Abstract
BACKGROUND: Oxytocin administration is increasingly considered a novel therapeutic support option for alleviating psychological distress in stress-related neuropsychiatric conditions, including anxiety disorders and depression. However, oxytocin as a stand-alone treatment may fail to consistently target the relevant central autonomic circuitry without a complementary supportive therapeutic context that similarly stimulates stress-regulatory states and behaviors. Recent findings suggest that the neurophysiological mechanisms underlying stress regulation induced by mindfulness may rely on an activation of the endogenous oxytocinergic system. Accordingly, combining oxytocin with a mindfulness-based training program may enhance efficacy compared to each intervention alone. METHODS: A randomized, double-blind, placebo-controlled clinical trial will be conducted in 120 adults with heightened stress complaints, randomly assigned to one of the following four treatment arms (n = 30 per group): (1) oxytocin + mindfulness, (2) mindfulness + placebo, (3) oxytocin, and (4) placebo (control). The oxytocin or placebo nasal spray will be administered four times a week in the morning before each mindfulness session for six weeks, followed by a six-week post-treatment follow-up session. Primary endpoints include self-reported behavioral measures of stress, depression, and anxiety. Secondary endpoints include self-reported behavioral measures of mood, mindfulness skills, quality of life, sleep quality, and negative thinking. Exploratory measures include (i) electroencephalography (EEG), electrocardiography (ECG), skin conductance, and respiration, measured during rest, meditation, stress induction, and stress recovery; (ii) intervention-induced changes in biological samples, including hormonal levels of oxytocin and cortisol and DNA methylation of the oxytocin receptor gene (OXTR); and (iii) stress reactivity in daily life, assessed through experience sampling and heart rate/sleep monitoring. All outcome measures will be assessed at baseline (T0), immediately post-intervention (T1), and at six-week follow-up (T2). DISCUSSION: These findings could provide valuable insights into how combining oxytocin and mindfulness-based interventions might enhance stress regulation, particularly in populations with impaired oxytocinergic function. TRIAL REGISTRATION: This trial was registered in the EU Clinical Trials Register (EU CT 2024-513482-39-00) on 18 March 2025.