A potent, rapid-onset psychedelic drug, dimethyltryptamine (DMT), was tested intravenously in a small pilot study with 7 treatment-resistant depressed individuals and 3 healthy controls. DMT was mostly safe and tolerated; no participants dropped out. Depression scores on the HAMD-17 scale dropped significantly the day after the higher dose (0.3 mg/kg), with an average decrease of 4.5 points. Side effects like increased blood pressure, heart rate, and anxiety resolved within 20-30 minutes. The findings suggest DMT may have next-day antidepressant effects in treatment-resistant depression, but more rigorous trials are needed to confirm and assess durability.
A novel compound, K-4, which positively modulates AMPA receptors, produced longer-lasting antidepressant-like effects in a rat model of treatment-resistant depression than ketamine alone. K-4 reduced expression of the enzyme NOX-1 in the medial prefrontal cortex. Blocking NOX-1, either with an inhibitor or by genetic knockdown, prolonged ketamine's antidepressant-like effects and reduced abnormal bursting in the lateral habenula, a brain region linked to depression. Suppressing NOX-1 may be a promising strategy for extending the benefits of ketamine in treatment-resistant depression.