Serotonergic hallucinogens and recognition of facial emotion expressions: a systematic review of the literature

This review (s=8) found that psychedelics (LSD, psilocybin) can aid in the recognition of emotions in facial expressions (REFE), which is thought to be a key aspect of social cognition. Psychedelics do this by modulating the activity of the amygdala.

Abstract

“Background: Recognition of emotions in facial expressions (REFE) is a key aspect of social cognition. Anxiety and mood disorders are associated with deficits in REFE, and anxiolytics and antidepressants reverse these deficits. Recent studies have shown that serotonergic hallucinogens (i.e. ayahuasca, dimethyltryptamine, psilocybin, lysergic acid diethylamide [LSD], and mescaline) have anxiolytic and antidepressant properties, but their effects on REFE are not well understood. The purpose of the study was to conduct a systematic review analyzing the effects of serotonergic hallucinogens on REFE in humans.

Methods: Studies published in the PubMed, PsycINFO, and Web of Science databases until 19 October 2018 which analyzed the effects of serotonergic hallucinogens on REFE in humans were included.

Results: Of the 62 studies identified, 8 studies were included. Included studies involved the administration of a single or a few doses of LSD or psilocybin, and most trials were randomized and controlled with placebo. LSD and psilocybin reduced the recognition of negative emotions in most studies and modulated amygdala activity to these stimuli, which was correlated with antidepressive effects in patients. Both drugs were well tolerated.

Conclusions: Serotonergic hallucinogens reduced the recognition of negative emotions by modulating amygdala activity. Despite the small sample sizes, results suggest that serotonergic hallucinogens show promising beneficial effects on deficits in REFE.”

Authors: Juliana M. Rocha, Flávia L. Osório, José Alexandre S. Crippa, José Carlos Bouso, Giordano N. Rossi, Jaime E. C. Hallak & Rafael G. Dos Santos

Summary

Introduction

Social cognition includes the ability to recognize emotions in facial expressions. People with anxiety and mood disorders have deficits in the recognition of facial expressions.

In the experimental and clinical setting, facial expression recognition is assessed through tasks. These tasks can be classified by means of accuracy4 or sensitivity1, and include identifying the emotion expressed to the presented stimuli or discriminating between two different facial expressions.

Serotonergic hallucinogens, such as ayahuasca, dimethyltryptamine, psilocybin, lysergic acid diethylamide [LSD], and mescaline, have been shown to have anxiolytic and antidepressant properties, but their effects on REFE are not well understood.

Research suggests that drugs used to treat anxiety and mood disorders may improve facial recognition skills. However, the observation of changed emotional recognition with acute SSRI administration has not been systematically replicated.

Serotoninergic hallucinogens such as LSD, psilocybin, ayahuasca/dimethyltryptamine (DMT) and mescaline act as agonists at 5-HT2A serotonergic receptors and have evident effects on emotion processing. These effects may be related to the effects of these drugs on brain areas linked to emotional processing in general and social cognition specifically.

The purpose of this study was to review the effects of serotoninergic hallucinogens on the recognition of facial expressions, one of the main factors involved in social cognition.

Search strategy

The electronic search was performed using the PubMed, PsycINFO, and Web of Science databases, and all studies published until 19 October 2018 were included.

Selection criteria and study selection

Inclusion criteria were: studies in humans without restrictions of sex and age, studies involving the administration of a serotonergic hallucinogen, studies evaluating the recognition of facial expressions, and studies in any language.

After excluding duplicates, all articles were reviewed for inclusion or exclusion. Two reviewers independently conducted the search and selection of articles, and a third author/reviewer decided on the inclusion of a particular article.

Recorded variables, data extraction and analysis

Researchers studied the effects of LSD, psilocybin, ayahuasca, DMT, and mescaline on facial recognition and neuroimaging.

Identification of studies

The review included seven studies with psilocybin and LSD, and two studies with mind theory. The studies were classified according to the substance under investigation, and included five double-blind, randomized, crossover, placebo-controlled trials and two open-label studies.

In spite of the limited number of studies, the results are unanimous for the good tolerability of serotoninergic hallucinogens for treatment anxiety and mood disorders. These drugs also reduced the recognition of negative emotions.

Drugs

Schmidt and colleagues conducted a study in 2013 using event-related potentials to compare the effects of psilocybin and ketamine on conscious and nonconscious facial processing. They found that both substances significantly reduced facial expression recognition of fear and happiness.

Psilocybin, a 5-HT2A receptor agonist, modulates the processing of facial expressions. In a randomized, double-blind, placebo-controlled study, psilocybin reduced the neural response to fear and neutral faces in the amygdala and parahippocampal gyrus and increased the response to happy faces in the limbic and temporo-occipital area.

In 2017, Roseman and colleagues conducted an open study in 20 patients with treatment-resistant depression to investigate the effects of psilocybin on facial emotional processing. They found that the amygdala was activated in response to faces of fear and happiness.

In 2018, the same group of researchers used the same sample of depressed patients and a control group of 16 healthy subjects to assess the effects of psilocybin on emotional processing. They found that the depressive patients had a reduced reaction time in face recognition and anhedonia reduction after the intervention.

In the same year, Grimm and colleagues tested whether psilocybin would alter the connective pattern of the amygdala during facial expression recognition using fMRI. They found that psilocybin increased reaction time and reduced functional connectivity in the amygdala and frontal medial cortex.

In 2016, Dolder and colleagues conducted two randomized, crossover, double-blind, and placebo-controlled studies involving the administration of LSD to healthy volunteers. They found that both doses of LSD significantly reduced fear expression recognition and increased emotional but not cognitive empathy and enhanced prosociality measures.

Mueller and colleagues evaluated the effect of LSD on the amygdala response to fear stimuli and found that this effect was associated with the subjective effects of LSD.

Discussion

We performed a systematic review of studies involving LSD and psilocybin to evaluate their effects on REFE. We found that these drugs reduced the recognition of negative emotions and modulated amygdala activity to these stimuli.

The studies selected met the basic methodological rigor required for clinical trials by using double-blind, placebo-controlled designs, but all were of small size, and some did not use placebo or an adequate control group. Moreover, the studies used different drugs, doses of the same drugs, and distinct tasks to evaluate REFE.

Classic hallucinogens act by modulating activity at cortical 5-HT2A receptors expressed in the amygdala, a region of the brain involved in the processing of anxiety and fear.

The present results show that classical serotoninergic hallucinogens cause similar and overlapping effects with traditional drugs used to treat anxiety and mood disorders regarding alterations in REFE. Furthermore, positive changes in REFE are predictive of clinical improvement.

The present review suggests that the effects of classic hallucinogens on REFE could be a mechanism involved in their anxiolytic and antidepressant effects. Furthermore, the serotonergic drug MDMA reduces identification of negative emotions in tasks of face recognition and decreases the activity of the amygdala.

Traditional antidepressants and anxiolytics do not necessarily share common pharmacological mechanisms of action, and serotonergic hallucinogens are partial agonists of cortical 5-HT2A receptors, while traditional antidepressants are often inhibitors of monoamine uptake. However, both drugs increase neuroplasticity, which may be involved in their capacity to improve symptoms.

After 7 days of treatment with an SSRI, the amygdala activity normalizes, and this normalization precedes changes in clinical status.3 Regarding classical hallucinogens, the amygdala activity decreases during REFE.

LSD and psilocybin show good tolerability, and the relationship between these substances and the amygdala in healthy subjects is interesting. However, the neural basis of the anxiolytic and antidepressant effects of these substances may be directly related to this brain structure.

Conclusion

This systematic review presented data suggesting that serotonergic hallucinogens reduce recognition of negative emotions, which could be useful in treating depression and anxiety symptoms.

Experimental studies using antagonists of the 5-HT2A receptor may shed light on the possible causal role of these receptors in the observed effects produce by serotonergic hallucinogens on facial expression recognition.

The present systematic review suggests that although the mechanisms of action of serotonergic hallucinogens are not fully understood, they reduce recognition of negative emotions and may be used to treat anxiety and mood disorders.

Funding

JMR, GNR, RGS, JASC, and JECH received funding from various sources, but had no role in the study design, data analysis, data interpretation, or writing of the report.