Effects of serotonin 2A/1A receptor stimulation on social exclusion processing

This double-blind, randomized, counterbalanced, cross-over study (n=21) examined the effects of psilocybin (15.05mg/70kg) on the neural response to social exclusion via multimodal brain imaging. Psilocybin reduced activity in key brain regions involved in social exclusion processing, specifically the anterior midcingulate cortex (aMCC) and the middle frontal gyrus (MFG), related to decreases in the experience of social pain and reduced affective distress following social rejection. Reduced response to social exclusion is also related to psilocybin changes in the experience of self.

Abstract

“Introduction: Social ties are crucial for physical and mental health. However, psychiatric patients frequently encounter social rejection. Moreover, an increased reactivity to social exclusion influences the development, progression, and treatment of various psychiatric disorders. Nevertheless, the neuromodulatory substrates of rejection experiences are largely unknown. The preferential serotonin (5-HT) 2A/1A receptor agonist, psilocybin (Psi), reduces the processing of negative stimuli, but whether 5-HT2A/1A receptor stimulation modulates the processing of negative social interactions remains unclear.

Methods: Therefore, this double-blind, randomized, counterbalanced, cross-over study assessed the neural response to social exclusion after the acute administration of Psi (0.215 mg/kg) or placebo (Pla) in 21 healthy volunteers by using functional magnetic resonance imaging (fMRI) and resting-state magnetic resonance spectroscopy (MRS).

Results: Participants reported a reduced feeling of social exclusion after Psi vs. Pla administration, and the neural response to social exclusion was decreased in the dorsal anterior cingulate cortex (dACC) and the middle frontal gyrus, key regions for social pain processing. The reduced neural response in the dACC was significantly correlated with Psi-induced changes in self-processing and decreased aspartate (Asp) content.

Conclusion: In conclusion, 5-HT2A/1A receptor stimulation with psilocybin seems to reduce social pain processing in association with changes in self-experience. These findings may be relevant to the normalization of negative social interaction processing in psychiatric disorders characterized by increased rejection sensitivity. The current results also emphasize the importance of 5-HT2A/1A receptor subtypes and the Asp system in the control of social functioning, and as prospective targets in the treatment of sociocognitive impairments in psychiatric illnesses.“

Authors: Katrin H. Preller, Thomas Pokorny, Andreas Hock, Rainer Kraehenmann, Philipp Stämpfli, Erich Seifritz, Milan Scheidegger & Franz X. Vollenweider

Summary

social cognition | serotonin | psilocybin | functional magnetic resonance imaging | magnetic resonance spectroscopy

Functional social cognition is a central charac-teristic of various psychiatric disorders and critically impacts the development, progression, and treatment of psychiatric illnesses. However, the neuronal and pharmacological bases of both normal and dysfunctional social cognition lack sufficient investigation.

Psilocybin, a serotonergic hallucinogen, induces an altered state of consciousness characterized by changes in sensory perception, emotion, thought, and the sense of self in a dose-dependent manner.

Psi modulates neural activity in prefrontal brain areas involved in social cognition and may have antidepressant properties. However, it is unclear whether this shift in emotional processing translates into the social domain, particularly regarding negative social interaction processing.

The present study used functional magnetic resonance imaging (fMRI) and proton magnetic resonance spectroscopy (1H-MRS) to investigate the effect of 5-HT2A/1A receptor stimulation by Psi (0.215 mg/kg orally) on social interaction processing.

Social pain is associated with increased brain activity in the anterior cingulate cortex, the insula, the inferior orbitofrontal cortex, and the middle frontal gyrus. Psi treatment decreased activation of these brain regions and also modulated the concentration of excitatory neurotransmitters and/or neurometabolic markers.

Results

Subjective effects and physical effects were investigated. The Altered States of Consciousness (5D-ASC) questionnaire showed increased ratings after Psi vs. Pla treatment, and blood pressure and pulse were slightly but significantly increased.

Cyberball Task.

Participants reported a reduced feeling of exclusion after Psi vs. Pla treatment, and both groups accurately gauged the number of throws received in each run.

We found that the right anterior midcingulate cortex (aMCC) and left inferior OFC were less activated after Psi administration than after Pla administration when compared to the “not receiving explicit social exclusion > receiving inclusion” contrast.

The left anterior and posterior MCC and the right pregenual ACC were significantly activated in the Pla condition when compared to the “not receiving implicit social exclusion (ISE) > receiving INCL” contrast. No significant differences in activation were found for the Psi > Pla comparison.

Relationship Between Social Exclusion Processing and Subjective

A correlation analysis was conducted to evaluate the association between BOLD responses to the contrast “not receiving ESE > receiving INCL” and subjective drug effects (5D-ASC, PANAS) and PTQ items. A significant positive correlation was found.

Relationship Between Social Exclusion Processing and Metabolite

After Psi treatment, activity in the dorsal ACC voxel was significantly reduced in response to the “not receiving ESE > receiving INCL” contrast. This activity overlapped with the dACC voxel used for MRS acquisition, and a significant correlation was obtained between activity in the dACC and aspartate concentration.

Discussion

The present study used a multimodal brain imaging approach to show that 5-HT2A/1A receptor stimulation by Psi reduces the experience of social pain. This decreased experience of social pain was associated with changes in cingulate Asp concentrations and changes in the experience of self.

In the Pla condition, participants’ aMCC, pMCC, and ventral ACC were activated by implicit social exclusion, while the MFG was not. Psi treatment reduced the activation of these areas, suggesting that Psi diminishes reactions to social exclusion even in an implicit, and therefore possibly more subtle, context.

Participants reported feeling less excluded in the Psi vs. Pla condition, but other ratings were not significantly altered. Additionally, there were no significant differences between Pla and Psi conditions for estimates of received throws.

In the present study, Psi-induced alterations on the 5DASC 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” were in accordance with previous studies suggesting that Psi is well tolerated. The Psi-induced feeling of being connected with and embedded in the environment may also lead to a stronger identification and empathic encounters with others, and may even help to reduce egocentric bias and render negative experiences more bearable.

To further examine the neurochemical substrates of altered social exclusion processing, changes in Asp concentrations were correlated with changes in the BOLD signal responses to social exclusion. These findings indicate that changes in Asp levels are related to social pain processing.

Glutamate and aspartate are present in high concentrations in the central nervous system and are involved in neurotransmission and brain energy metabolism. The effects of Psi on aspartate release are currently novel and require further investigation. Because spectroscopic imaging cannot distinguish between extrasynaptic and intrasynaptic pools of Asp and Glu, 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.

To our knowledge, this is the first multimodal brain imaging study to investigate the neuropharmacological grounds of social exclusion processing. The study suggests that the 5-HT receptor stimulation may reduce the experience of social pain itself without significantly influencing the awareness of being excluded. The current study shows that stimulation of the 5-HT2A/1A receptor system can regulate social pain processing and experience. This study also highlights the importance of the 5-HT2A/1A receptor system for social cognition and behavior.

The current results indicate that Psilocybin acts on brain areas associated with the experience of social pain via alterations in Glu/Asp metabolism. However, the results must be interpreted with the following limitation in mind: fMRI studies may be susceptible to drug effects on cerebral vasoactivity.

PET and fMRI studies show that glucose metabolism increases in the ACC after Psi administration, but this study reports task-specific alterations in regional brain activity.

Psi may attenuate social pain processing by adjusting dACC and frontal brain activity, and by changes in self-processing, possibly in parallel with alterations in Glu/Asp metabolism and release. This may have important implications for psychiatric patients with severe social exclusion experiences.

Understanding the neural and biochemical foundations of rejection experiences is important for increasing our knowledge about social and emotional processes, and may assist in the development of pharmacotherapies for sociocognitive deficits.