Psilocybin-Induced Decrease in Amygdala Reactivity Correlates with Enhanced Positive Mood in Healthy Volunteers

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

Biological Psychiatry, 2014.

http://dx.doi.org/10.1016/j.biopsych.2014.04.010

 

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.

Key Words : Amygdala, depression, emotion, fMRI, psilocybin, serotonin

 

The amygdala is a key structure in the serotonergic neurocircuitry of emotion processing and thus plays a crucial role in the perception and generation of emotions (1,2). Amygdala hyperactivity in response to negative stimuli and a relation between amygdala activity and negative mood states have consistently been found in depressed patients and individuals at risk of major depression (3–5). Amygdala hyperactivity in patients with major depression decreased after treatment with selective serotonin reuptake inhibitors (SSRIs) and this was associated with mood changes toward positive states (6,7). Growing evidence suggests that genetic dysfunctions in serotonergic neurotransmission underlie amygdala hyperactivity in major depression and constitute a vulnerability marker of major depression (8–10). The relevance of serotonin (5-hydroxytryptamine [5-HT]) neurotransmission in the pathogenesis and treatment of major depression is further supported by the finding that depletion of tryptophan, a precursor in the biosynthesis of serotonin, induced depression in vulnerable individuals (11) and that SSRIs have strong antidepressant properties (1). These and other findings (12–14) implicate the amygdala in the pathogenesis of major depression.

The hallucinogen psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine) is the main psychoactive principle of many species of the genus Psilocybe, commonly known as magic mushrooms (15). Psilocybin acts as a selective agonist on 5-HT1A/2A/2C receptors (16,17). In line with the notion that modulation of serotonergic neurotransmission may critically alter neural activity within circuits related to emotion processing, it has recently been shown (18–23) that psilocybin may alter neural activity as well as induce sustained neuroplastic adaptations within circuits related to emotion processing. These and previous studies (24–26) suggest that psilocybin has antidepressant properties, as it acutely induces mood changes toward positive states and reduces neural responses to negative stimuli in healthy subjects. This effect might counteract negative mood states and neural hyperactivity in response to negative perceptual input in patients with major depression. In support of this view, a recent clinical trial (27) of the effect of psilocybin in patients with depression and anxiety related to advanced stage cancer found that a single dose of psilocybin significantly decreased anxiety and increased positive mood state for up to 6 months. However, the neurobiological mechanisms by which psilocybin influences emotion processing remain poorly understood. In particular, there is sparse evidence (21) whether psilocybin modulates the activity of the amygdala, a region that plays a crucial role in the neural effects of antidepressants (28), during emotion processing and whether any psilocybin-induced effect on amygdala activity during emotion processing is related to changes in mood state.

Thus, in this pharmacologic functional magnetic resonance imaging (fMRI) study, we evaluated the neural effects of psilocybin on brain activity during emotion processing, focusing on the amygdala as a region of interest (ROI). We conducted statistical parametric mapping on fMRI blood oxygen level dependent (BOLD) responses during an established amygdala reactivity task (8) in healthy volunteers following administration of psilocybin and placebo. In addition, we assessed the effects of psilocybin on mood states using validated self-rating questionnaires. Thus, the present study provides an evaluation of the neural mechanisms underlying the acute effects of psilocybin on emotion processing in relation to mood changes. We hypothesized that a single dose of psilocybin would decrease amygdala reactivity to negative stimuli and increase positive mood state.

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Kraehenmann2014_psilocybinamygdalapositiveaffect