NCT06650800

Effect of Psilocybin on the Positive Valence System in Treatment-resistant Depression

Effect of Psilocybin on the Positive Valence System in Treatment-resistant Depression: a Pilot Clinical Neuroimaging Study

• Status: Completed
• Phase: N/A
• Study type: Interventional
• Enrollment: 10 (actual)
• Sponsor: Centre Hospitalier Universitaire de Nīmes · Academic / Other
• Sex: All
• Age: 25 Years – 60 Years
• Healthy volunteers: Not accepted

Summary

The study hypothesis is that the antidepressant effect of psilocybin is mediated by a normalization of the functioning of the positive valence system. Depressive states, especially moderate to severe depressions that associate a certain level of anhedonia, produce an overvaluation of the cost of efforts and an infra-evaluation of the possible rewards derived from an action. Psilocybin would reduce anhedonia and the cost of efforts, facilitating the anticipation of reward. Thus, the antidepressant effect of psilocybin would be mediated by a greater anticipation of rewards (reduction of anhedonia) and a more optimistic estimation of the results of efforts (increase in motivation). Psilocybin-induced changes in the positive valence system will be observable on brain MRI images, particularly in the effort evaluation circuits: basolateral amygdala, dorsal anterior cingulate cortex, ventral pallidum, ventral striatum (VS), ventral tegmental area (VTA). The mesolimbic circuit (VS, VTA) is the anatomical substrate of anticipation of rewarding stimuli (food, sex, drugs). The amygdala also fulfills an associative function between environmental cues and rewarding stimuli. Structural and functional alterations in this circuit are associated with depressive symptoms such as anhedonia or distortions in the perception and memories of rewards. This hypothesis will be tested on a population of patients with moderate or severe depressive symptoms who meet the criteria for TRD.

Detailed description

Depressive disorders are strongly associated with suicide risk and are the leading cause of disability in the world. Psilocybin is a natural alkaloid with psychedelic and hallucinogenic effects, produced by its active metabolite: psilocin. In recent years, there has been a resurgence of research aimed at using psilocybin in the treatment of psychiatric disorders, and in particular depression, combined or not with various psychotherapeutic programs. Psilocybin-assisted therapy is effective in treating cancer-associated depression and resistant depression. The Federal Drug Administration (FDA) has designated it as a "Breakthrough Therapy" in the treatment of treatment-resistant depression (TRD). Most researchers consider that the antidepressant effects of psilocybin are associated with the activation of the serotonin 5-HT2a receptor, with acute neuromodulation effects that modify the connectivity of cortico-striatal loops, but the mechanisms supporting this effect are unknown. The purpose of this study is to verify whether the antidepressant action of psilocybin is associated with an activation of the brain areas involved in the positive valence system, by comparing the activity of the neural circuits responsible for the evaluation of effort before and after taking psilocybin. The correlations between the activation of brain areas and the depression severity, behavioral activation and anhedonia scores will help establish a link with the response to treatment. Finally, the study authors wish to test the feasibility of a study with psilocybin in a French clinical population.

Conditions

• Depressive Disorder
• Depressive Disorder, Treatment-Resistant
• Hallucinogens
• Reinforcement, Psychology

Interventions

Type	Name	Description
DRUG	Psilocybin	Single-dose psilocybin administration: oral ingestion of one 25 mg capsule
OTHER	MRI	1.5 hour brain MRI before and after psilocybin administration

Timeline

• Start date: 2024-11-19
• Primary completion: 2025-03-26
• Completion: 2025-06-26
• First posted: 2024-10-21
• Last updated: 2025-08-20

Locations

1 site across 1 country: France