This review (2021) uses the Research Domain Criteria (RDoC) as a template to analyse the multimodal mechanisms underlying the transdiagnostic therapeutic effects of psychedelic therapy, covering molecular, cellular and network levels. This is the first review to use the RDoC to explore psychedelic therapies and may facilitate a precise-personalized psychedelic therapy paradigm.
Accumulating clinical evidence shows that psychedelic therapy, by synergistically combining psychopharmacology and psychological support, offers a promising transdiagnostic treatment strategy for a range of disorders with restricted and/or maladaptive habitual patterns of emotion, cognition and behavior, notably, depression (MDD), treatment resistant depression (TRD) and addiction disorders, but perhaps also anxiety disorders, obsessive-compulsive disorder (OCD), Post-Traumatic Stress Disorder (PTSD) and eating disorders. Despite the emergent transdiagnostic evidence, the specific clinical dimensions that psychedelics are efficacious for, and associated underlying neurobiological pathways, remain to be well-characterized. To this end, this review focuses on pre-clinical and clinical evidence of the acute and sustained therapeutic potential of psychedelic therapy in the context of a transdiagnostic dimensional systems framework. Focusing on the Research Domain Criteria (RDoC) as a template, we will describe the multimodal mechanisms underlying the transdiagnostic therapeutic effects of psychedelic therapy, traversing molecular, cellular and network levels. These levels will be mapped to the RDoC constructs of negative and positive valence systems, arousal regulation, social processing, cognitive and sensorimotor systems. In summarizing this literature and framing it transdiagnostically, we hope we can assist the field in moving toward a mechanistic understanding of how psychedelics work for patients and eventually toward a precise-personalized psychedelic therapy paradigm.
Papers cited by this study that are also in Blossom
Corrigan, K., Haran, M., Mccandliss, C. et al. · Irish Journal of Medical Science (2021)
Davis, A. K., Barrett, F. S., May, D. G. et al. · JAMA Psychiatry (2021)
Carhart-Harris, R. L., Giribaldi, B., Watts, R. et al. · New England Journal of Medicine (2021)
Carhart-Harris, R. L., Bolstridge, M., Rucker, J. et al. · Lancet Psychiatry (2016)
Dursun and colleagues situate this paper within the rapid expansion of translational psychedelic science and note accumulating clinical signals that psychedelic-assisted interventions, combining pharmacology and psychological support, may produce clinically meaningful benefits across multiple diagnostic categories. The authors foreground a central challenge: while early clinical and preclinical studies suggest antidepressant, anxiolytic and anti-addictive effects, the precise clinical dimensions and underlying neurobiological pathways responsible for those transdiagnostic effects remain poorly characterised. They highlight the primary pharmacological locus for classical psychedelics as 5-HT2A receptor activation, particularly on cortical layer 5 pyramidal cells, and introduce the REBUS (Relaxed Beliefs under Psychedelics and the Anarchic Brain) model as a contemporary explanatory framework that proposes a relaxation of higher-order priors and increased bottom-up information flow during the psychedelic state. The review sets out to map preclinical and clinical evidence onto the National Institute of Mental Health's Research Domain Criteria (RDoC) dimensional framework, examining how psychedelics modulate negative and positive valence systems, arousal/regulatory processes, social processing, cognitive systems and sensorimotor domains across multiple levels of analysis (genes to behaviour). The authors aim to synthesise multimodal mechanisms (molecular, cellular, network) in order to advance a systems-based, precise-personalised paradigm for psychedelic therapy and to guide future mechanistic and clinical work.
The extracted text describes a narrative, integrative review rather than a formal systematic review or meta-analysis. Dursun and colleagues explicitly anchor the discussion to the RDoC dimensional constructs and state that, within each RDoC domain, they consider evidence spanning multiple levels of analysis—from genes and molecules to circuits, physiology, behaviour and self-report—drawing on preclinical studies, healthy volunteer experimental work, open-label clinical studies, randomised controlled trials and observational surveys. The authors indicate their review complements prior meta-analyses and topical reviews but differs by organising evidence around RDoC constructs to promote a transdiagnostic systems perspective. The extracted material does not report a formal search strategy, explicit inclusion/exclusion criteria, databases searched, dates or a risk-of-bias assessment. Instead, the paper synthesises exemplar findings and trials (preclinical and clinical) relevant to each RDoC construct, and discusses mechanistic proposals, candidate biomarkers and ongoing clinical trials where cited. Where quantitative results are discussed, the authors generally report study sample sizes and key outcome metrics as presented in the original reports.
Across Negative Valence Systems (NVS), the review highlights multiple lines of evidence that psychedelic therapy can recalibrate responses linked to loss, fear and threat. In clinical samples, early modern-era double-blind RCTs of psilocybin in people with cancer-related distress produced immediate and sustained antidepressant and anxiolytic effects; some subgroups showed effects sustained for years. In an open-label proof-of-concept in treatment-resistant depression (TRD) (n = 12), two psilocybin sessions (10 mg then 25 mg) produced a clinically significant reduction in Montgomery–Åsberg Depression Rating Scale (MADRS) scores in 67% at 1 week and 40% maintained response at 3 months. A Phase II RCT (n = 59) found psilocybin therapy was at least as effective as escitalopram for major depressive disorder (MDD), and a Phase IIb TRD trial (n = 233) reported a statistically significant between-group difference favouring psilocybin 25 mg versus 1 mg at week 3 (−6.6 points on MADRS). Neural correlates include generally reduced amygdala reactivity to negative stimuli in healthy controls, though findings in clinical samples are mixed (for example increased amygdala responses to faces 1 day post-psilocybin in an open-label TRD cohort), and changes in corticolimbic connectivity have been associated with reductions in rumination. Preclinical studies indicate that psychedelics can accelerate fear extinction and reduce anxiety-like behaviour in rodents, with some agents producing durable changes in dendritic spine morphology and epigenetic marks in frontal cortex. Neuroendocrine and immune signals are modulated acutely (increased cortisol and other hormones after DMT, psilocybin and LSD) and there are preliminary human reports of reduced C-reactive protein after ayahuasca in TRD and healthy control groups; however, the clinical relevance of immunoendocrine changes remains unclear. On Positive Valence Systems (PVS) and reward circuitry, animal and human data suggest psychedelics modulate mesolimbic networks. Preclinical reports show psilocin alters extracellular dopamine and serotonin in nucleus accumbens and mPFC, and some studies implicate interactions between 5-HT and dopamine pathways. Clinical pilot studies in addiction report promising signals: an open-label psilocybin intervention (plus psychotherapy) reduced alcohol consumption in 10 participants, maintained to 36 weeks, and a pilot smoking cessation study (n = 15) reported 7-day point prevalence abstinence of 80% at 6 months. Subjective ‘mystical’ or insight-related features of the psychedelic experience correlated with better addiction outcomes in these small studies. For depression, the authors link reported increases in curiosity, meaning, intrinsic motivation and related constructs to possible re-engagement of reward systems, while also warning of risk in bipolar and psychosis-prone populations. Neuroplasticity is reviewed as a putative transdiagnostic mechanism: preclinical work demonstrates rapid increases in dendritic spine size and density (a 10% increase in medial frontal cortex within 24 h after a single psilocybin dose in mice, persisting for 1 month) and increases in synaptic markers (SV2A) in pigs. Molecular cascades tied to BDNF, TrkB and mTOR pathways are described, with some human peripheral blood studies reporting increased BDNF after ayahuasca or LSD while other small trials found null effects. Arousal and regulatory systems are acutely engaged by psychedelics: sympathetic activation (blood pressure, heart rate), transient increases in cortisol, ACTH and other hormones after DMT, psilocybin and LSD, and immune modulation via serotonergic receptors are reported. Psilocybin can increase REM latency and suppress slow-wave activity in early sleep cycles in one placebo-controlled study. Social processing data indicate enhanced prosocial behaviour, decreased feelings of social exclusion and increases in interpersonal closeness after single high-dose sessions in healthy volunteers; oxytocin rises have been observed but clinical relevance is undetermined. Empathy measures show acute increases in emotional empathy but mixed effects on cognitive empathy. Self-processing alterations, notably ego-dissolution, are linked to 5-HT2A receptor occupancy, mPFC and hippocampal glutamate changes, and DMN perturbations; intensity of subjective experience correlates with several reported longer-term shifts in meaning, gratitude and life appreciation. Neural-circuitry findings emphasise disruption of default mode network (DMN) connectivity in healthy subjects (reduced DMN rsFC and mPFC–PCC coupling) and broader changes in global and sensory/associative connectivity. However, results are not uniform: an open-label TRD study reported increased DMN rsFC 1 day post-psilocybin and Phase II data indicate psilocybin-associated decreases in network modularity that correlated with depression improvements, a pattern not observed with escitalopram. Cognitive systems show dose-dependent, acute impairments in attention, executive function and working memory in healthy volunteers; some open-label clinical data report improvements in select aspects of cognitive flexibility after psilocybin in depressed patients, but findings are heterogeneous and practice effects or subjective changes may confound self-report measures. Obsessive–compulsive disorder and eating disorder evidence is preliminary, with small uncontrolled studies suggesting potential benefits. Sensorimotor and perceptual domains are robustly engaged by psychedelics (visual imagery, time/space distortions, synaesthesia) and rare but important risks (for example hallucinogen persisting perception disorder) are noted. Finally, the authors discuss the microbiome as a potential additional unit of analysis in the RDoC framework, noting mechanistic plausibility via the gut–brain axis but emphasising the idea is speculative at present. Across domains, candidate predictors of response mentioned include baseline autonomic activity, functional connectivity patterns, cingulate cortical thickness, personality traits such as absorption and openness, and language-analytic markers, but the literature lacks validated psychobiological signatures.
Dursun and colleagues interpret the assembled evidence as supportive of a transdiagnostic therapeutic potential for psychedelic therapy that can be coherently framed within the RDoC dimensional systems model. They emphasise mechanistic convergence around 5-HT2A receptor activation, increased bottom-up information flow (per the REBUS model), modulation of corticolimbic circuits, and engagement of rapid neuroplasticity processes as plausible pathways by which psychedelics may recalibrate maladaptive patterns across multiple RDoC domains. The authors argue that organising research around RDoC constructs can help move the field toward precise-personalised interventions by identifying cross-cutting biosignatures and candidate predictors of response. The paper acknowledges substantial limitations and uncertainties: much of the clinical literature comprises small, open-label or uncontrolled studies; effects vary across populations and experimental paradigms; translation from animal models to humans is imperfect; and the substantial contribution of psychotherapy, set and setting complicates attribution of effects purely to pharmacology. The authors caution that psychedelics can exacerbate conditions characterised by insufficient top-down constraint (for example psychosis spectrum disorders) and may pose risks in bipolar I disorder. They call for well-powered, longitudinal RCTs and multimodal mechanistic studies to clarify efficacy, safety, probable mediators and moderators of response. In terms of implications, the authors propose that integrating RDoC constructs with ongoing and future trials could refine target selection, biomarker development and intervention personalization. They recommend comprehensive multi-omic and neuroimaging approaches, larger samples to support predictive modelling, and rigorous designs that better dissociate drug effects from psychotherapeutic processes. The discussion highlights ongoing Phase II and larger trials as critical to determining whether early transdiagnostic signals translate into reproducible clinical benefits.
Dursun and colleagues conclude that psychedelic science is progressing rapidly and that mechanistic advances across interacting systems may support the development of novel compounds and personalised treatment approaches. They suggest that deconstructing categorical psychiatric diagnoses into RDoC-aligned dimensional constructs could improve targeted applications of psychedelic therapy and potentially optimise outcomes. The authors emphasise that several large randomised controlled trials underway will be decisive in determining clinical utility for non-psychotic disorders, and they advocate for multimodal prediction algorithms and deeper mechanistic work to bridge the gap between neuroscience and psychiatry in the service of a precise-personalised psychedelic therapy paradigm.
Translational Psychedelic science is evolving rapidly. Initial data suggests that the dose dependent, transient, altered state of information processing induced by psychedelics can be harnessed by the psychotherapeutic process to lead to clinical benefits across a range of disorders. Accumulating preliminary clinical studies have shown that this synergistic combination of psychopharmacology and psychotherapy may improve outcomes in depression, treatment resistant depression (TRD)and addiction disorders. While results from ongoing well-powered double-blind randomized controlled trials (RCTs) will determine whether psychedelic therapy translates into clinical benefits for nonpsychotic disorders in clinical psychiatry, it has been proposed that psychedelic therapy may have broad therapeutic benefits via the attenuation of overly-restricted and maladaptive patterns of cognition and behavior. Exploratory studies suggest potential benefits of psilocybin therapy in OCD, eating disordersand migraine suppression, with ongoing RCTs of psilocybin therapy in MDD, bipolar disorder type II depression, alcohol use disorder, smoking cessation, cocaine addiction, opioid addiction, anorexia nervosa, depression in Mild Cognitive Impairment, OCD and various types of headaches. A precise mechanistic understanding of psychedelics is challenging because of the synergistic action of pharmacotherapy and psychotherapy, together with the induction of a wide range of complex subjective experiences with marked individual variation. The primary initial pharmacological target of the classical psychedelics appears to be activation of 5-HT2A receptors (Box 1) particularly in cortical layer 5 pyramidal cells. A contemporary explanatory model-the Relaxed Beliefs under Psychedelics and the Anarchic Brain (REBUS)-proposes that psychedelics via action at 5-HT2A receptors in higherorder cortical regionsrelax the typical constraints that higher order brain systems impose on emotions, cognitions, and sensory perceptions. This amounts to a decrease in the weight on (or precision of) prior beliefs, which in some disorders may be pathological (e.g., negative self-evaluations). This model proposes that psychedelics may facilitate an increase of information flow from bottom up signaling systems, opening the individual to information that they are otherwise biased to ignore or discount. The belief-recalibration process proposed by the REBUS model illustrates one mechanism through which psychedelic therapy may operate as a transdiagnostic therapeutic option for a broad range of disorders, particularly those with overly constrained beliefs or behaviors, such as major depression, anxiety and addiction disorders. This model provides a framework for understanding their lack of efficacy in conditions such as psychosis spectrum disorders, where some have hypothesized there is insufficient constraint imposed on lowerlevel perceptions and cognitions. It follows that these disorders are exacerbated by psychedelics. Other overlapping models, focus on 5-HT2A receptor induced altered thalamic gating in cortico-striato-thalamo-cortical (CSTC) feedback loops. As we accumulate more knowledge about the precise mechanisms of action, and how this might vary across individuals, we can begin to refine personalized treatment strategies. Currently available strategies to refine therapeutic outcomes include dose (and interval) optimization, modification of psychological interventions (perhaps dependent on the level of complexity or severity) and optimization of environmental ambiances/cues (setting). Precise-personalizedpredictive psychobiological markers are at an early stage of development, with exploratory clinical studies suggesting baseline Autonomic Nervous System activity, functional connectivity patternsand cingulate cortical thickness, together with psychological factors such as absorption and opennessand language analysisas potentially useful predictors of therapeutic outcomes. This research is reflective of a much broader advance toward individualized treatment approaches across all aspects of psychiatry, where the mantra is to move beyond one-size-fits-all toward more personalized care plans. In order to develop and build on these precision medicine approaches, there is growing consensus that research needs to traverse multiple levels of analysis. In this review, we aim to anchor the accumulation of basic and applied research in psychedelics to the National Institute of Mental Health's Research Domain Criteria (RDoC), thereby adding structure to a fast-growing field. The transdiagnostic dimensional RDoC constructs are negative and positive valence systems, arousal regulation, social processing, cognitive and sensorimotor systems (Figure). In each section we will discuss, where available, research that spans multiple levels of analysis from genes, molecules, proteins, cells, circuits, physiology, behavior, self-report, and paradigms (Figure). This review complements existing meta-analyses on the effects of psychedelic therapyand recent reviews on the topic. But in contrast, by framing and organizing the empirical data on psychedelics around the RDoC criteria, we aim to advance the field specifically toward a systems based precise-personalized psychedelic therapy paradigm.
Personalized-precision psychiatry is impeded by two major issues that are partially related-(i) the reliance on categorical diagnostic systems and high levels of comorbidity and heterogeneityand (ii) an over-reliance on small scale studies that cannot capture the complexity of mental health and illness, and as a result have failed to generate robust prediction/decision models needed for personalization. To the former point, there is broad consensus that categorical diagnostic labels, while necessary for pragmatic treatments in clinical settings, do not signify unitary, biologically credible, or informative markers of mental health and for example the overlap of previously presumed distinct psychiatric diagnoses, in terms of genes and brain networks, have been demonstrated by large neuroimagingand genetic data sets. To the latter, there is increasing awareness that effect sizes in mental health science are generally small, regardless of whether variables are biologicalor psychosocial. Thus, for personalization to occur, studies must move toward integrating multiple variables that have individually low predictive powersuch approaches require large samples for accurate model development. Absent large datasets, a transdiagnostic and dimensional approach (compared to a categorical one) may do something to resolve both issues; if we can more accurately, validly and reliably capture mental health phenomena and the underlying biosignatures, then the effect sizes we observe will increase. There are emerging signals that deconstructing categorical diagnoses into dimensional constructs may facilitate enhanced treatment precision. A recent clinical trial adopting an RDoC approach to the investigation of a selective κ-opioid receptor blocker for anhedonia across mood and anxiety disorders showed that this compound increased fMRI ventral striatum activation during reward anticipation compared to placebo. A study dividing MDD disorder symptoms into positive valence symptoms (impaired motivation, impaired energy, and anhedonia) and negative valence symptoms (anxiety and interpersonal sensitivity) showed that antidepressants were more effective for positive valence symptoms. The evolving neuroscientific framework of the RDoC aims to integrate developmental processes and environmental inputs over the trajectory of the life course to determine the mechanisms underlying normal-range functioning and then how disruptions correspond to psychopathology. It is anticipated that the identification of targetable biosignatures that either cut across traditional disorder categories or that are unique to specific clinical phenomenon will improve outcomes for people with mental health disorders. In the sections that follow, we will consider if and how psychedelic therapy operates across the RDoC domains in the hope that harnessing an integrative neuroscience systems model, encompassing environmental information exchange processes, may add the precision we need to transition to personalized psychedelic therapy practices that are transdiagnostic and evidence based. Although well-powered longitudinal clinical studies will be required to determine whether transdiagnostic dimensional biotypes or psycho-biotypes will optimize therapeutic response rates to psychedelic therapy, it is hoped that this review will lay a foundation for future research.
NVS are primarily responsible for responses to aversive (threat) situations or context, such as fear, anxiety, and loss. Specifically, RDoC breaks NVS into acute threat (fear), potential threat (anxiety), sustained threat, loss and frustrative nonreward constructs. As we will outline in the next sections, psychedelic therapy may recalibrate NVS hyper-responsivity and positive valence systems (PVS) deficits across a range of psychiatric disorders.
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. 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, which aligns with modern-era studies. The initial double-blind, randomized, placebo-controlled clinical studies in the modernera of psychedelic therapy (psilocybin) showed an immediate and sustained antidepressant and anxiolytic effect in people with depressive symptoms associated with life-threatening cancer(Table). In subgroups, these antidepressant and anxiolytic effects were sustained for several years, as were reductions in suicidal ideation and loss of meaning. Similarly, recent data suggest efficacy for another group with high levels of loss, those who survived Acquired immunodeficiency syndrome (AIDS) (). An open-label feasibility study of psilocybin therapy (10 mg) then 7 days later 25 mg, of 12 people diagnosed with treatmentresistant 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. Measures of anhedonia, which overlap with reward dysfunction (see below) and anxiety, which overlap with threat processing (as discussed above) also improved (Table). Furthermore, in some participants these antidepressant and anxiolytic effects were sustained at 6 month follow up. A randomized, waiting list-controlled clinical trial, though still without a placebo control, confirmed the immediate and sustained antidepressant effects of psilocybin therapy in (nontreatment resistant) MDD (). 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. 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). 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, crossover study in 23 in healthy controls (HCs) who received 14 days of escitalopram or placebo prior to psilocybin, 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. 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. 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. 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. In the same cohort of TRD participants, decreased cerebral blood flow in the amygdala correlated with reduced depressive symptoms 1-day post-psilocybin. 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. 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. 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 immunoendocrine 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. 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. 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. The TRD group treated with ayahuasca showed a significant correlation between larger reductions of CRP and lower depressive symptoms 48 h after ayahuasca. However, there were no significant changes in IL-6 levels. 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 Immediate and sustained reductions in anxiety and depression symptoms (HADS, BDI, STAI-S and STAI-T) that remained significant until final follow-up. At 6.5-months: anti-depressant (BDI) or anxiolytic response rates (HAD-A) 60-80% At 4.5 yrs follow-up (16 alive, 15 participated); ∼60-80% met criteria for clinically significant antidepressant or anxiolytic responses 71-100% attributed positive life changes to the psilocybin-assisted therapy and rated it among the most personally meaningful and spiritually significant experiences of their lives Reductions in suicidal ideation and loss of meaning(Continued) Frontiers in Psychiatry | www.frontiersin.org IL. 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. 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-4iodophenyl)-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. 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 cancerand the studies in depressionalso 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). 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. 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. 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. 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 corticolimbic 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 () 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 3,4ethylenedioxymethamphetamine (MDMA) therapy (). 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 hyperresponsivity coupled with hypoactivity of prefrontal regions, which overlaps with threat processing circuitry. 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 noncontrolled 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) (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. Moreover, higher baseline scores in the personality trait of absorption (focused attention)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, some propose that the subjective effects may not be necessary to produce long-lasting changes in mood and behavior (). The classical psychedelics may share glutamatergic activitydependent 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 plasticityrelated 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, 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).
PVS are primarily responsible for responses to positive motivational situations or contexts, such as reward seeking, consummatory behavior, and reward/habit learning.
Reward-pathway dysfunction is associated with a range of disorders, including but not limited to mood, anxiety, addiction disordersand eating disorders. 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. 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 (). 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. 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. 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 restingstate 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. 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. 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, 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.
The multi-layered complexities underlying addiction disorders are not only limited to reward and habit dysregulation but may include other constructs such as impulsivity and compulsivity (213). Compared to other recreational substances, psychedelics exhibit minimal reinforcing effects and are among the least harmful, with minor physiological side effects. Furthermore, preliminary clinical studies indicate a therapeutic use in alcohol use disorder, and for smoking cessation. An open label pilot study of oral psilocybin in one or two supervised sessions in addition to Motivational Enhancement Therapy reduced alcohol consumption, which was maintained at 36 weeks, in a group of 10 participants with alcohol dependence disorder. Although the mechanisms have yet to be fully elucidated, changes in alcohol consumption were associated with what is described as the "mystical" quality of the psilocybin experience. Consistent with this, a subsequent online survey (n = 343) of people with prior alcohol use disorder, reported that insight, mystical-type effects, and personal meaning of experiences, together with higher psychedelic dose, were associated with a greater reduction in alcohol consumption (219). However, the potential mediating influence of negative and positive valence system modulation should also be acknowledged. Interestingly, neither psilocybin nor LSD administered in a high dosage regimen or chronic microdosing regime had long-lasting effects on relapse-like drinking in an alcohol deprivation effect rat model (). Only sub-chronic treatment with psilocybin produced a short-lasting anti-relapse effect (220). A recent study showed that psilocybin restored alcohol dependence-induced metabotropic glutamate receptor (mGluR2) down-regulation and reduced alcohol-seeking behavior in rats (221). Interestingly, in a rodent food reward model, low dose psilocybin and ketamine failed to positively affect motivation or attention, though subtle improvements in attention and impulsive behavior were noted in "low performing" rats. A pilot study of psilocybin and cognitive-behavioral therapy in people with tobacco addiction reported that 12 of 15 participants (80%) showed 7-day point prevalence abstinence at 6-month follow-up. Smoking cessation outcomes were significantly correlated with measures of mystical experience, of whom 9 of the 15 participants (60%) met criteria for "complete" mystical experience, defined as a score of ≥60% on each of the following subscales: unity, transcendence of time and space, ineffability, sacredness, noetic quality, and positive mood (223). A follow up qualitative study of participants (n = 12) reported vivid insights into self-identity, together with experiences of interconnectedness, awe, and curiosity which persisted beyond the duration of acute dosing (224). Clinical trials across a range of addiction disorders are currently underway to determine whether these promising preliminary studies progress to clinical utility (Table).
Reward hyposensitivity and decreased approach motivation is related to anhedonia, a cardinal feature of the Depression. There are several psychological constructs by which psychedelic therapy may re-ignite reward deficits in states of anhedonia, including potential experiences of awe, curiosity, (explorative search), novelty, intrinsic motivation, psychological insight, and enhanced meaning/purpose (226). Conversely, reward hypersensitivity and elevated approach motivation is related to a subgroup of hypo/manic symptoms characterized by excessive approach motivation and psychomotor hyperactivation in the context of bipolar disorder. This reward hypohypersensitivity divergence maps onto the contra-indication of psychedelic therapy in bipolar type 1 disorders (BPAD I) (226, 227) and caution will be required in the treatment of the depressive phase of BPAD II (228). We await with interest the results of an open label safety and efficacy psilocybintherapy study in depressed participants with BPAD II and the future integration of dimensional approaches, such as rewardrelated reactivity assessments (Table).
RDoC's Arousal/Regulatory Systems are responsible for generating activation of neural systems as appropriate for various contexts and providing appropriate homeostatic regulation of such systems as energy balance and sleep.
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. Psychedelics acutely modulate the Autonomic Nervous System (ANS), 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. 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. 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. As discussed above, psychedelics also acutely stimulate the neuroendocrine system. In a seminal randomized placebocontrolled 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. 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, doubleblind, placebo-controlled cross-over study design. 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. Altered immune system function, mainly characterized by chronic lowgrade inflammation is associated with a range of psychiatric disordersand it remains an open question whether the potential anti-inflammatory activity of psychedelics will play a role in autoimmune disorders (252) or chronic pain.
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. 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).
RDoC broadly defines systems for social processes as mediating responses in interpersonal settings of various types, including perception and interpretation of others' actions. The biologically encoded time-lagged personal narrative is constantly under the influence of bidirectional information exchange processes with the wider socio-environmental system. The multifaceted neural circuitry and molecular signaling pathways underlying social cognition, under the influence of environmental cues, are of fundamental importance to social species (257-259). A complex intertwined relationship exists between social isolation, disconnectedness, perceived disconnection, and poor mental health. Psychedelic compounds alter social cognitive processes (Table) and studies in rodents are beginning to elucidate the underlying mechanistic pathways. A study in male mice showed that repeated doses of LSD (30 µg/kg, daily for 7 days), but not a single dose, resulted in more time interacting with a stranger mouse in the direct social interaction test, associated with potentiation of mPFC excitatory transmission via 5-HT2A and AMPA receptors and via an increasing phosphorylation of the mTORC1 protein (269). Moreover, the inactivation of mPFC glutamate neurotransmission impaired social behavior and negated the prosocial effects of LSD (269). Another study suggested that psilocybin attenuated some of the sociability deficits in a prenatal valproic acid mouse model of autism (270).
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). A placebo-controlled, doubleblind, 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. 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, 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. Taken together, psychedelic therapy induced changes in social processing systems and specifically social reward processing and behavior and enhanced experiences of connectednesshas 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).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. 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 selfprocessing as the primary mode of action of psychedelic therapy with downstream implications for social processing systems. 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). 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, 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. 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 modulationare key neurobiological substrates of selfprocessing 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 (). 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 ofHCs 1 day after consuming ayahuasca showed reductions in glutamate and glutamine in the posterior cingulate cortex (PCC), which correlated with increases in the "nonjudging" 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. 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).
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 ruminationand 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. 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. 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. 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, selfacceptance, 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 selfprocessing, a single neural correlate such as the DMN may not fully capture the complexities of the self-processing concept. 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. 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. This double-blind, placebo controlled, randomized, crossover study of 23 HCs who received oral psilocybin (0.2 mg/kg) and underwent resting-state functional connectivity fMRI scans at three time pointsshowed that psilocybin reduced associative, and concurrently increased sensory brainwide connectivity over time from administration to peak-effects. Furthermore, the participants who had the lowest values in hyper-connected areas and had the highest values in hypoconnected regions displayed the strongest psilocybin induced changes in global brain connectivity. 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. 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. Furthermore, the increased ventromedial prefrontal cortex-bilateral inferior lateral parietal cortex rsFC, 1-day post-dose, predicted treatment response at 5 weeks postdose. Data from this study (n = 16) () 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). This decrease in modularity was associated with improvements in depression scores at 6-weeks as measured by the Beck Depression inventory. In contrast, no changes in modularity were observed with escitalopram, suggesting a tentative biomarker of response to psilocybin therapy.
The RDoC organizes cognitive systems into attention, working memory, perception, memory (declarative), language, and cognitive control constructs.
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". 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. 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, retreatment 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. 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 (). 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. 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. 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 (). 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).
OCD, frequently comorbid with anxiety and depression, involves deficits in cognitive control, goal-directed planning habit, reward processing (313-315) and negative valence system dysregulation, including abnormal fear extinction (316). Rodent studies have shown that psilocybin reduced digging in the marble burying test-a surrogate for compulsive behavior. However, a recent rodent study showed that blockade of 5-HT2A or 5-HT2CRs did not attenuate the effect of psilocybin on digging, suggesting that a different mechanism dominates this effect (318). A psilocybin therapy proof of concept study of antidepressant free people diagnosed with OCD (n = 9) that had failed to respond to at least one SSRI, reported a 23-100% decrease in the Yale-Brown Obsessive Compulsive Scale in the 24 h following ingestion (YBOCS) (15) (Table). Limited conclusions can be drawn from this study due to lack of a control group and lack of a clear dose-response relationship to changes in the YBOCS. Results from ongoing clinical trials in OCD will give a clearer picture and it will be interesting to parse potential therapeutic effects of psychedelic therapy according to cognitive control, and negative and positive valence processing systems (Table).
Eating disorders also involve elements of altered cognitive control/reward processing (319, 320), together with aberrant fear/threat encoding processes or threat sensitivity associated with body/food/weight gain/body perception. Enhanced psychological flexibility induced by psychedelic therapy has been proposed as a potential therapeutic mechanism of psychedelic therapy in eating disorders (321). While a preliminary study suggested a benefit of psychedelic therapy in improving depression and well-being scores in people with a self-reported lifetime diagnosis of an eating disorder, we await results from ongoing clinical trials (Table) to determine whether psychedelic therapy will lead to clinically meaningful benefits in those with eating disorders (322). It is worth noting the possibility that psychedelic therapy may be of utility for disorders related to compulsive overeating, perhaps better categorized as food addiction.
The "psychological flexibility" concept lacks precise definition, but broadly refers to the ability to recognize and adapt to various situational demands and shift mind-sets/behavioral repertoires (323). It is associated with divergent thinking (DT), a spontaneous and free-flowing pattern where many solutions are possible, with the prospect of novel idea generation. Convergent thinking (CT), in contrast, focuses on the delivery of a single solution. Deficits in psychological flexibility underlie a broad spectrum of psychopathologies. Excessively constrained thought may occur in depression, PTSD/anxiety, OCD, addiction and eating disorders, whereas excessively variable thought may occur in ADHD or some personality disorders (324) and unconstrained thought may occur in psychosis. Psychological flexibility has been proposed as a potential transdiagnostic mediator of psychedelic therapy. However, the precise impact of psychedelics on psychological flexibility or on DT and CT are not fully clear. For example, a recent double blind, placebo-controlled study of sixty HCs, all of whom had previous psychedelic experiences, found that psilocybin (0.17 mg/kg) acutely decreased CT, which remained decreased for 7 days, whereas measures of DT including fluency and originality decreased, and scores of novelty increased compared to placebo, which were associated with alterations in the.
Psychedelics acutely and dose dependently impair attention (328, 329), memory task performanceand 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 methodsor 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. Psychedelics may induce visual imagery (334-336), distortions in the perception of time and space (337, 338) and synaesthesia. 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, 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. Interestingly, a recent EEG study in freely moving rats showed some overlap with human studies, with a time-dependent global decrease and desynchronizationSimilar 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).
Sensorimotor systems are primarily responsible for the control and execution of motor behaviors, and their refinement during learning and development. The Sensorimotor Dynamics subconstruct: "processes involved in the specification or parameterization of an action plan and program based on integration of internal or external information, such as sensations and urges and modeling of body dynamics. This process is continuously and iteratively refined via sensory information and reward-reinforced information." The highly complex Functional neurological disorders (FNDs), previously known as conversion disorders, involve not only sensorimotor, but also salience, central executive, and limbic networks (349-351). There are no modern era clinical studies of psychedelic therapy in FNDs and systematic reviews of studies from several decades ago are not able to draw firm conclusions due to small numbers of low-quality studies, often lacking control groups and valid outcome measures. It is also worth noting that LSD (100 µg) increased sensory-somatomotor brain-wide and thalamic connectivity in 24 HCs, while concurrently reducing associative networks. Using a Roving Somatosensory Oddball Task and simultaneous EEG/fMRI in 15 HCs, the same researcher showed that psilocybin (0.2 mg/kg) disrupted tactile prediction error processing in the mPFC, associated with increased salience attribution to non-salient stimuli (354). It remains an open question whether the complex and disrupted sensorimotor modeling of body dynamics and the accompanying emotional processing in conditions such as FNDs (or indeed eating disorders) can be therapeutically modulated by psychedelic therapy (Table).
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. 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. 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. 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. At the behavioral level, MGB axis signaling modulates cognitive function and patterns related to social interaction, locomotor activity and stress management. 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. 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. 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) 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. 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 (). 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.
Psychedelic science and its translational corollary psychedelic therapy are evolving rapidly. Advances in the mechanistic understanding of the underlying pathways, which involve multiple interacting systems may also prompt the development of novel compounds lacking undesirable properties. Several large scale RCTs will determine whether psychedelic therapy translates into the psychiatric clinic for a range of non-psychotic spectrum disorders. Given the translatable transdiagnostic antidepressant, anxiolytic, and anti-addictive therapeutic potential of psychedelic therapy, deconstructing categorical psychiatric diagnoses according to dimensional systems and constructs that align with neurobiological systems may advance more targeted applications, with the possibility of optimizing therapeutic outcomes. As such, integration of the RDoC transdiagnostic dimensional framework with psychedelic therapy as it advances toward the psychiatric clinic has potential to progress an interconnected systems based precise-personalized psychedelic therapy paradigm and narrow the translational gap between neuroscience and psychiatry. Further insights can be gained from clinical studies in progress with psychedelic therapy although the extent to which they have been designed with this in mind may hamper efforts at integration. Additionally, evolution of multimodal prediction estimation algorithms based on dimensional psychobiological signatures may optimize the delivery of psychedelic therapy and ultimately augment clinical assessments. Apart from the vitally important context (as broadly defined), exploratory studies have proposed baseline functional connectivity patterns and cingulate cortical thickness, autonomic nervous system activity, together with psychological factors as therapeutic predictors. Further unraveling the complex and dynamic molecular cascades and information processing pathways across all levels of analysis from micro to macro, within and between psychiatric disorders and how they converge on the acute and sustained therapeutic subjective trajectory may enhance a more complete systems level understanding of psychedelic therapy and is an important objective for translational neuroscience. (COMP 001, 003, 004) in Ireland. GC was supported by the HRB through (HRA POR/2011/23 and HRA-POR-2-14-647) and supported by a NARSAD Young Investigator Grant from the. CG was supported by grant funding from MQ: Transforming mental health (MQ16IP13), the Global Brain Health Institute (18GPA02), and Science Foundation Ireland (19/FFP/6418).
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Papers in Blossom that reference this study
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