Nitrous oxide (N₂O) is a colorless, non-irritating gas with a sweet aroma that has therapeutic roles in alleviating pain and anxiety in medical and dental procedures, as well as in the management of treatment-resistant depression. There are multiple purported mechanisms by which N₂O exerts its analgesic effect, including via activation of the endogenous opioid system and induction of a preventative blockade of pain hypersensitivity by interrupting nociceptive inputs [1]. To demonstrate the efficacy of N₂O in pain reduction, a randomized study published in 2019 indicated a statistically significant decrease in pain scores from 6.0 to 3.4 within five minutes of continuous inhalation [2]. Its role in treatment-resistant depression has been demonstrated in a double-blinded placebo-controlled crossover trial comprising 20 patients, where significant improvement in depressive symptoms was observed after two hours and sustained 24 hours post-treatment [3].

In addition to its therapeutic uses, N₂O is also an up-trending recreational drug of choice among the adolescent and young adult population due to its psychedelic and euphoric effects [4]. According to the World Health Organization and the National Drug Survey, adolescents are in the age group of 12-17 years, and young adults are in the age group of 18-25 years [5]. Its misuse plausibly arises from the resulting emotional state of relaxation, dissociation, increased somnolence, and occasional hallucinations [6]. Furthermore, N₂O produces physiological and psychological effects within seconds after inhalation, with peak impact at approximately one minute and a complete dissolution of these effects at three to five minutes [7]. Due to this quick inhalant experience, many individuals inhale N₂O several times to prolong the intoxication, leading to long-term adverse effects on the neuropsychiatric development of adolescents. 

It is known that adolescents misusing N₂O often present with a range of neuropsychiatric symptoms, most commonly auditory hallucinations and persecutory delusions. With long-term use, adolescents can experience agitation, depression, and personality changes [8]. There have also been reports of acute cognitive decline, such as memory impairment and confusion, which are noted to be early manifestations of repetitive use [9]. The National Institute on Drug Abuse (NIDA) highlights that chronic exposure can have a severe impact on the brain’s white matter, affecting essential functions like movement, vision, and cognition [10]. The study indicates that early exposure to inhalant use increases the risk of more severe substance use disorder, especially if use is started prior to the age of 18. This, combined with the stable, albeit minimal, uptrend in the use of N₂O among adolescents, demonstrates the need to understand the biochemical mechanisms, as well as both the psychiatric and physiological manifestations, to aid clinicians in prompt recognition and treatment of this disorder.

Thus, the purpose of this scoping review was to compile existing literature that focuses on the long-term effects of N₂O among adolescents. With the increasing prevalence of N₂O misuse among adolescents, there is an immediate need for further investigation in order to protect the neurological and psychological well-being of this vulnerable subset of the population. 

Historical context and usage trends

Overview of N₂O's History and Applications 

N₂O is one of the oldest pharmaceutical drugs that is still used in clinical practice. Originally synthesized by Priestley in 1772, this volatile gas was first reported for its medical use by American dentist Horace Wells for a dental extraction [11]. Since its discovery and debut for analgesic and anesthetic properties in 1844, N₂O pressure cylinders have been a staple for dental and minimally invasive medical procedures in the field of obstetrics, pediatrics, and chronic pain therapy, to safely administer the inhalant to patients [12]. In recent years, N₂O has also been shown to be efficacious in treating refractory depression. Patients who received a mean duration of N₂O treatment of 55.6 minutes at a median inspiratory concentration of 44% report a sustained improvement in mood and associated symptoms, days after treatment [3,13]. 

Recreational use of N₂O has become increasingly popular over the decades due to its ability to induce dissociative and hallucinogenic effects of depersonalization, derealization, euphoria, lightheadedness, and auditory distortion. It is now one of the common inhalants used by adolescents and young adults at festivals and parties, typically going by its street names such as “whippets”, “whippits”, or “hippy crack”. This gas is usually inhaled through a balloon, bulb, or N₂O canister in a process known as “nagging” [14]. This increase in use is found to be more prevalent among adolescents in rural or suburban areas, although misuse is documented in urban demographics as well. 

An investigative study conducted in 2022 by Inquimbert et al. probed into the factors contributing to the recreational use of N₂O among healthy individuals at the Montpellier University in France [15]. The sample size consisted of 593 students with a mean age of 22.3 years; 68.6% of this sample population were female. The study observed that older male students who were completing their medical or dental studies and were part of a student corporation had significantly higher usage. Harmful habits such as tobacco, alcohol, or cannabis consumption were significantly associated with N₂O use. It is also interesting to note that nearly one-quarter of N₂O users were not aware of their misuse. Desirable factors such as euphoria, impaired vision, or fun were significantly associated with an increased frequency and dosage of N2O use [15].

Statistics on Adolescent Use and Demographic Factors

There has been an increase in the prevalence of N₂O users in the Western world since the early 2000s. A 2014 global drug survey involving 17 countries and 74,684 participants concluded that N₂O has become increasingly popular. The United States reported a 29.4% use of this gas. While the timeline remains unclear on the origin of N₂O as a substance of misuse, the earliest known case report on the euphorigenic effects of N₂O was in 1961 [14]. The lifetime prevalence of this inhalant misuse among adolescents and young adults ranges between 2% and 15.8% [4,16].

The National Survey on Drug Use and Health (NSDUH) indicated that the lifetime use of N₂O across populations was 4.9% in 2004 (ages 12-17: 1.8%; ages 18-25: 10.2%; ages 26 and over: 4.4%) [17]. The most recent data in 2023 reported a lifetime N₂O use of 4.9% total (ages 12-17: 0.4%; ages 18-25: 3%; ages 26 and over: 5.3%) [18]. The data suggests a fairly stable rate of usage, with an increase in use observed among young adults aged 18-25 years.

A cross-sectional study conducted by van den Toren et al. investigated the socio-demographic characteristics associated with recreational N₂O use in a sample population of 555 adolescents [19]. The study concluded that students with a lower socioeconomic background, lower educational levels with externalized issues such as familial conflict or peer pressure, and frequent alcohol binging, had a statistically significant increase in N₂O use. This risk was observed in 15.6% of students from the study sample population [19].