Randomised, parallel delayed‑treatment trial (n=27) evaluating two moderately high oral psilocybin sessions for people with Major Depressive Disorder.
Randomised, parallel-group trial comparing immediate versus 8‑week delayed psilocybin treatment in adults with major depressive disorder; participants receive two oral dosing sessions (first session moderately high, second session moderately high or high).
Primary outcome (GRID-HAMD) assessed by blinded raters. Secondary assessments include mood, attitudes, behaviours and safety measures; concurrent stable psychotherapy allowed.
Participants begin psilocybin intervention immediately after enrollment.
Moderately high psilocybin dose in first session; second session moderately high or high dose per protocol. Two psilocybin sessions: 20 mg in session 1 and 30 mg in session 2.
Participants begin identical psilocybin intervention 8 weeks after enrollment (delayed/waitlist control).
Moderately high psilocybin dose in first session; second session moderately high or high dose per protocol. Two psilocybin sessions: 20 mg in session 1 and 30 mg in session 2.
In an open‑label study of 24 patients with major depressive disorder, psilocybin therapy produced an enduring increase in cognitive flexibility for at least four weeks and altered anterior cingulate cortex (ACC) biochemistry (reduced glutamate and N‑acetylaspartate) alongside increased ACC–posterior cingulate cortex dynamic functional connectivity (dFC). Paradoxically, larger post‑treatment ACC–PCC dFC increases were associated with smaller cognitive gains, while greater baseline ACC dFC predicted better baseline flexibility but less subsequent improvement, suggesting a nuanced relationship between neural and cognitive flexibility in therapeutic response.