Efficacy of Intranasal Oxytocin in Preventing Relapse in Patients with Substance Use Disorder: A Randomized, Placebo-Controlled Trial

The primary objective of this study is to investigate the efficacy of **Syntocinon** in reducing craving for drugs such as heroin and cocaine in individuals with **substance use disorder** and in preventing relapse to drug use. This is clinically relevant as it addresses the challenge of relapse prevention, a critical aspect of long-term recovery in substance use disorder treatment.

Secondary objectives include determining which neural substrate activation patterns underlie drug cue-incubation of craving and assessing whether the identified regions are sensitive to pharmacological treatment with Syntocinon in patients with substance use disorder. Understanding these neural mechanisms could provide insights into the biological underpinnings of craving and inform the development of targeted interventions.

The clinical trial focuses on individuals diagnosed with **substance use disorder**. The study population includes both males and non-lactating, non-pregnant females, aged between 18 and 55 years. Participants are required to have a primary diagnosis of substance use disorder according to DSMV criteria and must be capable of providing informed consent. Additionally, they should have an understanding of Italian and be able to provide an identity document. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants. The selection process for the trial population is based on specific inclusion criteria, ensuring that participants meet the necessary health and demographic requirements. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed to evaluate the efficacy of **oxytocin** in reducing cravings and preventing relapse in individuals with **substance use disorder**. This is a randomized, double-blind, placebo-controlled study, categorized as a Phase IV trial. The trial will involve the administration of **Syntocinon**, a nasal spray solution containing **oxytocin**, and a placebo, **sodium chloride** nasal spray, over a treatment period of four weeks. The study is expected to commence recruitment on July 1, 2023, and conclude by July 30, 2026.

Participants will undergo a series of study visits, beginning with an inclusion visit to screen for eligibility based on criteria such as a primary diagnosis of **substance use disorder** according to DSMV criteria, age between 18-55 years, and the ability to provide informed consent. Following the screening, eligible participants will be randomized to receive either the active treatment or placebo. The primary endpoint will be assessed through self-reported measures of craving and BOLD fMRI activation signals in specific brain regions, evaluated at day 7 and day 30 of the treatment period. Secondary endpoints will include measures of social/emotional cognition and duration of abstinence, with follow-up assessments at 3 and 6 months post-treatment.

The expected duration of participant involvement is approximately six months, including the treatment and follow-up periods. Conditions that may lead to early termination from the study include withdrawal of consent, adverse events, or non-compliance with study procedures. The trial aims to provide valuable insights into the potential role of **oxytocin** in managing cravings and preventing relapse in individuals with **substance use disorder**.

The clinical trial involves the administration of **Syntocinon**, a nasal spray solution containing the active substance **oxytocin**. This experimental medication is provided in a concentration of 40 IU/ml and is administered via the **intranasal route**. Participants will receive a maximum daily dose of 40 IU, with the treatment period extending up to four weeks. The pharmaceutical form is a nasal spray, solution, and it is manufactured by ALFASIGMA S.P.A. The administration schedule is designed to ensure consistent dosing, and participant compliance will be monitored throughout the trial to ensure adherence to the prescribed regimen.

In addition to the experimental treatment, a **placebo** comparator is utilized in the study, consisting of a nasal spray containing **sodium chloride**. This non-experimental treatment is administered in a similar manner to the active treatment, with a maximum daily dose of 1 ml. The sodium chloride nasal spray serves as a control to evaluate the efficacy of the active treatment. The placebo is not considered a medicinal product due to its route of administration. The dosing schedule for the placebo mirrors that of the experimental treatment, and participant compliance will be similarly monitored to maintain the integrity of the trial results.

Efficacy in this clinical trial will be assessed through both primary and secondary endpoints. The primary endpoint involves the evaluation of **cue-incubation of craving** and the BOLD fMRI activation signal in specific brain regions, including the amygdala, insula, ventral striatum, and anterior cingulate cortex. These measures will be assessed through self-reported craving following cue exposures at day 7 and day 30, compared to baseline measurements on day 1. Additionally, the BOLD fMRI signal will be evaluated on day 30 compared to day 1.

Secondary endpoints include measures of social and emotional cognition, which will be evaluated using tasks such as the Picture viewing task, Go/no-go task, Cyberball task, and Social Gaze task. Scores from these tasks will be recorded at day 7 and day 30, compared to baseline on day 1. Furthermore, the duration of abstinence will be assessed by evaluating drug use at follow-up visits 3 and 6 months after the termination of the treatment period. These assessments will provide comprehensive data on the efficacy of Syntocinon in reducing drug craving and preventing relapse in individuals with substance use disorder.