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Advanced neuroscientific insights surrounding post-traumatic stress disorder (PTSD) and its associated symptomatology should beget psychotherapeutic treatments that integrate these insights into practice. Deep Brain Reorienting (DBR) is a neuroscientifically-guided psychotherapeutic intervention that targets the brainstem-level neurophysiological sequence that transpired during a traumatic event. Given that contemporary treatments have non-response rates of up to 50% and high drop-out rates of &gt;18%, DBR is investigated as a putative candidate for effective treatment of some individuals with PTSD. To conduct an interim evaluation of the effectiveness of an eight-session clinical trial of videoconference-based DBR versus waitlist (WL) control for individuals with PTSD. Fifty-four individuals with PTSD were randomly assigned to DBR ( N  = 29) or WL ( N  = 25). At baseline, post-treatment, and three-month follow-up, participants’ PTSD symptom severity was assessed using the Clinician Administered PTSD Scale (CAPS-5). This is an interim analysis of a clinical trial registered with the U. S. National Institute of Health (NCT04317820). Significant between-group differences in CAPS-total and all subscale scores (re-experiencing, avoidance, negative alterations in cognitions/mood, alterations in arousal/reactivity) were found at post-treatment (CAPS-total: Cohen’s  d  = 1.17) and 3-month-follow-up (3MFU) (CAPS-total: Cohen’s  d  = 1.18). Significant decreases in CAPS-total and all subscale scores were observed within the DBR group pre – to post-treatment (36.6% CAPS-total reduction) and pre-treatment to 3MFU (48.6% CAPS-total reduction), whereas no significant decreases occurred in the WL group. After DBR, 48.3% at post-treatment and 52.0% at 3MFU no longer met PTSD criteria. Attrition was minimal with one participant not completing treatment; eight participants were lost to 3MFU. These findings provide emerging evidence for the effectiveness of DBR as a well-tolerated treatment that is based on theoretical advances highlighting alterations to subcortical mechanisms in PTSD and associated symptomatology. Additional research utilizing larger sample sizes, neuroimaging data, and comparisons or adjacencies with other psychotherapeutic approaches is warranted. Trial registration:ClinicalTrials.gov identifier: NCT04317820. .

A randomized controlled trial of Deep Brain Reorienting: a neuroscientifically guided treatment for post-traumatic stress disorder