Nitrous oxide causes peripheral neuropathy in a dose dependent manner among recreational users

Background: Nitrous oxide (N2O) has been used in clinical and recreational settings for over 150 years. Through inactivation of the Vitamin B12 dependent enzyme, methionine synthase, N2O can lead to the development of peripheral neuropathy. This study sought to determine the relationship between the exposure and risk of neurological symptoms in the largest ever sample of users. Design: Data are drawn from the Global Drug Survey (GDS) over three consecutive years (2014-2016). The Global Drug Survey is an online, cross-sectional survey of substance use, translated into multiple languages. Participants: Respondents to the Global Drug Survey who provided details on N2O use and the experience of paraesthesia in the previous 12 months. Measurements: Questions relating to N2O use, peripheral neuropathy, age and gender were explored among last year's users. Findings: Of 241,566 respondents, 41,181 (17.0%) indicated that they had ever used nitrous oxide; of these, 42.1% had used in the last 12 months. For the final model, data from 16,124 participants who had used N2O in the last 12 months and had provided responses on age, dose, gender and paraesthesia were used. Of these, the number of respondents reporting persistent numbness/tingling (paraesthesia) in their hands or feet was 537 (3.3%). Although the risk was very low among infrequent users, there was a strong dose-response relationship. For people indicating one or two doses per session, the probability of reporting paraesthesia was approximately 0.018 by comparison; for people indicating 100 doses per session the probability was approximately 0.085. The association, between dose and paraesthesia was influenced by gender and age. Conclusion: While infrequent, episodic users are not at risk, a minority of heavy users are at dose-dependent risk of developing serious neurological consequences. Better education and raised awareness of early symptoms are required.