This retrospective observational study aims to explore the neuropsychiatric effects of recreational N₂O in patients presenting to an ED in Melbourne, Australia. The findings highlight the growing clinical burden of N₂O misuse, particularly among younger people and those engaging in concurrent substance use. Psychiatric complications, including psychosis and suicidality, were the predominant presentations, while a smaller proportion of patients exhibited neurological features. These results provide valuable insight into the demographic, clinical, and risk profiles of individuals presenting with N₂O-related harms.

Internationally, increasing recreational N₂O use has raised significant concern [6]. Regulatory responses vary: in the United Kingdom, N₂O was restricted under the Psychoactive Substances Act 2016 with subsequent scheduling updates [7,8]; in the United States, sales to minors are prohibited; and in Australia, measures include labelling requirements, restrictions on sales to under-18 s, and state-level prohibitions on recreational supply. However, online availability remains widespread, and enforcement is inconsistent [3]. Including these updates provides a more current and comprehensive overview of international regulatory frameworks relevant to recreational N₂O use.

The patients in this study had a mean age of 29.3 years, with a range from 16 to 47 years, indicating that recreational N₂O use spans a wide age group. A predominance of younger users is consistent with surveys reporting higher N₂O use among adolescents and young adults. Data from Western Australia showed that 18–19-year-olds were five-times more likely to report recent N₂O use compared to their counterparts over 24-years [9]. In the UK, N₂O is the second most used drug among 16–24-year-olds [7,8], with similar data from the US showing the use of the drug is most common between the ages of 13–39 years [5]. Social acceptance of the drug, ease of access, perceived harmlessness and low cost are likely explanations for the skew in use towards younger populations. These factors, coupled with associated experimentation with substances and risk-taking behaviours in adolescents frames N₂O as a widely accepted mainstream drug among these populations, with a subsequently unsurprising high experimentation rate of N₂O [10].

Gender distribution in our cohort was balanced, aligning with previous studies showing that N₂O misuse occurs across genders [11,12,13], though some studies suggest males may be more likely to engage in frequent or high-volume use [14,15]. The near-equal representation in our sample highlights the importance of recognising N₂O misuse as a concern not limited to one gender and underscores the need for gender-inclusive prevention and intervention strategies.

More than half of our patients identified as CALD, particularly of Asian background. While this likely reflects the demographics of Melbourne’s western suburbs, it is also consistent with emerging reports of N₂O misuse in Asian countries where regulation remains limited [14,16]. This finding highlights the need to consider sociocultural factors in prevention strategies.

A significant proportion of the patients, 83%, had concurrent AOD use, with stimulants, cannabis and alcohol being the most commonly used substances alongside N₂O. Such patterns complicate attribution of symptoms to N₂O alone and present challenges for clinical management. Easy accessibility may further encourage use in social and party contexts. These observations reinforce the importance of situating N₂O misuse within the broader landscape of polysubstance use and youth drug culture.

We operationalized ‘predominantly psychiatric’ vs. ‘predominantly neurological’ presentations using explicit criteria (psychosis, suicidality, or other acute mental health syndromes vs. documented objective neurological signs). While this improves reproducibility, some overlap exists, and cases with mixed features were classified according to the dominant presenting problem.

Psychiatric features dominated our cohort, with nearly half presenting with psychosis and more than one-third with suicidal ideation or self-harm. These acute presentations underscore the substantial mental health burden associated with N₂O use and align with case reports describing psychosis, mood disturbance, and, in rare cases, suicide [12,17,18]. Notably, psychiatric symptoms have been reported to precede neurological complications in some cases, underscoring the importance of early identification and intervention [10,17].

There remains a paucity of robust studies specifically examining psychiatric outcomes related to N₂O use, as many published accounts focus on vitamin B12 deficiency as the primary mechanism of neurotoxicity. While psychiatric symptoms are often mentioned in relation to B12 depletion, few studies explore their occurrence independently or in the context of polydrug use, which complicates attribution. This challenge is reflected in our sample as discussed above. The role of N₂O as a potential gateway substance or risk amplifier in individuals already vulnerable to psychiatric illness warrants further investigation.

No cases of B12 deficiency were documented; however, serum B12 levels alone are not a fully reliable indicator of functional B12 status, as they can be influenced by prior supplementation. Functional B12 deficiency may still exist despite normal or elevated serum B12 levels, and more specific markers, such as MMA and homocysteine, are typically required to detect such cases. These markers were not measured in this study, which limits our ability to assess subclinical functional B12 deficiency. This limitation is acknowledged and highlights the need for future studies to include functional B12 markers to better understand the relationship between N₂O use and neurological complications.

Neurological complications were less frequent in our sample compared with neurology-led cohorts, likely reflecting the psychiatric referral pathway. 5 patients in this study reported neurological symptoms, namely paraesthesia, weakness and ataxia. These are consistent with symptoms of subacute combined degeneration of the spinal cord and peripheral neuropathy—known complications of chronic N₂O exposure due to its inactivation of vitamin B12. Only 1 patient underwent further imaging (MRI brain and whole spine) for neurological symptoms. Given emerging data from countries such as Australia and the Netherlands, where an increase in N₂O-related neurological presentations among young people has been noted [8], more consistent screening, such as B12 monitoring and neuroimaging, should be considered, especially in patients with a history of frequent or high-volume use.

From a clinical perspective, our findings support the need for structured assessment of N₂O-related presentations in ED. We recommend taking a targeted history of N₂O and other substance use, performing a focused neurological examination, and assessing vitamin B12 and folate levels, with MMA and homocysteine where available. Neuroimaging should be considered in patients presenting with neurological deficits, and early administration of hydroxocobalamin is advised in cases of suspected functional B12 deficiency. Incorporating these measures may facilitate timely diagnosis, prevent progression of neurological injury, and guide appropriate psychiatric and medical management.

Finally, clinical outcomes in our cohort varied, with one third of patients (n = 8) being admitted to the hospital (7 under psychiatric care and 1 under general medicine), while another 8 were discharged with follow-up by community mental health teams. 5 patients were discharged with care instructions from their general practitioners. These results highlight the need for tailored care approaches, as the severity of the psychiatric and neurological symptoms may vary significantly between individuals.