CompletedNCT06650800PSILODACUpdated Aug 20, 2025

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

An interventional study of Psilocybin and MRI in Depressive Disorder, Depressive Disorder, Treatment-Resistant and Hallucinogens, sponsored by Centre Hospitalier Universitaire de Nīmes. Completed at 1 site in France. Open to participants aged 25 Years to 60 Years. Per ClinicalTrials.gov, last updated 2025-08-20.

Sponsored by Centre Hospitalier Universitaire de Nīmes · Not applicable, Interventional, and Other

Phase: Not applicable
Study type: Interventional
Enrollment: 10
Allocation: Not applicable
Ages: 25 Years to 60 Years
Sex: All

Study 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.

Read the 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 studied

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

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In context

Depressive Disorder

4,845 studies on the registry are indexed under Depressive Disorder; 514 are open to participants now.

This study's enrollment of 10 is below the median of 80 across 3,999 interventional studies indexed under Depressive Disorder.

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Lead sponsor

Centre Hospitalier Universitaire de Nīmes is the lead sponsor of 587 studies on the registry; 96 are open to participants now.

Counted across the registry records on this site, refreshed daily.

Who can participate

Ages eligible: 25 Years to 60 Years
Sexes eligible: All
Accepts healthy volunteers: No

Inclusion criteria

The patient must have given their free and informed consent and signed the consent form
The patient must be a member or beneficiary of a health insurance plan
Patient with a current DSM-IV diagnosis of moderate or severe major depressive episode (MDE) without psychotic features (based on clinical assessment and confirmed by the MINI interview and the QIDS).
Patient who has not responded to at least two antidepressant treatments of different classes, administered appropriately in terms of dose and duration, for a moderate to severe major depressive episode.
Patients receiving antidepressant treatment of the SSRI (Selective Serotonin Reuptake Inhibitors) or SNRI (Serotonin Norepinephrine Reuptake Inhibitors) classes may maintain this treatment for the duration of the trial, without modification • Patient with a score > 10 on the QIDS scale.
Patient available for a 4-month follow-up.
Patient able to speak and understand French easily.

Exclusion criteria

Exclusion Criteria:

The patient is participating in a medical product-based interventional study, or is in a period of exclusion determined by a previous study
Patient unable to express consent
It is impossible to give the subject informed information
The patient is under safeguard of justice or state guardianship
Patient with allergy, hypersensitivity or other adverse reaction to previous use of psilocybin or other hallucinogens.
Patient who has used hallucinogenic substances (excluding cannabis) more than 5 times in his/her lifetime or at any time in the last twelve months.
Patient on medication or illicit substances likely to interfere with the effects of psychedelics (urine analysis and breathalyzer on D0).
Patient with regular consumption of alcoholic beverages (>20 drinks/week)
Any other major clinically significant concomitant disease that, in the opinion of the investigator, may interfere with the interpretation of the study results or constitute a risk to the health of the participant, if he or she participates in the study
Patient with a prolonged QTc interval (interval corrected by the Fridericia formula >450 ms for men and >470 ms for women
Participant planning to donate sperm within three months of psilocybin administration
Female participant having sexual intercourse that could result in pregnancy and not agreeing to use a highly effective contraceptive method (combined hormonal contraception (containing estrogen and progestin), contraception associated with inhibition of ovulation, hormonal progestin-only contraception associated with inhibition of ovulation, intrauterine device intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomized partner, and sexual abstinence) throughout their participation in the study and for at least three months after psilocybin administration.
Positive serum pregnancy test at inclusion for participants of childbearing potential. NB: a urine pregnancy test will also be performed on the day of psilocybin administration.
Pregnant patient (confirmed by pregnancy test), parturient or breastfeeding, or wishing to become pregnant during their participation in the study
Active substance dependence according to the MINI questionnaire (excluding tobacco).
Patient whose psychotropic treatment (anxiolytics, antipsychotics, hypnotics, mood stabilizers) has been modified in the last month.
Patient on antidepressant treatment other than SSRIs or SNRIs. (Antidepressant treatments other than SSRIs or SNRIs are prohibited in the trial. Patients receiving antidepressant treatment of a different class (MAOIs, tricyclics, tetracyclics), alone or in combination, will not be included in the study).
Patient suffering from intellectual disability (IQ less than or equal to 75).
Patient with a history of bipolar disorder, schizophrenia, schizoaffective disorder or psychosis not otherwise specified during life.
Patient with a family history of schizophrenia, schizoaffective disorder or bipolar disorder type 1 in first or second degree relatives.
Patient who has started psychotherapy in the 30 days preceding the screening visit, or whose psychotherapy is likely to undergo changes during the clinical trial.
Patient who has received in the last 6 months treatments such as: ECT, vagus nerve stimulation, deep brain stimulation, transcranial magnetic stimulation.
Patient with any disease or unstable physical condition determined by clinical examination, history or laboratory tests (ECG, blood test at inclusion) These pathologies include cardiovascular comorbidities: history of stroke, myocardial infarction, heart failure, intracranial hypertension, arrhythmia, uncontrolled hypertension (greater than 140/90 mmHg at screening), tachycardia (resting heart rate > 100 beats per minute); organic epileptic syndrome and active neurological comorbidities; endocrine pathologies (dysthyroidism and adrenals, type I diabetes or insulin-requiring type II diabetes, history of severe hypoglycemia requiring hospitalization); significant impairment of liver function; glaucoma; symptomatic prostatic hypertrophy or bladder neck obstruction; renal failure; respiratory failure; presence of fever or inflammatory syndrome.
Patient with contraindications to magnetic resonance imaging: patients with a metallic foreign body, pacemaker, neurostimulator or any electronic medical equipment implanted in a non-removable manner, implantable cardiac defibrillators, prostheses, transdermal patches (placed under the skin), catheters (tubes introduced into a vessel or organ), implantable pumps, artificial heart valves, implants to treat deafness.
Patient at moderate or severe risk of suicide based on clinical judgment (according to the MINI Suicidality Module).
Patient at high risk of adverse emotional or behavioral reaction based on the investigator's clinical assessment (e.g., severe personality disorder, antisocial behavior, severe current stressors, lack of significant social support, or any psychotic symptoms identified during interviews).

Study design

Phase: Not applicable
Primary purpose: Other
Allocation: Not applicable
Intervention model: Single group
Masking: None (open label)
Enrollment: 10 participants (actual)

Study arms

Experimental
Patient with major depressive episode
Drug: Psilocybin · Other: MRI

Interventions

DrugPsilocybin
Single-dose psilocybin administration: oral ingestion of one 25 mg capsule
OtherMRI
1.5 hour brain MRI before and after psilocybin administration

What researchers measure

Primary outcomes

Activity of the neural circuits responsible for the evaluation of effort before taking psilocybin
Brain activity measured by fMRI at resting state and during Effort Expenditure for Rewards Task in the basolateral amygdala, dorsal anterior cingulate cortex, ventral pallidum, ventral striatum and ventral tegmental area
Time frame: Two days before administration of psilocybin
Activity of the neural circuits responsible for the evaluation of effort after taking psilocybin
Brain activity measured by fMRI at resting state and during Effort Expenditure for Rewards Task in the basolateral amygdala, dorsal anterior cingulate cortex, ventral pallidum, ventral striatum and ventral tegmental area
Time frame: Five days after administration of psilocybin

Secondary outcomes

Effect of a single-dose administration of psilocybin on self-reported treatment-resistant depression
Quick Inventory of Depressive Symptomatology (QIDS-SR16); 16 items rated from 0 to 3. Total scores range from 0 to 27, with scores of 11 to 15 indicating moderate depression, 16 to 20 reflecting severe depression, and total scores greater than 21 indicating very severe depression.
Time frame: Day 0
Effect of a single-dose administration of psilocybin on self-reported treatment-resistant depression
Quick Inventory of Depressive Symptomatology (QIDS-SR16); 16 items rated from 0 to 3. Total scores range from 0 to 27, with scores of 11 to 15 indicating moderate depression, 16 to 20 reflecting severe depression, and total scores greater than 21 indicating very severe depression.
Time frame: Day 4
Effect of a single-dose administration of psilocybin on self-reported treatment-resistant depression
Quick Inventory of Depressive Symptomatology (QIDS-SR16); 16 items rated from 0 to 3. Total scores range from 0 to 27, with scores of 11 to 15 indicating moderate depression, 16 to 20 reflecting severe depression, and total scores greater than 21 indicating very severe depression.
Time frame: Month 1
Effect of a single-dose administration of psilocybin on self-reported treatment-resistant depression
Quick Inventory of Depressive Symptomatology (QIDS-SR16); 16 items rated from 0 to 3. Total scores range from 0 to 27, with scores of 11 to 15 indicating moderate depression, 16 to 20 reflecting severe depression, and total scores greater than 21 indicating very severe depression.
Time frame: Month 3
Effect of a single-dose administration of psilocybin on clinician-rated treatment-resistant depression
Inventory of Depressive Symptomatology, clinician-rated (IDS-C-30); 30 items with each symptom rated from 0 to 3.
Time frame: Day 0
Effect of a single-dose administration of psilocybin on clinician-rated treatment-resistant depression
Inventory of Depressive Symptomatology, clinician-rated (IDS-C-30); 30 items with each symptom rated from 0 to 3.
Time frame: Day 4
Effect of a single-dose administration of psilocybin on clinician-rated treatment-resistant depression
Inventory of Depressive Symptomatology, clinician-rated (IDS-C-30); 30 items with each symptom rated from 0 to 3.
Time frame: Month 1
Effect of a single-dose administration of psilocybin on clinician-rated treatment-resistant depression
Inventory of Depressive Symptomatology, clinician-rated (IDS-C-30); 30 items with each symptom rated from 0 to 3.
Time frame: Month 3
Effect of a single-dose administration of psilocybin on anhedonia
Behavioral Activation for Depression Scale (BADS); 9 questions, each rated on a seven-point scale ranging from 0 (not at all) to 6 (completely) for a total score 0-36.
Time frame: Day 0
Effect of a single-dose administration of psilocybin on anhedonia
Behavioral Activation for Depression Scale (BADS); 9 questions, each rated on a seven-point scale ranging from 0 (not at all) to 6 (completely) for a total score 0-36.
Time frame: Day 4
Effect of a single-dose administration of psilocybin on anhedonia
Behavioral Activation for Depression Scale (BADS); 9 questions, each rated on a seven-point scale ranging from 0 (not at all) to 6 (completely) for a total score 0-36.
Time frame: Month 1
Effect of a single-dose administration of psilocybin on anhedonia
Behavioral Activation for Depression Scale (BADS); 9 questions, each rated on a seven-point scale ranging from 0 (not at all) to 6 (completely) for a total score 0-36.
Time frame: Month 3
Effect of a single-dose administration of psilocybin on behavioral activation scores
Snaith-Hamilton Pleasure Scale (SHAPS); score ranging from 0-14.
Time frame: Day 0
Effect of a single-dose administration of psilocybin on behavioral activation scores
Snaith-Hamilton Pleasure Scale (SHAPS); score ranging from 0-14.
Time frame: Day 4
Effect of a single-dose administration of psilocybin on behavioral activation scores
Snaith-Hamilton Pleasure Scale (SHAPS); score ranging from 0-14.
Time frame: Month 1
Effect of a single-dose administration of psilocybin on behavioral activation scores
Snaith-Hamilton Pleasure Scale (SHAPS); score ranging from 0-14.
Time frame: Month 3
Acceptability of a clinical protocol for psilocybin-assisted therapy in France
SATMED-Q; six dimensions for an overall score from 17 items rated from 0 to 4.
Time frame: Day 4
Feasibility of a clinical protocol for psilocybin-assisted in France
Adverse events or tolerance problems collected using the PRISE (Patient Rated Inventory of Side Effect) questionnaire
Time frame: Day 4
Effect of psilocybin treatment on states of consciousness.
5-Dimensional Altered States of Consciousness Questionnaire; 94 items rated on a visual analog scale, marked as "no, no more than usual" to "yes, much more than usual", with higher values indicating stronger effects.
Time frame: Day 0

Study locations

1 site

CHU de Nîmes, Hôpital Universitaire Carémeau
Nîmes, 30029, France

Updates

Tracking since Sep 25, 2026

No changes since tracking began. The registry record was last updated on Aug 20, 2025, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗

Registry details

Key details

Study ID: NCT06650800
Lead sponsor: Centre Hospitalier Universitaire de Nīmes
Responsible party: Sponsor
First posted: Oct 21, 2024
Start date: Nov 19, 2024
Primary completion: Mar 26, 2025
Completion: Jun 26, 2025
Last update: Aug 20, 2025

Study contacts

Ismaël Conejero

principal investigator · CHU Nimes

Oversight

Data monitoring committee: No
FDA-regulated drug: No
FDA-regulated device: No

View the source record on ClinicalTrials.gov ↗

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