BackgroundPost-traumatic stress disorder (PTSD) involves maladaptive long-term memory formation which underlies involuntary intrusive thoughts about the trauma. Preventing the development of such maladaptive memory is a key aim in preventing the development of PTSD. We examined whether the N-methyl d-aspartate receptor (NMDAR) antagonist gas nitrous oxide (N₂O) could reduce the frequency of intrusive memories by inhibiting NMDAR-dependent memory consolidation in a laboratory analogue of psychological trauma.MethodParticipants were randomized to inhale N₂O (N = 25) or medical air (N = 25) after viewing a negatively valenced emotional film clip (‘trauma film’). Participants subsequently completed a daily diary assessing frequency of intrusive thoughts relating to the film clip. A week later, participants completed an explicit memory recall task related to the film.ResultsPost-encoding N₂O sped the reduction in intrusive memory frequency, with a significant reduction by the next day in the N₂O group compared to 4 days later in the air group. N₂O also interacted with post-film dissociation, producing increased intrusion frequency in those who were highly dissociated at baseline. Sleep length and quality the night after viewing the film did not differ between the groups.ConclusionN₂O speeds the reduction of intrusive analogue trauma memory in a time-dependent manner, consistent with sleep-dependent long-term consolidation disruption. Further research with this drug is warranted to determine its potential to inoculate against enduring effects of psychological trauma; however, caution is also urged in dissociated individuals where N₂O may aggravate PTSD-like symptomatology.