Role of the 5-HT2A Receptor in Self- and Other-Initiated Social Interaction in Lysergic Acid Diethylamide-Induced States : A Pharmacological fMRI Study, Katrin H. Preller et al., 2018

Role of the 5-HT2A Receptor in Self- and Other-Initiated Social Interaction in Lysergic Acid Diethylamide-Induced States : A Pharmacological fMRI Study

Katrin H. Preller, Leonhard Schilbach, Thomas Pokorny, Jan Flemming, Erich Seifritz,
and Franz X. Vollenweider

The Journal of Neuroscience, 2018, 38, (14), 3603–3611.

Doi : 10.1523/JNEUROSCI.1939-17.2018


Distortions of self-experience are critical symptoms of psychiatric disorders and have detrimental effects on social interactions. In light of the immense need for improved and targeted interventions for social impairments, it is important to better understand the neurochemical substrates of social interaction abilities. We therefore investigated the pharmacological and neural correlates of self- and other-initiated social interaction. In a double-blind, randomized, counterbalanced, crossover study 24 healthy human participants (18 males and 6 females) received either (1) placebo/placebo, (2) placebo/lysergic acid diethylamide (LSD; 100g, p.o.), or (3) ketanserin (40 mg, p.o.)  LSD (100 g, p.o.) on three different occasions. Participants took part in an interactive task using eye-tracking and functional magnetic resonance imaging completing trials of self- and other-initiated joint and non-joint attention. Results demonstrate first, that LSD reduced activity in brain areas important for self-processing, but also social cognition; second, that change in brain activity was linked to subjective experience; and third, that LSD decreased the efficiency of establishing joint attention. Furthermore, LSD-induced effects were blocked by the serotonin 2A receptor (5-HT2AR) antagonist ketanserin, indicating that effects of LSD are attributable to 5-HT2AR stimulation. The current results demonstrate that activity in areas of the “social brain” can be modulated via the 5-HT2AR thereby pointing toward this system as a potential target for the treatment of social impairments associated with psychiatric disorders.

Key words : eye-tracking; hallucinogens; joint attention; psychedelics; serotonin; social cognition

Significance Statement

Distortions of self-representation and, potentially related to this, dysfunctional social cognition are central hallmarks of various psychiatric disorders and critically impact disease development, progression, treatment, as well as real-world functioning. However, these deficits are insufficiently targeted by current treatment approaches. The administration of lysergic acid diethylamide (LSD) in combination with functional magnetic resonance imaging and real-time eye-tracking offers the unique opportunity to study alterations in self-experience, their relation to social cognition, and the underlying neuropharmacology. Results demonstrate that LSD alters self-experience as well as basic social cognition processing in areas of the “social brain”. Furthermore, these alterations are attributable to 5-HT2A receptor stimulation, thereby pinpointing toward this receptor system in the development of pharmacotherapies for sociocognitive deficits in psychiatric disorders.



The coherent experience and sense of our “self” is a critical feature of human waking consciousness (Northoff, 2013; Carhart-Harris et al., 2014). The so-called “minimal self” incorporates immediate aspects of self-experience such as senses of ownership, agency, and embodiment, and gives rise to the “narrative self” involving cognition and conceptual thought about memories of the past and intentions toward the future (Gallagher, 2000). Distortions of self-experience, particularly of the fundamental, minimal self, are a critical symptom of major psychiatric disorders such as depression, personality disorder, and schizophrenia (Grimm et al., 2009; Moutoussis et al., 2014b; Nordgaard and Parnas, 2014; Picard and Friston, 2014; Gerrans, 2015).

Furthermore, the concept of the self is closely intertwined with the concept of the other (Decety and Sommerville, 2003; Metzinger and Gallese, 2003). The ability to distinguish between self and other plays a crucial role in establishing a coherent selfrepresentation (Moutoussis et al., 2014a,b). Moreover, important dimensions of the self, such as awareness of individuality, are only meaningful when considering the self in the context of the other (Decety and Sommerville, 2003). In light of the immense need for improved and targeted interventions for transdiagnostic social impairments, it is important to better understand the neurochemical substrates of our sense of self and social interaction abilities, and the importance of coherence of self-experience for social interactions (Crockett and Fehr, 2014; Schilbach, 2016).

Pharmacological neuroimaging provides the opportunity to study specific neurotransmitter systems that are involved in psychiatric disorders and lead to a mechanistic understanding of clinically relevant processes underlying our sense of self and social cognition (Anticevic et al., 2013; Crockett and Fehr, 2014). A unique opportunity to study the self is to identify the neuronal correlates of pharmacologically induced altered states of consciousness in which the experience of the self is temporarily altered.

Lysergic acid diethylamide (LSD) is a classic hallucinogen that transiently produces, dependent on dose, discrete to profound changes in the sense of self, such as a loosening of self boundaries, a state of oneness with the external world, and changes in meaning processing and self-relevance (Geyer and Vollenweider, 2008; Schmid et al., 2015; Preller and Vollenweider, 2016; Preller et al., 2017). LSD has predominantly agonist activity at 5-HT2A/C,-1A/B,-6, and -7, and dopamine (D2 and D1) receptors (Rs; Marona-Lewicka et al., 2002; Nichols, 2004; De Gregorio et al., 2016).

Pretreatment with the selective 5-HT2A and -adreno R antagonist ketanserin has been shown to block the overall subjective effects of LSD and therefore offers the possibility to investigate the specific contribution of the 5-HT2A R system to self-processing and its relationship to social interaction (Preller et al., 2017).

Therefore, the present study set out to investigate the role of the 5-HT2A R system in self- and other-initiated social interaction by combining neuroimaging with pharmacological manipulations (LSD with and without ketanserin pretreatment, and placebo). The applied task was specifically designed to capture the reciprocal and interactive nature of social encounters where participants engage in a gaze-based interaction with an anthropomorphic virtual character in real time (Schilbach et al., 2010; Preller et al., 2014) and furthermore giving the opportunity to investigate self- versus other-initiated interaction, as well as jointand non-joint attention processing. Engagement in joint attention is considered to reflect our understanding of another person’s point of view and a perquisite of advanced social skills such as theory of mind (Charman et al., 2000; Shepherd, 2010).

Impaired joint attention processing is found in neurodevelopmental and psychiatric disorders (Charman, 2003; Preller et al., 2014; Timmermans and Schilbach, 2014). Furthermore, the 5-HT system is suggested to play an important role in illnesses, such as autism spectrum disorders, which are characterized by deficits in joint attention execution and processing (Muller et al., 2016; Bolis and Schilbach, 2017). We therefore hypothesized that LSD, at the dose tested, leads to alterations in self-experience, in particular, experiences of loosening of self-boundaries accompanied by decreased differentiation between self and other, and thus modulates the processing of self- versus other-initiated social interaction. Joint attention, i.e., an integration of perspectives while maintaining a robust sense of self can be disturbed by the loosening of self-boundaries as for instance in schizophrenia (Fuchs, 2015). Based on this line of thought, we furthermore hypothesized that LSD would affect measures of joint attention both behaviorally as well as at the neural level in brain areas relevant for self-processing as well as social cognition such as the precuneus and posterior cingulate cortex (PCC), temporal cortex, and medial prefrontal cortex (Schilbach et al., 2012). Additionally, we hypothesized that LSD-induced alterations of self- and socialinteraction processing would be at least partially blocked by ketanserin.