Pivotal mental states

Introduction

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 texts (Miller and C’de Baca, 2001; Paul, 2014) as well as influential therapeutic programmes (Wilson and Cohen, 2015), 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 post-traumatic stress disorder (PTSD) or post-traumatic growth (Tedeschi, 1999), 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 1). This process will later be linked to the phenomenon of bifurcation as described in dynamical systems theory (Kielhöfer, 2011). PiMSs share many parallels with so-called ‘quantum change’ experiences, which have been defined as ‘vivid, surprising, benevolent, and enduring personal [psychological] transformation[s]’ (Miller and C’de Baca, 2001). As will become clear, however, we offer a more precise state (as opposed to outcome) focused, neurobiologically grounded definition of PiMSs that links their hypothesized neuropharmacology and systems-level neurophysiology with their phenomenology. Our 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.

OPEN IN VIEWER

Figure 1.

Process-based representation of the pivotal mental state (PiMS). Chronic stress is the primer and acute stress is the trigger of a PiMS, which functions as a mediating state for rapid psychological change.

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 perspectives (Hayes, 2019; Hayes et al., 2013) as well as the biopsychosocial approach to mental health (Engel, 1977), 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’ (Hayes, 2019) 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 2).

OPEN IN VIEWER

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).

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 (Carhart-Harris et al., 2018c; Hartogsohn, 2016; Hayes, 2019; Johnson et al., 2008; Leary et al., 1963). 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.

The psychopharmacology of PiMSs takes centre stage in this article. We place special focus on the serotonin system and its 2A receptor (5-HT2AR) subtype in particular, which has been shown to be particularly implicated in biology x environment interactions (Chang et al., 2017; Dressler et al., 2016; Fiocco et al., 2007; Jiang et al., 2016; Jokela et al., 2007; Lebe et al., 2013; Mellman et al., 2009; Parade et al., 2017; Salo et al., 2011). Various acute stressors appear to be reliable and robust inducers of serotonin release (Adell et al., 1997; Amat et al., 1998, 2005; Bastani et al., 2017; Beitia et al., 2005; Bland et al., 2003; Cohen et al., 2015; Ferres-Coy et al., 2013; Fuenmayor and Garcia, 1984; Fujino et al., 2002; Gardner et al., 2005; Hale et al., 2011; Higuchi et al., 2019; Ishida et al., 1997; Ishiwata and Greenwood, 2018; Johnson et al., 2005; Keeney et al., 2006; Kelly et al., 2011; Li et al., 2015; Myers and Beleslin, 1971; Nakajima et al., 2009; Neugebauer, 2020; Paul et al., 2011; Rex et al., 2005; Yoshioka et al., 1995) and different types of stressor, such as sleep deprivation (Elmenhorst et al., 2012; Maple et al., 2015; Zhao et al., 2019), hypoxia (Anju et al., 2011), chronic tryptophan depletion (Cahir et al., 2007), inflammation (Zhang et al., 2001), tonic pain (Kupers et al., 2009), repeated forced swim (Takao et al., 1995), repeated shock (Dwivedi et al., 2005), administration of stress hormones (Jitsuiki et al., 2000; Kuroda et al., 1992, 1994), amygdala stimulation (Kalynchuk et al., 2006), time-dependent stress (Harvey et al., 2003), novelty stress (Aloyo and Dave, 2007), maternal separation (Benekareddy et al., 2010, 2011; Godar et al., 2019; Vazquez et al., 2000; although see Ohta et al., 2014), isolation rearing (Preece et al., 2004; Rilke et al., 1998), isolation housing (Günther et al, 2008; Schiller et al., 2003; although see Bibancos et al., 2007; Schiller et al., 2003) and social defeat (Berton et al., 1997; McKittrick et al., 1995; although see Visser et al., 2014) all appear to upregulate 5-HT2AR expression, particularly in the cerebral cortex (Anju et al., 2011; Benekareddy et al., 2010, 2011; Berton et al., 1997; Cahir et al., 2007; Dwivedi et al., 2005; Elmenhorst et al., 2012; Godar et al., 2019; Günther et al, 2008; Harvey et al., 2003; Jitsuiki et al., 2000; Kalynchuk et al., 2006; Kupers et al., 2009; Kuroda et al., 1992, 1994; Maple et al., 2015; McKittrick et al., 1995; Ossowska et al., 2001; Preece et al., 2004; Rilke et al., 1998; Takao et al., 1995; Vazquez et al., 2000; Zhao et al., 2019; see also Table 1), which is well known to be massively expanded in humans.

OPEN IN VIEWER

Table 1.

The 5-HT2AR mediates responses to various types of stress.

Stress	Type	Finding	Citations
Cognitive stress	Chronic stress Anxiety Depression Neuroticism Panic Trauma Suicide	Upregulated 5-HT2AR binding or expression	Amidfar et al., 2017; Anisman et al., 2008; Bhagwagar et al., 2006; Dwivedi et al., 2005; Fernandes et al., 1997; Frokjaer et al., 2008; Meyer et al., 2003; Ossowska et al., 2001; Pandey et al, 2002; Shelton et al., 2009; Stanley and Mann, 1983; Takao et al., 1995; Turecki et al., 1999
		Contradictory or negative findings	Chaouloff et al., 1994; Mann et al., 2019; Steinberg et al., 2019; Xu et al., 2016
		5-HT2AR-mediated responses	Buchanan et al., 2015; Chang et al., 2017; Chaouloff et al., 1994; Jaggar et al., 2017; Lee et al., 2007; Magalhaes et al., 2010; Mellman et al., 2009; Miller et al., 2016; Xiang et al., 2019
		Contradictory or negative findings	Jaggar et al., 2017; Peričić, 2003; Xu et al., 2016; Yamada et al., 1995
Social stress	Social defeat Social isolation	Upregulated 5-HT2AR binding or expression	Benekareddy et al., 2011; Berton et al., 1997; Godar et al., 2019; Günther et al., 2008; McKittrick et al., 1995; Preece et al., 2004; Rilke et al., 1998; Vazquez et al., 2000
		Contradictory or negative findings	Bibancos et al., 2007; Ohta et al., 2014; Schiller et al., 2003; Visser et al., 2014
		5-HT2AR-mediated responses	Beig et al., 2009; Benekareddy et al., 2010, 2011; Brotto et al., 1998; Clinard et al., 2015; Geyer et al., 1999; Gorzalka et al., 1998; Rillich and Stevenson, 2018; Sakaue et al., 2002; Sinh and Ootsuka, 2019; Wright et al., 1991
		Contradictory or negative findings	None found
Physiological stress	Inflammation Hypoxia Pain Food restriction Sleep deprivation Temperature regulation	Upregulated 5-HT2AR binding or expression	Anju et al., 2011; Cahir et al., 2007; Dwivedi et al., 2005; Elmenhorst et al, 2012; Kupers et al., 2009; Maple et al., 2015; Zhao et al., 2019
		Contradictory or negative findings	Cahir et al., 2007
		5-HT2AR-mediated responses	Abbott et al., 1996; Billac and Nichols, 2019 (review); Buchanan et al., 2015; Courteix et al., 2018 (review); da Silva Soares et al., 2019; Dean et al., 2019; Flanagan et al., 2019a, 2019b; Mazzola-Pomietto et al., 1995; Nau et al., 2013; Nisijima et al., 2001; Pawlyk et al., 2006; Seyrek et al., 2010; Sinh and Ootsuka, 2019; Yu et al., 2008; Zuo et al., 2019
		Contradictory or negative findings	Courteix et al., 2018 (review); Zamfir et al., 1992

Accumulating evidence implicates the 5-HT2AR system in relation to cognitive, social and physiological stressors. In the ‘citations’ column are citations of studies that found increased 5-HT2AR binding, protein or mRNA expression in response to a variety of relevant stressors (in bold). Contradictory or negative findings are listed directly below. In the rows entitled ‘5-HT2AR-mediated responses’ we cite studies that have reported evidence of 5-HT2AR mediated responses to, and sensitization in response to, relevant stressors. It is worth noting this table is not intended to be exhaustive but does cover stressors that have been closely associated with 5-HT2AR signaling and PiMS-related outcomes.

5-HT2AR: serotonin 2A receptor.

Social isolation and defeat also reliably sensitize behavioural responses to 5-HT2AR agonists (Benekareddy et al., 2010; Brotto et al., 1998; Gorzalka et al., 1998; Sakaue et al., 2002; Sood et al., 2018; Wright et al., 1991; see also Table 1). The role of stress and the 5-HT2AR system has been the focus of two recent review papers (Carhart-Harris and Nutt, 2017; Murnane, 2019). 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 (Briere et al., 2015; Hefferon et al., 2009; Joëls et al., 2006), as can occur via traumatic encounters. Psychedelics have also been shown to increase the release of stress hormones (Alper, 1990; Calogero et al., 1989; Dos Santos et al., 2012; Hasler et al., 2004; Owens et al., 1991; Schmid et al., 2015; Strajhar et al., 2016; see Schindler et al., 2018 for review).

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 (Camporesi, 1988; Farré-i-Barril, 2012; Garrett et al., 2011; Grof and Grof, 2010; Janssen et al., 2016; Macmillan, 2013; Naor and Mayseless, 2017).

In keeping with principles of bidirectional translation (Jia, 2016), 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 (Carhart-Harris and Goodwin, 2017), plus other methods of manipulating PiMSs for psychotherapeutic ends (Fosha, 2000; Grof and Grof, 2010; Kuijpers et al., 2007). All classic serotonergic psychedelic drugs have direct agonist properties at the 5-HT2AR (Nichols, 2016), 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 (Glennon et al., 1984; Rasmussen et al., 1986; Sadzot et al., 1989); (b) a plethora of antagonist pre-treatment studies (e.g. Preller et al., 2017; Quednow et al., 2012; Vollenweider et al., 1998); and (c) evidence of a 5-HT2AR occupancy by subjective effects relationship (Madsen et al., 2019). A wealth of evidence now exists that, via their action at the 5-HT2AR (Madsen et al., 2019), psychedelics, at relevant dose ranges, reliably trigger conditions conducive to psychological transformation (Carhart-Harris and Goodwin, 2017).

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 (Jaynes, 1976), and more recently in two separate reviews (e.g. Carhart-Harris and Nutt, 2017; Murnane, 2019), 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 pre-determined. We propose that the surrounding context and relational frame in which a given PiMS occurs is a vital determinant of how it manifests (Hayes et al., 2013). 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 event (Carhart-Harris et al., 2018c; Kornfield, 2001) can enable PiMS-related psychotherapy to be delivered most safely and effectively.

We focus on psychedelic therapy as a prototypical PiMS-focused 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 (Carhart-Harris, 2018a). We believe that a growing appreciation of PiMSs could inspire a healthy pivot in mental healthcare and research, more firmly towards the biopsychosocial model (Engel, 1977). Psychedelic therapy, and the PiMS-based model more generally, are quintessentially ‘biopsychosocial’ (Deacon, 2013) 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 (World Health Organization, 2017). 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’ (Grof and Grof, 2010), meditation (Kuijpers et al., 2007) and accelerated psychotherapies (Fosha, 2000), 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 (Erritzoe et al., 2017; Strassman, 1984), if the surrounding context is negative, for example, as is often the case in the aetiology of psychosis (Varese et al., 2012b) and perhaps even more plainly, PTSD (Kilpatrick et al., 2003). 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 (Carhart-Harris et al., 2018c; Kornfield, 2001; Schlosser et al., 2019). 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 (Carhart-Harris et al., 2018c; Kessler et al., 2010).

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; see Letheby (2016) for 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 (Olthof et al., 2019). Themes of psychological flexibility (Zhang et al., 2018) and experiential acceptance (Rochefort et al., 2018; Watts et al., 2017) are 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 predisposition (Davis et al., 2016) and early life adversity (Szyf, 2013; Varese et al., 2012b) in 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 2). 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 (Kielhöfer, 2011). In the schematic below (Figure 3), 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.

OPEN IN VIEWER

Figure 3.

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 (Kielhöfer, 2011); the details of this are beyond the scope of this article.

Pivotal mental states and their divergent outcomes

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 (Baldacchino, 2016; Buckley, 1981; Cangas et al., 2008; Crespi et al., 2019; Grof and Grof, 1989; Hunt, 2000, 2007; Jackson, 1997; Jaynes, 1976; Luhrmann, 2017; Lukoff, 1985, 2007, 2018; Murray et al., 2012; Parnas and Henriksen, 2016; Perry, 1977; Polimeni, 2018; Powers and Corlett, 2018; Ross and McKay, 2018; Willard and Norenzayan, 2017). All three phenomena are reliably induced by 5-HT2AR agonist psychedelics (Carhart-Harris, 2007; Carhart-Harris and Friston, 2010; Kraehenmann et al., 2017; Letheby, 2016; Millière, 2017; Nour et al., 2016), 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 (Jackson, 1997). Indeed, a negative or positive outcome is the paramount criterion for distinguishing between mystical and psychotic experience, respectively (DeHoff, 2015; James, 2003 [1902]). Moreover, scales used to measure trait schizotypy and spirituality also contain items relating to social and emotional adjustment, behaviour and appearance (Davidson et al., 2016; Garssen et al., 2016; Raine, 1991; Raine et al., 1994), which capture divergent responses to ego-disturbance, perceptual aberration and magical thinking (Crespi et al., 2019). 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 4). 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 oscillates (Oxford English Dictionary, pivot, def. 1., n.d.) and 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.

OPEN IN VIEWER

Figure 4.

How an outcome-biased or outcome-focused perspective can obscure the role of a common root state preceding a bifurcation that led to the outcome. Although a particularly stark outcome may manifest (e.g. the development of a psychotic episode or disorder), 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.

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’ (Day, 2005). 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 mechanisms – such as heightened plasticity – that is, the quality of being more shapeable (Oxford English Dictionary, plasticity entry, n.d.). 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 (van der Steen et al., 2017).

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 5). For example, if a PiMS is not expected and the experience is protracted, then the net effect of this is likely to be distressing (Rekhi et al., 2019; van der Steen et al., 2017). 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 (Selten and Cantor-Graae, 2005, 2007; Selten et al., 2013, 2016). In contrast, spiritual experiences appear to be more likely to arise in positive environmental contexts, such as in nature (Anderson et al., 2018).

OPEN IN VIEWER

Figure 5.

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.

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-fragmentation (Millière, 2017; Parnas and Henriksen, 2016) is often felt as invasive and torturous, whereas sensations of ‘mystical union’ or ‘inter-connectedness’ (Carhart-Harris et al., 2018b) appear to lie at the heart of positive experiences of ego-dissolution in naturally occurring (Stace, 1960) and psychedelic-induced spiritual experiences (Millière, 2017; Nour et al., 2016; Roseman et al., 2018). See Parnas and Henrikson (2016) for 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 (Masters, 2010).

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 (Roseman et al., 2019). Relatedly, feelings of ‘awe’ in nature have been found to mediate improvements in wellbeing via nature exposure (Anderson et al., 2018). The active suppression of emotion is associated with the nature and severity of symptomatology in psychosis and PTSD (Laloyaux et al., 2016; Roemer et al., 2001; Tull et al., 2018) and the duration of negative affect (but not its intensity) has been found to predict negative long-term outcomes after psychedelic drug use (Carbonaro et al., 2016).

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 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 disorder (Disner et al., 2011) would 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 (Roseman et al., 2019). 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 (Haijen et al., 2018). Negative affect predominates in schizophrenic psychosis and is associated with delusions of persecution (Paolini et al., 2016) and general cognitive disorganization (Carrigan and Barkus, 2017). Conversely, positive affect predominates in western conceptions of spiritual experience (DeHoff, 2015; Hardy, 1979) as well as psychedelic drug experiences (Liechti et al., 2017), 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 delusions (Iyassu et al., 2014; Wessinger, 2000) and manic psychoses (Picardi et al., 2018). 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 Carhart-Harris et al., 2013). 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 symptoms (Cardno and Owen, 2014; Craddock et al., 2009; Laursen et al., 2009) and 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 (Masters, 2010). For example, the zealous promotion of self/ego transcendence in the absence of subsequent psychological integration could be regarded as a (subtly) negative, or at least ‘imperfect’, context (Kornfield, 2001).

Psychotic episodes and spiritual experiences are both commonly preceded by a dissatisfaction with reality and one’s place within it (Hardy, 1979; James, 2003 [1902]; Miller and C’de Baca, 2001). 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 (Corcoran et al., 2011; DeVylder et al., 2014; Rietdijk et al., 2013). 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 (James, 2003 [1902]: 149–155). One should be mindful how transition into a psychotic episode or spiritual experience can be construed as a ‘manic defence’ (Winnicott, 1935), that is, an escapist ‘flight from reality’. See again Masters (2010) on 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 (Møller and Husby, 2000, 2003). Thoughts may begin to feel unrelated to the self and emotionally distant (Parnas and Handest, 2003). Individuals may find themselves examining their thoughts and behaviours from a third-person perspective (Nelson et al., 2016), as aware yet dissociated subjects (Parnas and Handest, 2003). 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) (Parnas and Henriksen, 2016) as well as the related notions of ‘non-dual awareness’ (Josipovic, 2014) and the ‘unitive experience’ (Stace, 1960).

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’ (Merriam-Webster, salvation entry, def. 3., n.d.). 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 healing (Csordas and Lewton et al., 1998; Lang et al., 2015) and 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, stress and the 5-HT2AR

Psychedelics, pivotal mental states and the 5-HT2AR

The adaptive function of pivotal mental states

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 Table 1 for a review of the relevant literature). Moreover, evidence that acute stress causes the release of 5-HT is compelling (Adell et al., 1997; Amat et al., 1998, 2005; Bastani et al., 2017; Beitia et al., 2005; Bland et al., 2003; Cohen et al., 2015; Ferres-Coy et al., 2013; Fuenmayor and Garcia, 1984; Fujino et al., 2002; Gardner et al., 2005; Hale et al., 2011; Higuchi et al., 2019; Ishida et al., 1997; Ishiwata and Greenwood, 2018; Johnson et al., 2005; Keeney et al., 2006; Kelly et al., 2011; Li et al., 2015; Myers and Beleslin, 1971; Nakajima et al., 2009; Neugebauer, 2020; Paul et al., 2011; Rex et al., 2005; Yoshioka et al., 1995) and 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 (Kuypers et al., 2018; Liechti et. al., 2000; Pitts et al., 2017; van Wel et al., 2012). These factors have led us (Carhart-Harris and Nutt, 2017) and others (Murnane, 2019) to 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’ (Brodersen and Glock, 2016; White, 2004) or allostatic recalibration (Ellis and Del Giudice, 2019). 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 allostasis (McEwen, 2019; Sterling and Eyer, 1988) and the adaptive calibration model of stress response (Ellis and Del Giudice, 2019), 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’ (Broome et al., 2007; Freeman et al., 2014; Lyon et al., 1994) or progressive reinforcement of other psychological defence mechanisms. Consistent with previous work (Carhart-Harris, 2018a; Carhart-Harris and Nutt, 2017), 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 (Murnane, 2019). Thus, the principle is that accelerating learning (Harvey, 2003) and extinction learning or ‘unlearning’ (Cameron et al., 2018) 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 (Stephan et al., 2009), including both increases (Yee et al., 2018) and decreases (Javitt et al., 1996; Umbricht and Krljes, 2005) in neuroplasticity markers, for example, particularly during critical developmental windows, may bear relevance to the reliable increases in plasticity linked to 5-HT2AR agonism (Ly et al., 2018; Olson, 2018), 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 (Bull et al., 2004; Erritzoe et al., 2011; Muguruza et al., 2014; Reneman et al., 2002; also see Madsen et al., 2020). 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 hyper-plasticity, potentially mediated by either the massive release of 5-HT or indeed endogenous 5-HT2AR agonists such as DMT during the dying process (Dean et al., 2019). 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 (Carhart-Harris and Friston, 2019). 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 (Carhart-Harris and Friston, 2019). 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 (Tedeschi, 1999). The notions of allostasis (McEwen, 2019; Sterling and Eyer, 1988) and ‘adaptive plasticity’ and ‘adaptive calibration’ (see Ellis and Del Giudice, 2019 for review) are also relevant here.

A relevant recent perspective on the evolutionary origin and potential treatment of PTSD (Murnane, 2019) is largely consistent with an earlier perspective piece on 5-HT2AR-mediated ‘active coping’ and radical adaptation proposed by Carhart-Harris and Nutt (2017), as well as animal work linking serotonergic functioning to faster learning rates (Harvey, 2003; Iigaya et al., 2018), plasticity (Iigaya et al., 2018) and adaptability (Matias et al., 2017). 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 (Carhart-Harris and Goodwin, 2017; Nutt et al., 2020; Rucker et al., 2018). A crucial component of the 5-HT2AR-mediated active coping model (Carhart-Harris and Nutt, 2017) was 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 plasticity (Olson, 2018) and its evolutionary and adaptive function is to aid radical psychological change when its need is perceived (Carhart-Harris and Nutt, 2017). Evidence for such nonlinearities in the functioning of the 5-HT2AR system do indeed exist (Dwivedi et al., 2005; Madsen et al., 2019) and 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 hierarchically (Felleman and Van, 1991; Margulies et al., 2016) and it is proposed that relevant predictive mechanisms are encoded in the brain’s multi-level functional and anatomical hierarchies (Clark, 2013; Friston, 2018; Rao and Ballard, 1999; Seth, 2013). 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 (Alamia et al., 2020; Girn et al., 2020), argues that the de-weighting (decreased ‘precision’) of internal predictive models (‘prior probability distributions’) under psychedelics opens a window for their subsequent revision (Carhart-Harris and Friston, 2019). 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’ (White, 2004) and have received particular attention under the construct of ‘quantum change’ (C’De Baca and Wilbourne, 2004; Miller and C’de Baca, 2001). 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 (Carhart-Harris and Friston, 2019), the therapeutic application of psychedelics (Watts et al., 2017; Watts and Luoma, 2019) and the Acceptance and Commitment Therapy (ACT) psychotherapeutic model (Walsh and Thiessen, 2018), 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 papers (Sloshower et al., 2020; Walsh and Thiessen, 2018; Watts and Luoma, 2019) and is now being supported by empirical findings (Close et al., 2020; Davis et al., 2019).

Therapeutic implications

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 (Carhart-Harris et al., 2018c; Carhart-Harris and Friston, 2019; Griffiths et al., 2006; Harvey, 1996; Ly et al., 2018). 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 (Bogenschutz and Johnson, 2016; Carhart-Harris et al., 2018a; Carhart-Harris and Goodwin, 2017; Johnson, 2018). 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 (Richards, 2015; Walsh and Thiessen, 2018). 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’ (Carhart-Harris et al., 2018c; Hartogsohn, 2016) as part of a broader notion of ‘context’ (Carhart-Harris et al., 2018c).

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 (Carhart-Harris and Friston, 2019; Hinton and Kimayer, 2017). This realization implies a broad, ‘transdiagnostic’ therapeutic value (Figure 6). Relatedly, data indicate the deployment of this intervention may yield benefits beyond diagnosed mental illness. For example, given observed improvements in psychological wellbeing (Jungaberle et al., 2018; Walsh, 1982) including resilience-related changes (Close et al., 2020; Davis et al., 2019), it is conceivable that psychedelic therapy could be used as a prophylactic or preventative intervention, for example, promoting adaptability in adversity (Close et al., 2020; Davis et al., 2020; Murphy Beiner and Soar, 2020). We are aware that similar inferences have been made about ACT and psychological flexibility, namely that ACT can be transdiagnostically effective and ‘psychological flexibility’ is universally relevant to mental health (Hayes, 2019).

OPEN IN VIEWER

Figure 6.

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’.

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 (DeHoff, 2015; Parnas and Henriksen, 2016). It is easy to appreciate the sensitivity of this debate: the negative stigma, prognoses and interventions that come with a diagnosis of a psychotic disorder (Wong et al., 2009) are a heavy burden, whereas evidence that spiritual experiences and religious conversions are often associated with positive mental health outcomes (Griffiths et al., 2011) argues 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 (Kornfield, 2001). 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 (Hillen et al., 2017). 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 (Timmermann et al., 2019). 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’ (Masters, 2010), 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 (Hayes, 2019). 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 (Rovelli, 2018).

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. MDMA (Siegel, 1986) and ketamine (Bowdle et al., 1998) are two relevant examples in this regard (Kuypers et al., 2018; Lin et al., 2018; Schmid et al., 2014, Szlachta et al., 2017). Like the classic psychedelics, MDMA and ketamine have both been used as adjuncts to psychotherapy, with notable success (McGirr et al., 2017; Sessa et al., 2019; Wilkinson et al., 2017). 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 (van Wel et al., 2012), the non-specific nature of MDMA’s pro-serotonergic, and indeed noradrenergic and DA effects, complicates our understanding of its (pharmaco)therapeutic mechanisms (Liechti et al., 2000).

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 (Moncrieff, 2008; Omachi and Sumiyoshi, 2018; Whitaker, 2011). Accordingly, remaining unmedicated might provide greater opportunity for self-development (Whitaker, 2011).

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 (Emsley et al., 2013; Omachi and Sumiyoshi, 2018). It is also debatable whether the incipient phase of a recurrent psychotic episode that emerges inadvertently, with few warning signs (Emsley et al., 2013) and features severe paranoia and cognitive and behavioural disturbances, really represents a viable situation for (psycho)therapeutic intervention (Omachi and Sumiyoshi, 2018). 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’ (Doidge, 2007), 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.

Limitations

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 consensual (Barrett and Griffiths, 2017; Carhart-Harris et al., 2016b; Gonzalez-Maeso and Sealfon, 2009) but 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 (Carhart-Harris, 2007; Carhart-Harris and Nutt, 2014; Hobson et al., 2014; McNamara, 2016; Sanz et al., 2018), particularly given its phenomenological qualities (McNamara, 2019), sensitivity to 5-HT2AR manipulation (Monti et al., 2018; Monti and Jantos, 2006), evidence for its role in processing stressful scenarios (Suchecki et al., 2012) and similarities between its neural correlates and those of the psychedelic state (Carhart-Harris, 2007; Carhart-Harris and Nutt, 2014; Kraehenmann, 2017). Other candidates include the ‘dreamy-state’ aura of temporal lobe epilepsy (Carhart-Harris, 2007), meditative states (Millière, 2017) and certain states observed in dissociative identity disorder (Laddis et al., 2017).

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 (Nutt et al., 2013). 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 (Angela and Dayan, 2005), glutamate (Corlett et al., 2016), dopamine (Howes and Kapur, 2009) as well as the endocannabinoid (Ibarra-Lecue et al., 2018) and opiate systems (Butelman and Kreek, 2015) will 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 psychedelic (Carhart-Harris et al., 2018b; Carhart-Harris and Nutt, 2014) and spiritual states (Woodsworth, 1884) and is a period during which we are particularly sensitive to contextual influences that may have an exaggerated influence on our psychological development (Gopnik et al., 1999; Rapoport and Gogtay, 2008; Weimer et al., 2013). 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 se (Kuypers et al., 2019) and, 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 (Feixas and Winter, 2019). This theory is consistent with the ‘Decentring’ model of religious experience (McNamara, 2009), the social defeat hypothesis of schizophrenia (Selten et al., 2016) and 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 hippocampus (Conrad et al., 2017) and may also cause certain functional impairments (McEwen, 1999). This apparent inconsistency needs to be addressed, if not reconciled. Attempting this, one might propose that plasticity is not a singular homogenous phenomenon (Gray et al., 2013) and (like the PiMS itself) neither is it intrinsically salutogenic, that is, promoting of health (Doidge, 2007). Moreover, there is good evidence that stress can facilitate aspects of learning (Joëls et al., 2006) as is the case with trauma, for example (Deppermann et al., 2014; Joëls et al., 2006). Thus, it would be hasty to cite evidence of the negative impact of chronic stress on regionally specific neuronal integrity (e.g. McEwen, 1999) or aberrant synaptic plasticity in schizophrenia (Stephan et al., 2009) as 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’De Baca and Wilbourne, 2004; Miller and C’de Baca, 2001) and ‘transformative experiences’ (Paul, 2014). 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 (Miller and C’de Baca, 2001). 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 (Miller and C’de Baca, 2001). Some other potentially relevant constructs include: (a) the ‘healing crisis’ or Jarisch-Herxheimer reaction (Bryceson, 1976), 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 (Campbell, 2008); and (c) the notions of allostasis (McEwen, 2019; Sterling and Eyer, 1988) and adaptive plasticity and calibration (Ellis and Del Giudice, 2019).

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 non-human animals, such as sleep deprivation (Elmenhorst et al., 2012; Maple et al., 2015; Zhao et al., 2019) or CO₂ inhalation-induced hypercapnia (Buchanan et al., 2015). A 5-HT2AR antagonist pre-treatment 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.

Conclusion

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 (Carhart-Harris and Friston, 2019). We propose that 5-HT2AR-mediated PiMSs have evolved to aid major perspective shifts, when conditions demand them. The 5-HT2AR-mediated PiMS may represent a ‘last gasp’ attempt to resolve an intolerable situation, for example, after the expiration of mere tolerance (Carhart-Harris and Nutt, 2017). 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’ (Rambo, 1993). 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.