Intranasal Oxytocin for Reducing Craving and Preventing Relapse in Adults with Substance Use Disorder: Randomized, Placebo-Controlled Trial

The primary objective is to evaluate the efficacy of intranasal oxytocin (Syntocinon) in reducing drug craving (e.g., heroin, cocaine) and in preventing relapse among individuals diagnosed with substance use disorder, addressing a central therapeutic need for relapse mitigation. The secondary objective is to identify the neural activation patterns that underlie drug‑cue‑induced incubation of craving and to determine whether these neural substrates are modulated by oxytocin treatment in this patient population.

The trial enrolled adult individuals aged 18–55 years, inclusive of both males and females who were not pregnant or lactating. All participants had a primary diagnosis of substance use disorder according to DSM‑V criteria. The study population comprised patients meeting these diagnostic criteria as well as healthy volunteers, as indicated by the trial’s grouping structure. Enrollment required the ability to provide informed consent, comprehension of Italian, and presentation of a valid identity document. The sponsor did not provide information regarding the total number of participants enrolled.

The study is a randomized, double-blind, placebo-controlled parallel‑group trial evaluating intranasal oxytocin (Syntocinon 40 IU/mL) versus a saline/hyaluronic‑acid nasal spray in individuals with substance use disorder. After a screening visit to confirm eligibility, participants receive a baseline assessment (day 1) and are then allocated to active or placebo treatment for a 30‑day period. Follow‑up visits occur on day 7 and day 30 to collect self‑reported craving, functional MRI data, and social cognition measures; the day 30 visit also serves as the end‑of‑study assessment for the treatment phase. Additional safety and abstinence evaluations are performed at 3‑month and 6‑month visits after treatment completion. Participant involvement therefore spans approximately six months, including the treatment phase and post‑treatment follow‑up. Early termination may occur if a participant experiences a serious adverse event, withdraws consent, or fails to adhere to the dosing schedule or study procedures.

The investigational product is Syntocinon 40 IU/ml nasal spray solution. It contains the active substance oxytocin. The formulation is a sterile solution for intranasal use. Each administered spray delivers 40 IU of oxytocin. The product is supplied as a nasal spray device and is administered by the intranasal route. Dosing is performed according to the study protocol, with the specified number of sprays given at each dosing visit.

The comparator is Ialu Clenny nasal spray, a CE‑marked medical device composed of hyaluronic acid and isotonic saline solution. This product serves as the placebo and does not contain the investigational active ingredient. Although marketed as a medical device, it is managed in the trial under Annex 13 GMP requirements for investigational medicinal products, including appropriate labeling and qualified person certification.

Both the active and placebo nasal sprays are administered under direct observation to ensure correct technique. Dosing schedules are recorded in the case report form. Compliance is assessed by documenting each administered dose and by verifying the integrity of the remaining product at each visit.

Efficacy will be evaluated using both a primary endpoint and several secondary endpoints. The primary endpoint, cue‑incubation of craving, will be assessed by a self‑report measure of craving obtained after standardized cue‑exposure sessions on day 7 and day 30, each compared with baseline (day 1). In parallel, neural activation will be quantified with BOLD fMRI focusing on the amygdala, insula, ventral striatum and anterior cingulate cortex; scans will be performed on day 30 and compared to baseline scans obtained on day 1.

Secondary efficacy assessments include measures of social/emotional cognition and duration of abstinence. Cognitive performance will be captured using a battery of tasks (Picture viewing, Go/No‑Go, Cyberball, and Social Gaze) with scores recorded on day 7 and day 30 relative to day 1. Abstinence duration will be determined by drug‑use verification at follow‑up visits 3 months and 6 months after the end of the treatment period.