<b><i>Introduction:</i></b> The number of patients with excessive nitrous oxide (N₂O) use and neurological disorders has been rising, indicating an addictive potential of N₂O. We studied the incidence of self-reported substance use disorder (SUD)-related symptoms, signs of neuropathy, and the patterns of use in N₂O-intoxicated patients. <b><i>Methods:</i></b> The Dutch Poisons Information Center (DPIC) provides information by telephone on the management of intoxications to healthcare professionals. Retrospective data on signs of neuropathy and patterns of use were collected for all N₂O intoxications reported to the DPIC in 2021 and 2022. Frequent and heavy use were self-reported as “often/frequent/weekly use” and as “use of tanks or &gt;50 balloons/session,” respectively. From this cohort, we included patients with excessive N₂O use or signs of neuropathy in a prospective observational cohort study. Online surveys were sent 1 week, 1 month, and 3 months after DPIC consultation. The survey included the drug use disorder questionnaire (validated to measure self-reported substance abuse [SA] and substance dependence [SD] based on Diagnostic and Statistical Manual of Mental Disorders [DSM]-IV-TR criteria) and questions on patterns of use and signs of neuropathy. DSM-IV-TR criteria were translated to DSM-V criteria to score for mild, moderate, or severe SUD, with 2–3, 4–5, or ≥6 symptoms, respectively. <b><i>Results:</i></b> We included 101 N₂O-intoxicated patients in the retrospective study. Of these, 41% showed signs of neuropathy (<i>N</i> = 41), 53% used N₂O tanks to fill balloons (<i>N</i> = 53), 71% used them frequently (<i>N</i> = 72), and 76% used them heavily (<i>N</i> = 77). We included 75 patients in the prospective study and 10 (13%) completed the first survey. All 10 patients fulfilled the criteria for SA and SD (DSM-IV-TR, median number of questions answered “yes” = 10/12), all used N₂O tanks to fill balloons, and 90% (<i>N</i> = 9) experienced signs of neuropathy. After 1 and 3 months, 6/7 and 1/1 patients, respectively, continued to fulfill SA and SD criteria. Translating to DSM-V criteria, 1/10 patients fulfilled the criteria for (self-reported) mild SUD, 1/10 patients for moderate SUD, and 8/10 patients for severe SUD, 1 week after consultation. <b><i>Conclusion:</i></b> The high proportion of N₂O-intoxicated patients reporting frequent and heavy use of N₂O indicates an addictive potential of N₂O. Although follow-up rate was low, all patients fulfilled self-reported SA, SD (DSM-IV-TR), and SUD (DSM-V) criteria for N₂O. Somatic healthcare professionals treating patients with N₂O intoxications should be aware of possible addictive behavior in patients. The screening, brief intervention, and referral to treatment approach should be considered to treat patients with self-reported SUD symptoms.