Modulation of Social Cognition via Hallucinogens and “Entactogens”

This literature review (2019) discusses controlled experimental studies on the effects of psychedelics (e.g. LSD, psilocybin, MDMA) on social cognition and behavior to treat disorders characterized by social dysfunctions such as depression, post-traumatic stress disorder (PTSD), anxiety, and autism spectrum disorders (ASD). It also discusses persisting knowledge gaps into sex-specific drug effects and objective data on social behavior within the framework of MDMA- and hallucinogen-assisted therapy. The study suggests hallucinogen-based treatment methods and the development of novel medication for trans-diagnostic dysfunction in social cognition and noted that entactogens and hallucinogens have consistently shown prosocial effects and have identified alterations in social processing and behavior as major factors for the efficacy of treatments involving them.

Abstract

Social cognition is a fundamental ability in human everyday lives. Deficits in social functioning also represent a core aspect of many psychiatric disorders. Yet, despite its significance, deficits in social cognition skills are insufficiently targeted by current treatments. Hallucinogens and entactogens have been shown to have the potential to modulate social processing. This article reviews the literature on the influence of hallucinogens and entactogens on social processing in controlled experimental studies in humans and elucidates the underlying neurobiological and neuropharmacological mechanisms. Furthermore, it identifies current knowledge gaps and derives implications for hallucinogen-assisted treatment approaches as well as the development of novel medication for trans-diagnostic impairments in social cognition.

Authors: Katrin H. Preller & Franz X. Vollenweider

Summary

INTRODUCTION

Humans are social species, and we use capabilities which are subsumed under the term “social cognition” to function in this social environment. Deficits in social functioning represent a core aspect and important diagnostic criterion of many psychiatric disorders, yet they are insufficiently targeted by current treatment approaches.

Entactogens and hallucinogens are psychoactive substances that induce transient perceptual anomalies and an altered state of consciousness. These substances may be used to treat disorders characterized by social impairment, such as depression, anxiety, post-traumatic stress disorder, and autism spectrum disorders.

This review focuses on the effects of hallucinogens and entactogens on social cognition in clinical populations, healthy volunteers, and the neuropharmacological basis of these modulatory effects. It does not include literature on survey data or studies completed with recreational drug users. This review discusses the effects of two entactogens, MDMA and GHB, and two hallucinogens, LSD and psilocybin, on social functioning in humans. GHB is included in this review because of its prosocial effects.

MODULATION OF SOCIAL COGNITION IN CLINICAL POPULATIONS

MDMA-assisted psychotherapy reduces social anxiety in autistic adults and improves relationships with friends and family. These effects may be important for preventing relapse and increasing the long-term success of MDMA-assisted therapy.

Psilocybin has shown promising results in preliminary studies on mood disorders and addiction, with 12 out of 15 treatment-seeking smokers being nicotine abstinent 6 months after two to three administrations of psilocybin.

Psilocybin has been shown to increase extraversion and openness scores and decrease authoritarian political views in patients suffering from treatment-resistant depression. In this study, patients who received psilocybin treatment reported increased speed of emotional face recognition, reduced anhedonia, and decreased amygdala reactivity toward fearful faces. This may explain why they reported to be able to “re-connect” with family members, friends, strangers, and even people who had wronged them after treatment.

ACUTE EFFECTS OF ENTACTOGENS AND HALLUCINOGENS ON SOCIAL COGNITION IN HEALTHY vOLUNTEERS

MDMA is a prototypical entactogen and is recreationally used for its prosocial effects. LSD and psilocybin have been shown to significantly modulate social processing and have acute pro-social effects.

MDMA has been shown to increase the desire to engage in social activities, increase pleasantness of affective social touch, and increase the subjective experience of being close to others and trusting others.

MDMA, GHB, psilocybin, and LSD have different effects on social cognition, including empathy, mentalizing, and emotion recognition.

Empathy, Mentalizing, and Emotion Recognition

Empathy is the ability to vicariously experience and/or understand the affect of others, and is thought to be critical for prosocial behavior. Empathy is a multidimensional construct, comprising of both emotional and cognitive components.

Various tasks have been applied to study empathy after the administration of hallucinogens and entactogens. These tasks capture both, emotional and cognitive empathy and include the Multifaceted Empathy Task (MET), the Movie for the Assessment of Social Cognition (MASC), the Reading the Mind in the Eyes Task (RMET), and different versions of the Facial Emotion Recognition Task (FERT).

Various studies have consistently shown that MDMA increases emotional empathy. This increase is particularly pronounced in response to positive stimuli and in male participants, but does not influence sex or trait empathy.

MDMA, psilocybin, and LSD have been shown to increase emotional empathy, assessed with the MET. However, the effect of these substances on cognitive functions is not consistent across studies and substances.

The effect of MDMA, GHB, and psilocybin on cognitive empathy is less clear. However, MDMA (125 mg) increases the recognition of positive and decreases the identification of negative emotions on the RMET.

MDMA decreased the accuracy of identifying fear and anger on the face expression recognition task and increased the intensity required to identify anger. It also decreased corrugator muscle activity to happy facial expressions in female participants and increased zygomatic muscle activity to happy facial expressions in all participants.

Emotional face identification was not altered by small doses of LSD, but psychedelic doses of LSD impaired the recognition of fearful and sad faces on the FERT. Psilocybin reduced the subjective discrimination between fearful and neutral faces and the encoding of fearful faces measured with EEG.

Using functional magnetic resonance imaging, researchers found that psilocybin decreased connectivity between the amygdala and the striatum during angry face discrimination.

Hallucinogens and the entactogen MDMA increase emotional empathy, but cognitive empathy remains unchanged. This effect may contribute to the clinical efficacy of hallucinogens in patients with substance use disorders. LSD and psilocybin decreased the correct interpretation of ecologically valid stimuli, while MDMA increased the ability to infer positive emotions from the eye region. This result might be clinically relevant, since it may reduce social withdrawal behavior and improve the patient-therapist relationship.

Moral and Altruistic Behavior

Using moral dilemma tasks, it has been shown that neither MDMA nor psilocybin influence moral decision making. However, no other studies have investigated this influence.

To understand the effects of hallucinogens and entactogens on altruistic behavior, researchers used the Social Value Orientation Test. Male participants made more altruistic choices after the administration of 125 mg MDMA.

Altruistic behavior was increased after placebo administration, MDMA administration, and LSD administration, but only if the other person was a friend, not a stranger. GHB administration also increased altruistic behavior, but only after high scorers were excluded from the analysis.

Gabay et al. (66) found that psilocybin (2 mg, i.v.) and MDMA (100 mg) reduced altruistic punishment in male participants, and that male participants recovered from breaches of trust more quickly after the administration of MDMA (100 mg).

Hallucinogens and entactogens have been shown to increase altruistic behavior, but no effect has been found on moral decision making. It is possible that higher doses are needed to change moral behavior, and that post-acute effects may only occur post-acutely.

Social Rejection Sensitivity

Increased sensitivity to social rejection is observed in many psychiatric disorders. Normalizing increased rejection sensitivity could help avoid a vicious circle.

A paradigm called Cyberball is used to investigate the reaction to social rejection. It consists of an interactive virtual ball-tossing game that simulates a real-life interactive experience of social exclusion.

MDMA has been shown to reduce the effect of social rejection on self-reported lower mood and self-esteem, but not the effect of social exclusion on the Trier Social Stress Test.

LSD did not affect the feeling of social rejection induced by the Cyberball game, but psilocybin did. Psilocybin reduced the neural response to social rejection and increased the experience of unity, which may be of interest in the treatment of psychiatric disorders characterized by an increased self-focus like depression.

Psilocybin and MDMA have been shown to attenuate the processing of negative stimuli, which extends to negative social interaction. It is conceivable that reducing rejection sensitivity is critically involved in the potential therapeutic effects of entactogens and hallucinogens.

Sexual Arousal and Perception of Romantic Relationships

Only a few neuropsychopharmacological studies have so far explored how hallucinogens influence sexual arousal and the perception of romantic relationships. Results suggest that hallucinogens have only subtle effects on these processes, but may reflect an increased willingness to disclose personal information.

GHB has been reported to increase self-reported sexual arousal and desire. Further research is needed to determine the effects of hallucinogens on sexual arousal and the perception of intimate relationships.

Social Influence Processing

The influence of hallucinogens and entactogens on suggestibility and social influence processing has been investigated in two studies, both investigating the influence of LSD on suggestibility. The impact of alterations in social feedback processing in a clinical setting should be evaluated and therapists trained accordingly.

LONG-LASTING EFFECTS IN HEALTHY PARTICIPANTS

Experimental studies investigating the long-term effects of hallucinogens on social cognition and behavior remain scarce. However, recreational MDMA users showed increased cognitive empathy and less-self-serving behavior, but these effects were not influenced by acute administration of MDMA in controlled studies.

Self-reported increases in interpersonal closeness and positive/altruistic social effects were reported 1 to 14 months after psilocybin administration in healthy participants.

The long-term effects of hallucinogens on social processes are still scarce, but negative emotions are still increased after seven days.

NEUROPHARMACOLOGICAL UNDERPINNINGS OF ALTERATIONS IN SOCIAL COGNITION INDUCED BY HALLUCINOGENS AND ENTACTOGENS

To understand the neuropharmacological mechanisms underlying the prosocial effects of hallucinogens and entactogens, studies have investigated the neuroendocrineology after drug administration, and the effects of these substances after blocking specific receptors or transporters.

MDMA releases 5-HT, NE, and DA from nerve terminals and increases plasma levels of oxytocin, prolactin, and cortisol. It is also a low-potency partial agonist of 5-HT receptors.

Psilocybin binds to several serotonin receptors, including the 5-HT2A receptor, and has been shown to agonist activity on the 5-HT1A receptor. LSD also binds to the 5-HT2A receptor.

To date, only a few studies have investigated the pharmacology of MDMA-induced alterations in social cognition via blocking specific receptors. Duloxetine was most effective in reducing the acute subjective MDMA effects, implicating the serotonin system as a key mechanism of action.

MDMA-induced increases in oxytocin levels may be another candidate mechanism underlying MDMA’s prosocial effects.

MDMA increases emotional empathy, impaired identification of negative emotions, enhanced decoding of positive facial expressions, and increased altruistic choices, but oxytocin does not. Additionally, animal studies indicate that oxytocin plays an important role in MDMA-related social effects.

Studies have shown that MDMA has a different effect profile than other amphetamines, and that MDMA increases misclassifications of emotions as happy, whereas methylphenidate and modafinil increase misclassifications as angry. MDMA also increases empathy, but methylphenidate lacked these properties.

One study investigated the relationship between GHB-induced prosocial effects and neuroendocrine effects. Low progesterone levels at baseline were predictive of prosocial behavior after GHB administration.

Hallucinogens have been reported to reduce the recognition of negative emotions, and to affect self/other differentiation, social influence processing, and joint attention processing.

MDMA and hallucinogens have similar effects on social cognition, and 5-HT2A receptors may be involved in this process. However, the role of other receptors is scarcely investigated, and additional studies are needed to comprehensively uncover the neuropharmacology underlying hallucinogen-induced modulations of social cognition.

CONCLUSION

Hallucinogens and entactogens are potent modulators of social cognition and behavior. MDMA and hallucinogens may promote re-connection with patients’ social environment, support seeking and reductions in social withdrawal, and may also enhance the patient-therapist relationship.

Studies on the effects of hallucinogens and entactogens on social cognition are scarce, and the dose-dependency of modulations in social cognition induced by hallucinogens and entactogens is still unknown. Sex-specific effects are also poorly understood.

Data on the effects of hallucinogens and entactogens on social cognition are lacking. These substances have consistently shown prosocial effects and have been identified as key factors for the efficacy of treatments involving these substances.