Using multimodal brain imaging, the study shows that stimulation of serotonin 2A/1A receptors modulates neural processing of social exclusion and associated emotional responses. This implicates the 2A/1A receptor system as a potential pharmacological target for treating sociocognitive deficits in psychiatric disorders.
Significance Social cognition critically impacts the development, progression, and treatment of psychiatric disorders. However, social cognition skills are insufficiently targeted by current treatment approaches. By applying a multimodal brain imaging strategy, the present study demonstrated the importance of the serotonin 2A/1A receptor system in the modulation of social exclusion processing. Understanding the biochemical underpinnings of the social rejection experience is important for increasing our knowledge about social/emotional processing and the related neural responses. The identification of relevant neural responses is in turn crucial for the efficacious management of disorders influenced by social factors. Our findings may help to diminish a knowledge gap that currently restrains the development of pharmacotherapies for sociocognitive deficits in psychiatric disorders.
Social ties are crucial for physical and mental health, and increased reactivity to social exclusion contributes to the development, progression, and treatment challenges of multiple psychiatric disorders. Previous work implicates the serotonin (5-HT) system in mood, affect and social cognition, and psilocybin (Psi) — a preferential 5-HT2A/1A receptor agonist — has been shown to attenuate processing of negative emotional stimuli and alter self-experience. However, research to date has largely examined non-interactive emotional stimuli, leaving unclear whether direct 5-HT2A/1A receptor stimulation modulates the neural and subjective processing of negative social interactions such as rejection or ostracism. Preller and colleagues designed a multimodal brain imaging study to address this gap. Using a double-blind, randomised, counterbalanced within-subject cross-over design, the investigators compared acute oral psilocybin (0.215 mg/kg) with placebo in 21 healthy volunteers while measuring functional MRI responses during an interactive social exclusion paradigm (Cyberball) and proton magnetic resonance spectroscopy (1H-MRS) in the dorsal anterior cingulate cortex (dACC). The primary aim was to determine whether Psi reduces neural and subjective responses to social exclusion and to explore whether changes in excitatory neurometabolites, particularly aspartate (Asp) and glutamate (Glu), relate to any observed effects. This study is notable for combining task-based fMRI of a real-time social interaction with spectroscopic probing of dACC biochemistry, permitting exploration of receptor-level modulation of social pain processing and its putative neurochemical substrates in humans.
Papers cited by this study that are also in Blossom
Kraehenmann, R., Preller, K. H., Scheidegger, M. et al. · Biological Psychiatry (2015)
Halberstadt, A. L., Geyer, M. A. · Neuropharmacology (2011)
Carhart-Harris, R. L., Erritzoe, D., Williams, T. et al. · PNAS (2012)
Vollenweider, F. X., Leenders, K. L., Maguire, P. et al. · Neuropsychopharmacology (1997)
Participants were 21 healthy adults (12 males, 9 females; mean age 26.48 y, SD 4.76, range 20–37). All provided written informed consent; psilocybin use was authorised by Swiss authorities and the study had ethical approval. Two subjects had MRS data excluded due to premature termination of acquisition, so MRS analyses were based on 19 participants. Further screening and eligibility details are reported in the supplementary information (SI Methods), which is cited but not reproduced in the extracted text. The investigation used a randomised, double-blind, placebo-controlled within-subject cross-over design. Each participant completed two sessions at least 10 days apart, receiving oral psilocybin (0.215 mg/kg) in one session and placebo (maltose) in the other. The chosen Psi dose was based on prior work indicating tolerability and emotion-modulatory effects. Participants completed behavioural questionnaires and physiological measures (blood pressure, pulse) alongside imaging. During fMRI, subjects played three separate runs of Cyberball, a virtual ball-tossing paradigm simulating interactive social inclusion and exclusion. The three conditions were: implicit social exclusion (ISE; participants watched because of an ostensible connectivity problem), inclusion (INCL; normal play), and explicit social exclusion (ESE; participants received five throws then were excluded for the remainder). Post-scan, participants completed a posttask questionnaire (PTQ) probing subjective feelings of exclusion and related constructs. MRI data were acquired on a Philips Achieva 3.0T scanner. Task fMRI used a 32-channel head coil; 1H-MRS used a different transmit–receive coil, requiring participants to be repositioned between modalities. A JPRESS (J-resolved) 1H-MRS protocol collected spectra from a dACC voxel (32 × 21 × 24 mm3). Spectra were quantified with Profit2 software to estimate up to 18 metabolites including Asp and Glu. fMRI analyses used an event-related general linear model implemented in SPM8. Statistical analyses of behavioural and physiological data used repeated-measures ANOVAs and paired t tests with Bonferroni correction where applicable; correlation analyses examined relationships among BOLD differences, subjective effects (5D-ASC, PANAS, PTQ), and metabolite concentrations.
Subjective and physiological effects: Psilocybin produced robust changes on the Altered States of Consciousness (5D-ASC) questionnaire. A repeated-measures ANOVA showed significant main effects of treatment [F(1,20) = 93.54, P < 0.001], scale [F(10,200) = 18.98, P < 0.001], and a treatment × scale interaction [F(10,200) = 19.67, P < 0.001], with simple effects indicating increased ratings on all 5D-ASC scales after Psi versus placebo (all P < 0.05). The authors report low anxiety ratings on the 5D-ASC (mean 7.5%, maximum 46%), and an increase in basic positive mood measures; detailed PANAS results are provided in the supplementary information. Systolic and diastolic blood pressure and pulse showed slight but significant increases after Psi compared with placebo (all P < 0.05). Behavioural response to Cyberball: On the posttask questionnaire participants reported feeling less excluded after Psi than after placebo [t(20) = 2.71, P < 0.01]. Other PTQ items (self-esteem, meaningful existence, control, inclusion, belongingness, liking) did not differ significantly between conditions (all P > 0.1). Estimates of the number of throws received did not differ between Psi and placebo, indicating comparable awareness of exclusion across treatments. fMRI task activation and drug effects: In the placebo condition, the explicit social exclusion (ESE > INCL) contrast activated regions typically linked to social pain: bilateral anterior midcingulate cortex (aMCC), posterior MCC (pMCC), left inferior orbitofrontal cortex, and bilateral middle frontal gyrus (MFG). Comparing placebo versus psilocybin for ESE > INCL revealed significantly reduced activation under Psi in the right aMCC and left MFG; no regions showed greater activation under Psi for this contrast. For the implicit exclusion contrast (ISE > INCL), placebo showed activation in left anterior/posterior MCC and right pregenual ACC; Psi reduced activation bilaterally in anterior/posterior MCC and in the left pregenual ACC versus placebo. The context-specific contrast (not receiving INCL > receiving INCL) recruited subgenual ACC under placebo but showed no significant Psi versus placebo differences, suggesting Psi's effects were specific to exclusion contexts rather than to not receiving the ball per se. Correlations with subjective effects: A correlation analysis examined differences in BOLD responses (placebo > Psi) and subjective drug effects. A significant positive correlation emerged between reduced activation in the right MCC and the 5D-ASC 'experience of unity' scale in the Psi condition (r = 0.53, P < 0.02). No other significant correlations between BOLD responses and 5D-ASC, PANAS or PTQ items were reported (all P > 0.08 to P > 0.1). Relationships with MRS metabolites: The dACC voxel used for MRS overlapped the region where Psi reduced activation for ESE > INCL. Changes in dACC activity (placebo minus Psi) were strongly correlated with baseline-corrected aspartate concentrations after Psi (r = 0.80, P < 0.001, n = 19). Additionally, Asp concentration at the Psi follow-up measurement correlated with dACC activity (r = -0.56, P < 0.02, n = 19). No significant correlations were observed for other metabolites or metabolite measures (all P > 0.17).
Preller and colleagues interpret their multimodal results as evidence that acute 5-HT2A/1A receptor stimulation with psilocybin attenuates the neural and subjective experience of social pain. Task-based fMRI showed that Psi reduced exclusion-related activation in regions centrally implicated in social pain processing — notably the dorsal anterior cingulate cortex (dACC/aMCC) and middle frontal gyrus — and participants reported feeling less excluded during the Psi condition. The authors propose that reduced activation in the MFG may reflect a diminished need for frontal regulatory processes because affective distress was lower under Psi. The investigators further link neural changes to alterations in self-experience: decreased dACC responses correlated with higher scores on the 5D-ASC 'experience of unity' scale, suggesting that changes in the sense of self or boundary dissolution may modify interpersonal processing and make negative social experiences more tolerable. In addition, spectroscopic findings associated reductions in dACC BOLD responses with decreases in aspartate (Asp) concentrations; the authors discuss Asp as an excitatory amino acid that preferentially activates NMDA receptors and consider possible ties to glial–neuronal metabolic pathways, including the malate–aspartate shuttle and a proposed neuron-to-astrocyte Asp transcellular pathway relevant to glutamate–glutamine cycling. Several caveats are acknowledged. The complex resonance pattern of Asp challenges in vivo quantification, although the authors report JPRESS acquisition and fitting parameters that yielded acceptable Cramér–Rao lower bounds and data quality. They note that MRS cannot distinguish synaptic from extrasynaptic pools, so metabolite concentration changes do not directly prove altered neurotransmission. Potential confounds from drug effects on cerebral vasoactivity are also discussed; prior work cited by the authors found no evidence that non-neural vascular changes account for psilocybin-related BOLD effects, and the task-specific nature of contrasts in this study argues against a global vascular explanation. The authors further recognise conflicting PET versus fMRI findings in the literature regarding resting ACC activity after psilocybin and emphasise that their task contrasts do not permit conclusions about global increases or decreases in ACC activity. In terms of broader relevance, the authors suggest that modulating 5-HT2A/1A receptors — and potentially targeting Glu/Asp-related metabolic pathways — could be pertinent to disorders characterised by heightened rejection sensitivity, such as major depression and social anxiety, and that Psi's capacity to reduce negative social bias could relate to putative antidepressant effects. They caution, however, that the present findings derive from healthy volunteers and may not directly generalise to clinical populations. Finally, the study is presented as the first multimodal human imaging demonstration that direct 5-HT2A/1A receptor stimulation can regulate social pain processing and that Asp-related biochemistry in the dACC is associated with these effects.
Subjective Effects and Physical Effects. An ANOVA (treatment × scale) was conducted for the Altered States of Consciousness (5D-ASC) questionnaire, and revealed significant main effects for treatment [F(1, 20) = 93.54, P < 0.001] and scale [F(10, 200) = 18.98, P < 0.001] and a significant interaction of treatment × scale [F(10, 200) = 19.67, P < 0.001]. Simple main effect analyses showed increased ratings on all 5D-ASC scales after Psi vs. Pla treatment (all P < 0.05; Fig.). No order effects with regard to the sequence of substance administration were observed (SI Results). For Positive and Negative Affect Schedule (PANAS) ratings, see SI Results and Fig.. Systolic and diastolic blood pressure as well as pulse were slightly but significantly increased after Psi administration compared with Pla (all P < 0.05; Table). Cyberball Task. Posttask questionnaire. Participants reported a reduced feeling of exclusion after Psi vs. Pla treatment [t(20) = 2.71, P < 0.01; Fig.]. Additional posttask questionnaire (PTQ) items revealed no significant differences between Psi and Pla conditions (all P > 0.1). In particular, participants accurately gauged the number of throws received in each run, indicating equal awareness of exclusion under both treatment conditions (Table). fMRI data. The "not receiving explicit social exclusion (ESE) > receiving inclusion (INCL)" contrast in the Pla condition revealed significant activation in brain regions of interest (ROIs) commonly associated with social exclusion processing: the bilateral anterior midcingulate cortex (aMCC), bilateral posterior MCC (pMCC), left inferior OFC, and bilateral MFG (see Tablefor wholebrain results). To assess whether social exclusion was processed differently after Psi vs. Pla administration, we compared the "not receiving ESE > receiving INCL" contrast between Pla and Psi conditions. Brain activation was significantly less pronounced in the right aMCC and left MFG for Psi vs. Pla (Fig.; see Tablefor whole-brain results). Because these areas have been shown to represent key regions for social exclusion processing, these results suggest that Psi administration reduced the processing of social pain. No significant differences in activation were found for the inverse comparison (Psi > Pla) for the "not receiving ESE > receiving INCL" contrast. The "not receiving implicit social exclusion (ISE) > receiving INCL" contrast in the Pla condition revealed significant activation in the left anterior and posterior MCC and the right pregenual ACC (Table). Comparison of the "not receiving ISE > receiving INCL" contrast revealed significantly reduced activation in the bilateral anterior and posterior MCC and the left pregenual ACC in the Psi vs. Pla condition (Table). No significant differences in activation were found for the Psi > Pla comparison for the "not receiving ISE > receiving INCL" contrast. Context-specific effectswere investigated by computing the "not receiving INCL > receiving INCL" contrast. This contrast revealed significant activation in the left subgenual ACC for Pla (Table). The same contrast showed no significant differences in activation for Psi vs. Pla administration (Table), indicating that Psi did not significantly modulate the processing of "not receiving the ball" without an exclusion context. Again, no significant differences in activation were found for the Psi > Pla comparison for the "not receiving INCL > receiving INCL" contrast.
The present study used a multimodal brain imaging approach to show that the processing of social pain is reduced after 5-HT2A/1A receptor stimulation by Psi; furthermore, this reduced response to social exclusion involved changes in cingulate Asp concentrations and changes in the experience of self. In agreement with previous studies of social exclusion and rejectionfor reviews see refs., we demonstrated that experiences of social exclusion vs. inclusion in the Pla condition involved the aMCC, pMCC, MFG, and inferior OFC. These brain areas are commonly associated with feelings of exclusion. Importantly, 5-HT2A/1A receptor stimulation by Psi significantly reduced activation of the aMCC and MFG in response to social exclusion. The aMCC, also termed the dACC, represents a key region in social exclusion processing. In particular, dACC activation is related to experiences of fear and anxiety, emotional distress, and social pain. Consistent with these observations, the current findings strongly suggest that Psi decreases the experience of social pain. Moreover, the frontal cortex also plays a regulatory role in social exclusion processing. More specifically, activation in the MFG can lead to inhibition of affective distress and social pain. Because Psi seems to reduce affective distress following social rejection, the decreased BOLD signal in the MFG observed herein after Psi administration possibly stemmed from a diminished need to block stressful experiences. Here, implicit social exclusion relative to inclusion significantly recruited the aMCC, pMCC, and ventral ACC in the Pla condition. Activation in the MFG was not significant for ISE, contrary to ESE. This result supports previous findings showing increased ACC activity, but not self-regulatory responses, in frontal areas for ISE. Psi treatment reduced the response to ISE in the aMCC, pMCC, and ventral ACC, suggesting that Psi diminishes reactions to social exclusion even in an implicit, and therefore possibly more subtle, context. To investigate whether Psi-induced alterations in neural responses to the event of "not receiving the ball" are attributable to this specific event or are instead sensitive to the game context, we also analyzed the "not receiving > receiving the ball" contrast while participants were included in the game. In line with a previous study applying an event-related analysis to the Cyberball paradigm, this contrast recruited the subgenual ACC in the Pla condition. However, no significant differences were found between Pla and Psi for this contrast, indicating that Psi modulates the response to "not receiving the ball" only in conditions where the participant is actually excluded from the game, corroborating the interpretation that 5-HT2A/1A receptor stimulation by Psi apparently weakens the distressing affective response to social rejection. In agreement with a decreased neural response to social exclusion, participants reported that they felt less excluded in the Psi vs. Pla condition on the PTQ. However, other ratings (e.g., self-esteem, meaningful existence, control, inclusion, belongingness, and liking) were not significantly altered by Psi; this suggests that Psi-mediated stimulation of the 5-HT2A/1A receptor may specifically reduce the feeling of being excluded, which is apparently not influenced by other social parameters. Additionally, no significant differences were found between Pla and Psi conditions for estimates of received throws, indicating that participants were equally aware of exclusion in both treatment conditions. Therefore, the reduced response to social exclusion is unlikely due to decreased attentiveness to the exclusion. In the present study, the Psi-induced alterations on the 5D-ASC and increased scores for basic positive mood were generally similar to those observed in previous studies using comparable drug doses. The low ratings on the 5D-ASC scale "anxiety" (mean score: 7.5%, maximum score: 46%) are in accordance with previous studies suggesting that even during peak effects Psi is well tolerated and rarely produces profound or psychotic anxiety in a controlled clinical setting in healthy human subjects. Moreover, the Psi-induced reduction in dACC activity in response to social exclusion showed significant correlations with scores for the feeling of unity. The 5D-ASC feeling of unity scale incorporates items assessing alterations in the sense of self/self-boundaries, such as feelings of being connected and/or one with the environment. The correlation between experience of unity and social pain processing may indicate that alterations in the sense of self after Psi administration are important for changes in social interaction processing, adding empirical evidence to the notion that concepts of self and others are closely intertwined, which suggests that the sense of self can profoundly impact the experience of interpersonal relationships. The Psi-induced feeling of being connected with and embedded in the environment may also lead to an intensified connection between oneself and other human beings, as well as stronger identification and empathic encounters with others. This feeling may assist in reducing egocentric bias and consequently render negative experiences more bearable. This interpretation is also supported by previous studies reporting that the ACC is particularly involved in self/other representations and theory of mind. Moreover, the Psi-mediated feeling of being embedded in the environment may even be beneficial in therapeutic settings, supporting the relationship between patient and therapist, and facilitating the discussion of painful experiences in a protective and secure environment. In contrast to earlier work investigating the effect of Psi on nonsocial negative stimuli, the current data did not reveal any significant associations between BOLD responses and social exclusion or mood. Therefore, modulations of social interaction processing may be mostly independent of Psi-induced increases in positive mood. To further examine the neurochemical substrates of altered social exclusion processing, changes in metabolite concentrations obtained by 1 H-MRS measurements were correlated with changes in the BOLD signal responses to social exclusion. These analyses showed that a reduction in Asp content between baseline (before drug administration) and follow-up (Psi condition, measured after subjects had completed the Cyberball task) was significantly correlated with a reduced BOLD signal in the dACC in response to social exclusion (Psi vs. Pla condition). Even though the complex resonance pattern of Asp showing overlaps with various other metabolites is difficult to quantify with in vivo MRS, the used JPRESS acquisition together with Profit2 fitting allowed an Asp quantification with CRLBs around 6% and low SD, indicating good and homogeneous data quality. Together, these findings may indicate that changes in Asp levels are related to social pain processing. Glutamate (Glu) and Asp are present in high concentrations in the central nervous system; both have excitatory effects on neurons, with Asp preferentially activating NMDA receptors. Moreover, functionally or pharmacologically induced changes in neurotransmission and brain energy metabolism underlying the origin of the BOLD signal are linked to changes in Glu and Asp concentrations as a consequence of an increased rate of the malate-aspartate shuttle, which is associated with the increased flux into the tricarboxylic acid cycle. Interestingly, the structurally related psychotropic 5-HT2A/1A agonist lysergic acid diethylamide increases extracellular medial prefrontal Glu release and prefrontal pyramidal cell activity in rodents. However, in our study, BOLD reductions to social exclusion in the dACC were related to changes in Asp content exclusively, and no correlations with changes in Glu concentrations were found. Hence, the interpretation of our findings remains somewhat speculative because the effects of Psi on Asp release are currently novel and have not yet been reported in animal and human studies and therefore require further investigation. Because extrasynaptic and intrasynaptic pools of Asp and Glu cannot be distinguished by spectroscopic imaging, no general conclusions can be drawn from metabolite concentrations to the process of neurotransmission. However, recent studies have consistently reported small concentration changes in lactate, Glu, Asp, and glucose in the human cortex during prolonged stimulation. Positive linear relationships between metabolic and BOLD responses in the presence of excitatory sensory inputs could be found for Glu and lactate concentrations. In contrast, inverse correlations between BOLD responses and MRS measures were found for GABA concentrations. In line with these findings, we argue in favor of an emerging conceptual framework to interpret multimodal imaging findings including changes in metabolite concentrations and BOLD signals in terms of brain energetics and neurotransmission. In addition, a recent study proposed the existence of a neuron-to-astrocyte Asp transcellular pathway required for astrocyte Glu synthesis and subsequent glutamine formation. Accordingly, the relationship among decreased Asp levels, reduced BOLD responses, and social pain might indicate a possible role of glial Glu metabolism in the processing of social pain signals in the dACC. In conclusion, further studies would be needed to corroborate the hypothetical functional links between Asp levels and BOLD responses that we observed in our study. To our knowledge, the current study represents the first multimodal brain imaging approach to investigate the neuropharmacological grounds of social exclusion processing, and particularly the influence of 5-HT receptor stimulation on negative social interactions. Evidence from animal studies suggests that the opioid system may similarly participate in the experience of pain and distress in response to maternal-infant separation. Furthermore, another study showed that chronic administration of the analgesic acetaminophen reduced neural responses to social rejection in the dACC and anterior insula, but not selfreported social distress after exclusion. However, the exact action mechanism of acetaminophen is still unclear. Additional behavioral analyses suggested that oxytocin does not buffer against the experience of social pain after social rejection. Moreover, recent workfound that administration of 3,4-methylenedioxy-methamphetamine (MDMA), a 5-HT, dopamine, and norepinephrine releasing agent/reuptake inhibitor, decreased the effect of social exclusion on mood and selfesteem, but not on physiological measures. The authors proposed that MDMA selectively decreased the perceived intensity of rejection, as indicated by increased estimates of received throws in the exclusion condition. Therefore, whereas MDMA seems to affect the perception of social exclusion, Psi may actually reduce the experience of social pain itself without significantly influencing the awareness of being excluded. The current study therefore represents to our knowledge the first indication that stimulation of the 5-HT2A/1A receptor system can regulate social pain processing and experience. The results are consistent with previous reports suggesting that the 5-HT system plays a role in emotional regulation, and may also be relevant for social cognition and behavior; they likewise support earlier studies showing that 5-HT2A receptors are highly expressed in prefrontal brain areas and emphasize the importance of these receptors for prefrontal brain function. Considering that most previous studies investigating the role of 5-HT in social processes were conducted by using selective serotonin reuptake inhibitors to increase 5-HT levels, the current study extends these findings by showing that direct receptor simulation contributes to modulations of social cognition. Furthermore, our work highlights the importance of the 5-HT2A/1A receptor system not only in perception but also in the actual experience of social encounters, as indicated by the interactive nature of the Cyberball paradigm. The multimodal brain imaging approach applied in this study offers the possibility of exploring neurobiological processes underlying the experience of social pain. Our findings indicate that Psi acts on brain areas associated with the experience of social pain via alterations in Glu/Asp metabolism. The current results must be interpreted with the following limitation in mind-namely, that the results of pharmacological MRI studies may be susceptible to drug effects on cerebral vasoactivity. However, two previous fMRI investigations of Psi actions found no effect of nonneural physiological changes or Psi itself on the vascular system of the brain. Furthermore, psilocybin has been shown to reduce the BOLD signal in the dACC during resting state. It is therefore possible that the reduction of BOLD signal in the dACC reported in the current study might relate to a general reduction of neuronal activity within this area; however, this is unlikely considering that no decrease in BOLD signal was found for the "not receiving INCL > receiving INCL" contrast after Psi administration compared with Pla, indicating that the decreased BOLD response is related to the exclusion context. Furthermore, conflicting results have been obtained between PET and fMRI regarding resting state activity in the ACC after Psi administration, with a previous study showing increases in glucose metabolism in the dACC PET. However, the current study reports alterations in regional brain activity that are task specific and rely on contrasts between two conditions of this task. Therefore, we cannot make any conclusions about a general increase or decrease in neuronal activity in the ACC after Psi administration. In summary, the present results suggest that 5-HT2A/1A receptor stimulation by Psi attenuates social pain processing, possibly in parallel with alterations in Glu/Asp metabolism and release. Furthermore, receptor stimulation is also associated with changes in self-processing, particularly the feeling of being connected with the environment. Social ties have repeatedly been shown to be crucial for physical and mental health, and psychiatric patients often encounter social rejection. Additionally, perceived social isolation has a negative impact on social and general cognition, often leading to negative social interactions and a vicious cycle of social rejection. Patients suffering from major depressive disorder exhibit information acquisition and processing that is biased toward negative stimuli, which features predominantly in the development and maintenance of depression. This negative emotional bias is related inter alia to functional alterations in the ACC and frontal brain areas. Therefore, the current study validates reports suggesting that Psi may have antidepressant characteristics, possibly by mitigating negative emotional bias. Last, the present results show that Psi may normalize the processing of negative social interaction in disorders characterized by increased rejection sensitivity through the adjustment of dACC and frontal brain activity, and by changes in self-processing. However, because this study was conducted in healthy volunteers, it has to be interpreted with the limitation in mind that the results may not directly translate to psychiatric patients with severe social exclusion experiences, such as schizophrenia patients. Understanding the neural and biochemical foundations of rejection experiences is important for increasing our knowledge about social and emotional processes, and is crucial for the treatment of conditions influenced by social factors. Therefore, our findings may assist in diminishing a knowledge gap that restrains the development of pharmacotherapies for sociocognitive deficits in psychiatric disorders. The current results also emphasize the contribution of 5-HT2A/1A receptor subtypes and the Glu/Asp system in the regulation of social functioning, and their utility as prospective targets in the management of sociocognitive impairments.
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