Lysergic acid diethylamide (LSD) alters the activity in brain regions involved in establishing one’s sense of self and in differentiating between oneself and someone else during social interactions, new research shows.
Investigators used functional MRI (fMRI) and eye-tracking to study three groups of healthy volunteers who received either LSD, the serotonin 2A receptor (5-HT2AR) antagonist ketanserin (a drug that blocks the effects of LSD), or a placebo. Participants then engaged in a gaze-following computerized game with a virtual humanlike character.
The researchers found that LSD reduced activity in brain areas important for self-processing and social cognition.
Additionally, LSD-induced effects were blocked by ketanserin, suggesting that the effects of LSD can attributed to 5-HT2AR stimulation.
“With LSD, the border between the self and the other person becomes more blurry, and you see when you look at the midline structures of the brain under LSD that the differentiation between self and other is reduced,” lead author Katrin H. Preller, PhD, senior researcher, University of Zurich, Switzerland, told Medscape Medical News.
“Differentiation between self and other has important implications on social interaction ability, and this relationship and those abilities seem to be modulated by one particular receptor in the brain — the serotonin 2A receptor,” she said.
“We can see a potential role for blocking and antagonizing this receptor to decrease symptoms in people with disorders characterized by blurred self boundaries, such as schizophrenia, or stimulating and agonizing the receptor in disorders where people show increased self-focus and rumination, like depression,” she added.
The study was published online March 19 in the Journal of Neuroscience.
Unique Opportunity
“The coherent experience and sense of our ‘self’ is a critical feature of human waking consciousness,” the authors write. They note that “distortions of self-experience” are “critical symptoms” of major psychiatric disturbances, such as depression, personality disorder, and schizophrenia.
Identifying neuronal correlates of pharmacologically induced altered states of consciousness that affect the experience of the self may represent a “unique opportunity” to develop “improved and targeted interventions for transdiagnostic social impairments,” they write.
LSD is useful for exploring this possibility because it induces changes in the sense of self by agonizing several receptors, including 5-HT2AR.
Becase ketanserin, an α-adreno R antagonist, blocks the subjective effects of LSD, studying its impact can facilitate exploration of the 5-HT2AR system’s contribution to self-processing and its relationship to social interaction.
To investigate the role 5-HT2AR in self- and other-initiated social interactions, the researchers used neuroimaging together with “pharmacological manipulations” (ie, LSD with and without ketanserin pretreatment and placebo).
Participants engaged in a task “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,” the authors explain.
The tasks enabled investigation of self-initiated vs other-initiated interaction, as well as joint attention processing (JA) and nonjoint attention processing (NJA).
“We knew LSD affects how people perceive themselves, but we wanted to study not only the impact on self-report but also the impact in a social interaction setting,” Preller said.
Real-Time Interaction
The researchers randomly assigned 24 healthy volunteers (aged 20 to 34 years; 18 men and 6 women) to receive either placebo pretreatment followed by placebo (designated “Pla”); placebo pretreatment followed by LSD (designated “LSD”); or ketanserin pretreatment followed by LSD (designated Ket+LSD).
Pretreatment occurred 1 hour before treatment. The task was conducted 310 minutes after treatment administration.
Twelve hours after drug treatment, articipants completed the 5-Dimensional Altered States of Consciousness Rating Scale (5D-ASC), a retrospective self-report questionnaire that assesses altered states of consciousness; and 10 minutes before pretreatment and 12 hours after treatment, participants completed the Positive and Negative Affect Schedule (PANAS).
Participants were told that they would be engaging in an interactive game with a participant in another room, who would be represented by an avatar on the screen.
During the game, they were instructed to either lead or follow the gaze of the avatar to one of two objects on the screen. They were told that their gaze behavior would be tracked and transferred to the other participant’s computer.
Likewise, they were told that they would see the other participant’s gaze behavior, “allowing for real-time interaction.”
Eye-tracking technology was used to record gaze directions. The experimental conditions were subjected to fMRI imaging.
The researchers created five experimental conditions: selfjoint, selfnonjoint, otherjoint, othernonjoint, and a baseline condition.
During the self condition (selfjoint and selfnonjoint), participants chose one of the two objects on the screen but could peripherally observe the gaze direction of the other participant, who would either follow the gaze (JA) or look at another object (NJA).
During the other condition (otherjoint and othernonjoint), participants were told that the other person had to choose one of the objects, and that they had to react by either looking at the same object (JA) or choosing another object (NJA).
In the baseline condition, the participant was instructed to look at one of the objects, and the avatar closed its eyes after eye contact was established.
The fMRI computed four different contrasts for each participant: self>other; JA>NA; self-initiated JA>self-initiated NJF, and other-initiated JA>other-initiated NJA.
Social Interaction Settings
For participants in the LSD group, scores on all 5D-ASC scales were higher than the scores for participants in the Pla and Ket+LSD groups (for all, P < .05) except for the spiritual experience and anxiety scales (for all, P > .20).
Scores for the Pla and LSD+Ket groups did not differ on any scale.
Scores on the PANAS did not differ between treatments before drug administration (for all, P > .9).
However, after drug administration, the PANAS score on the positive affect scale was significantly greater in the LSD treatment condition than in both the Pla and Ket+LSD treatment conditions (for all, P < .05).
The score on the negative affect scale was also greater in the LSD treatment condition than in the Pla treatment condition (P < .05).
Scores did not differ between the Pla and Ket+LSD treatment conditions for either the positive or negative affect scale (for all, P > .9).
Significant effects were found for the self>other contrast in the right and left middle temporal gyrus (P < .05).
When the researchers compared the self>other contrast between Pla and LSD treatment conditions, they observed a greater blood oxygen–level dependent (BOLD) signal in the left posterior cingulate cortex (PCC) in the Pla condition, compared to LSD (P < .05).
However, for the selfjoint>selfnonjoint contrast, the analysis revealed significantly higher BOLD signal in the medial prefrontal cortex in the Pla condition (P < .05).
When they compared the self>other contrast between Ket+LSD and LSD treatment conditions, they found a significantly higher BOLD signal in the left PCC and the right middle temporal gyrus after Ket+LSD treatment (P < .05).
Moreover, comparison of the otherjoint>othernonjoint contrast revealed a significant increase in BOLD signal in the left PCC and the left middle temporal gyrus after Ket+LSD treatment (P < .05).
No significant differences between Ket+LSD and Pla treatment conditions were observed.
There was a significantly longer latency period for establishing JA in the LSD condition than in the Pla and the Ket+LSD conditions.
A significant positive correlation was found between the LSD-induced decrease in BOLD signal in the PCC in the self>other contrast, compared to both Pla and LSD+Ket.
The LSD-induced decrease in BOLD signal in the PCC, compared to both Pla and Ket+LSD in the self>other contrast, was significantly correlated with the 5D-ASC scale score regarding “changed meaning of percepts.”
“Our results show that LSD decreased the response to participation in self- compared to other-initiated social interaction in the PCC and the temporal gyrus — more precisely, the angular gyrus,” the authors comment.
The PCC is part of the cortical midline structures, which are important in generating a model of the self and are involved in disturbances of self-experience in schizophrenia patients.
“What’s new about this study is that self-reported alteration in the sense of self also holds true in social interaction settings,” Preller reported.
“It was also surprising that we were able to block effects of LSD on self-other differentiation and social interaction by blocking the serotonin-2A receptor, since LSD stimulates a lot of receptors,” she said.
Treating Intertwined Deficits
Commenting on the study for Medscape Medical News, George Greer, MD, president of the Heffter Research Institute, who was not involved with the study, said the research utilizes a “new method” that “can lead to better understanding of how brain changes affect our ability to understand and participate in social relationships, and hopefully find ways to improve them in people with a variety of psychiatric problems.”
He called LSD “an effective tool for studying how our nervous system processes our sense of identity and how social relationships affect our state of mind.”
Preller suggested that a “take-home message for people who think about developing new medications is that we should consider the serotonin-2A receptor when we want to treat intertwined deficits on social cognition and self-perception.”
The study was supported by grants from the Heffter Research Institute, the Swiss Neuromatrix Foundation, the Usona Institutem, and the Swiss National Science Foundation. The authors have disclosed no relevant financial relationships. Dr Greer is the president of Heffter Research Institute but was not involved in the design or execution of the study.
J Neurosci. Published online March 19, 2018. Abstract
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