Mechanisms of Ketamine: Insights from Ben Yudkoff, MD

Ben Yudkoff, MD, discussed the evolving understanding of ketamine and esketamine as interventional treatments for psychiatric disorders. He noted that “there have been multiple proposed mechanisms of action for the efficacy of ketamine,” and outlined several that are most supported by emerging evidence.¹

He first described ketamine’s induction of brain-derived neurotrophic factor and its downstream promotion of neuroplasticity. He explained that enhanced synaptogenesis may counteract synaptic deficits observed in depression, and create a biologic substrate more amenable to psychotherapeutic change. In this more neuroplastic state, patients might more readily establish adaptive cognitive and behavioral patterns.

He next highlighted preclinical findings regarding astrocytes and norepinephrine signaling. Ketamine appeared to attenuate astrocytic support of norepinephrine-releasing neurons implicated in futility responses. In translational terms, Yudkoff observed that patients sometimes demonstrated increased persistence in goal-directed behaviors even before subjective mood improved, suggesting a potential mechanism for early functional gains.

Yudkoff also reviewed ketamine’s activity at mu and kappa opioid receptors. Upregulation of mu-opioid receptors may enhance sensitivity to endogenous endorphins, whereas kappa-opioid antagonism could modulate stress-related and trauma-associated neurocircuitry. Although clinical implications remained under investigation, he suggested these pathways might contribute to observed benefits in trauma-spectrum conditions.

Turning to large-scale brain networks, Yudkoff discussed the default mode network and its role in self-referential processing and negative attribution bias in depression. He noted that “while ketamine is in the system, this network ceases to be as networked,” potentially disrupting rigid maladaptive interpretations. Posttreatment reintegration of network connectivity might resemble a functional reset.

Finally, Yudkoff addressed the phenomenology of ketamine-induced psychedelia. He described experiences of awe, unity, and revised autobiographical meaning-making, which for some patients facilitated resilience and motivational renewal. He emphasized that ketamine’s therapeutic impact reflected both neurobiological mechanisms and profound subjective effects, underscoring its unique role within contemporary interventional psychiatry.

Dr Yudkoff is a psychiatrist and chief medical officer at Lumin Health.

References

1. Abdallah CG, Adams TG, Kelmendi B, et al. Ketamine’s mechanism of action: a path to rapid-acting antidepressants. Depress Anxiety. 2016;33(8):689-697.

2. Price K. Ketamine's antidepressive effects tied to opioid system in brain. Stanford Medicine. August 29, 2018. Accessed March 2, 2026. https://med.stanford.edu/news/all-news/2018/08/ketamines-antidepressive-effects-tied-to-opioid-system-in-brain.html