Psilocybin-induced decrease in amygdala reactivity correlates with enhanced positive mood in healthy volunteers

This double-blind, placebo-controlled, fMRI study (n=25) found that a moderate dose of psilocybin (11.2mg/70kg) lowered amygdala (which is hyperactive in those with major depression) reactivity to negative and neutral (visual) stimuli. The decrease in emotional processing was correlated with an increase in positive mood.

Abstract

“Background The amygdala is a key structure in serotonergic emotion-processing circuits. In healthy volunteers, acute administration of the serotonin 1A/2A/2C receptor agonist psilocybin reduces neural responses to negative stimuli and induces mood changes toward positive states. However, it is little-known whether psilocybin reduces amygdala reactivity to negative stimuli and whether any change in amygdala reactivity is related to mood change.

Methods This study assessed the effects of acute administration of the hallucinogen psilocybin (.16 mg/kg) versus placebo on amygdala reactivity to negative stimuli in 25 healthy volunteers using blood oxygen level-dependent functional magnetic resonance imaging. Mood changes were assessed using the Positive and Negative Affect Schedule and the state portion of the State-Trait Anxiety Inventory. A double-blind, randomized, cross-over design was used with volunteers counterbalanced to receive psilocybin and placebo in two separate sessions at least 14 days apart.

Results Amygdala reactivity to negative and neutral stimuli was lower after psilocybin administration than after placebo administration. The psilocybin-induced attenuation of right amygdala reactivity in response to negative stimuli was related to the psilocybin-induced increase in positive mood state.

Conclusions These results demonstrate that acute treatment with psilocybin decreased amygdala reactivity during emotion processing and that this was associated with an increase of positive mood in healthy volunteers. These findings may be relevant to the normalization of amygdala hyperactivity and negative mood states in patients with major depression.“

Authors: Rainer Kraehenmann, Katrin H. Preller, Milan Scheidegger, Thomas Pokorny, Oliver G. Bosch, Erich Seifritz & Franz X. Vollenweider

Notes

This paper is followed-up by Kraehemann and colleagues (2015) where the group looked at threat/fear responses.

This paper is included in the meta-analytical review by Galvão-Coelho and colleagues (2021) that found psychedelics to improve mood (for those with mood disorders) both in the short and long-term (up to 60 days).

Summary

Psilocybin, a serotonin 1A/2A/2C receptor agonist, decreased amygdala reactivity to negative stimuli in healthy volunteers and was associated with an increase in positive mood state. This finding may be relevant to the normalization of amygdala hyperactivity and negative mood states in patients with major depression.

The amygdala is a key structure in the serotonergic neurocircuitry of emotion processing, and plays a crucial role in the perception and generation of emotions. Amygdala hyperactivity is associated with negative mood states in depressed patients, and decreases after treatment with selective serotonin reuptake inhibitors. Psilocybin, the main psychoactive principle of many species of the genus Psilocybe, acts as a selective agonist on 5-HT-1A/2A/2C receptors and induces sustained neuroplastic adaptations within circuits related to emotion processing. This effect may counteract negative mood states and neural hyperactivity in response to negative perceptual input in patients with major depression.

In a randomized, double-blind, placebo-controlled, cross-over design, subjects received either placebo or 0.16 mg/kg oral psilocybin in two separate imaging sessions at least 14 days apart. The amygdala reactivity task was analyzed using both left and right amygdala masks.

Kraehenmann et al. (6, 38) used an automated anatomical labeling atlas (37) to define amygdala masks, and then extracted BOLD signal responses from the left and right amygdala for each emotion condition (negative vs. shapes and neutral vs. shapes) and from each session separately (psilocybin and placebo). We extracted BOLD signal responses from bilateral amygdala ROIs for the control condition during the baseline tasks and used paired t-tests and an exploratory whole-brain ANOVA to determine whether psilocybin affected non-hypothesized brain regions. We conducted Pearson correlations between the activity in the right amygdala during the negative emotional condition and each of the five mood rating scores.

The whole-brain voxel-wise fMRI data analysis showed that psilocybin significantly reduced activation of the right amygdala to negative and neutral pictures, but not to neutral pictures. In addition, psilocybin preferentially reduced activation of the left amygdala to negative, but not to neutral pictures. During both placebo and psilocybin sessions, no significant differences were found in primary motor cortex activation.

Psilocybin reduced right amygdala activation to both negative and neutral pictures, and did not increase activation in the control condition during the baseline task.

Psilocybin significantly attenuated activation in bilateral occipital gyri, lingual gyrus, fusiform gyrus, and temporal gyri in response to both negative and neutral pictures. This attenuation was driven by decreased activation to negative stimuli during the emotional picture discrimination task, but not by increased activation to the control condition during the baseline task.

Kraehenmann et al. 11 found no significant drug by emotion interaction, and psilocybin reduced amygdala reactivity in response to both negative and neutral pictures. This is in line with previous electrophysiological studies that found valence-specific effects of psilocybin on emotion processing, but only for positive stimuli, and only within the first 200 ms after stimulus onset. Psilocybin attenuated right amygdala responses to negative and neutral stimuli, which is in accordance with recent evidence that SSRIs preferentially attenuate right amygdala responses to negative stimuli. However, the relevance of the observed lateralization effect remains inconclusive.

Psilocybin decreased activation in the visual cortex, which was related to hyperexcitability of neurons in the visual cortex and to visual perceptual alterations. However, the decrease in activity was driven by decreased BOLD responses to negative stimuli, and not by increased BOLD responses to the baseline condition. Psilocybin may have affected the activation of the visual cortex in response to threat-related visual stimuli by attenuating amygdala activation. However, future connectivity studies are warranted to investigate the effects of psilocybin on emotion processing and amygdala reactivity in relation to distant brain regions.

Psilocybin increases positive mood state by activating 5-HT2A receptors and decreases right amygdala reactivity. These results indicate that 5-HT2A receptor stimulation critically underlies the observed effects of psilocybin on right amygdala reactivity. Psilocybin activates 5-HT2A receptors in the brainstem raphe nuclei and also activates 5-HT1A and 5-HT2C receptors in the amygdala, which are located on GABAergic interneurons that inhibit postsynaptic cell firing. This may explain the attenuation of amygdala reactivity observed in experimental models of anxiety and depression.

A study by Fisher et al. demonstrated that 5-HT1A autoreceptor density in the brainstem region of the dorsal raphe nucleus accounted for 44% of the variability in right amygdala reactivity during emotion processing. However, 5-HT2C activation might theoretically have contributed to the acute effects observed here. In conclusion, our study showed that acute treatment with psilocybin causes a marked decrease of amygdala reactivity in healthy volunteers, and that this decrease is related to an increase in positive mood state. This finding is in line with previous models of antidepressant action.

Figure 1 shows the behavioral and subjective effects of a 0.16-mg/kg dose of oral psilocybin on the negative amygdala reactivity task, the positive and negative affect schedule, and the state-trait anxiety inventory. Figures 2 and 3 show that the altered state of consciousness scale was higher during psilocybin treatment than during placebo treatment for all symptoms except spiritual experience and anxiety, and that the amygdala was more activated during psilocybin treatment than during placebo treatment.