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At the behavioral unit of analysis, the loss construct includes attentional biases to negative information, loss of motivation/drive, sadness, shame and rumination and is a component of several disorders but shares most features with depressive disorders (75). Some of the most important evidence for the operation of psychedelics on the NVS unsurprisingly comes from studies in depression. Pre-modern studies conducted during the 1950-60's first indicated a role of psychedelic therapy for depression and anxiety symptoms (76), which aligns with modern-era studies (77–79). The initial double-blind, randomized, placebo-controlled clinical studies in the modern-era of psychedelic therapy (psilocybin) showed an immediate and sustained antidepressant and anxiolytic effect in people with depressive symptoms associated with life-threatening cancer (80–82) (Table 1). In subgroups, these antidepressant and anxiolytic effects were sustained for several years (97), as were reductions in suicidal ideation and loss of meaning (98). Similarly, recent data suggest efficacy for another group with high levels of loss, those who survived Acquired immunodeficiency syndrome (AIDS) (101).

An open-label feasibility study of psilocybin therapy (10 mg) then 7 days later 25 mg, of 12 people diagnosed with treatment-resistant depression (TRD) showed that 67% of participants had significantly reduced depression symptoms (measured by MADRS) at 1 week, with 40% of participants showing a sustained response at 3 months post-dose (6). Measures of anhedonia, which overlap with reward dysfunction (see below) and anxiety, which overlap with threat processing (as discussed above) also improved (Table 1). Furthermore, in some participants these antidepressant and anxiolytic effects were sustained at 6 month follow up (7).

A randomized, waiting list-controlled clinical trial, though still without a placebo control, confirmed the immediate and sustained antidepressant effects of psilocybin therapy in (non-treatment resistant) MDD (4). This study also comprised two psilocybin sessions but at higher doses (20 mg/70 kg and 30 mg/70 kg) than the previous study. This study showed that 16 participants (67%) at week 1 and 17 (71%) at week 4 had a clinically significant response (GRID-HAMD), whereas 14 participants (58%) at week 1 and 13 participants (54%) at week 4 were in remission (4). A phase 2, double-blind, randomized, controlled trial (n = 59) showed that psilocybin therapy was at least as effective as escitalopram in reducing depressive symptoms in MDD (5). Preliminary data from a phase 2b TRD trial (n = 233) demonstrated that psilocybin 25 mg resulted in a statistically significant treatment difference of −6.6 points on change from baseline in MADRS total scores compared to 1mg dose at week 3 (8) (Table 1). Whereas exploratory studies are underway to determine the safety and efficacy of psilocybin therapy in conjunction with SSRI's (102). Interestingly, a recent double-blind, placebo-controlled, cross-over study in 23 in healthy controls (HCs) who received 14 days of escitalopram or placebo prior to psilocybin (25 mg), suggested that escitalopram had minimal effects on subjective, pharmacokinetic, or physiological readouts (103).

It is established that the limbic system and specifically the amygdala (104, 105) are important transdiagnostic nodes in the therapeutic modulation of negative-positive valence systems. Hyper-reactivity of the amygdala is associated with negative processing/affectivity and an attentional bias to negative valenced information, which can occur across a range of stress related disorders, such as depression and various anxiety disorders (106–109). Increased access to information flow from the limbic system during psychedelic therapy is one of the mechanisms thought to underlie therapeutic change (13). In keeping with a recalibration of NVS and PVS responsivity, several studies in HCs have demonstrated attenuation of amygdala reactivity, associated with predilection toward positive compared to negative stimuli in the acute phase post-psilocybin (110–112). This effect may be sustained for up to 1 month (113). Overlapping effects have also been demonstrated for LSD in HCs, which impaired the recognition of sad and fearful faces (114) and reduced reactivity of the left amygdala and the right medial prefrontal cortex (mPFC) relative to placebo during the presentation of fearful faces (115). Very low dose LSD (13 mcg) decreased amygdala connectivity with the left and right postcentral gyrus and the superior temporal gyrus, and increased amygdala seed-based connectivity with the right angular gyrus, right middle frontal gyrus, and the cerebellum in 20 young HCs, though there were “weak and variable effects on mood” (116). While not investigating the amygdala, a recent pilot randomized trial in HCs, perhaps limited by a small sample size of 22, did not show acute or protracted alterations in the recognition of emotional facial expressions after a single dose of ayahuasca (117).

In contrast to the above studies in HCs, which generally show decreases in amygdala reactivity, an open label study of 19 antidepressant free TRD subjects, found increased amygdala responses to emotional faces 1 day after psilocybin (84). In the same cohort of TRD participants, decreased cerebral blood flow in the amygdala correlated with reduced depressive symptoms 1-day post-psilocybin (40). While the loss construct encompasses several transdiagnostic components, rumination and increased self-focus may be particularly important transdiagnostic psychedelic therapy targets. Rumination refers to recursive self-focused negative thinking and is a component of a variety of disorders across mood, anxiety, addiction, and some personality disorders (118–120). The aforementioned TRD study showed that decreased ventromedial prefrontal cortex-right amygdala functional connectivity during face processing was associated with reduced ruminative thinking at 1 week (85).

The corticolimbic system and the immuno-endocrine system are intrinsically linked. However, at this point limited conclusions can be drawn about the loss construct and immuno-endocrine mechanisms. An 8-week social isolation model in juvenile marmosets, resulted in decreased fecal cortisol levels in both ayahuasca and saline treated groups, though in the male animals, ayahuasca reduced scratching behavior and increased feeding (121). In humans, a single dose of ayahuasca acutely increased salivary cortisol levels in both TRD patients and in HCs in a parallel arm, randomized double-blinded placebo-controlled trial (92). Before ayahuasca the TRD group had a blunted salivary cortisol awakening response and hypocortisolemia compared to HCs, though 48 h after ayahuasca there were no differences in the cortisol awakening response or plasma cortisol levels between the groups (92). In the same cohort ayahuasca reduced C-reactive protein (CRP) levels in both TRD (which were higher at baseline) and HCs compared to placebo, though this may be related to the increases in cortisol (89, 93). The TRD group treated with ayahuasca showed a significant correlation between larger reductions of CRP and lower depressive symptoms 48 h after ayahuasca (93). However, there were no significant changes in IL-6 levels (93).

A non-controlled study of 11 HCs, that analyzed salivary cortisol and immune markers 30 min before after 90 min after inhaled 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) found a significant increase in cortisol levels and decrease in IL-6 concentrations, whereas there were no changes in CRP and IL-1β (122). Although this was an exploratory study, neither the cortisol nor the immune markers correlated with subjective experiences (122). The precise impact of psychedelic induced acute cortisol activation and whether this is a therapeutic component is not fully clear, nor is the predictive implications of baseline cortisol or hormonal levels on the response to psychedelic therapy or on sustained effects. Similarly, the clinical relevance of the immune-modulatory effects is not yet clear.

When threat systems become excessively or repeated activated, which then exceeds an organism's ability to meet the demands (allostatic overload), psychopathology may ensue (123, 124). Psychedelics modulate acute and sustained fear/threat responses. A study in mice injected with low doses of psilocybin resulted in extinguished cued fear conditioning significantly more rapidly than high-dose psilocybin or saline-treated mice (125). A previous study in rats showed that N,N-DMT initially resulted in anxiogenic responses, but the long-lasting effects tended to reduce anxiety by facilitating the extinction of cued fear memory (126). Similarly, chronic, intermittent, low doses of DMT produced enhanced fear extinction learning without impacting working memory or social interaction and exhibited an antidepressant-like effect in the forced swim test (FST) in rats (127).

A recent study in male mice using the relatively selective 5-HT2A/2C receptor agonist DOI (1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane) showed that it accelerated fear extinction, reduced immobility time in the FST, increased the density of transitional dendritic spines in the frontal cortex, and for the first time showed epigenetic changes in enhancer regions of genes involved in synaptic assembly which lasted for 7 days, in conjunction with more transient transcriptomic changes (128). The clinical relevance of putative epigenetic changes in humans are not yet clear (129).

From the neuroendocrine mechanistic perspective, a study of psilocybin treatment in male mice, showed that psilocybin acutely increased plasma corticosterone and anxiety like behaviors in the open field test (OFT) (130). The acute anxiogenic effects correlated with the post-acute anxiolytic effects and chronic corticosterone administration suppressed the psilocybin induced acute corticosterone and behavioral changes (130). The authors postulated that psilocybin may act as an initial stressor that provides resilience to subsequent stress (130). Indeed, this transient acute anxiety and subsequent attenuation of anxiety can occur in some individuals who undergo psychedelic therapy. It is important to note that not all pre-clinical studies are consistent, in part due to strain and model effects. The aforementioned study did not find significant changes in the sucrose preference test or the FST following psilocybin in C57BL/6J male mice (130), echoing a previous study which did not show effects of psilocin or psilocybin on the FST or in the OFT in Flinders Sensitive Line rats (131).

Another rodent study comparing psilocybin to the N-methyl-D-aspartate receptor antagonist—ketamine—showed that rats that received psilocybin and 5-min weekly arena exposure for the first 3 weeks exhibited significantly less anxiety-like behavior in the elevated plus-maze (EPM) compared to controls, whereas rats that received the ketamine and weekly arena exposure did not display a significant decrease in anxiety in the EPM (132). Rats that received psilocybin or ketamine and no arena exposure did not display a significant decrease in anxiety in the EPM (132). The authors postulated that psilocybin facilitates a period of “behavioral flexibility” in which exploration of a non-home-cage environment reduces their anxiety during future exploration of a novel environment (132). In the same study, psilocybin decreased immobility in the FST for up to 5 weeks after administration compared to control rats, whereas ketamine injected rats displayed decreased immobility up to 2 weeks, suggesting a longer lasting therapeutic effect of psilocybin over ketamine (132). It will be intriguing to see if clinical trials comparing psilocybin to ketamine reproduce the putative longer lasting therapeutic effect of psilocybin (NCT03380442).

In humans, dysregulated fear and threat responses underlie a range of psychiatric disorders and psychedelic therapy may revise dysregulated or maladaptive fear/threat responses. A review of 20 human studies of psychedelics in ICD-10 anxiety disorders from 1940 to 2000, albeit of sub-optimal methodological rigor (e.g., lack of control groups, blinding and standardization), indicated improvements in anxiety levels (133). The subsequent clinical trials in people diagnosed with cancer (80–82, 134) and the studies in depression (4, 6) also suggest anxiolytic effects of psychedelic therapy.

One of the notable conditions associated with dysregulated fear conditioning (and avoidance of conditioned contextual cues), together with emotional regulation, and dysfunctional neural activity in cortico-amygdala circuits, involving exaggerated amygdala and attenuated mPFC activity, is Post-Traumatic Stress Disorder (PTSD) (109, 135–139). Other anxiety disorders share overlapping neurobiological pathways linked to fear/threat circuitry and attentional bias of negative valenced information, though there is variability in the fear evoking stimuli (106, 140, 141).

While PTSD overlaps with other conditions in the domains of hypervigilance, avoidance and altered emotional valance, the vivid re-experiencing of the trauma is perhaps a point of divergence from many other conditions. Memory reconsolidation dysregulation is a cardinal clinical feature of PTSD and memories can be strengthened or weakened according to new experiences. Classical psychedelics have the capacity to acutely enhance the vividness and recall of autobiographical memories (142) which in the context of psychedelic therapy requires great care and attention. These autobiographical memories are highly influenced by environmental inputs such as music (143), which is linked to increased parahippocampal cortex-visual cortex enhanced visual imagery, including imagery of an autobiographical nature (144). In terms of therapeutic utility, it is noteworthy that psilocybin leads to more vivid and visual recollections, associated with enhanced activation of visual and sensory cortical regions after viewing positive autobiographical memory cues (145). In terms of advancing the mechanistic understanding, undoubtedly future preclinical studies will delve into the impact of psychedelics on memory engram storage and retrieval (146, 147).

It is not known whether psychedelic therapy has the potential to augment therapies, such as cognitive processing therapy or prolonged exposure therapy in PTSD or indeed in any other anxiety disorder. However, there are preliminary indicators that psychedelic therapy may be useful in PTSD (148, 149). A retrospective, self-report survey of Veterans 30 days before and 30 days after participation in a psychedelic clinical program utilizing ibogaine and 5-MeO-DMT reported significant reductions in symptoms of PTSD, depression, anxiety, suicidal ideation and cognitive impairment (148). Increases in psychological flexibility (discussed below) were associated with the improvements in self-reported PTSD symptoms, depression, and anxiety (148). It will be interesting to ascertain whether the same psychedelic therapy induced modulation of cortico-limbic circuits (as discussed in section Loss construct above) will underpin therapeutic changes in PTSD and other anxiety disorders. As with all these studies, future challenges include precisely disentangling the contribution of psychedelics from psychotherapy, with some suggesting that the only way to definitively achieve this would be via the rather challenging process of administering psychedelic compounds under general anesthesia or sleep (150).

Excessive fear/anxiety may lead to maladaptive patterns of avoidance. Some of the potential therapeutic subjective experiences induced by psychedelics involve the transition from experiential (151, 152) and emotional (88) avoidance to acceptance. Interestingly, attachment avoidance at baseline may be linked with psilocybin-related challenging experiences (153). Similarly, high neuroticism has been associated with unpleasant/anxious reactions in 3,4-ethylenedioxymethamphetamine (MDMA) therapy (154). This again highlights the vital importance of preparation sessions, particularly pertinent in those with marked threat sensitivity/anxiety.

The neural circuitry underling aggressive reactions (in the context of negative emotions) involve amygdala hyper-responsivity coupled with hypoactivity of prefrontal regions, which overlaps with threat processing circuitry (155, 156). The frustrative non-reward construct refers to “reactions elicited in response to withdrawal/prevention of reward, i.e., by the inability to obtain positive rewards following repeated or sustained efforts.” This could potentially be associated with some aspects of depression or aggression (157). Sensitivity to frustration, particularly in relation to interpersonal rejection and negative emotions focused on others (158) are components of emotionally unstable personality (disorder) (EUPD) (borderline personality disorder). It has been proposed that psychedelic therapy could assist with emotion regulation, mindfulness, and self-compassion in people with EUPD (159). There are tentative indicators of potential utility. For example, a non-controlled observational study of 45 HCs who participated in an ayahuasca session reported significant improvements in mindfulness capabilities and emotional regulation in the subgroup with borderline-personality traits (Table 1) (160). However, it is premature to draw any conclusions about the utility of psychedelic therapy in EUPD or other maladaptive personality traits/disorders (161).

In terms of other personality traits, data suggests that psychedelics may increase openness (44, 162–164). Moreover, higher baseline scores in the personality trait of absorption (focused attention) (45, 46) and openness may be useful predictors of a therapeutic psychedelic experience, reportedly linked to increases in brain entropy as measured by fMRI (and experiences of “ego-dissolution”) (165), though 5-HT2AR binding did not appear to correlate with variations in openness (166, 167), highlighting the individual variability in 5-HT2AR levels after psilocybin and the complex relationship with subjective changes.

In terms of RDoC, structural and functional neuroplasticity broadly falls under molecular and cellular units of analysis and probably applies, at least some degree, to all domains. The ability of psychedelics to rapidly rewire neural circuitry by engaging plasticity mechanisms has given rise to the term—“psychoplastogens” (168–173). While, it is generally accepted that the quality of the subjective experience, dependent on the optimization of set and setting (context) is a critical component of the therapeutic mechanism of action of psychedelic therapy (87, 174), some propose that the subjective effects may not be necessary to produce long-lasting changes in mood and behavior (171).

The classical psychedelics may share glutamatergic activity-dependent neuroplastic effects with ketamine (175) and on a longer timescale, with some types of conventional antidepressants (176). A study in rats utilized fluorescence microscopy and electrophysiology techniques to show that changes in neuronal structure are accompanied by increased synapse number and function, and the structural changes in the PFC and increase in glutamate induced by serotonergic psychedelics appear to lead to BDNF secretion, neurotrophin receptor tyrosine kinase (TrkB) stimulation, and ultimately mammalian target of rapamycin (mTOR) activation (177). Furthermore, both LSD and ketamine activated cortical neuron growth mechanisms after <1 h, an effect which lasted for several days (178) and could be divided into an initial stimulation phase requiring TrkB activation and a growth period involving sustained mTOR and AMPA receptor activation (178).

In mice, a single dose of psilocybin resulted in a 10% increase in spine size and density in the medial frontal cortex, which occurred within 24 h and persisted for 1 month (179). In pigs, a single dose of psilocybin compared to saline resulted in 4% higher levels of hippocampal synaptic vesicle protein 2A (SV2A) and lowered hippocampal and PFC 5-HT2AR density (180). Seven days post-psilocybin, there was still significantly higher SV2A density in the hippocampus and the PFC, whereas there were no longer any differences in 5-HT2AR density (180). Previous studies showed psychedelics increase early response genes in the PFC (181, 182) and this was further confirmed by a rapid dose dependent preferential modulation of plasticity-related genes in the PFC compared to the hippocampus in rats (183).

A recent pre-clinical study compared ketamine to Tabernanthalog (TBG)—a water-soluble, non-hallucinogenic, non-toxic analog of ibogaine (184). Both TBG (50 mg/kg) and ketamine reduced immobility in mice in the FST, though the effects of ketamine were more durable and ketanserin blocked the effect of TBG (184). TBG promoted structural neural plasticity, produced antidepressant-like effects and in keeping with the transdiagnostic effects, also reduced alcohol and heroin-seeking behavior in rodents (184). A single lower dose of TBG (10 mg/kg) administered to mice after unpredictable mild stress, rescued deficits in anxiety like behavior and cognitive flexibility, associated with restoration of excitatory neuron dendritic spines (185), thus echoing the effects of ketamine (186), albeit via different primary pathways.

Notwithstanding the gap between animal and human studies in demonstrating molecular changes in plasticity, there are indicators of alignment with the pre-clinical data. For example, a magnetic resonance spectroscopy (MRS) imaging study in HCs showed psilocybin modulated glutamate levels in the medial PFC (187). In blood, one small preliminary clinical trial showed that 2 days after ayahuasca BDNF levels increased in both the TRD and the HC groups (90), whereas other studies in HCs showed that LSD increased blood BDNF levels (188, 189). However, BDNF levels did not increase in a recent randomized pilot study in 22 HCs after a single dose of ayahuasca (117).

Reward-pathway dysfunction is associated with a range of disorders (190, 191), including but not limited to mood (192, 193), anxiety (194, 195), addiction disorders (196, 197) and eating disorders (198, 199). Psychedelic therapy induced attenuation of maladaptive reward signaling, or a recalibration of reward/fear systems (PVS/NVS) may be useful targets across the various disorders. Psychedelics may alter maladaptive signaling in the mesolimbic reward circuitry, either indirectly via 5-HT signaling in the case of psilocybin or directly via activation of dopamine receptors (D1 and D2) like LSD (200, 201). A microdialysis study in awake rats found that intraperitoneal administration of psilocin significantly increased extracellular dopamine but not serotonin in the nucleus accumbens, increased serotonin and decreased dopamine in the mPFC, but neither were altered in the ventral tegmental area (202). An electrophysiological study in male mice showed that LSD altered neuronal activity in both the reticular and mediodorsal thalamus, partially mediated by the D2 receptor (34). Another recent study in chronically stressed male mice suggested that 5-HT2A independent mechanisms may be of importance in psilocybin induced anti-hedonic responses and associated cortico-mesolimbic reward circuit modulation (203).

The functional interaction between 5-HT and dopamine systems across molecular and neural networks was further expounded by a recent study in mice showing psilocybin increased FC between 5-HT-associated networks and resting-state networks of the murine DMN, thalamus, and midbrain, whereas it decreased FC within dopamine-associated striatal networks (204). It should be noted that this contrasts with the majority of human studies in HCs (as discussed below) that report acute decreases in DMN FC, thus highlighting the challenges of translation (32, 205–208).

In healthy humans, a structural MRI study showed a positive correlation between psilocybin induced feelings of unity, bliss, spiritual experience, and insightfulness subscales of the 5-Dimensional Altered States of Consciousness Rating Scale (5D-ASC) and right hemisphere rostral anterior cingulate thickness in HCs after controlling for sex and age (43). Whereas, a double-blind placebo-controlled study of 38 healthy experienced mediators that received psilocybin, reported positive changes in appreciation for life, self-acceptance, quest for meaning/sense of purpose at 4 months post-psilocybin (209). A pooled sample of HCs (n = 110) who had received between 1 and 4 oral doses of psilocybin (45–315 μg/kg) from eight double-blind placebo-controlled experimental studies (1999–2008), reported that the majority of subjects described the experience as pleasurable, enriching, and non-threatening (210).

A Positron emission tomography (PET) study in healthy humans showed that psilocybin increased striatal dopamine concentrations, and this increase correlated with euphoria and depersonalization phenomena (211), whereas the mixed 5-HT2/D2 antagonist risperidone attenuated the effects of psilocybin (212). This again re-enforces the divergence between the potential therapeutic benefit of psychedelic therapy in some reward dysregulated conditions, like depression, anxiety, and addiction, while exacerbating conditions like psychosis spectrum and manic disorders.

Arousal is a continuum of sensitivity of the organism to stimuli, both external and internal. Several interacting systems are involved in arousal regulation, including but not limited to, the sympathomedullary and the immuno-endocrine system, which act as mediators to alter neural circuitry and function, particularly in the corticolimbic system. Psychedelics are highly context sensitive, “non-specific amplifiers” (229) of internal and/or external signals (immediate environment), in part due to the effects of 5-HT2AR signaling (230, 231). Psychedelics acutely modulate the Autonomic Nervous System (ANS) (39), neuroendocrine (232), and immune systems (233).

Psychedelics activate the sympathetic nervous system, including blood pressure, heart rate, body temperature, and pupillary dilation, probably via 5-HT2A and/or α1-adrenergic receptor-mediated mechanisms (114, 234–236). A recent randomized, placebo-controlled crossover trial in 25 HCs using electrocardiographic recordings showed that LSD increased sympathetic activity, which was positively associated with a range of subjective effects, measured by 5D-ASC (39). However, it should be noted that similar correlations were found for the placebo condition. In contrast, ketanserin increased parasympathetic tone and negatively associated with the subjective effects of LSD (39).

As discussed above, psychedelics also acutely stimulate the neuroendocrine system. In a seminal randomized placebo-controlled study of healthy experienced psychedelic users, IV DMT acutely and dose dependently increased blood cortisol, corticotropin, and other hormones such as prolactin and growth hormone (and ß-endorphin) (237). By 5 h post-dose, all endocrine markers returned to baseline values (237, 238). A double-blind, placebo-controlled study showed high dose psilocybin (315 μg/kg) acutely increased plasma ACTH and cortisol (and prolactin and thyroid stimulating hormone) in HCs (239). LSD (200 μg) increased plasma concentrations of the cortisol, cortisone, corticosterone, and 11-dehydrocorticosterone compared with placebo in 16 HCs using a randomized, double-blind, placebo-controlled cross-over study design (240). Other studies have also shown acutely increased plasma levels of cortisol, prolactin, oxytocin, and epinephrine due to LSD administration (234).

Psychedelics modulate the immune system via 5-HT1, 5-HT2, and sigma-1 receptor activity (18, 233, 241–248). Altered immune system function, mainly characterized by chronic low-grade inflammation is associated with a range of psychiatric disorders (57, 249–251) and it remains an open question whether the potential anti-inflammatory activity of psychedelics will play a role in autoimmune disorders (252) or chronic pain (253, 254).

Sleep interference is almost ubiquitous across psychiatric disorders (255). Psilocybin (0.26 mg/kg) increased REM sleep latency in a randomized, double-blind placebo controlled cross over study of 20 HCs (256). Psilocybin suppressed slow-wave activity in the first sleep cycle but did not affect NREM sleep, EEG power spectra in NREM or REM sleep across the whole night (256).

Experiences of disconnection or exclusion are common across psychiatric disorders and can manifest as social withdrawal, apathy, and anhedonia (260). Using a paradigm designed to induce feelings of social exclusion, a double-blind, randomized, counterbalanced, cross-over study of healthy participants (n = 21) reported that psilocybin induced reduced feelings of social exclusion (267) (Table 2). A placebo-controlled, double-blind, random-order, crossover study conducted using LSD (100 μg) in 24 HCs and LSD (200 μg) in 16 HCs, enhanced the participants' desire to be with other people and increased their prosocial behavior on the Social Value Orientation test (114, 234). In addition to significant positive changes in gratitude, life meaning/purpose, forgiveness and death transcendence, a double-blind study comparing low and high dose psilocybin therapy in HCs reported sustained increases in experiences of interpersonal closeness at 6 month follow up, associated with mystical-type experiences (266). It is interesting to note that psychedelics can increase oxytocin plasma levels (234), though the therapeutic relevance is not yet clear.

In keeping with possible increases in openness (210) and connectedness (88, 271, 272), studies have shown that psychedelic use may be associated with increases in nature relatedness (273–275), pro-environmental behaviors (276) and more broadly experiences of personal meaning (81, 148, 209, 219, 277). Taken together, psychedelic therapy induced changes in social processing systems and specifically social reward processing and behavior and enhanced experiences of connectedness (88) has potential therapeutic implications not only for depressive, anxiety, addiction, some personality disorders, but perhaps for social deficits in subtypes of adult autism spectrum disorders.

There are preliminary indictors that classical psychedelics may enhance certain types of empathy (Table 2). LSD (114, 234) and psilocybin (268) acutely increased explicit and implicit emotional empathy, using the multifaceted empathy test and moral dilemma task in HCs, compared to placebo (268). Psilocybin did not affect the ability to take another person's perspective or affect the understanding of another person's mental state (cognitive empathy), nor did it affect moral decision-making (268). Using an aesthetic judgment task involving social feedback, LSD increased social adaptation to group opinions that were relatively similar to the individuals own opinions, associated with 5-HT2A activation and increased activity of the mPFC (263). Comparisons of psychedelic therapy delivered in individual settings compared to group settings offers an intriguing avenue to further explore how social processing domains and constructs such as perception and understanding of others may be shaped by the context in which the therapy is delivered. Non-controlled group studies have suggested that shared experiences, including acute relational experiences of perceived togetherness, may facilitate enhanced perception and understanding of others (272, 278). Controlled transdiagnostic studies directly comparing group to individual psychedelic therapy could decipher the relative therapeutic contribution of a group setting either before, during or after psychedelic administration.

Notwithstanding the challenges of disentangling self from self-as social agent, current thinking implicates altered self-processing as the primary mode of action of psychedelic therapy with downstream implications for social processing systems (33). However, elucidating the precise temporal dynamics of altered self and self-as social agent, whilst also considering the pervasive emotional background is challenging. Nonetheless, the experience of a transient attenuation of the demarcation between self and other/environment or “ego dissolution” appears to be a pivotal transdiagnostic therapeutic mechanism (Table 2). This is especially relevant for excessive self-referential processes, which often manifest with negative valence. For example, ruminative or obsessional thoughts, which are components across a range of disorders, such as depression, anxiety disorders, eating disorders, addiction disorders and some types of personality disorders.

In contrast to disorders of constrained “self-focus,” which may benefit from a “broader spectrum of thought patterns and emotions” induced by psychedelic therapy (13, 33, 279), psychosis spectrum disorders appear not to benefit. This may be due to baseline features which include aberrant stability between intrinsic and extrinsic self-processing networks (280), aberrant salience attribution (281) and a loosening of higher-level priors (13). Some of these experiences are attenuated by second generation antipsychotics (e.g., clozapine, olanzapine, quetiapine, and risperidone), which block 5-HT2A and dopamine receptors (282). A previous study in HCs showed that risperidone attenuated the effects of psilocybin (212).

The intensity of psilocybin induced subjective experiences, including ego dissolution are dose dependent and appear to correlate with cerebral 5-HT2ARs occupancy and plasma psilocin levels (261). While the molecular cascade initiated by 5-HT2AR activation and downstream cortical glutamate modulation (24, 177) are key neurobiological substrates of self-processing alterations, the full molecular pathways and how they map onto the self-concept have yet to be fully determined, and at least in this regard, only partial assistance can be derived from preclinical models. From the perspective of refining personalized-precision psychedelic therapy, a PET study in 16 HCs showed that lower neocortical 5-HT2AR binding before psilocybin was associated with longer peak effects, a more rapid decrease in subjective drug intensity effects and higher scores on the Mystical Experience Questionnaire (283).

An MRS study in HCs showed that psilocybin acutely elevated mPFC glutamate, which was associated with negatively experienced ego dissolution, whereas lower levels in hippocampal glutamate secondary to psilocybin, were associated with positively experienced ego dissolution (187). A previous MRS study of 16 HCs 1 day after consuming ayahuasca showed reductions in glutamate and glutamine in the posterior cingulate cortex (PCC), which correlated with increases in the “non-judging” subscale of the Five Facets Mindfulness Questionnaire (264). Similarly, one week after psilocybin therapy, glutamate and N-acetylaspartate concentrations were decreased in the Anterior Cingulate Cortex (ACC) in an open-label study of 24 patients with MDD (83). A double blind, randomized, counterbalanced, crossover study of 24 HCs utilizing MRI and eye tracking showed that LSD decreased the response to participation in self-initiated compared with other-initiated social interaction in the PCC and the temporal gyrus, more precisely the angular gyrus (262) (Table 2).

One of the higher-order brain networks modulated by psychedelics that has gained attention in recent years is the DMN, associated with a range of experiences and conditions (284), including but not limited to self-reflection and rumination (13, 120, 265, 285, 286) and meta-cognitive processes (287). Alterations in DMN rsFC have been demonstrated across a range of disorders. However, a clear and consistent DMN signature specific to any disorder has yet to emerge, underscoring the complexities of mapping correlates of subjective experiences, but also the limitations of biosignature exploration utilizing categorical diagnoses.

Psychedelics reliably alter DMN circuitry and studies in HCs reported decreases in rsFC within the DMN induced by psilocybin (205), LSD (32, 207) and ayahuasca (206). In fifteen HCs intravenous psilocybin resulted in a significant decrease in the positive coupling between the mPFC and PCC (205). LSD (75 μg) 100 min after IV administration decreased connectivity between the parahippocampus and retrosplenial cortex and correlated strongly with ratings of ego-dissolution and altered meaning in 20 HCs (207). Notwithstanding the differences between experienced users who may be more receptive to psychedelic therapy compared to people with mental health disorders, ayahuasca resulted in a significant decrease in activity through most parts of the DMN, including the PCC and the medial mPFC in a group of ten experienced users (206). A decoupling of the mPFC and PCC was associated with positively experienced ego dissolution in a psilocybin double-blind placebo controlled study of 38 healthy experienced mediators (208). Furthermore, the meditators in the psilocybin group reported increased meditation depth and positively experienced ego-dissolution, while at 4 months post-psilocybin they reported positive changes in appreciation for life, self-acceptance, quest for meaning and sense of purpose (209). Interestingly, alteration of the DMN is not limited to classical psychedelics. Oral administration of MDMA (125 mg) to 45 HCs in a randomized, placebo-controlled, double-blind, crossover design showed decreased connectivity within the DMN, two visual networks, and the sensorimotor network (288). Another recent placebo controlled study of 12 healthy males using vaporized salvinorin A, acutely attenuated the DMN during peak effects (first half of 20 min scan) (289), highlighting the overlap with classical psychedelics.

Unsurprisingly given the complex multi-modal nature of self-processing, a single neural correlate such as the DMN may not fully capture the complexities of the self-processing concept (33, 290). Psychedelics alter global brain connectivity, of which the DMN is but one. For example, increased global FC correlated with ego dissolution in an LSD study of 15 HCs (291) and more recently the subjective effects of LSD have been shown to be non-uniform in time, depending on the particular state of the brain at a given point in time (290, 292), with multi-modal imaging techniques (fMRI, diffusion MRI, PET) highlighting the importance of 5-HT2A receptors (27). Previous studies in HCs showed that psilocybin (2 mg) IV destabilized a frontoparietal subsystem (293), whereas IV LSD (75 μg) and IV psilocybin increased the fractal dimension of bold blood oxygen level dependent (BOLD) time-series from regions assigned to the dorsal-attention network (294). Furthermore, a recent rsFC fMRI study in 10 healthy volunteers showed that the executive control network was decreased at 1-week, which was associated with increased mindfulness at 3 months, but there were no other significant changes in other networks (295).

From a personalized point of view, a study suggested that baseline brain connectivity may be a useful predictive marker (41). This double-blind, placebo controlled, randomized, cross-over study of 23 HCs who received oral psilocybin (0.2 mg/kg) and underwent resting-state functional connectivity fMRI scans at three time points (41) showed that psilocybin reduced associative, and concurrently increased sensory brain-wide connectivity over time from administration to peak-effects (41). Furthermore, the participants who had the lowest values in hyper-connected areas and had the highest values in hypo-connected regions displayed the strongest psilocybin induced changes in global brain connectivity (41).

In contrast to the aforementioned psychedelic induced acute decreases in DMN integrity in HCs, an open-labeled study in TRD (n = 20) reported an increase in DMN rsFC 1-day post-psilocybin (40). The reduction of depressive symptoms at 5 weeks was predicted by high scores of acutely experienced pleasurable self-dissolution and by low scores for dread of ego dissolution (87). Furthermore, the increased ventromedial prefrontal cortex-bilateral inferior lateral parietal cortex rsFC, 1-day post-dose, predicted treatment response at 5 weeks post-dose (40). Data from this study (n = 16) (40) combined with the psilocybin therapy vs. escitalopram study (n = 43) indicated that psilocybin was associated with a global decrease in network modularity, indicative of enhanced flexibility (as high modularity scores indicate a greater degree of separation between brain networks) (42). This decrease in modularity was associated with improvements in depression scores at 6-weeks as measured by the Beck Depression inventory (42). In contrast, no changes in modularity were observed with escitalopram, suggesting a tentative biomarker of response to psilocybin therapy.

Cognitive control refers to a “system that modulates the operation of other cognitive and emotional systems, in the service of goal-directed behavior, when prepotent modes of responding are not adequate to meet the demands of the current context. Additionally, control processes are engaged in the case of novel contexts, where appropriate responses need to be selected from among competing alternatives” (74). This collection of executive control processes include goal-selection, maintenance, updating, as well as response selection and inhibition denotes the ability to switch between different mental sets, tasks, or strategies and plays a vital role in an individual's ability to adapt to environmental changes (296). The underlying neural circuitry involves the default mode, salience, and executive networks, with 5-HT2ARs playing an important role (297–299).

Psychedelics transiently impair certain aspects of cognition in a dose-dependent manner (142, 300–302). For example, a study in HCs showed that LSD (100 μg) compared to placebo acutely impaired executive functions, cognitive flexibility, and working memory on the Intra/Extra-Dimensional shift task, and Spatial Working Memory task, but did not influence the quality of decision-making and risk taking on the Cambridge Gambling Task (302). Similarly, psilocybin decreased attentional tracking ability in HCs, which the authors speculated was due to the inability to inhibit distracting stimuli (303). More recently, re-treatment with ketanserin (40 mg) normalized all LSD-induced cognitive deficits (302). Psychedelic induced impairment of aspects of cognitive flexibility was also observed in a probabilistic reversal learning paradigm in 19 HCs who received IV LSD (75μg) or placebo at two sessions, two weeks apart (Kanen 2021). In this study LSD resulted in more perseverative responding, though the reward learning rate and to a lesser degree the punishment learning rate were enhanced (304).

The complex relationship between cognitive flexibility, neural flexibility, and emotion has recently been highlighted by an open-label study of 24 patients with MDD (83). This study showed that psilocybin therapy decreased perseverative errors in a set-shifting task but did not impact response inhibition, selective attention, or abstract reasoning (83). The improvements in selective aspects of cognitive flexibility did not correlate with improvements in depression. Unexpectedly, greater increases in neural flexibility as measured by dynamics of FC (dFC) between the ACC and PCC, and greater baseline dFC from the ACC were associated with less improvement in cognitive flexibility (83). The practical inferences for the precise-personalized psychedelic therapy paradigm are not fully clear.

A retrospective survey self-report survey of U.S. Veterans in a psychedelic clinical program, reported significant reductions in cognitive impairment as measured by the Medical Outcomes Study—Cognitive Functioning subscale (148). However, changes in the negative valence domain may have led to secondary subjective improvements in the self-reported cognitive domains in this study. Similarly, limited conclusions can be drawn from a non-controlled study in self-selected HCs showing improvements in Cognitive flexibility and the Wisconsin Picture Card Sorting Task 24 h after ayahuasca, which the authors acknowledge could be attributed to practice effects (305).

The acute impairment in some executive domains induced by psychedelic compounds is especially relevant to neurodevelopmental disorders such as schizophrenia, which notwithstanding the inter-individual variability are associated with deficits in cognitive flexibility (306). The further acute impairment in cognitive control induced by psychedelics may in part explain the detrimental negative effects of these substances in psychosis or in those with predispositions to psychosis. Indeed, LSD induced “cognitive bizarreness” associated with loss of self-boundaries and cognitive control as measured by the 5D-ASC in 25 HCs (307) and “mind-wandering” (308) may be counterproductive for those at risk of developing psychosis.

A recent study focused on the claustrum, a thin sheet of gray matter, embedded in the white matter of the cerebral hemispheres and situated between the putamen and the insular cortex, with a rich supply of 5-HT2A receptors and glutamatergic connectivity to the cerebral cortex. The claustrum is thought to be associated with cognitive task switching (309, 310) and salience processing (311), known to be dysfunctional in psychosis (312). Psilocybin acutely reduced claustrum activity and altered its connectivity with the DMN and frontoparietal task control network (FPTC) in a study involving 15 HCs, thus implicating this region as a potential mediator in psilocybin therapy (310).

Psychedelics acutely and dose dependently impair attention (328, 329), memory task performance (142, 300, 302) and spatial working memory (212). On the other hand, it appears that other domains such as the recall and vividness of autobiographical memory may be accentuated (142–145).

A computational analysis of semantic and non-semantic language in HCs who received IV LSD (75 μg) and placebo reported that LSD was associated with unconstrained speech (increased verbosity and a reduced lexicon) which was noted to be similar to speech changes during manic psychoses (330). Automated natural language processing methods (331, 332) or digital text analysis (333) may have the potential to improve prediction of psychosis outcomes and there are early indicators that quantitative descriptions of psychedelic experiences derived using Natural Language Processing may play a role in predicting therapeutic outcomes or trajectory in psychedelic therapy (47).

Psychedelics may induce visual imagery (334–336), distortions in the perception of time and space (337, 338) and synaesthesia (339, 340). Auditory and tactile perceptual changes occur less frequently but can occur at higher doses (210, 341). The implications of alterations in these systems for personalized psychedelic therapy are not fully clear, though it is interesting to note the recent proof of concept study showing a role for psilocybin therapy in migraine suppression (17), a condition known to be associated with aberrant connections from the somatosensory cortex to the frontal lobe (342).

Psychedelics over-engage primary sensory cortices and mostly encompasses visual hallucinations (often geometric) with preserved insight monitoring whereas hallucinations in psychosis, are mostly related to overactivation of associative networks, mainly include auditory hallucinations and poor reality monitoring (341). Electrophysiological correlates of IV DMT induced complex visionary experiences during “breakthrough” periods in 13 HCs were associated with a delta/theta rhythmicity (343). A further analysis of the same EEG data with eyes closed reported an EEG wave signal similar to those observed during eyes-open visual stimulation (344). The changes in resting state EEG, which included decreased spectral power in the alpha/beta bands, accompanied by widespread increases in signal diversity, were not specific to the visual system, but also correlated with somatic and metacognitive/affective domains (343, 344). Interestingly, a recent EEG study in freely moving rats showed some overlap with human studies, with a time-dependent global decrease and desynchronization of EEG activity, particularly in the frontal and sensorimotor cortex (345).

Similar to the previously discussed vulnerability to adverse effects of psychedelics in people with incoherent self-concept/aberrant salience in the context of psychosis spectrum disorder, baseline dysfunction in the some of the perceptual systems may increase the risk of adverse events in psychedelic therapy. For example, there is limited high-quality data on the rare condition—Hallucinogen Persisting Perception Disorder (HPPD) (346–348), which in most cases is due to a “subtle over-activation of predominantly neural visual pathways that worsens anxiety after ingestion of arousal-altering drugs, including non-hallucinogenic substances” (347). The authors note that a personal or family history of anxiety and pre-drug use complaints of tinnitus, eye floaters, and concentration problems may predict vulnerability for HPPD (347).

In keeping with an interconnected systems based psychiatry paradigm that conceptualizes the individual as a complex composite of interacting systems across all levels of organization, it has been proposed that the microbial ecosystem (microbiome) may serve as an additional transdiagnostic unit of analysis in the RDoC framework (355, 356). At the interface between the individual and the environment, the microbiome is intrinsically linked to human health and may play a contributory physiological role in some psychiatric disorders (357–359). This microbial signaling system communicates with the brain through the gut-brain axis via the immune system (360), tryptophan metabolism (361), the HPA axis (362), the vagus nerve (363) and by the production of microbial metabolites, such as short chain fatty acids (SCFA's) (364). The microbiota-gut-brain (MGB) signaling system operates throughout life but is particularly important during early development when it influences the development of the neural circuitry underlying social, cognitive, and emotional brain domains (365, 366). Preclinical research has revealed that neurotransmission, neurogenesis, myelination, dendrite formation and blood brain barrier organization are partially under the influence of this MGB axis signaling system (367–371). At the behavioral level, MGB axis signaling modulates cognitive function and patterns related to social interaction, locomotor activity and stress management (362, 372, 373). The gut microbiome also modulates psychotropic drug metabolism and absorption, which in turn modifies gut microbiota composition (374–376). Thus, the gut microbiome is an unconscious processing system that contributes to emotional, cognitive, and behavioral regulation (377). Acute and sustained psychedelic responses are influenced by bidirectional biofeedback information signals from the periphery and the environment. Consequently, the interaction of the classical psychedelics and the microbiome and mycobiome (fungal community) and associated signaling pathways, together with the potential mediating influence of the microbiome on the interaction between psychedelic therapy and acute and sustained dietary behavioral patterns may have implications for the optimization of precise-personalized-systems based psychedelic therapy (378).

The precise-personalized transdiagnostic paradigm is not without critics and major challenges. As yet, it has not delivered discernible translational benefits to patients (379). Regrettably, there are no psychobiological signatures to guide clinical practice, which still involves clinical assessment and trial and error treatment approaches (380). It is not yet clear whether a transdiagnostic paradigm will add translatable precision to clinical psychiatry, which comprises the severe end of the dimensions (381, 382). Some argue that the RDoC's utility may be limited for the most serious of mental disorders, including dementia, autism, schizophrenia, and bipolar disorder, and may be more useful for depression, anxiety disorders (including PTSD/OCD) and some personality disorders (383, 384).

However, the precise-personalized integrative neuroscience framework is at an early evolutionary stage (385) and the divergence between therapeutic utility for some disorders and exacerbation of others, indicates a role for the RDoC constructs and associated underlying units of analysis, to enhance the understanding and application of psychedelic therapy. While transdiagnostic treatments are not unique to psychedelic compounds, the potential for psychedelics to induce profound transient changes in emotion, thought and perception with marked inter-individual variation, together with the potential to exacerbate underlying pre-dispositions to psychosis and mania (30, 226, 227) compels a greater emphasis on a precise-personalized paradigm. Echoing the general lack of personalized precision in clinical psychiatry, comprehensive clinical assessments are the only available method to identify and exclude participants with disorders that may be exacerbated by psychedelic therapy.

Notwithstanding the reliance on clinical measures, currently available strategies to optimize therapeutic outcomes involve refinement of pharmacotherapy and psychotherapy schedules, though the precise ratio has yet to be determined. It appears that body weight adjusted dosing, albeit over a narrow dosing range of 20–30 mg, may have limited impact on the subjective effects of psilocybin (386) and it remains to be seen whether potential pharmacological modulators such as 5-HT2A receptor gene polymorphisms influence therapeutic response. Moreover, the precise interaction of other psychotropics (SSRI, SNRI, antipsychotics, and mood stabilizers) (387) and psychedelic therapy has yet to be determined. From the psychotherapeutic angle, a high-quality systematized foundation is a vital (388), though there is major scope for the advance of personalization/individualization in the context of an RDoC framework. It will also be interesting to consider the implications of psychedelic therapy for the Neuroscience-based Nomenclature project, developed to progress a more precise neuroscience based psychopharmacological nomenclature (389).

There are preliminary indicators that the advances in the mechanistic understanding of psychedelics may translate into more precise-personalized approaches (41, 42). As translational psychedelic science advances, a complete understanding of the molecular cascades and bidirectional information exchange processes between internal and environmental systems will require analysis across genome, transcriptome, proteome, metabolome, microbiome, epigenome, connectome, physiome and exposome (environmental) levels (390). Deciphering the precise interaction between these systems may advance treatment personalization algorithms, perhaps assisted by advances in technology, such as virtual reality (391, 392), smartphones (393) and biosensors/biofeedback (394). Yet, it should be noted that even if the whole endeavor reduces down to an elaborate set of multi-layered fluctuating ones and zeros or some superposition thereof, or special molecular configurations and information processing pathways yet to be discovered, it is the relationship between the complex configurations underlying our experiences and the empathetic sharing and compassionate understanding of those experiences with others and the environment that is the matter of meaning and the potential of psychedelic therapy.