceivably prevent conversion to psychosis via suppressing the occurrence of a mediating pre-or peri-psychotic PiMS. Consistently, 5-HT2AR antagonism has been found to blunt or reduce cortical plasticity. Whether such actions have net positive or negative repercussions for long-term mental health is a complicated question, but seefor an interesting and relevant perspective. Most post-mortem studies that have assessed 5-HT2AR levels have reported downregulated 5-HT2AR mRNA and protein expression in the cortex of individuals who had schizophrenia, and in vivo imaging of 5-HT2AR binding in schizophrenia also suggests decreased cortical receptor densities (see. Decreased 5-HT2AR expression in schizophrenia may be state specific, as decreased 5-HT2AR binding in first-episode psychosis correlates with severity of positive symptomsand healthy monozygotic siblings of affected persons do not display decreases in 5-HT2AR binding. It is plausible that in prolonged psychoses, the 5-HT2AR becomes adaptively downregulated after an initial period of heightened activity, consistent with agonist-induced downregulation of the 5-HT2AR. Evidence of epigenetic modification of the 5-HT2AR in schizophreniais also relevant here. It seems plausible that a cortical abnormality mediated by increased 5-HT2AR signaling and related glutamatergic activityand featuring abnormal plasticityand associative learning -as mediators of major psychological change -is an important early component of the psychotic process in schizophrenia; whereas 5-HT2ARmediated dysregulation of dopamine activity is a consequential, and perhaps defining component, namely 'the final common pathway'. If we allow ourselves to be instructed on the pharmacology of the psychotic process via its phenomenology, then an initial state characterized by ego-disturbance and cognitive and perceptual disturbance preceding subsequent inflexible or perseverative cognitive and behavioural stylesmight fit with an initial serotonergic (5-HT2AR) component (although see, followed by a final pathway that is dominated by a hyperactive mesolimbic dopamine system. However, converging evidence also suggests that upregulation, sensitization, and direct agonismof 5-HT2AR contributes to dopamine-induced psychoses. Indeed, manic states might precipitate incipient psychoses in a similar fashion. It may be relevant in this sense that some shared features have been found in the phenomenology of spiritual experiences and positive psychotic symptoms and the psilocybin experience whereas manic symptoms appear to be mimicked more reliably by pro-DA stimulant drug experiences. Beyond psychosis, psychedelics offer a reliable model of 'peak', 'god-encounter', 'mystical-type', near-deathand other such anomalous experiencesthat bear an undeniable resemblance to experiences designated as 'religious' or 'spiritual'. Trait absorption is one of the most reliable predictors of sensitivity to the subjective effects of psychedelicsand has also been found to predict spiritual experiences induced via various means. The 5-HT2AR rs6313 TT genotype is associated with trait absorption and altered time-perception in humans, both of which are implicated in spiritual experiences and NDEs. NDEs and psychedelic experiences feature 'time-dilation'and altered time perception has also been reported in psychotic states (seefor review) and PTSD.
We begin this section with a focus on the psychology of the psychedelic experience before turning our attention to its neurobiology, with specific reference to human brain imaging studies with psychedelics. Psychedelics induce cognitive-perceptual instability, relax one's normal sense of agency and ownership over perceptual objects, including one's own body and at higher doses, reliably produce different degrees of 'ego-dissolution'. Psychedelics also elicit an increased emotional lability -not inconsistent with infancy, early psychosis and spiritual experiences. The recently developed RElaxed Beliefs Under pSychedelics (REBUS) model proposes that, via a 5-HT2AR-induced entropic effect on cortical activity, psychedelics relax the precision weighting (i.e. inverse variance) of high-level priors (internal predictive models), thereby allowing bottom-up information ('prediction error') to flow more freely up the brain's functional hierarchy to impress on highlevel cortices and enter conscious awareness. It is proposed that this process is necessary for the effective revision of priors or beliefs. This model has recently received support from the application of travelling wave analyses to DMT electroencephalogram (EEG) data, where a rapid shift from top-down to bottom-up dominating waves coincided very closely the onset and subjective intensity of the DMT experience. The REBUS model is consistent with much of the phenomenology of the psychedelic experience, including intense spiritual, 'peak' or 'mystical-type' experiences (see. In these (typically high-dose) experiences, discriminative beliefs (e.g. A is different to B) are often moderated and replaced by a sense of reciprocal interconnectedness, which is referred to as the 'unitive experience' in studies of 'mystical' or 'spiritual' experiences. Such experiences may account for lasting psychological changes seen with psychedelics, such as enduring increases in the personality trait 'openness'as well as improvements in wellbeing. Thus, during and after profound psychedelic experiences, specific beliefs and the emotional valences attached to them seem particularly susceptible to change, consistent with so-called 'quantum change experiences' (C'De. Returning to the phenomenology of the psychedelic state, peak, mystical-type or spiritual experiences and associated feelings of oceanic boundlessness have been found to reliably predict positive outcomes in psychedelic therapy. However, they may also represent an extreme experience only achievable (to most people) through pharmacological manipulation. Achieving the same quality and intensity of experience may be difficult via spiritual practice alone; although a recent study comparing the interaction between psychedelics and meditation has suggested a potential synergistic effect; see also. Given our focus on stressinduced PiMSs and associated psychological transformation, it is worth taking a closer look at the common themes of psychological struggle and breakthrough in psychedelic experience. Through the relinquishment of top-down control effected by high-level priors, psychedelics may free suppressed emotions and memories so they may more easily percolate into consciousness awareness. Such emotions and memories may be felt as being emotionally challenging. Feelings of anxiety are common during and after psychedelic experiencesas are symbolic/archetypal themes;. Intense personal and transpersonal themes can rise to the forefront of awareness. Values can be 'remembered'and affect-laden beliefs that previously seemed 'abstract' (e.g. 'love is fundamental') can be deeply felt. Cathartic release under psychedelicsmay foster an emotional re-evaluation of cognitive) and philosophical perspectives) that may have previously been closely tied in with a person's pathology. Appropriately managed, psychedelic experiences can lead to an increased willingness and an ability to engage with emotionally difficult psychological material. In therapeutic contexts, this experience is generally positive and is associated with an enhanced sense of emotional empathyand prosocial feelings and behaviour. It warrants stating, however, that extreme negative affect, including paranoid ideation and occasional injurious behaviour, can also arise during psychedelic experiences, particularly if the contextual frame in which the experience occurs is not sufficiently well controlled and supportive.
The following psychological factors have been found to be altered in an enduring way with psychedelics: (a) personality; (b) mental health and wellbeing; (c) political perspective; (d) lifestyle preferences; and (e) feelings towards the environment/nature.
Functional brain imaging studies of the acute psychedelic state using a variety of psychedelics have observed decreases in the functional modularity of a broad range of functional modules, including high-level networks such as the default-mode and fronto-parietal control network. Moreover, decreases in the integrity of these networksas well as their reduced presence at any given point in timeappear to relate to high-level aspects of the drug-induced subjective experience, including 'ego-dissolution'. Under psychedelics, the normal functional segregation or specialization in the brain is instead replaced by a globally interconnected profile. It is natural to speculate that this increase in global connectivity in the brain under psychedelics relates to the weakening of discriminative cognition (e.g. A versus B), exemplified by the unitive experience as well as 'non-dual awareness'. It is easy to see how something akin to the unitive experience may occur in early psychosis, in which compromised ego-boundaries are reportedand similar changes in functional connectivity have been seen in early psychosis as with psychedelics. Decreased orthogonality between high-level networks (e.g. the default mode and salience networks) may also be a sub-acute effect of ayahuasca, although this effect has not been seen consistently (sub-acutely) with psilocybin. Psychedelics have been shown to promote extinction-learning through 5-HT2AR agonismas well as low-level associative learning, for example, as has been nicely demonstrated by the catalysing influence of LSD (a 5-HT2AR agonist) on learning rate versus the impairing influence of ritanserin, a 5-HT2AR antagonist. Consistently, psychedelics have been shown to potently increase cortical neuroplasticity. A doubling of BDNF mRNA was found in the parietal cortex after administration of the 5-HT2AR agonist DOIand markedly increased functional and structural neuroplasticity has been found after DMT, LSD and 2,5-Dimethoxy-4iodamphetamine (DOI)-leading the senior author to introduce the term 'psychoplastogen' for these and any other relevant compounds that can rapidly elicit appreciable increases in neuroplasticity. We have preliminary evidence of increased visual evoked long-term potentiation (LTP) in healthy individuals under the influence of psilocybin, and long-term changes in network functionality have also been observed 1 day, 1 weekand 1 month after psilocybinin clinicaland non-clinical populations. Increased (spontaneous) brain (activity) entropy or complexity is a highly reliable marker of the acute functional brain effect of psychedelics. Increased brain complexity has also been observed during rapid eye movement (REM) sleep, meditation, musical experiencesand certain psychotic states, with medication status, age and the stage of the psychotic process the key parameters to consider when assessing this. Acute brain entropy under LSD, measured with functional magnetic resonance imaging (fMRI), was found to predict psychological changes 2 weeks later, namely increased trait 'openness'and in a more recent study, increased brain complexity under psilocybin was found to predict both long-term changes (1 month later) in brain network functional connectivityas well as related improvements in wellbeing. Future neuroimaging analyses of ours will assess how acute brain complexity relates to functional proxies of LTP as well as long-term anatomical changes in the human brain. It is tempting to speculate that the acute brain changes seen with psychedelics, including increased complexity or entropy, are reflective of a hyper-plastic state that mediates subsequent functional and potentially structural brain changes that correlate with long-term psychological changes.
How could you rise anew if you have not first become ashes. (Nietzsche, Thus Spoke Zarathustra) As discussed in previous sections, certain types of stress upregulate 5-HT2AR expression and activity (see Tablefor a review of the relevant literature). Moreover, evidence that acute stress causes the release of 5-HT is compellingand it is logical to surmise that increased endogenous 5-HT release will engage the 5-HT2AR system, an assumption backed up by evidence of increased 5-HT2AR associated responses with drug-induced 5-HT release. These factors have led usand othersto speculate that the 5-HT2AR system is a stress response system that services adaptability. Natural questions that follow from this model include why does this function exist and what evolutionary purpose does it serve? Our proposal is that PiMSs have evolved to allow the experiencer a psychological 'fresh start', akin to a psychological 'rebirth'or allostatic recalibration. Rather than simply referring to adaptive responses to stress and adversity, which could include many of the symptoms of psychiatric disorders, the PiMS model is intended to invoke the idea that such adaptation can be radical, rapid and discrete, rather than moderate, slow and continuous. These ideas are at least partially consistent with the notion of allostasisand the adaptive calibration model of stress response, which, like the PiMS model, refuses to characterize adaptive responses to stress as necessarily 'toxic' or pathological. Thus, according to the PiMS model, the outcome of an allostatic recalibration process can be 'positive' (e.g. in terms of a therapeutic or spiritual breakthrough) but the same mechanisms could just as easily result in a new or reinforced maladaptive strategy, perhaps best exemplified by a psychotic 'flight from reality'or progressive reinforcement of other psychological defence mechanisms. Consistent with previous work, it was recently hypothesized that 5-HT2AR signaling forms part of a 'stress response system' that serves the adaptive function of reconfiguring responses to environmental stimuli co-occurring with or preceding major perceived existential threats or crises. Thus, the principle is that accelerating learningand extinction learning or 'unlearning'in such extreme situations should aid the individual in the future by causing a domain-general 'overhaul' in their outlook. Evidence of aberrant neuroplasticity in psychosis, including both increasesand decreasesin neuroplasticity markers, for example, particularly during critical developmental windows, may bear relevance to the reliable increases in plasticity linked to 5-HT2AR agonism, which are linked here with the PiMS construct. As discussed above, one way in which apparent inconsistencies in the literature may be reconciled is to consider process relevant dynamics, where, during a process, a phase of upregulation in a particular parameter (e.g. 5-HT2AR signaling and associated plasticity) can be followed by a phase of adaptive downregulation is the same parameter (e.g. decreased 5-HT2AR expression). Indeed, agonist-induced downregulation of the 5-HT2AR is entirely consistent with this principle; also see. From a neurodevelopmental perspective, we must also acknowledge that hyperactivation of 5-HT2ARs coinciding with childhood stress or chronic drug-use could negatively affect neurodevelopmental processes. Again, however, the influence of context here must be considered. Near-death experiences are relevant to the theory that the 5-HT2AR system has evolved to aid psychological transformation for adaptive ends. Altered perceptual processing, heightened emotional tone, time dilation and enhanced episodic memory encoding are all features of NDEs. The major shifts in perspective following NDEs may be the product of a period of hyperplasticity, potentially mediated by either the massive release of 5-HT or indeed endogenous 5-HT2AR agonists such as DMT during the dying process. One view is that NDE, and associated hyper-plasticity, may function to aid the individual if such life-or-death-type scenarios were to be met with again in the future. However, another, not incompatible view, is that the dramatic cognitive set-shifts seen after NDEs reflect a more fundamental 'opening-up' of high-level mental schemata to revision, consistent with a generic recalibration process and the recent REBUS model. Major cognitive revisions may enable an individual to 'start afresh' in both the behavioural and cognitive sense, with a refined and recalibrated ('judgement light') perspective. The same functional explanation could also be used in reference to 'post-traumatic growth', a construct that, at least by name, is only two decades old. The notions of allostasisand 'adaptive plasticity' and 'adaptive calibration' (seefor review) are also relevant here. A relevant recent perspective on the evolutionary origin and potential treatment of PTSDis largely consistent with an earlier perspective piece on 5-HT2AR-mediated 'active coping' and radical adaptation proposed by, as well as animal work linking serotonergic functioning to faster learning rates, plasticityand adaptability. It is also consistent with a growing literature base supporting the value of classic (5-HT2AR agonist) psychedelic therapy in the treatment of a broad range of psychiatric disorders. A crucial component of the 5-HT2ARmediated active coping modelwas that the relationship between stress and upregulated 5-HT2AR signaling is non-linear, in the sense that once stress crosses a critical threshold (the specifics of which are presently not clear) -in terms of its severity or chronicity -there is an abrupt shift in a system's functioning (e.g. global brain function) into a radically different mode (also consistent with bifurcation theory). The PiMS model maintains that the emergence of this mode is mediated by increased 5-HT2AR activity and associated plasticityand its evolutionary and adaptive function is to aid radical psychological change when its need is perceived. Evidence for such nonlinearities in the functioning of the 5-HT2AR system do indeed existand should be the focus of future PiMS-relevant hypothesis testing. Hierarchical predictive processing is an increasingly influential model of global mind and brain function that essentially posits that brains evolve and develop into predictive models of the environments they inhabit. Much of brain anatomy and function appears to be organized hierarchicallyand it is proposed that relevant predictive mechanisms are encoded in the brain's multi-level functional and anatomical hierarchies. The hierarchical predictive processing perspective has recently been applied to the action of psychedelics (i.e. in the so-called 'REBUS' model). This model, which is receiving growing empirical support, argues that the de-weighting (decreased 'precision') of internal predictive models ('prior probability distributions') under psychedelics opens a window for their subsequent revision. Consistently, it can be hypothesized here that in individuals undergoing intense PiMSs, the brain inhabits a mode of functioning that is conducive to the modulation or recalibration of internal predictive models, including how they are weighted. Major recalibrations to fundamental beliefs or outlooks have been referred to in the psychology literature as psychological 'transformations' or 'rebirths'and have received particular attention under the construct of 'quantum change' (C'De. We believe the present PiMS model extends this previous (largely phenomenological) work by proposing a plausible mechanistic account for these phenomena. One may draw parallels between the so-called REBUS model, the therapeutic application of psychedelicsand the Acceptance and Commitment Therapy (ACT) psychotherapeutic model, where the ACT approach endeavours to promote 'psychological flexibility', that is, flexible acceptance and integration of emotionally challenging memories and emotions, and seeks to do this via techniques such as 'cognitive de-fusion', which are exercises intended to foster an open, tolerant, inquisitive and accepting stance on psychological suffering and its causes. The possible combination of ACT or related mindfulness-based techniques with psychedelic therapy has been discussed in recent review papersand is now being supported by empirical findings.
The primary purpose of this review is to introduce a new psychological and neurobiological construct, the PiMS, and examine its potential causes, mechanisms and functions. PiMSs are defined by three key criteria: elevated cortical plasticity, enhanced associative learning (including extinction learning) and a special capacity to mediate psychologically transformative change. The psychedelic state can be considered a prototypical PiMSs and there is clear evidence this particular state meets all three of its defining properties. Importantly, however, it is our view that PiMSs represent a more fundamental state. We have argued that the same molecular or proteomic gateway (i.e. 5-HT2AR signalling) is implicated in non-drug, 'naturally' occurring PiMSs, as in the psychedelic state. Moreover, we argue that the psychological properties of psychedelics depend on their ability to hijack this natural system, which has evolved for mediating rapid, major and potentially lasting adaptive change. In this section, we address the therapeutic implications of the PiMSs model. Clinically supervised psychedelic experiences are showing promise for the alleviation of a large number of psychiatric symptoms and unhealthy lifestyle habits. Psychedelic therapy appears to mediate positive mental health change in a customizable and structured way, achieving a remarkable degree and reliability of therapeutic change, often via a small number of isolated therapeutic sessions, supported by subsequent psychological integration work, designed to sustain the relevant positive outcomes. In contrast to the often-distressing conditions that naturally agitate the manifestation of a PiMS, psychedelic treatment primes positive transformation via the structuring of 'set and setting'as part of a broader notion of 'context'. In addition to the treatment of diagnosed psychiatric illness, present findings indicate that psychedelic therapy offers an opportunity for the de-weighting of a plethora of maladaptive cognitive/ perceptual schemas or 'sets' about self, others and the world. This realization implies a broad, 'transdiagnostic' therapeutic value (Figure). Relatedly, data indicate the deployment of this intervention may yield benefits beyond diagnosed mental illness. For example, given observed improvements in psychological wellbeingincluding resilience-related changes, it is conceivable that psychedelic therapy could be used as a prophylactic or preventative intervention, for example, promoting adaptability in adversity. We are aware that similar inferences have Figure. A conceptual schematic illustrating the putative transdiagnostic relevance of over-weighted internal predictive models or 'priors' and how they may be effectively targeted by carefully engineered pivotal mental states (PiMSs). This is represented metaphorically by a dart (serotonin 2A receptor (5-HT2AR) signaling inducing a PiMS), targeting the central space where different psychopathologies overlap. The shared characteristic of these psychopathologies is hypothesized to be over-weighted predictive models. Such over-weighted priors may be thought of as aberrant habits or biases (e.g. negative cognitive biases in depression, aberrant self-image in eating disorders or compulsive behaviours in OCD or addiction). Effective PiMS-based therapy should aim to remediate this problematic over-weighting by: (a) acutely 'relaxing' problematic priors and then (b) working on promoting a more permanent recalibration of beliefs or bias, for example via a commitment to a healthy behavioural change. Note: the schematic should not be (mis)interpreted as implying psychedelic therapy is a 'cure all' . been made about ACT and psychological flexibility, namely that ACT can be transdiagnostically effective and 'psychological flexibility' is universally relevant to mental health. There are (emotional) pros and cons to recognizing PiMSs as important -perhaps universally accessible -states of mind and brain and we welcome future critique of the idea. For example, it may be (emotionally) preferable to maintain strong distinctions between spiritual experiences and psychotic episodes and reject or ignore some of the similarities. It is easy to appreciate the sensitivity of this debate: the negative stigma, prognoses and interventions that come with a diagnosis of a psychotic disorderare a heavy burden, whereas evidence that spiritual experiences and religious conversions are often associated with positive mental health outcomesargues against them being linked with pathology. Relatedly, we anticipate some pushback to what is, essentially, a secular, naturalistic/scientific approach to phenomena others might consider 'supernatural', particularly given the aforementioned emotional function that these beliefs may serve. As discussed above with reference to predictive coding, in advocating a particular framework of belief that is meant to be held with the highest level of certainty, believers are promised an escape from an existential uncertainty. Given the emotional appeal of such a prospect, it may be unsurprising that a readiness to endorse metaphysical or supernatural beliefs after a psychedelic experience is associated with (at least short-term) improvements in psychological wellbeing. However, important questions need to be asked here about the sustainability of any such effect. One should be mindful of how recourse to supernatural belief may offer the believer a means of emotional escape, consistent with the phenomenon known as 'spiritual bypassing', which was also highlighted above. One must also be mindful, however, how an excessive recourse to the rationalism of science could promote a 'cognitive fusion' working against rather than for psychological flexibility and associated wellbeing. The key here may be to retain a healthy and appropriate scepticism and uncertainty (e.g. of both specific scientific principles and religious dogma), balanced with respect for assumptions that have been found (e.g. via the scientific method) to be reliable and robust to scrutiny. We have placed significant emphasis on the 5-HT2AR system throughout this paper, but it should be acknowledged that some prefer to extend the definition of psychedelics beyond action at this particular receptor. MDMAand ketamineare two relevant examples in this regard. Like the classic psychedelics, MDMA and ketamine have both been used as adjuncts to psychotherapy, with notable success. However, the duration of the therapeutic response associated with classic (direct 5-HT2AR agonist) psychedelics (Carhart-Harris and Goodwin, 2017) appears to exceed that associated with a single exposure to ketamine and although MDMA causes an appreciable increase in activity at the 5-HT2AR through its potent release of 5-HT, the nonspecific nature of MDMA's pro-serotonergic, and indeed noradrenergic and DA effects, complicates our understanding of its (pharmaco)therapeutic mechanisms. It is relevant to ask whether we feel it possible for PiMSs to occur without the involvement of increased 5-HT2AR activity. Although it is plausible to imagine this possibility, for example via a non-5-HT2AR-induced increase in cortical excitation, it also seems reasonable to assume that increased 5-HT2AR signaling may be a particularly robust and reliable inducer. One implication of this is that blocking the 5-HT2AR, as is done routinely in psychiatry via a broad range of psychiatric medications, would make PiMSs, and thus, transformative psychological change, less likely. If this is the case, it might support the fear of some that chronic medication with conventional psychiatric medication diminishes the chances of spontaneous remission and renders the medicated person vulnerable to relapse if the stabilizing medication is withdrawn. Accordingly, remaining unmedicated might provide greater opportunity for self-development. The obvious counterargument to this perspective, however, is that untreated psychoses render an individual more susceptible to relapse and that recurrent psychotic episodes serve to further reinforce illness chronicity. It is also debatable whether the incipient phase of a recurrent psychotic episode that emerges inadvertently, with few warning signsand features severe paranoia and cognitive and behavioural disturbances, really represents a viable situation for (psycho)therapeutic intervention. Certain remote contextual factors contributing to the emergence of psychotic features, such as polygenics and or early-life trauma, might make the shepherding of a PiMS in a positive direction particularly challenging and, indeed, risky to attempt. This debate speaks to an important cautionary point about presenting PiMSs as inherently therapeutic. Although PiMSs, by definition, represent opportunities for major change, change is not inevitable and neither are 'positive' outcomes necessarily more likely than negative ones. In keeping with the so-called 'plastic paradox', in the same way that states of hyper-plasticity can aid unlearning in the service of new perspectives and behaviour, they can also serve to reinforce old beliefs and biases if the relevant entraining conditions exist.
This paper is a theoretical piece with a narrative style. Such approaches inevitably sacrifice self-critique and counterargument in favour of placing the spotlight on supportive evidence. There are obvious limitations to this style, with a 'cherry-picking' confirmation bias being one notable problem. We therefore strongly encourage critiques of this work. Moreover, although we have tried to be thorough in our coverage of the literature, it not feasible to be entirely exhaustive and it is inevitable that some truncation and oversight of relevant material has occurred. For example, the perspective that psychedelics model aspects of both (early and acute) psychosis and spiritual experience is treated as largely consensualbut either of these positions could be challenged. This paper's focus on a small number of example PiMSs could also be questioned. One might argue that the chosen examples are not necessarily ideal and, more specifically, that too much emphasis has been placed on psychosis in particular, ahead of other compelling alternatives, such as trauma or panic attacks. Our preferential focus on psychosis stems from: (a) the wealth of research that has been conducted on psychosis, particularly in relation to the role of the 5-HT2AR system, and (b) that it has a history of having been compared and contrasted with spiritual experiences, which is a conflict that the PiMS model bears special relevance to. Other states we could have looked at in relation to PiMSs include REM sleep, particularly given its phenomenological qualities, sensitivity to 5-HT2AR manipulation, evidence for its role in processing stressful scenariosand similarities between its neural correlates and those of the psychedelic state. Other candidates include the 'dreamystate' aura of temporal lobe epilepsy, meditative statesand certain states observed in dissociative identity disorder. Our emphasis on the importance of contextual factors may seem neglectful of possible genetic and neurodevelopmental predispositions to psychosis and the heterogeneous aetiologies of psychotic disorders more generally. We do accept that not all psychoses have their origins in easily identifiable PiMSs and that genetic and neurodevelopmental factors can influence both the occurrence and outcome of a PiMS. Thus, contrary to dismissing remote aetiological factors, it is our hope that this review will increase interest in translational research and a biopsychosocial perspective that appreciates the relevance of conditional and relational dependencies. Our selective focus on the 5-HT2AR might also be critiqued but we feel this is justified by the wealth of supportive evidence for its association with PiMS-relevant phenomena and that this may have been overlooked in the past. The present upsurge in interest in classic psychedelics should be welcomed as it has historically been unreasonably difficult to conduct research with these compounds. It is inevitable that progress in our understanding of the 5-HT2AR system will have suffered as a result. We acknowledge that other neurotransmitters such as noradrenaline and acetylcholine, glutamate, dopamineas well as the endocannabinoidand opiate systemswill likely play a role in shaping the quality of PiMSs and their outcome but we maintain that the 5-HT2AR plays a particularly central role, deserving of special attention. We might also consider whether PiMSs are always transient states or whether they can occur as more protracted episodes or phases, perhaps with more attenuated characteristics in each of the three defining criteria. Infancy, and childhood more generally, might be considered a protracted PiMS or pivotal mental phase. Indeed, the quality of consciousness in infancy has been likened to psychedelicand spiritual statesand is a period during which we are particularly sensitive to contextual influences that may have an exaggerated influence on our psychological development. Perhaps a period of 'microdosing' with a psychedelic might be considered another valid example of a pivotal mental phase rather than a singular state per seand, similarly, the at-risk mental state may express more as a protracted phase or process, rather than an entirely discrete state. The PiMS model could also be applied to processes of ideological radicalization and deradicalization. According to one constructivist model of radicalization, self-invalidation and uncertainty lead to a creative reconstruing of the self, followed by a tightening of beliefs around a newfound identity. This theory is consistent with the 'Decentring' model of religious experience, the social defeat hypothesis of schizophreniaand our proposal that psychological flexibility often gives way to psychological rigidity (e.g. delusional ideation) in the psychotic process, as in many psychopathologies. Drastic recalibrations of beliefs in response to interpersonal stresses and uncertainties are common features of psychotic, religious and radical conversion experiences. Throughout this review, we have placed emphasis on the role of stress in increasing 5-HT2AR expression and signaling and cited evidence linking increased 5-HT2AR signaling with aspects of neuroplasticity. However, there is also evidence that stress can negatively impact neuronal integrity, particularly in the hippocampusand may also cause certain functional impairments. This apparent inconsistency needs to be addressed, if not reconciled. Attempting this, one might propose that plasticity is not a singular homogenous phenomenonand (like the PiMS itself) neither is it intrinsically salutogenic, that is, promoting of health. Moreover, there is good evidence that stress can facilitate aspects of learningas is the case with trauma, for example. Thus, it would be hasty to cite evidence of the negative impact of chronic stress on regionally specific neuronal integrity (e.g.or aberrant synaptic plasticity in schizophreniaas evidence against the model being presented here. One should also note that we have specifically identified cortical plasticity as a key criterion for PiMSs. One other point of critique is that our central construct, the PiMS, merely repackages previously introduced psychological constructs such as 'quantum change' (C'Deand 'transformative experiences'. There is, however, surprisingly little scientific literature on the latter phenomenon and both constructs lay emphasis on change or outcome rather than the mediating state itself. Moreover, there is little-to-no discussion of the underlying neurobiology of quantum change and an arguably one-sided emphasis on positive outcomes. Thus, we feel there is a great deal of scientific and pragmatic value in focusing more on the psychological and neurobiological nature and function of an outcome agnostic, yet (outcome) pivotal, mediating state. We do, however, encourage the reading of literature on quantum change in particular, as it provides a rich coverage of PiMS-relevant phenomenology, including the prevalence with which individuals report psychological crises prior to the onset of a PiMS/quantum change experience. Some other potentially relevant constructs include: (a) the 'healing crisis' or Jarisch-Herxheimer reaction, namely, the principle that a period of heightened pain/suffering can be part of a healing process; (b) the 'hero's journey', which is the notion that a process of overcoming existential struggle and suffering can be positively (trans)formative; and (c) the notions of allostasisand adaptive plasticity and calibration. Finally, we are mindful that a significant amount of validation work must now be done to better define the PiMSs construct as well its usefulness as a model. This process should include demonstrating what the PiMS is not -discriminate validity. Relatedly, although good evidence has been provided that the psychedelic state meets all three defining properties of a PiMS, the same evidence has not been collated for other candidate PiMSs. This must be addressed if the case for the fundamental nature of PiMSs is to be strengthened. One way we could model the natural occurrence of PiMS in humans would be to use stress-induction paradigms that are proven to reliably upregulate the 5-HT2AR system in nonhuman animals, such as sleep deprivationor CO 2 inhalation-induced hypercapnia. A 5-HT2AR antagonist pretreatment or combined EEG and positron emission tomography (PET)-fMRI technology could be utilized to examine the neurochemistry, neurophysiology and phenomenology of the relevant state. Thus, this review should be regarded as a first step in what may be a lengthy but ultimately fruitful validation process.
This paper has proposed that certain traumatic, spiritual, psychedelic and psychosis-relevant experiences can be viewed as examples of what we call PiMSs: transient, intense hyper-plastic states of mind and brain that have the potential to mediate rapid, major and potentially enduring psychological change. Various stressors have been found to upregulate the 5-HT2AR system and converging evidence implies that increased 5-HT2AR signaling may be a key molecular gateway through which PiMSs arise. The pharmacology, systems-level neurobiology and phenomenology of the (5-HT2AR agonist) psychedelic drug state is treated as particularly informative in this regard. PiMSs represent special opportunities for psychological transformation and we propose this may occur through the recalibration of mental schemata, consistent with a recent model of the therapeutic action of psychedelics. We propose that 5-HT2AR-mediated PiMSs have evolved to aid major perspective shifts, when conditions demand them. The 5-HT2ARmediated PiMS may represent a 'last gasp' attempt to resolve an intolerable situation, for example, after the expiration of mere tolerance. Suicide and psychosis are tragic but not inconsistent 'solutions' within this framework but positive, psychological 're-birth' is another. Before the relatively recent advent of secular psychology, religious traditions provided useful resources to prepare and guide individuals through PiMSs, for example, for purposes of self-transformation and growth. Note, in this regard, religions have excellent narrative and infrastructural resources for dealing with 'psychological rebirth'. In modern secular environments, we presently lack the same quality of integrated support, shared values and unified vision. Thinking towards the future, consideration could be given to the value of creating humanistic contexts supportive of positive self-transformation. Consistent with principles of new-wave psychotherapies, including psychedelic therapy, one can envision an ideal future in which psychological crises are seen less as emergencies requiring immediate suppressive intervention and more as opportunities for development and growth, if, of course, appropriately supportive contexts can be provided for this.
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