A systematic review examining the neuroimaging and clinical changes associated with psychedelics and ketamine/esketamine in depressive disorders found that these compounds work through distinct but complementary mechanisms. Depression affects approximately 280 million people globally and constitutes the second leading cause of disability worldwide. Despite the availability of multiple treatment options, approximately 30–50% of patients with depression do not achieve complete symptom remission even after multiple treatment steps, prompting investigation of rapid-acting compounds with novel mechanisms.
Psychedelic Mechanisms and Neuroimaging
The review analyzed 49 studies, with the majority focused on ketamine/esketamine (n = 44) and fewer on psychedelic tryptamines (n = 5, including one on ayahuasca and four on psilocybin). Psilocybin studies demonstrated that the drug resets Default Mode Network (DMN) activity, with significant relationships between decreased cerebral blood flow in the left amygdala and reduction of depressive symptoms. Psilocybin administration in four studies showed significant reduction in depressive symptoms 4 to 5 weeks after treatment, with all studies reporting mystical experiences associated with treatment. A single ayahuasca study found significant decreases in depressive symptoms from 80 minutes to day 21.
Ketamine’s Cognitive and Emotional Effects
Ketamine exhibits a more specific action on networks involving prefrontal areas that act indirectly on the DMN. Following ketamine administration, increased global brain connectivity was documented in dorsal prefrontal cortices in treatment-resistant depression patients compared to healthy controls. Several studies highlighted ketamine’s anti-anhedonic action, with significant reduction of anhedonia scores after multiple infusions. Increased connectivity was observed between the dorsal caudate and right ventrolateral prefrontal cortex immediately after ketamine infusion, and dorsal caudate-subgenual anterior cingulate connectivity increased 10 days after, significantly correlating with improvement of anhedonic symptoms.
Clinical Outcomes and Safety
Ketamine administration reduced depression rating scales compared to placebo. Psilocybin was never associated with adverse events, while ayahuasca induced vomiting in 47% of subjects and dissociative symptoms. Ketamine-related adverse effects included dissociation, dizziness, nausea, chest tightness, fatigue, inattention, sedation, light-headedness, restlessness, and palpitations, with rare cases of suicide and suicidal ideation recorded.
This article is an AI-assisted summary. All facts and figures are drawn from the original report: https://www.nature.com/articles/s41398-025-03654-3