LSD-induced increases in social adaptation to opinions similar to one’s own are associated with stimulation of serotonin receptors

Abstract

Adapting one's attitudes and behaviors to group norms is essential for successful social interaction and, thus, participation in society. Yet, despite its importance for societal and individual functioning, the underlying neuropharmacology is poorly understood. We therefore investigated its neurochemical and neural correlates in a pharmacological functional magnetic resonance imaging study. Lysergic acid diethylamide (LSD) has been shown to alter social processing and therefore provides the unique opportunity to investigate the role of the 5-HT 2A receptor in social influence processing. Twenty-four healthy human volunteers received either (1) placebo + placebo, (2) placebo + LSD (100 µg), or (3) the 5-HT 2A receptor antagonist ketanserin (40 mg) + LSD (100 µg) at three different occasions in a doubleblind, randomized, counterbalanced, cross-over design. LSD increases social adaptation but only if the opinions of others are similar to the individual's own. these increases were associated with increased activity in the medial prefrontal cortex while participants received social feedback. furthermore, pretreatment with the 5-HT 2A antagonist ketanserin fully blocked LSD-induced changes during feedback processing, indicating a key role of the 5-HT 2A system in social feedback processing. our results highlight the crucial role of the 5-HT-system in social influence and, thus, provide important insight into the neuropharmacological basis of social cognition and behavior. The quality and quantity of individuals' social relationships has been tightly linked to morbidity and mortality 1. Social influence is omnipresent in our everyday life and reacting to the opinions of others is deeply rooted in human nature 2. Every time people interact or communicate, be it in real life or virtually, people are influenced by each other. Social adaptation refers to the act of changing one's attitudes, beliefs, or behaviors to match social norms that are implicitly or explicitly shared by a group of individuals 3. Zaki et al. 4 suggest that exposure to social norms directly influences participants' neural representations of the value they assign to stimuli. Being susceptible to social influence is essential for successful social interaction and communication, and also for the functioning and organization of an entire society. However, it can also have negative consequences if misused 5,6. In recent years, social neuroscience has advanced our understanding of the neural systems underlying social influence processing 7-9. Amongst other brain regions, it has been shown that frontal regions as well as the reward system are strongly implicated in adaptation to group norms 10-12. In particular, when exposed to a mismatch between the own and the group opinion, participants showed a deactivation of the ventral striatum and an

Psychedelics in Psychiatry: Neuroplastic, Immunomodulatory, and Neurotransmitter Mechanisms

“…Recently, it was reported that a 12-day ayahuasca retreat in traditional settings significantly reduces neuroticism scores in an inversely proportional fashion to the intensity and quality of the mystical experiences associated, and these changes are still appreciable at 6-month follow-up (Netzband et al, 2020). Agreeableness was also increased in this cohort, corroborating recent research on the acute prosocial effects elicited by LSD in humans (Duerler et al, 2020;Netzband et al, 2020). Interestingly, adolescents who regularly ingest ayahuasca scored lower for psychiatric symptoms such as anxiety, body dysmorphism, and attentional problems compared with controls, suggesting no psychiatric sequelae arising from regular consumption of ayahuasca during adolescence (Da Silveira et al, 2005).…”

“…Oxytocin is thought to mediate at least partially the empathogenic, antidepressant, and anxiolytic effects elicited by psychedelic compounds and SSRIs (Uvnäs-Moberg et Schindler et al, 2018) via modulating corticolimbic circuits (Lahoud and Maroun, 2013;Sobota et al, 2015;Triana-Del Rio et al, 2019). Transient OT increase and prosocial effects were reported in response to LSD (Schmid et al, 2015a;Duerler et al, 2020) and MDMA (Dumont et al, 2009;Kirkpatrick et al, 2014a,b) in healthy subjects through 5-HT 1A/2A receptor stimulation (Thompson et al, 2007). Such enhancing effects over the oxytocinergic system also observed with MDMA and DOI in preclinical models (Van de Kar et al, 2001;Thompson et al, 2007) suggest that these compounds might be useful for the treatment of ASD (Dolder et al, 2016;Parker et al, 2017).…”

“…Aside from serotonergic interaction, the pharmacological and behavioral effects of LSD, and likely of other psychedelics, require activation of the 5-HT 2A -mGluR2 complex in glutamatergic pyramidal neurons (discussed below in the Biased Signaling, Biased Phosphoproteomics, and Psychedelic Compounds section) (Moreno et al, 2011). Recently, LSD was reported to increase the social adaptation to opinions similar to one's own through stimulation of 5-HT 2A receptors, which increase neuronal activity in the mPFC in response to social feedback processing (Duerler et al, 2020).…”

“…The activation of presynaptic 5-HT 2A receptors in deep-layer cortical neurons is thought to mediate the psychedelic effects of LSD and other serotonergic psychedelics (Titeler et al, 1988;Vandermaelen and Aghajanian, 1983;Jakab and Goldman-Rakic, 1998;Peyron et al, 1998;Vollenweider and Kometer, 2010;Duerler et al, 2020;Puig et al, 2003). It has been suggested that this interaction might be the driver of the cortico-striato-thalamo-cortical (CSTC) feedback loop modulation observed in imaging studies (Höflich et al, 2015;Müller et al, 2017;Preller et al, 2018Preller et al, , 2019.…”

LSD and psilocybin flatten the brain’s energy landscape: insights from receptor-informed network control theory

“…Details for obtaining the serotonin receptor density distribution have been previously described 46 , however we provide a brief summary here. PET data for 210 participants were acquired on a Siemens HRRT scanner operating in 3D acquisition mode with an approximate in-plane resolution of 2mm (1.4 mm in the center of the field of view and 2.4 mm in cortex) 73 .…”