Examination of oxidative stress and glutamate as potential mechanisms of N-acetylcysteine in the treatment of non-suicidal self-injury in young people assigned female at birth: randomised trial.

Background: Non-suicidal self-injury (NSSI) often emerges during adolescence and young adulthood. A prior open-label pilot study suggested that N-acetylcysteine (NAC) may reduce NSSI frequency in young individuals.

Aims: This study investigated potential NSSI-related biological markers for NAC in young adults with a history of NSSI using a placebo-controlled, randomised clinical trial of two NAC dosage regimens.

Method: Forty-three individuals (assigned female at birth) aged 16-24 years and with a history of NSSI were randomly assigned to either low-dose NAC (3600 mg/day), high-dose NAC (5400 mg/day) or placebo treatment for 4 weeks. Participants underwent blood draws, magnetic resonance imaging with spectroscopy and clinical assessments before and after treatment. Primary outcomes included brain glutathione (GSH), blood reduced to oxidised GSH ratio and brain glutamate. Secondary outcomes included antioxidant protein levels, brain gamma-aminobutyric acid concentrations, functional connectivity (between amygdala and insula) and clinical outcomes. Pharmacokinetics, tolerability and correlations among measures were also explored.

Results: For 39 participants who completed study assessments at follow-up, weekly NSSI and depression symptoms improved similarly across both treatment and placebo groups, with no significant group differences in primary or secondary outcomes at follow-up. Some significant correlations emerged.

Conclusions: The study did not support the proposed biological signatures of NAC in young adults with NSSI, although exploratory findings suggested potential biological correlates of clinical improvement. Further research is necessary to explore neurobiologically based treatments for young adults with NSSI.