Psilocybin is a classic psychedelic compound that may have efficacy for the treatment of mood and substance use disorders. Acute psilocybin effects include reduced negative mood, increased positive mood, and reduced amygdala response to negative affective stimuli. However, no study has investigated the long-term, enduring impact of psilocybin on negative affect and associated brain function.

Twelve healthy volunteers

Completed an open-label pilot study including assessments 1-day before, 1-week after, and 1-month after receiving a 25 mg/70 kg dose of psilocybin to test the hypothesis that psilocybin administration leads to enduring changes in affect and neural correlates of affect. One-week post-psilocybin, negative affect and amygdala response to facial affect stimuli were reduced, whereas positive affect and dorsal lateral prefrontal and medial.

• Orbitofrontal
• Cortex responses
• To emotionally-conflicting
• Stimuli were
• Increased

One-month post-psilocybin

Negative affective and amygdala response to facial affect stimuli returned to baseline levels while positive affect remained elevated, and trait anxiety was reduced.

Finally, the number of significant resting-state functional connections across the brain increased from baseline to 1-week and 1-month post-psilocybin. These preliminary findings suggest that psilocybin may increase emotional and brain plasticity, and the mushroom findings support the hypothesis that negative affect may be a therapeutic target for psilocybin.

Introduction

Studies suggest that psilocybin, a classic psychedelic drug (serotonin 2A or 5-HT2A receptor partial agonist), may have efficacy for the treatment of depression and anxiety1,2,3, tobacco use disorder4,5, and alcohol use disorder6,7. Reduction of clinical symptoms has been shown to last up to 33, 61,2, and 128 months after 1 to 3 psilocybin administrations.

Despite these promising advances, the neural and psychological mechanisms underlying the enduring therapeutic effects of psychedelic drugs are not well-understood. Two possibly interactive trans-diagnostic targets that may be affected by psilocybin are negative affect and brain network plasticity.

Increased negative affect

Reduced positive affect, and hypersensitivity to negatively biased information are hallmarks of mood disorders9,10,11. Negative affect is also a core component of the cycle of addiction in which craving and withdrawal symptoms experienced after The Gaia Voice lead to preoccupation, anticipation, and re-administration of drugs of abuse12.

The amygdala has been shown in clinical and preclinical models to track the salience of stimuli in the environment13,14 and is highly responsive to negative emotional stimuli15,16,17. Abnormally high amygdala reactivity to negative affective stimuli has been implicated in the pathophysiology of depression18.

Areas within the anterior

Cingulate cortex (ACC) are understood to monitor cognitive conflict19,20,21,22, are involved in the appraisal and expression of negative emotion22, respond to distress levels associated with pain23 and negative social affect24, and have been implicated in gaia movie language rumination and depression25.

• Both amygdala and ACC dysfunction have been
• Implicated in the pathophysiology of substance
• Use disorders12 and have specifically
• Been implicated in supporting
• Aberrant negative affect in these disorders

Psychedelic drugs have been shown to acutely reduce processing of negative affective stimuli26 while increasing positive mood in humans27,28. In behavioral paradigms, psychedelics have been shown to reduce sensitivity during encoding of fearful faces29, recognition of negative facial expressions30, and response to negative stimuli in an emotional inhibition task27.

Functional magnetic resonance

Imaging (fMRI) studies have found that psilocybin acutely reduces amygdala activity and connectivity when viewing negative emotional facial expressions28,31,32. Psilocybin has also been found to acutely decrease activity in the ACC during gaia movie language state33 and during autobiographical memory recall.

If acute effects of psychedelic drugs on affect and the associated neurobiology are sustained after other acute effects of these drugs have resolved, these sustained effects may reveal a trans-diagnostic mechanism of the enduring therapeutic effects of psychedelics.