Psilocybin as a Psychophysical Adaptogen in Chronic Pain Rehabilitation

Abstract

Those living with chronic pain and comorbid functional disabilities are often confronted by a physically and emotionally transformative experience, impacting their identity and ability to derive meaning in life. Despite the use of various pharmacological and non-pharmacological treatments to moderate symptoms, the degree of analgesia and functional recovery are far from optimal. Psychological disorders including depression and anxiety, and maladaptive cognitive-affective states such as pain catastrophizing and fear of movement collectively impact participant engagement with rehabilitation services, leading to further deteriorations in functional status while perpetuating pain symptoms into a continuous and distressing cycle of avoidance and sedentary behavior. Psilocybin is known to produce altered states of consciousness through altered functional connectivity among key brain regions responsible for self-referential and sensorimotor processing. While preliminary evidence suggests drastic and favorable therapeutic effects among those with psychiatric disorders and unhelpful coping skills, there is limited research examining its analgesic potential and ability to foster participation in structured rehabilitation programs through changes in self-perception and meaning-making processes. The current focus article examines the application of psilocybin as a psychophysical adaptogen among those suffering from chronic pain. We propose psilocybin may be used to simultaneously improve illness identity and neuromotor outcomes through a reframing of perceived barriers to exercise engagement.

Perspective:

This focus article examines the potential of psilocybin to enhance patient engagement in chronic pain rehabilitation by modulating self-perception and meaning-making processes—two underexplored yet critical barriers to successful pain management. We also propose a novel integrative framework embedding targeted movement therapy sessions into psilocybin study protocols.

Introduction

Chronic pain is characterized by an interwoven and often distressing set of physical and cognitive-emotional symptoms.^1–5 Over 50 million United States adults live with chronic pain, with more than 19 million suffering from high impact pain that significantly restricts daily activities.⁶ Chronic musculoskeletal conditions, including back pain, arthritis, stroke, limb amputation, traumatic brain injury (TBI), multiple sclerosis (MS), spinal cord injury (SCI) and Parkinson’s disease (PD) are leading causes of pain-related disability requiring rehabilitation services within the United States, with an estimated annual treatment cost (direct and indirect) approximating half a trillion dollars.^7–9 While etiologically heterogenous, this cluster of disorders converge on their elevated risk for the development of chronic pain and other psychological comorbidities—limiting the ability of patients to recover physical function.^10–13 Individuals with chronic pain are 5 times more likely to report comorbid symptoms of depression and anxiety when compared to their pain free counterparts and 3–3.5 times more likely to report difficulties in completing daily errands and engaging in social activities, likely reinforcing daily patterns of sedentary behavior, isolation and negative affect.¹⁴ In the wake of such diagnoses, individuals may also be confronted with a discontinuity between their body and self-image, forcing a reframing of their personal identity and the capacity to find meaning in life.¹⁵ This may be especially troubling for those living with physical restrictions that impact their independence. Despite the availability of existing treatments to ease pain and psychological distress, patients often report inadequate symptom relief.^16–24 Moreover, most available pharmacological interventions carry a substantial side effect profile, and there is considerable concern about the potential over-prescription of numerous classes of habituating drugs.^25–27 Those living with chronic pain also report a variety of barriers to physical rehabilitation, including depression, negative perceptions related to treatment efficacy, lack of exercise motivation and fear of movement (kinesiophobia)²⁸—which collectively thwart their recovery. Such drawbacks necessitate investigations into alternative therapies that may complement the rehabilitation process while providing individuals with a means to reconceptualize their identity and generate meaning in life.

The recent revival of clinical interest in the use of psychedelic substances provide a significant path forward to potentially address this unmet need. The tryptamine alkaloid 4-phosphoryloxy-N,N-dimethyltryptamine (psilocybin) and it’s dephosphorylated psychoactive metabolite 4-hydroxy-N,N-dimethyltryptamine (psilocin),²⁹ belong to a class of psychedelic drugs known for their primary action on the serotoninergic (5-HT) system and ability to produce what has been described as peak, profound, or mystical experiences.³⁰ Such experiences drastically alter personality structures and neural network dynamics, fostering increased openness,³¹ reduced experiential avoidance³² and enhanced cognitive flexibility,³³ which support novel insights and engagement with healthy behaviors. In 2018, psilocybin was granted emergency breakthrough status by the Food and Drug Administration for treatment resistant depression.³⁴ Since this decision, clinical research has primarily progressed within psychiatric populations.^35–42 Despite this mental health focus, limited evidence suggests that psilocybin can be used to treat chronic pain symptoms.^43–54 This article will advance this line of inquiry further, proposing that psilocybin is a psychophysical adaptogen—defined as naturally derived plant extracts or synthetic compounds that bolsters the body’s ability to handle stress and improve physical performance^55–57—that may uniquely target cognitive-emotional aspects of chronic pain, while synergistically improving sensorimotor outcomes during structured rehabilitation programs. Notably, when properly administered in a supportive context, the risk profile and number of doses needed to produce analgesic,⁴⁸ anti-depressive, and anxiolytic effects appears to be more favorable than many commonly prescribed medications.⁵⁸ The field is still in its nascency, requiring caution in interpreting empirical data, which to date have primarily derived from small and poorly controlled studies. However, several clinical trials testing the efficacy of psilocybin for various chronic pain conditions are ongoing (NCT06355414, NCT05351541, NCT05068791, NCT05224336, NCT06368492), and the framework for a regulated psilocybin therapy industry is presently being considered across the country.^59,60

Several recent reviews highlight the potential efficacy of psychedelic substances broadly within chronic pain populations,^54,61–64 however, there has been little attention to the explicit role of psilocybin in the clinical context of chronic pain rehabilitation. Specifically, there is a need to consider the potential of psilocybin to alter self-perception, meaning-making processes, maladaptive cognitions and sensorimotor impairments associated with exercise engagement. While exercise is known to be an effective treatment strategy across many chronic pain conditions, some patients may view exercise as inherently distressing and a major facilitator of pain symptoms.^65–67 Individuals may also experience functional limitations coupled to their respective conditions as frustrating or demoralizing, further diminishing motivation to participate in physical activity.⁶⁸ Engagement with such programs may thus be bolstered by increased motivation, attention, and behavioral activation.⁶⁹ Psilocybin may provide the initial springboard to elicit such cognitive-behavioral changes. The current focus article offers a theoretical foundation from which future clinical trials can develop and test falsifiable hypotheses within a holistic framework of psilocybin-assisted chronic pain rehabilitation.

Self-Pain Enmeshment and Meaning-Making as Proposed Targets for Chronic Pain Rehabilitation

Pain is evolutionarily understood to be a protective process arising from tissue damage and inflammation, both of which promote survival and facilitate healing. However, pain that persists beyond the acute injury and natural recuperation period may become chronic and progressively debilitating. Chronic pain directly impacts the perception of functional capabilities and the sense of self—ultimately limiting adaptive behaviors (including exercise) and restricting overall autonomy.^70,71

Preclinical and human studies have advanced our understanding of how chronic pain emerges through neuroanatomical alterations within each level of the nociceptive hierarchy.² Current models suggest nociceptive inputs propagate from peripheral afferents to spinothalamic, spinoreticular and spinomesencephalic pathways, ultimately converging within corticolimbic and other deep brain circuitry to produce the conscious awareness of pain.^2,72–74 However, excessive inflammation and dysregulated neurotransmitter release in response to trauma exacerbates pain signal transduction, causing a structural transformation and reorganization of existing synapses, cells, and supraspinal circuitry.^72–75 Resultant alterations in functional connectivity between key brain regions responsible for pain processing—spanning structures within the default mode (DMN), frontoparietal (FPN) and larger salience (SN) networks—serve to cannulize pain perception into distressing, recurrent, and dysfunctional feedback loops.^74,76–79 As a consequence, many patients develop secondary cognitive-affective symptoms that reinforce pain symptoms, leading to a general erosion of mental health, decreased physical function and poorer quality of life.^1,5

Resultant sensorimotor dysfunction, distorted body representations,⁸⁰ altered social dynamics,⁸¹ and worsening negative self-beliefs⁸² can deeply disrupt the lives of those living with chronic pain, ultimately threatening their identity or sense of self.⁸³ The notion of one’s identity or self-awareness is thought to be the end result of numerous information processing systems (conscious and unconscious) that converge into higher order brain regions to form a unitary representation.⁸⁴ Once thought to be fixed, the self is now understood to be highly malleable, contingent on beliefs, memories, emotions, interpersonal relationships and the processing of real-time sense data.⁸⁵ In 1977 Markus proposed the term self-schema, which describes cognitive generalizations about the self as a repository of past and present information, enabling the categorization or organization of behavioral patterns that guide imminent judgements, decisions, inferences and predictions about the self.⁸⁶ Those living with chronic pain commonly report significant negative perceptions about their physical body and social identity, leading to emotional distress,^87–89 depression,^90,91 anxiety,^92,93 kinesiophobia⁹⁴ and pain catastrophizing,^95,96 all of which contribute to the maintenance of pain and disability. Further, individuals with negative self-perceptions commonly fall into a pattern of escape and avoidance, embodied by hypervigilance of the wounded area, negative cognitive appraisals, and decisions to limit movement.⁹⁷ These patterns consequently stifle rehabilitation efforts, creating significant barriers to treatment⁹⁸ and adversely altering notions of the self.

In 2001, Pincus and Morley proposed a cognitive processing bias model⁷¹ for chronic pain, wherein available cognitive resources are predominantly diverted to painful stimuli, culminating in a reattribution of the conceptualized self as indistinct from chronic pain symptoms. This construct is called self-pain enmeshment (See Figure 1). The theory postulated that pain, illness/disability, and self-schemas may become inexplicably bound, leaving individuals trapped within a cycle of negative self appraisals, dependence and distress that limit the lens through which they view their current and future lives. Subsequent evidence indicates that stronger enmeshment between self- and pain-schemas is associated with greater pain, suffering, anxiety and helplessness.⁹⁹ Moreover, hierarchical regression analysis indicates that depression and pain acceptance, after taking into account demographic (sex, age) and pain related variables (pain intensity and duration, pain interference), predicts the degree to which individuals identify their capacity to live fulfilling lives contingent on the absence of pain (i.e., conditional hoped for self). Emotional maladjustment among chronic pain patients therefore appears to be directly associated with judgments about the conditional relationship to their pain symptoms.¹⁰⁰ Moreover, the experience of recurrent pain symptoms and ensuing impediments to goal acquisition aligned with premorbid conceptions of self can challenge deeply held beliefs and values,⁸³ making the reconstruction of meaning a critical process for adaptation.

Figure 1: Variations in the overlap of pain, disability, and self-schemas within self-pain enmeshment.

The pain schema represents sensory aspects of pain perception involving both the intensity and spatial-temporal features of pain symptoms. The disability schema includes information pertaining to the affective and behavioral consequences of chronic pain, including physical function, autonomy and goal attainment. The self-schema is a multidimensional construct containing autobiographical memories and generalized trait-like information about the self, including behavioral tendencies and other general information about the individual within the environment. The magnitude of self-pain enmeshment and resulting level of distress is depicted by the degree of overlap between the three schemas.⁷¹

As pain persists, individuals may experience a loss of meaning in life, especially when physical and emotional symptoms conflict with former pain-free identities.^88,96,101 The Meaning Making Model¹⁰² proposes that meaning in life serves as an orienting system providing individuals with a framework to interpret their lived experiences. When challenges arise that conflict with such meaning systems, meaning-making processes are initiated to help people appraise their current circumstances and integrate new information into their world view. Core tenants of the Meaning Making Model have been used to describe how chronic pain patients understand and manage their symptoms. Patients tend to interpret the cause, controllability and threat value of their pain and when such appraisals violate their broader sense of meaning, processes of accommodation and assimilation—both attributed to meaning-making— are initiated to help individuals reinterpret and recognize their symptoms as an opportunity for personal growth and the development of acceptance.¹⁰³ While research predominately focuses on the physical and psychological symptoms of chronic pain, less emphasis has been placed on such existential dimensions including processes of meaning-making.^101,104 Consequently, meaning-making may be a viable therapeutic target that provides individuals with a psychologically adaptive advantage when faced with painful experiences through an expanded ability to cope and integrate emotionally challenging circumstances into their lives.^101,104,105

Reed et al (2023) showed that the successful management of chronic pain symptoms is at least partially contingent on the restoration of assistive meaning-making systems that inform global and situational interpretations, attributions, appraisals and personal narratives surrounding trauma or the pain experience.¹⁰⁴ The same research group found that belief in living a meaningful life despite pain symptoms is significantly associated with less pain interference, and reductions in the experience of posttraumatic stress, anxiety and depression symptoms.¹⁰⁶ Using longitudinal designs, Dezutter and colleagues (2015)¹⁰⁷ also provided evidence for this theory, showing that well-being was strongly predicted by the presence and not search for meaning in life among chronic pain patients. Different meaning profiles also impacted pain adjustment, where higher levels of meaning in the present, resulted in fewer depressive symptoms and greater life satisfaction. Conversely, greater search for meaning was associated with higher levels of depression. Boring et al (2022)¹⁰⁸ also demonstrated that a greater life coherence, a dimension of meaning in life, was associated with fewer and less severe pain experiences, and served as a protective factor in limiting the transition from acute to chronic pain. Together, such studies emphasize that targeting meaning-making processes within chronic pain populations may provide an untapped resource to facilitate adaptive behaviors, including engagement with rehabilitation services to improve movement outcomes and overall prognosis.

In an effort to address dysfunctional cognitive-evaluative constraints around pain and how such disruptions may limit rehabilitation, novel therapeutic frameworks that simultaneously target physical function, self-pain enmeshment, and meaning in life would represent an innovative approach in the way chronic pain is understood and treated. For example, rehabilitation programs typically target pain symptoms in conjunction with improved movement outcomes while simultaneously fostering adaptive cognitions associated with pain catastrophizing, kinesiophobia and motivation.¹⁰⁹ However, currently available approaches do not emphasize meaning-making and cognitively-biased sensorimotor information processing implicated in self-pain enmeshment. As a consequence, the transformative experiences, insight, and alterations in sensory processing afforded by the consciousness-altering substance psilocybin, may help to bridge this gap.

Interface Between Psilocybin, Self-Pain Enmeshment and Meaning-Making

Psilocybin produces altered states of consciousness in a dose dependent fashion, where the magnitude of perceptual, emotional and cognitive disturbances predicts its therapeutic efficacy.^110–112 Subjective effects of psilocybin including drowsiness becomes noticeable at approximately 3 – 5mg, however, strong psychedelic effects occur at dosages approaching 20 – 30 mg.¹¹³ Within this higher dose range, patients commonly report acute somatosensory effects (e.g., synesthesia and paresthesia), ego-dissolution, impaired perception of time and space and altered life meaning,¹¹⁰ with longitudinal studies indicating persistent and positive shifts in attitudes and behaviors months after drug administration.^114,115 These converging effects directly align with the proposed targets of sensorimotor impairment, self-pain enmeshment, and disrupted meaning-making processes that jointly reinforce chronic pain symptoms. Moreover, psilocybin is known to increase state measures of optimism¹¹⁶ and trait openness,³¹ both of which may buffer against depression, anxiety, pain catastrophizing and kinesiophobia symptoms that collectively hinder engagement with structured exercise programs. Albeit such benefits, it is also crucial to note psilocybin administration also carries the risk of adverse side effects such as increases in blood pressure and the experience of intense emotions/paranoia canonically identified as a “bad trip.”¹¹⁰ While such experiences may impede the execution of the currently proposed model, systematic preparation and proper dosing in a controlled environment has been shown to mitigates the severity of such symptoms.¹¹⁷

Numerous theories of the neuropsychological bases of psilocybin’s effects on health, wellbeing, and consciousness have been proposed, including the cortico-striatal thalamo-cortical model,¹¹⁸ the entropic brain hypothesis¹¹⁹ and its updated relaxed beliefs under psychedelic substances and the anarchic brain,¹²⁰ the self-entropic broadening theory,¹²¹ and the cortico-claustrum-cortical model.¹²² Although these theories propose distinct structure-function mechanisms of action within the brain, they share the underlying premise that psilocybin induces altered states of consciousness primarily through 5-HT_2A receptor agonism and, downstream of that, reorganization of neural network dynamics. More specifically, the emotional, cognitive and perceptual effects that follow network wide disruptions across key brain regions responsible for sensorimotor and self-referential processing are postulated to subvert or loosen previously held beliefs/priors governed by structures spanning the DMN and SN. In turn, a release of such top-down constraints theoretically enables salient information typically constrained by maladaptive cognitive distortions (i.e., fears, autobiographical memories, expectations), to propagate up the brains hierarchy and new associations to form within the forefront of consciousness. These profound or mystical experiences commonly provide individuals with insights that may not have been available to them in their prior state. Such catharsis may be particularly advantageous for individuals with maladaptive pain-self enmeshment boundaries, helping foster an adaptive reconceptualization of the self in pain. Given that chronic pain is exacerbated by affective dysregulation and a cognitive bias towards pain-related stimuli,⁷¹ leading to enmeshment of the cognitive-affective self and the experience of pain, psilocybin may offer a viable therapeutic route to improving pain-related disability. Such gains could compliment the potential analgesic benefits of psilocybin, which have been reported in patients with cluster headache disorders,^48,123,124 phantom limb pain¹²⁵ and in mood disorders.^35–40 Below we propose a framework through which psilocybin may serve as a psychophysical adaptogen, sublimating self-pain enmeshment while simultaneously initiating meaning-making processes that allow the chronic pain patient the opportunity to reform their identity in the face of their illness and engage in adaptive behaviors, including exercise.

Psilocybin as a Psychophysical Adaptogen in Chronic Pain Rehabilitation

How might psilocybin improve sensorimotor outcomes among patients undergoing chronic pain rehabilitation? A partial answer may reside within the intrinsic organization of the nervous system and how motor activity^126–131 and sensory information^132–135 is modulated through 5-HT circuitry. 5-HT receptors are highly expressed within the basal ganglia, cerebellum and spine—suggesting widespread functional coordination across key movement centers.¹²⁹ Nearly all 5-HT cell bodies are housed within the midbrain structure known as the raphe nucleus, with the rostral and caudal aspects of the nucleus carrying projections down the dorsal and ventral regions of the spinal cord.^126,130 Moreover, 5-HT_2A receptors are highly expressed within the primary and somatosensory cortices, temporal association areas, and occipital regions implicating their role in the function of numerous sensory systems.¹³⁶ These findings lead to the hypothesis that the perceptual effects elicited through psilocybin may enhance cutaneous sensory feedback in populations with disrupted sensorimotor control, thereby promoting functional restoration and improved neuromuscular capabilities through an increased ability for motoric exploration and execution.

As a neuromotor effector, psilocybin is shown to increase motoneuron excitability within spinally transected models,^137,138 suggesting stimulatory effects occur in the absence of descending motor signals. Evidence indicates 5HT₂ agonism inhibits resting K+ leak channels and hyperpolarization-activated cationic currents,¹³⁹ facilitates low voltage gated Ca+ channel (e.g., Ca_V1.3) activation,^140,141 and increases persistent inward Na+ currents among motoneurons,¹⁴² subsequently shifting the membrane potential to a more stable pre-threshold level. This may also apply to muscle spindles and Golgi tendon organs responsible for detecting muscular tension and proprioceptive feedback, though this hypothesis has not been previously investigated. However, early human studies suggest that psilocybin dose dependently reduces the threshold required to elicit a knee jerk response¹⁴³ and promotes synesthesia and paresthesia by altering sensorimotor information processing,^110,144,145 suggesting such effects could be harnessed/synergized within targeted exercise programs.

In addition to the potential underlying neuromotor effects of psilocybin, it is important to consider the timing and sequencing of rehabilitation therapy relative to psilocybin administration (see Figure 2 for a proposed clinical framework for the integration of rehabilitation within the psilocybin-assisted therapy paradigm). Psilocybin administration commonly involves a preparation phase during which patients work with session facilitators to set expectations and intentions, a dosing phase involving the administration of psilocybin in a controlled setting, and an integration phase during which patients work with session facilitators to identify insights derived from the psilocybin dosing experience. As such, opportunities to leverage those insights for enhanced wellbeing and/or symptom management through exercise engagement may be warranted. There has been no empirical work to identify the optimal timing and sequence of therapeutic rehabilitation activities relative to the three major phases of psilocybin administration, but there are several possibilities to consider for future research designs. For example, the provision of physical training under an acute psychedelic state may present an unacceptably high safety risk in some patients, as disruptions in cognitive functioning including acute disorientation may increase fall risk or lead to other safety concerns. Alternatively, the psilocybin dosing session and subsequent integration period could be used to amplify rehabilitation gains made during the preparation phase.

Figure 2: Timecourse of psilocybin administration within clinical research protocols.

Psilocybin-assisted therapy is commonly divided into a preparation phase, dosing phase, and integration phase, with the number of sessions occurring within each phase varying across studies (the example outlined above represents one potential configuration of sessions within each phase). The psychoactive effects of psilocybin may occur over variable timeframes and magnitudes depending on the dosage administered. Typically, acute perceptual changes begin to emerge within 30–60 minutes and may last anywhere between 4–8 hours. The majority of available treatment paradigms make attempts to harness the acute subjective effects by helping participants to integrate any novel insights gained during the experience into their worldview. This period is often characterized by vivid sensorial states, including profound or mystical type experiences. Crucially, alterations in mood and energy levels, relief from past concerns, guilt and anxiety, and social connectedness may occur in the days to weeks following drug administration, in what’s commonly referred to as the afterglow or post-acute period. We propose that this time interval may be used to deploy targeted rehabilitation approaches to improve functional outcomes in those with chronic pain and comorbid psychological conditions. Such training may also be used to bolster the proclivity for positive long-term changes including alterations in mindset, personality traits and willingness to adopt positive health behaviors over the integration period.

A third option would be to leverage the transiently open mental state in the integration phase as a therapeutic window to employ rehabilitation therapies in an effort to facilitate movement, reduce pain-related outcomes, and establish positive behavioral change. Known as the post-acute afterglow period, or the open neuroplastic window lasting weeks to months after drug administration (See Figure 2), this time frame is associated with elevations in mood and energy levels, relief from past concerns, guilt and anxiety, social connectedness¹⁴⁶ and alterations in life values and notions of the self.¹⁴⁷ Such shifts in attitude could be exploited during the integration process by incorporating specific motor learning tasks in relation to movement goals into standard psilocybin assisted therapy models. Given that maladaptive cognitions including depression, anxiety, catastrophizing¹⁴⁸ and kinesiophobia exemplify barriers to exercise engagement,²⁸ increased openness to try novel approaches to rehabilitation may afford patients the opportunity to unbind negative associations perpetuating pain self-enmeshment, including maladaptive fear avoidant beliefs associated with specific movements. Furthermore, insights gained during the acute psychedelic experience could potentially alter meaning-making processes during the integration phase, increasing the patient’s ability to redefine self-related beliefs and update information into adaptive long-term behaviors, especially with regard to perceived physical capabilities.

Taken together, psilocybin’s capacity to modulate the threshold at which lower extremity reflexes are initiated and ability to alter the functional connectivity between key brain networks involved with multisensory and self-referential processing, it is possible that such effects may be used to bolster neuromuscular control among those with functional disabilities. Those with pain related disability may be subsequently provided with access to basic movements and perceptual information that was previously unavailable. Additionally, the post-acute afterglow interval of the psychedelic experience may represent a low-risk rehabilitation period that can be systematically used to combat maladaptive and fear-avoidant frames of reference to instantiate long term positive behavioral change. The proposed approach could represent a paradigm shift in chronic pain management, simultaneously targeting pain related disability, cognitive-emotional processes and mechanisms of meaning-making to improve prognosis in this heterogenous and often treatment resistant population. See Figure 3 for a proposed model of therapeutic effects.

Figure 3: Psilocybin as a psychophysical adaptogen in chronic pain rehabilitation.

A: Depicts a strong self-pain enmeshment cycle. The red spots and lightning bolts indicate maladaptive communication between key brain regions responsible for pain processing. The circle to the left also represents one-way top-down control and cognitive bias towards negative self-referential processes mediated by the DMN, SN and FPN, locking the pain patient into acute and recurrent maladaptive cognitive-affective states that give rise to fear avoidance, pain catastrophizing, kinesiophobia, and symptoms of depression and anxiety (Note, red bars imply rigid/entrenched activity patterns). Such preestablished priors are also reinforced by aberrant bottom-up sensorimotor processing and hypervigilance associated with the wounded area. B: Represents a putative pathway through which psilocybin may engender a loosening of the self-pain enmeshment cycle. Alterations in pain related self-conceptions and flexible meaning making processes allow the patient to reevaluate the significance of bottom-up sensorimotor information in a novel way. The circle to the left also notes altered network dynamics between the DMN, SN, and FPN facilitating a reorganization of high-level priors previously prohibiting exercise engagement and increasing other adaptive faculties including increased mood and openness to experience. The subsequent release of entrenched top-down cognitions allows the patient to assume a premorbid identity less encumbered by their pain symptoms. Abbreviations: DMN; Default Mode Network, SN; Salience Network, FPM; Frontoparietal Network; ROM; Range of motion, Enmeshment model adapted from Pincus and Morley (2001).⁷¹

Clinical Considerations and Future Investigations

In order to evaluate the potential of psilocybin in chronic pain rehabilitation, several clinical considerations must be addressed. Notably, psilocybin’s unique receptor activation profile may interfere with commonly prescribed medications used in pain management. For example, coadministration of antidepressant (e.g., buspirone) or anti-psychotic medication (e.g., haloperidol and risperidone) are known to either blunt the perceptual effects¹⁴⁹ of psilocybin or increase the phenomenology of ego dissolution.¹⁵⁰ Moreover, psilocybin is primarily metabolized through UDP-glucuronosyltransferases (UGT) 1A10 and 1A,¹⁵¹ suggesting potential interactions may occur with antagonists of this pathway. For example, commonly prescribed anti-inflammatory and uricosuric agents including diclofenac and probenecid inhibit UGT1A9 and 1A, potentially altering the metabolism of psilocybin, however, such hypothesis have not been explicitly examined.¹⁵² It is also pertinent to highlight that while emerging evidence suggests that certain selective serotonin reuptake inhibitors (e.g., escitalopram) can be used in conjunction with psilocybin administration,^152–154 other psychiatric medication including tricyclic antidepressants remain contraindicated.¹⁵⁵ Relatedly, as with other clinical trials, those with a history of psychiatric illness (e.g., schizophrenia or bipolar disorder) or cardiovascular disease may also be at greater risk of experiencing negative reactions following drug administration, including acute anxiety and elevated blood pressure.¹⁵⁶ Such effects may lead to adverse events and other challenging experiences that alter the efficacy of psilocybin as an adaptogenic aid during the afterglow period. Therefore, standard screening guidelines and proper oversight currently used in ongoing clinical trials should be followed among chronic pain populations to determine the appropriateness of this approach.

Recently, the emergence of a peripherally mediated serotonin syndrome-like cluster of symptoms among those living with SCI has been reported, whereby individuals described increases in spasticity following psilocybin use.¹⁵⁷ Though not experimentally manipulated, increased spasticity risk among those with stroke, SCI and MS may need to be addressed within this therapeutic context through the coadministration of antispastic medication and increased monitoring. Given the lack of experimental trials examining such hypotheses, future studies should develop safety protocols examining the risk profile of spasticity in patients undergoing psilocybin administration.

Aside from these potential challenges, there are several empirical questions that require further investigation. In elaborating potential mechanistic pathways involved with psilocybin’s salutatory effects, investigations into functional connectivity changes between the DMN, FPN and SN are required among those living with chronic pain. If the emotional and cognitive aspects of pain can be modulated through altered communication between the medial prefrontal cortex, insula, somatosensory and motor cortices or other brain regions responsible for pain processing and movement—such alterations may potentially help patients to shift their attention away from a particularly aggravating symptom and provide them with the ability to execute specific motor learning tasks in a more efficient manner. Therefore, the inclusion of imaging modalities in conjunction with targeted movement training paradigms is warranted. If such mechanistic insights could be captured in vivo, leveraging these responses in controlled settings may provide patients with the opportunity to integrate multisensory information through alternative processing pathways, modulating the way pain, motor output and proprioceptive cues are experienced in conscious awareness. In the case of stroke, MS, SCI and PD, such effects could be advantageous, providing patients with increased volitional control or enhanced sensorimotor feedback during locomotor execution. But more crucially, the psychological and/or existential shift accompanying the gain of basic bodily functions, such as increasing range of motion, standing without support or the bolstering of the ability to grasp, could elicit drastic changes across illness identity and provide the individual with clear and objective improvements that reinforce further engagement with rehabilitation programs. Although such propositions have yet to be experimentally tested and a definitive safety profile developed, preliminary studies are needed to not only assess the analgesic potential of psilocybin, but also its application in altering somatic functionality and proprioceptive acuity through changes in key brain regions spanning the DMN, FPN and SN.

Finally, there are a variety of targeted exercise modalities (e.g., aerobic, strength, flexibility and proprioceptively oriented) that could be used to enhance neuromuscular performance in those living with chronic pain, depending on their level of pain, the degree of sensorimotor impairment and their overall rehabilitation goals. However, given the increased utility and low impact nature of yoga, tai-chi and other mind-body techniques among chronic pain populations,^158–160 such approaches appear particularly attractive, especially with regard to their emphasis on balance, proprioceptive refinement and other mental health applications. If such approaches were to be operationalized and tested within psychedelic clinical trials, it is crucial that physical therapists or other exercise specialists be appropriately trained within conventional psilocybin administration paradigms. Such preparation would simultaneously ensure safety during the rehabilitation process while also allowing movement therapists to add their expertise to the multidimensional care team required to effectively address the nature of chronic pain.

In summary, exercise-based rehabilitation programs targeting physical and cognitive-emotional skill-based strategies are highly effective for many patients with chronic pain.¹⁶¹ However, individuals suffering from comorbid depression, anxiety and other psychological factors including pain catastrophizing, commonly report that it is difficult to meaningfully engage with structured exercise programs and achieve their desired goals.⁹⁸ Those with diminished neuromuscular function may also have trouble effectively integrating sensorimotor information required to effectively execute targeted movement tasks. Psilocybin administration is known to produce profound changes across measures of openness, social connection, depression, anxiety and the way in which the self is perceived.^31,162,163 Therefore, its application, especially within the post-acute afterglow period, may be well suited to synergistically improve physical and psychological comorbidities among those living with chronic pain through adaptive psychophysiological processes. With appropriate support, the cognitive-evaluative and motivational sequalae provided by the psychedelic experience may prove to be a particularly useful impetus to reframe preconceived notions of pain and help individuals to integrate their premorbid identities within current self-conceptions in a more healthy and open way. Alterations in the activity of brain regions involved with self-referential processing may alter deeply held priors constituting how one views their condition,¹²⁰ thereby allowing the individual to experience novel insights that may not have been previously accessible, including the way in which bottom-up sensorimotor information is experienced and top down motor commands are executed. In turn, the integration of novel stimuli could serve as a foundation to deconstruct notions of self-pain enmeshment and generate meaning in life despite the burden of chronic pain symptoms. Consequently, the enduring experiences afforded by psilocybin as a psychophysical adaptogen may help to shift individual perspectives, thereby permitting individuals to initiate or reengage with their rehabilitation efforts from a place of equanimity and purpose.

Highlights.

• Pain related sensorimotor dysfunction may be improved through psilocybin administration.

• Psilocybin may also target pain-related disruptions in identity and meaning-making processes.

• Psilocybin assisted rehabilitation may simultaneously impact psychological and physical outcomes.