Advancing cancer neuroscience through stress modulation: Interdisciplinary potential of psilocybin and ketamine.

Psychological stress not only undermines quality of life for people with cancer but also fuels tumor growth. Emerging evidence from the nascent field of cancer neuroscience suggests that adrenergic signaling from direct tumor-neuron interactions drives cancer progression, resistance to treatment, and worse outcomes. Cancer neuroscientists are increasingly seeking to repurpose psychoactive medications (e.g., β-blockers and others) to augment primary cancer therapies. Preclinical models reveal that psychological stress can be a key activator of the sympathetic pathways that promote pathological tumor-neuron crosstalk. However, conventional antidepressants/anxiolytics used to address psychological distress are often less effective in this population. Conversely, while sample sizes are limited, psilocybin has achieved 60-80% long-term remission of cancer-related depression and anxiety and peri-palliative ketamine studies demonstrate rapid but short-lived symptom control. In preclinical models these agents appear to normalize hypothalamic-pituitary-adrenal (HPA) axis function while upregulating neurotrophic factors, mechanisms which putatively promote stress reductions and resilience. In this review, we propose that this neuroplastic recalibration may reduce sustained adrenergic tone, thereby interrupting the stress-driven tumor-neuron signaling that accelerates cancer progression. Integrating these rapid agents into oncology practice could thus disrupt maladaptive adrenergic signaling, enhance treatment adherence, and ultimately improve survival. Hospital-based psychiatrists are uniquely positioned to lead this effort by collaborating with oncologists, embedding biomarker-rich clinical trials, and monitoring both psychiatric and tumor-neuron interaction metrics. Advancing interdisciplinary research with ketamine and psilocybin will clarify whether targeting systemic stress indices represents a cancer-relevant endpoint beyond psychological symptom relief itself, while advancing research in cancer neuroscience mechanisms to improve oncologic outcomes.