Nitrous Oxide (N2O) was discovered by Joseph Priestly in 1772 and championed as a surgical analgesic by Humphry Davy , founder of the Royal Institution. Despite a long and illustrious history in anaesthesiology and analgesia , its primary exposure in the public eye over the past decade has been with regard to highly politicised negative consequences of its recreational use [3 – 6].
However, 50% N2O in oxygen (Entonox) is widely used in the NHS in obstetrics, paediatrics, and dentistry and as a pre-hospital analgesic. It targets a range of central neurotransmitter pathways, and an important mechanism-of-action is through antagonism at the NMDA-receptor , which is likely responsible for its powerful amnestic effects .
Given this mechanism-of-action, and the known involvement of the NMDA receptor in memory consolidation  we hypothesised that N2O might interfere with the consolidation of traumatic memories if administered shortly after such events. This could be beneficial for preventing Post-Traumatic Stress Disorder (PTSD) by blocking visual and sensory memory traces that contribute to flashbacks. However, a broader effect on memory might be problematic. In particular if N2O interfered significantly with the consolidation of contextual and verbal information – the ‘where,’ ‘what,’ ‘when’ and ‘how,’ – which protects against development of PTSD [6, 7], it might actually impede natural recovery. This consolidation of contextual and verbal information may be affected by ‘dissociation’, or becoming cognitively detached from one’s surroundings, in the aftermath of trauma. Dissociating means less attention can be paid to encoding the ‘where,’ ‘what,’ ‘when’ and ‘how’ of the trauma. As N2O itself tends to make people dissociated, it could potentially worsen PTSD symptoms by reducing these resources further. The current use of N2O by paramedic services in the UK and its effects on PTSD are therefore as yet unknown.
We therefore ran an experiment using a model of PTSD in healthy volunteers. This involves showing participants an extremely unpleasant film, which reliably produces involuntary thoughts or ‘intrusions’ about its depicted contents for a few days afterwards. We used this model due to the obvious ethical concerns of running the first tests of a drug for a new purpose in a real clinical setting.
We assessed the following hypotheses:
- That 30 minutes of 50% N2O would interfere with the consolidation of the memory of the unpleasant film, reducing the frequency of self-reported ‘intrusions’ compared to placebo.
- That this effect of N2O would interact with levels of dissociation post-film, with less benefit being seen in those who dissociated more in response to the film.
Method: Using the ‘trauma film’ paradigm, model of psychological trauma. Healthy participants viewed a highly unpleasant 15 minute film clip before being randomly assigned to inhale 50% N2O (Entonox) or placebo (medical air) for 30 minutes, single-blind. We monitored heart rate variability and dissociation following the film and during gas inhalation. Over the following week, participants recorded the occurrence of spontaneous, involuntary memories or ‘intrusions’ about the film using a daily online diary. They were assessed a week later on memory for contextual and verbal elements from the film.
We found that intrusions following N2O disappeared significantly more quickly (after 1 day) than after placebo (after 4 days). These findings are consistent with the blockade of visuospatial/sensory emotional memory consolidation by N2O. Importantly, however this effect of N2O was dependent on how dissociated people were following the trauma film. Those who became highly dissociated (i.e. cognitively detached) following the film did not experience the benefit of N2O, with some evidence of worsened intrusions. Importantly, there was no difference between groups in recall of the contextual and verbal details of the film, indicating that N2O did not interfere with this potentially protective aspect of trauma memory.
These findings, if replicated clinically, have important implications for the use of N2O for prevention of PTSD. Due to its portability, ease of administration and excellent safety profile, it could be administered following traumatic events in a combat or pre-hospital scenario to potentially reduce the time-course of subsequent distressing intrusions. However, caution is required due to its interaction with dissociation and it may therefore be not recommended for individuals who are highly dissociated following trauma. These effects need to be assessed further, however. Primarily, it will be informative to begin naturalistic long-term studies of the occurrence and severity of PTSD where N2O was administered as an analgesic following trauma. These will tell us whether and in what scenarios, N2O may be helpful for prevention of PTSD/
We hope these findings, along with its recently demonstrated rapid anti-depressant effects  broaden public perception of N2O as an important research compound with unrealised therapeutic potential, rather than being simply written off as potentially dangerous ‘Hippy Crack’.
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- Shimizu, E., et al., NMDA receptor-dependent synaptic reinforcement as a crucial process for memory consolidation. Science, 2000. 290(5494): p. 1170-1174.
- Brewin, C.R., Memory processes in post-traumatic stress disorder. International Review of Psychiatry, 2001. 13(3): p. 159-163.
- Brewin, C.R. and E.A. Holmes, Psychological theories of posttraumatic stress disorder. Clinical psychology review, 2003. 23(3): p. 339-376.
- Nagele, P., et al., Nitrous oxide for treatment-resistant major depression: a proof-of-concept trial. Biological psychiatry, 2015. 78(1): p. 10-18.