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Mechanisms Involved in the Neurotoxicity and Abuse Liability of Nitrous Oxide: A Narrative Review

Department of Psychiatry, Amsterdam UMC, Location Academic Medical Center, University of Amsterdam, P.O. Box 22660, 1100 DD Amsterdam, The Netherlands
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2022, 23(23), 14747;
Submission received: 30 October 2022 / Revised: 21 November 2022 / Accepted: 22 November 2022 / Published: 25 November 2022


The recreational use of nitrous oxide (N2O) has increased over the years. At the same time, more N2O intoxications are presented to hospitals. The incidental use of N2O is relatively harmless, but heavy, frequent and chronic use comes with considerable health risks. Most importantly, N2O can inactivate the co-factor cobalamin, which, in turn, leads to paresthesia’s, partial paralysis and generalized demyelinating polyneuropathy. In some patients, these disorders are irreversible. Several metabolic cascades have been identified by which N2O can cause harmful effects. Because these effects mostly occur after prolonged use, it raises the question of whether N2O has addictive properties, explaining its prolonged and frequent use at high dose. Several lines of evidence for N2O’s dependence liability can be found in the literature, but the underlying mechanism of action remains controversial. N2O interacts with the opioid system, but N2O also acts as an N-methyl-D-aspartate (NMDA) receptor antagonist, by which it can cause dopamine disinhibition. In this narrative review, we provide a detailed description of animal and human evidence for N2O-induced abuse/dependence and for N2O-induced neurotoxicity.

1. Introduction

Over the past decade, the prevalence of recreational nitrous oxide (N2O) use has increased in the Western world [1]. For instance, the 2019 Global Drug Survey (GDS), an online drug survey among a self-selected sample of drug users from over 30 countries, showed that 91% of all participants (n = 123,814) had used N2O at least once, suggesting that N2O is the 10th most popular drug, excluding alcohol and tobacco, in the Western world [2]. According to the 2019/2020 ‘Household Survey’, the highest rate of last year’s N2O use in adolescents (16–24 years) in the United Kingdom was 8.7% in England and Wales, which implies that N2O was second only to cannabis in use among those aged 16–24 in England and Wales [3]. N2O use also seems to have increased in the United States [4]. Similarly, among French students, N2O use comes in second place after cannabis; last year, the rates were 14% and 35%, respectively [5]. Interestingly, N2O use in the Netherlands is especially high among young non-Western immigrants, such as second generation immigrants from Morocco or Turkey, aged 12–16 years, with rates of ever use and last-month use of 12.8% and 3.9%, respectively (their Dutch peers: 8.9% and 2.0%, respectively) [6]. However, the public health consequence of this widespread N2O use is low, because N2O is a relatively safe drug when used only occasionally and in low doses [7]; typical recreational users consume less than 10 bullets (‘whippets’; each containing 10 mL of pressurized N2O) per session.
However, recently, the number of young excessive users has risen—for instance, among young non-Western immigrants [6]. Likewise, the Dutch Poisons Information Center reported a steep increase in N2O intoxications from 0.12% in 2010 to 11% in 2020, with an average monthly rate of 3.8% of all reported intoxications [8], 79% of the patients indicating heavy and frequent use in 2019 and 2020 and 42% using N2O from large cylinders. These alarming increases in N2O abuse or intoxications have also been reported in other countries during the same period, such as Australia [9,10], the United States [4], China [11] and France [12]. N2O is used in largely the same way across all these countries, with whippets (or bullets) being the most prevalent. However, the use from larger canisters has also been seen more recently, such as in the United States [13]. Frequent and heavy use (up to 700 whippets per day) has been reported in Australia [14]. This is of serious concern because repeated exposure to high doses of N2O for a prolonged time is known to induce neurological damage, such as (irreversible) neuropathy and paralysis due to N2O-induced cobalamin deficiency [15,16,17,18,19]. The increasing trend of recreational users with N2O-induced neurological damage at emergency departments confirms the urgency of this development [9,20,21].
In some recreational N2O users, N2O abuse and/or dependence seems to develop with craving, a loss of control and continued use despite social and/or physical damage. Obviously, psychosocial factors are important factors in the development of excessive N2O use, abuse and dependence [6]. For instance, among young non-Western Muslim immigrants, marginalization, boredom, unemployment, deteriorated social interactions, social isolation, macho behaviour, shame and distrust of the Dutch medical system appeared to be important drivers of N2O abuse [6]. In addition, the recent introduction and availability of larger tanks or ‘smart whip’ cylinders, containing 0.6–10 kg of N2O, have certainly facilitated higher repeated N2O dosing and N2O abuse in the Netherlands [8] and France [22]. Others, such as those in France or China, claim that N2O abuse has increased during the COVID-19 pandemic due to boredom as a result of the lock-downs [12,18,23], although evidence for this claim is rather weak.
Whereas there have been many case reports, some case-series and a number of reviews about N2O intoxication and its supposed mechanisms, relatively few studies have been conducted on the dependence potential of N2O. Additionally, there seems to be some controversy about the mechanisms by which N2O might induce abuse (binge use) or dependence, as was recently illustrated by an article of Kamboj et al. [24], showing that N2O rewarding effects are mainly mediated through the blockade of the N-methyl-D-aspartate (NMDA) receptors by N2O. This was followed by a comment in the same journal by Gillman [25], who has done pioneering work on the neuropsychological mechanisms of action of N2O in the past, stipulating that N2O’s actions were more likely due to its ability to interact with the opioid system. Therefore, in this review, we will give an overview of the animal and human evidence on the mechanisms of action involved in N2O-induced neurotoxicity, which may arise from N2O-induced abuse/dependence (frequent and prolonged use), two issues that were never combined in previous reviews.

2. Neurotoxicity of N2O

2.1. Acute Neurotoxicity

In a meta-analysis on hospitalized cases presented after N2O exposure, the most frequent clinical symptoms were paresthesia (80%), unsteady gait (58%) and limb weakness (43%) [17]. Similar clinical symptoms were reported by other (clinical) studies, as well as paraplegia, numbness and vestibular problems [8,26,27]. In a global drug user survey, alongside these clinical symptoms, mental symptoms were reported, such as hallucinations and confusion [28]. When used sporadically, about 3% of the users reported paresthesia [26,27,29].

2.2. Chronic Neurotoxicity

The chronic use of N2O has been associated with serious consequences, such as peripheral neuropathy, myelopathy and demyelizing diseases, collectively referred to as generalized demyelinating polyneuropathy (GDP) [17]. This is expressed in clinical symptoms such as muscle weakness, vestibular disturbances and paralysis [30]. Recent MRI studies showed the progressive degeneration of the spinal cord in N2O users [31]. A correlation was found between the extent of N2O use (in whippets or balloons) and the degree of myelopathy and GDP [32], and most chronic users (mean: 300 balloons/day for 6 months) displayed signs of neuropathy. Cobalamin deficiency in patients with GDP has been a common finding in a number of studies [16,17,27], and cobalamin (vitamin B12) supplementation induces substantial neurological improvement or even recovery in most patients [27]. Nonetheless, some of these patients will only partly recover, with persistent neuropathies, such as paresthesia’s, limb weakness and/or partial paralysis, and are therefore in continuous need of medical devices [14,33]. Furthermore, chronic N2O use has been associated with psychiatric symptoms, such as anxiety, depression, neurocognitive deficits and delirium [15]. However, these psychiatric symptoms did not seem to result from cobalamin deficiency [34].

3. The Molecular Mechanisms behind N2O Neurotoxicity

Although cobalamin has been found to be decreased in chronic N2O users with neurological damage, this is not always the case, making it unlikely that vitamin B12 deficiency is the only cause of neurological damage. In fact, many studies in chronic N2O users did not find a correlation between cobalamin levels and neurological damage [14,26,31]. In fact, elevated serum levels of homocysteine and methylmalonate (methylmalonic acid) were better biomarkers for the neurological damage after prolonged N2O exposure [14,16,26]. This raises the issue of which metabolomic mechanisms are exactly involved in N2O-induced toxicity.
At the core of the neurological damage associated with chronic N2O use lies a disturbance of cobalamin metabolism [35]. Cobalamin functions as an essential co-factor in the regeneration of methionine and the formation of tetrahydrofolate, which is involved in biosynthetic pathways of nucleic acid and amino acid metabolism [36,37]. N2O induces irreversible oxidation of the cobalt-ion in cobalamin, whereby it no longer functions, as the co-factor methylcobalamin, in the enzymatic formation of methionine and tetrahydrofolate. DNA/RNA/protein methylation by methionine is an essential step in the production of phospholipids of the myelin sheath [38]. Disrupted DNA/RNA methylation by decreased levels of methionine, through the oxidation of cobalamin by N2O, has been implicated in many neurodegenerative disorders [39,40]. A grieve medical condition that has been ascribed to N2O exposure is subacute combined degeneration, which is characterized by the degeneration of the spinal cord columns due to demyelination, presented through paresthesia, weakness, ataxia, gait disturbance and, if untreated, paraplegia [33,41]. This is caused by the accumulation in the myelin sheath of other substrates of cobalamin, such as methylmalonate [42]. Animal studies found that methylmalonate accumulation (methylmalonate aciduria) is neurotoxic [43,44]. Methylmalonic aciduria in rat striatal neurons resulted in the inhibition of respiratory chain complex II, the tricarboxylic acid cycle, toxic organic acids and synergistic secondary excitotoxic mechanisms [45,46]. Methylmalonate is a precursor in the biochemical conversion of methylmalonyl-CoA to succinyl-CoA by methylmalonyl-CoA mutase, and this conversion is blocked by the oxidation of cobalamin by nitrous oxide. A schematic overview of some of the main toxic mechanisms of N2O is depicted in Figure 1.
Whereas these factors are proposed to be at the center of N2O neurotoxicity, other contributing factors have also been proposed. Homocysteine, which accumulates under chronic N2O exposure, can be neurotoxic, causing the overstimulation of N-methyl-D-aspartate (NMDA) receptors, leading to an increase in cytoplasmic calcium ions and the accumulation of reactive oxygen species (oxidative stress), causing apoptosis [47,48]. N2O itself is a noncompetitive antagonist of the NMDA receptor, which would result in a neuroprotective effect, but this may only be on the short term [49,50]. A prolonged blockade by N2O might result in neuronal vacuolation [11]. Disrupted methylation, by the oxidation of cobalamin, has also been linked to the deleterious functioning of the immune system by a reduced proliferation of lymphocytes on one hand and cobalamin’s direct effects on cytokines and growth factors on the other [36,51].
Taken together, (frequent) exposure to N2O leads to the inactivation of cobalamin, the blockade of NMDA receptors and a cascade of metabolic effects that all contribute to neurotoxicity, which is responsible for the adverse events observed in the clinical practice, such as spinal cord degeneration.

4. From Incidental Use to N2O Abuse (Binging)

When looking at N2O’s harmful effects, it seems that there is a great disparity between incidental N2O exposure and prolonged N2O exposure in its propensity to generate toxic effects [7,8]. This raises the issue of whether N2O can induce a pattern of frequent use, binging, abuse or even dependence. Several studies have tried to resolve this issue throughout the years; efforts have been undertaken to explain the abuse/dependence potential of N2O. We will discuss this below.

5. Dependence Liability

5.1. Human Data

The abuse and dependence liability of N2O is a currently underexposed and poorly investigated topic. N2O is often used repetitively in one session, mainly due to its short half-life of approximately 5 min [52]. However, highly frequent sessions of N2O use with a longer duration (several hours to all day with 150–700 10 mL bullets used daily) for several days have also been described, suggesting that N2O may have a dependence potential [11,14,29]. Interestingly, anecdotal evidence (Sebastiaan Verboeket, Jellinek Addiction Clinic, The Netherlands, personal communication) indicates that N2O abusers are more or less binging N2O, i.e., they heavily use N2O for 3–5 days (mostly using 2 kg tanks), refrain from using N2O for 3–6 weeks and restart heavy N2O use for some days again. Moreover, some users maintain such high dosing despite N2O-related physical harm, which is another hallmark of dependence. Unlike with other substances of abuse, N2O abuse does not cause direct physical withdrawal symptoms upon the acute cessation of N2O use [53]. For this reason, N2O and other short-lived inhalants were originally classified as a separate group of abused substances without a dependence potential [54], mainly because N2O does not cause withdrawal symptoms, which is typical for substances of dependence. In the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), N2O use disorder was categorized under “other substance use disorders” [55], indicating that it is not a substance of dependence.
However, N2O is regarded as a substance of dependence by some [56,57], despite the fact that the evidence for this is not unambiguous. For instance, human volunteers did not favor the inhalation of N2O (in concentrations ranging from 20–80%) over oxygen [58,59], indicating a lack of reinforcement effects (craving) of N2O, and both brief and extended exposures to N2O yielded the same results. In a more recent study based on the information of 59 subjects who had used N2O in larger quantities and for longer than intended, Fidalgo et al. [60] identified, in 2019, an ‘N2O use disorder’ according DSM-5 criteria and suggested that N2O has a low degree of dependence potential. Their data suggest just a mild substance use disorder (SUD), as only two to three DSM-5 criteria were met. Whereas N2O lacks reinforcing effects in humans, tolerance for its analgesic effects was found [61].
Finally, it appeared that N2O, at subanaesthetic concentrations, acts as an opioid receptor agonist [25]. Interestingly, naltrexone, an opioid receptor antagonist which is used for treating opioid and alcohol dependence, was reported to be an effective treatment in a case of N2O abuse [62]. Interestingly, naltrexone also was proven effective in a case of ketamine dependence, a substance with similar anaesthetic applications as N2O [63]. However, being a partial opioid agonist (see below), it has, by definition, a lower dependence liability than full opioid agonists, such as morphine or heroin. Recreational N2O use is routinely practiced at subanaesthetic doses, i.e., users remain fully conscious, indicating that the possible dependence potential of N2O might be linked to the opioid receptor agonism.
Summarizing the human evidence, N2O does not seem to fulfil the traditional criteria for a substance of dependence, as it is not associated with withdrawal and lacks reinforcing effects in clinical human studies. However, tolerance for its effects occurs, and the abuse potential for N2O was shown, with 2 to 3 criteria of the definition of a substance of dependence being met, indicative of a mild N2O use disorder, which would be a more appropriate term.

5.2. Animal Studies

So far, there are limited animal studies (e.g., self-administration, drug discrimination) about compulsive N2O use or N2O abuse/dependence. Typical for addictive substances is that they show self-administration, induce tolerance and show withdrawal upon the acute cessation of heavy use.
To begin with, self-administration studies in animals may give evidence for reinforcing properties of a substance. However, conflicting results have been obtained in such studies following the administration of N2O. In one conditioned place preference study in rats, N2O failed to induce reinforcement [64]. In another study, the intracranial self-stimulation of N2O in mice showed a mild reinforcing effect [65]. In squirrel monkeys, N2O could be self-administered by pressing a key, which showed a progressive administration ratio in comparison to controls [66], indicating that nitrous oxide can function as a reinforcer.
Tolerance for the effects of a drug is another criterium of a substance of dependence. In animal and human studies, tolerance for the analgesic effects of N2O was proven [61,67], which is some evidence for N2O being a substance of dependence. Furthermore, tolerance was also shown in a study on N2O-induced locomotion and visual-evoked potentials (VEP) in rats [68]. Withdrawal is another criterion needed for physical dependence. As such, the acute cessation of chronic exposure to N2O is expected to elicit in signs of withdrawal such as excitation, psychomotor stimulation, convulsions and hypertension. Indeed, during N2O withdrawal, mice convulsed when gently lifted by the tip of the tail [69,70]. For instance, the cessation of the exposure of mice to nitrous oxide (at 50, 65 and 80% for 34 or 68 h) resulted in characteristic dose- and exposure time-dependent convulsions very similar to those seen in alcohol-dependent mice upon withdrawal. Convulsions were maximal within 2–3 min after the cessation of N2O use and declined over 6 h [71]. Other studies found stress in rats during N2O withdrawal, which was linked to decreases in beta-endorphin [72], and N2O exposure blocked morphine-induced conditioned place preference [73].
Taken together, animal studies show contrasting evidence for a dependence potential of N2O. It has some degree of tolerance and withdrawal but only a low reinforcing activity. Given these uncertainties, it remains dubious as to whether N2O is a typical addictive substance.

6. Molecular Mechanisms of N2O Abuse and Dependence

As proposed and further elaborated by the group of Gilman, N2O exerts its analgesic actions via interaction with the opioid system [25,74,75]. N2O activates opioid neurons in the brainstem, relieving pain throughout the central nervous system [76]. Endogenous opioid activation in the brainstem inhibits gamma-aminobutyric acid (GABA)-releasing neurons, in turn activating descending noradrenergic pathways that inhibit pain [52,56,57,75,77,78,79,80]. It was found that the antinociceptive effects of N2O are likewise mediated through the adrenergic α1 and α2-receptors in the spinal cord [76].
The mechanisms by which N2O interacts with the opioid system have been under investigation for several decades. It was thought that N2O exerts its antinociceptive—and possibly also addictive—effects mainly as a partial agonist of the opioid receptors [56]. In studies that followed, the κ-opioid receptor was identified as the main target for N2O’s antinociceptive effects, as selective κ-receptor antagonists and spinal pretreatment with antiserum directed against the endogenous κ-receptor ligand dynorphin blocked N2O’s antinociceptive effects [52]. An important finding was that of the cross-tolerance to N2O of morphine-tolerant rodents [81]. This cross-tolerance was unidirectional, because morphine (and other opioids) still produced antinociception in N2O-tolerant rodents [82], meaning that the responsiveness of the opioid receptors was not altered [52]. In this regard, N2O seemed to act in more ways than merely an opioid receptor agonist, considering that N2O is able to release endogenous opioids directly from the periaqueductal area in the midbrain [75,82,83,84]. Regarding N2O’s possible potential to induce abuse or dependence, the mechanism of the release of endogenous opioids makes the most sense, as dependence is mainly mediated through the μ-opioid receptor and not the κ-opioid receptor [85].
Another mechanism of the possible addictive properties of N2O is its antagonism at the NMDA-receptor [49]. Like ketamine, another NMDA-receptor antagonist, it is used as both an anaesthetic and ketamine is a substance of abuse with a proven risk of dependence [86]. The mechanism that is proposed for the rewarding properties of these anaesthetics is that the blockade of NMDA-receptors uplifts the inhibition on dopamine neurons by GABAergic neurons, especially in the ventral tegmental area and the nucleus accumbens, creating dopamine burst firing [87,88], an effect also demonstrated in humans through brain imaging [89]. In 1983, Hynes and Berkowitz showed that haloperidol inhibited N2O-induced locomotor activity in mice and showed direct involvement of the dopaminergic system, while ten years later, the depletion of catecholamine synthesis was also reported to block N2O-induced locomotor activity [52,77]. Subsequent studies showed region-dependent effects of N2O on dopamine and/or noradrenaline levels or turnover in the brain following the exposure of rats to N2O. Thus, considering that ketamine produces strong psychotomimetic effects, it was suggested that the euphoric effects induced by N2O are (at least partly) due to the similar inhibition of NMDA receptor-mediated neural substrates [90]. There is some debate on the issue of at which levels of N2O exposure these effects occur [49], but a recent study indicates that N2O shows ketamine-like excitatory effects at subanesthetic but therapeutically relevant concentrations [91]. Figure 2 shows a schematic overview of the putative mechanisms of action of N2O on dependence and abuse.

7. Conclusions

N2O affects various biomolecular pathways that are possibly relevant to its abuse potential and thereby contribute to its neurotoxicity. However, both animal and human studies investigating whether or not N2O is actually able to induce dependence, as was also defined by the DSM-5, provided inconclusive data. Based on the available literature, a mild N2O use disorder seems to be the most appropriate term. Mechanistically, there are some modes of action that are described by which N2O could induce this abuse/mild dependence potential. N2O does seem to release opioids from the periaqueductal grey area that interact with GABAergic neurons in the midbrain, disinhibiting dopamine release. This seems like a plausible mechanism by which N2O could cause reward and craving. However, NMDA-antagonism, as another explanation, cannot be ruled out, as this also disinhibits dopamine release in the ventral tegmental area and the nucleus accumbens, similar to how another anaesthetic and recognized addictive substance, ketamine, works. Both mechanisms are not mutually exclusive and most likely reinforce each other. Previously, it was thought that NMDA-antagonism only occurred at anaesthetic levels, but recent evidence showed that this mechanism also occurs at subanaesthetic levels in recreational and frequent N2O users.
Frequent N2O abuse gradually inactivates cobalamin, with the degeneration of the spinal cord being a possible consequence, mainly through the disrupted DNA/RNA/protein methylation needed for the production of phospholipids of the myelin sheath. Cobalamin deficiency-induced homocysteine accumulation adds to the N2O-induced neurotoxicity by NMDA receptor overstimulation, and homocysteine and methylmalonic acid are the most consistent clinical biomarkers of chronic N2O abuse and intoxication. When detecting early signs of N2O toxicity (such as paraesthesia and numbness), this calls for systematic screening for those biomarkers when considering N2O-related toxicity or abuse/dependence, perhaps in conjuncture with a spinal cord MRI. Besides neurotoxicity, other N2O-related toxicity has also been documented, such as adverse reproduction effects in females after N2O exposure [92]. For N2O-related neurotoxicity, most symptoms can be reversed by vitamin B12 suppletion.
For suspected N2O-related substance use disorder, current state-of-the-art dependence therapy can be offered, possibly with special attention to non-Western immigrants [6]. Furthermore, opioid antagonism can be considered, as naltrexone therapy proved effective in a case of N2O dependence. In accordance, patients displaying early symptoms of N2O toxicity should be educated by physicians and addiction professionals about the potentially dangerous consequences of prolonged heavy N2O use to prevent further, irreversible harm and emerging N2O use disorders.

Author Contributions

Conceptualization. T.M.B. and J.v.A.; methodology, T.M.B.; software, T.M.B.; validation, J.v.A.; formal analysis, T.M.B.; investigation, T.M.B. and J.v.A.; resources, W.v.d.B.; data curation, T.M.B.; writing—original draft preparation, T.M.B.; writing—review and editing, J.v.A. and W.v.d.B.; visualization, T.M.B.; supervision, J.v.A.; project administration, T.M.B.; funding acquisition, T.M.B. All authors have read and agreed to the published version of the manuscript.


This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.


  1. Van Amsterdam, J.G.C.; Nabben, T.; van den Brink, W. Increasing Recreational Nitrous Oxide Use: Should We Worry? A Narrative Review. J. Psychopharmacol. 2022, 36, 943–950. [Google Scholar] [CrossRef] [PubMed]
  2. Global Drug Survey. Global Drug Survey 2019 Executive Summary. Available online: (accessed on 16 August 2022).
  3. Office for National Statistics. Drug Misuse in England and Wales: Year Ending March 2020. Available online: (accessed on 12 July 2021).
  4. Forrester, M. Nitrous Oxide Misuse Reported to Two United States Data Systems during 2000–2019. J. Addict. Dis. 2021, 39, 46–53. [Google Scholar] [CrossRef]
  5. Perino, J.; Tournier, M.; Mathieu, C.; Letinier, L.; Peyré, A.; Perret, G.; Pereira, E.; Fourrier-Réglat, A.; Pollet, C.; Fatseas, M.; et al. Psychoactive Substance Use among Students: A Cross-Sectional Analysis. Fundam. Clin. Pharmacol. 2022, 36, 908–914. [Google Scholar] [CrossRef]
  6. Nabben, T.; Weijs, J.; van Amsterdam, J. Problematic Use of Nitrous Oxide by Young Moroccan-Dutch Adults. Int. J. Environ. Res. Public Health 2021, 18, 5574. [Google Scholar] [CrossRef]
  7. van Amsterdam, J.; Nabben, T.; van den Brink, W. Recreational Nitrous Oxide Use: Prevalence and Risks. Regul. Toxicol. Pharmacol. 2015, 73, 790–796. [Google Scholar] [CrossRef] [PubMed]
  8. van Riel, A.J.H.P.; Hunault, C.C.; van den Hengel-Koot, I.S.; Nugteren-van Lonkhuyzen, J.J.; de Lange, D.W.; Hondebrink, L. Alarming Increase in Poisonings from Recreational Nitrous Oxide Use after a Change in EU-Legislation, Inquiries to the Dutch Poisons Information Center. Int. J. Drug Policy 2022, 100, 103519. [Google Scholar] [CrossRef]
  9. Bethmont, A.; Harper, C.; Chan, B.; Dawson, A.; McAnulty, J. Increasing Illicit Use of Nitrous Oxide in Presentations to NSW Emergency Departments. Med. J. Aust. 2019, 211, 429–429.e1. [Google Scholar] [CrossRef] [PubMed]
  10. Redmond, J.; Cruse, B.; Kiers, L. Nitrous Oxide-Induced Neurological Disorders: An Increasing Public Health Concern. Intern. Med. J. 2022, 52, 740–744. [Google Scholar] [CrossRef] [PubMed]
  11. Xiang, Y.; Li, L.; Ma, X.; Li, S.; Xue, Y.; Yan, P.; Chen, M.; Wu, J. Recreational Nitrous Oxide Abuse: Prevalence, Neurotoxicity, and Treatment. Neurotox. Res. 2021, 39, 975–985. [Google Scholar] [CrossRef] [PubMed]
  12. Dufayet, L.; Caré, W.; Laborde-Casterot, H.; Chouachi, L.; Langrand, J.; Vodovar, D. Possible Impact of the COVID-19 Pandemic on the Recreational Use of Nitrous Oxide in the Paris Area, France. Rev. Med. Interne 2022, 43, 402–405. [Google Scholar] [CrossRef] [PubMed]
  13. Marcus, E. Nitrous Nation: A Party Drug Endures. The New York Times, 30 January 2021; 1–6. [Google Scholar]
  14. Swart, G.; Blair, C.; Lu, Z.; Yogendran, S.; Offord, J.; Sutherland, E.; Barnes, S.; Palavra, N.; Cremer, P.; Bolitho, S.; et al. Nitrous Oxide-Induced Myeloneuropathy. Eur. J. Neurol. 2021, 28, 3938–3944. [Google Scholar] [CrossRef] [PubMed]
  15. Garakani, A.; Jaffe, R.J.; Savla, D.; Welch, A.K.; Protin, C.A.; Bryson, E.O.; McDowell, D.M. Neurologic, Psychiatric, and Other Medical Manifestations of Nitrous Oxide Abuse: A Systematic Review of the Case Literature. Am. J. Addict. 2016, 25, 358–369. [Google Scholar] [CrossRef]
  16. Marsden, P.; Sharma, A.A.; Rotella, J.A. Review Article: Clinical Manifestations and Outcomes of Chronic Nitrous Oxide Misuse: A Systematic Review. Emerg. Med. Australas. 2022, 34, 492–503. [Google Scholar] [CrossRef] [PubMed]
  17. Oussalah, A.; Julien, M.; Levy, J.; Hajjar, O.; Franczak, C.; Stephan, C.; Laugel, E.; Wandzel, M.; Filhine-Tresarrieu, P.; Green, R.; et al. Global Burden Related to Nitrous Oxide Exposure in Medical and Recreational Settings: A Systematic Review and Individual Patient Data Meta-Analysis. J. Clin. Med. 2019, 8, 551. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  18. Vollhardt, R.; Mazoyer, J.; Bernardaud, L.; Haddad, A.; Jaubert, P.; Coman, I.; Manceau, P.; Mongin, M.; Degos, B. Neurological Consequences of Recreational Nitrous Oxide Abuse during SARS-CoV-2 Pandemic. J. Neurol. 2022, 269, 1921–1926. [Google Scholar] [CrossRef] [PubMed]
  19. Yu, M.; Qiao, Y.; Li, W.; Fang, X.; Gao, H.; Zheng, D.; Ma, Y. Analysis of Clinical Characteristics and Prognostic Factors in 110 Patients with Nitrous Oxide Abuse. Brain Behav. 2022, 12, e2533. [Google Scholar] [CrossRef]
  20. ANSES. Nitrous Oxide Poisoning on the Increase; ANSES: Maisons-Alfort, France, 2021. [Google Scholar]
  21. Lin, J.P.; Gao, S.Y.; Lin, C.C. The Clinical Presentations of Nitrous Oxide Users in an Emergency Department. Toxics 2022, 10, 112. [Google Scholar] [CrossRef]
  22. Micallef, J.; Mallaret, M.; Lapeyre-Mestre, M.; Daveluy, A.; Victorri-Vigneau, C.; Peyrière, H.; Debruyne, D.; Deheul, S.; Bordet, R.; Chevallier, C.; et al. Warning on Increased Serious Health Complications Related to Non-Medical Use of Nitrous Oxide. Therapie 2021, 76, 478–479. [Google Scholar] [CrossRef]
  23. Wu, G.; Wang, S.; Wang, T.; Han, J.; Yu, A.; Feng, C.; Wang, Y.; Liu, S. Neurological and Psychological Characteristics of Young Nitrous Oxide Abusers and Its Underlying Causes During the COVID-19 Lockdown. Front. Public Health 2022, 10, 854977. [Google Scholar] [CrossRef]
  24. Kamboj, S.K.; Zhao, H.; Troebinger, L.; Piazza, G.; Cawley, E.; Hennessy, V.; Iskandar, G.; Das, R.K. Rewarding Subjective Effects of the NMDAR Antagonist Nitrous Oxide (Laughing Gas) Are Moderated by Impulsivity and Depressive Symptoms in Healthy Volunteers. Int. J. Neuropsychopharmacol. 2021, 24, 551–561. [Google Scholar] [CrossRef] [PubMed]
  25. Gillman, M.A. Opioid Properties of Nitrous Oxide and Ketamine Contribute to Their Antidepressant Actions. Int. J. Neuropsychopharmacol. 2021, 24, 892–893. [Google Scholar] [CrossRef] [PubMed]
  26. Einsiedler, M.; Voulleminot, P.; Demuth, S.; Kalaaji, P.; Bogdan, T.; Gauer, L.; Reschwein, C.; Nadaj-Pakleza, A.; de Sèze, J.; Kremer, L.; et al. A Rise in Cases of Nitrous Oxide Abuse: Neurological Complications and Biological Findings. J. Neurol. 2021, 269, 577–582. [Google Scholar] [CrossRef] [PubMed]
  27. Zheng, D.; Ba, F.; Bi, G.; Guo, Y.; Gao, Y.; Li, W. The Sharp Rise of Neurological Disorders Associated with Recreational Nitrous Oxide Use in China: A Single-Center Experience and a Brief Review of Chinese Literature. J. Neurol. 2020, 267, 422–429. [Google Scholar] [CrossRef]
  28. Winstock, A.; Ferris, J. Nitrous Oxide Causes Peripheral Neuropathy in a Dose Dependent Manner among Recreational Users. J. Psychopharmacol. 2020, 34, 229–236. [Google Scholar] [CrossRef]
  29. Kaar, S.J.; Ferris, J.; Waldron, J.; Devaney, M.; Ramsey, J.; Winstock, A.R. Up: The Rise of Nitrous Oxide Abuse. An International Survey of Contemporary Nitrous Oxide Use. J. Psychopharmacol. 2016, 30, 395–401. [Google Scholar] [CrossRef]
  30. Patel, K.K.; Mejia Munne, J.C.; Gunness, V.R.N.; Hersey, D.; Alshafai, N.; Sciubba, D.; Nasser, R.; Gimbel, D.; Cheng, J.; Nouri, A. Subacute Combined Degeneration of the Spinal Cord Following Nitrous Oxide Anesthesia: A Systematic Review of Cases. Clin. Neurol. Neurosurg. 2018, 173, 163–168. [Google Scholar] [CrossRef]
  31. Gao, H.; Li, W.; Ren, J.; Dong, X.; Ma, Y.; Zheng, D. Clinical and MRI Differences Between Patients With Subacute Combined Degeneration of the Spinal Cord Related vs. Unrelated to Recreational Nitrous Oxide Use: A Retrospective Study. Front. Neurol. 2021, 12, 626174. [Google Scholar] [CrossRef]
  32. Dang, X.T.; Nguyen, T.X.; Nguyen, T.T.H.; Ha, H.T. Nitrous Oxide-Induced Neuropathy among Recreational Users in Vietnam. Int. J. Environ. Res. Public Health 2021, 18, 6230. [Google Scholar] [CrossRef]
  33. Lan, S.Y.; Kuo, C.Y.; Chou, C.C.; Kong, S.S.; Hung, P.C.; Tsai, H.Y.; Chen, Y.C.; Lin, J.J.; Chou, I.J.; Lin, K.L. Recreational Nitrous Oxide Abuse Related Subacute Combined Degeneration of the Spinal Cord in Adolescents—A Case Series and Literature Review. Brain Dev. 2019, 41, 428–435. [Google Scholar] [CrossRef]
  34. Paulus, M.C.; Wijnhoven, A.M.; Maessen, G.C.; Blankensteijn, S.R.; van der Heyden, M.A.G. Does Vitamin B12 Deficiency Explain Psychiatric Symptoms in Recreational Nitrous Oxide Users? A Narrative Review. Clin. Toxicol. 2021, 59, 947–955. [Google Scholar] [CrossRef] [PubMed]
  35. Stockton, L.; Simonsen, C.; Seago, S. Nitrous Oxide-Induced Vitamin B12 Deficiency. Proc. Bayl. Univ. Med. Cent. 2017, 30, 171–172. [Google Scholar] [CrossRef] [PubMed]
  36. Hathout, L.; El-Saden, S. Nitrous Oxide-Induced B₁₂ Deficiency Myelopathy: Perspectives on the Clinical Biochemistry of Vitamin B₁₂. J. Neurol. Sci. 2011, 301, 1–8. [Google Scholar] [CrossRef] [PubMed]
  37. Toohey, J.I. Vitamin B12 and Methionine Synthesis: A Critical Review. Is Nature’s Most Beautiful Cofactor Misunderstood? Biofactors 2006, 26, 45–57. [Google Scholar] [CrossRef]
  38. Richardson, P.G. Peripheral Neuropathy Following Nitrous Oxide Abuse. Emerg. Med. Australas. 2010, 22, 88–90. [Google Scholar] [CrossRef]
  39. Landgrave-Gómez, J.; Mercado-Gómez, O.; Guevara-Guzmán, R. Epigenetic Mechanisms in Neurological and Neurodegenerative Diseases. Front. Cell. Neurosci. 2015, 9, 58. [Google Scholar] [CrossRef] [Green Version]
  40. Miller, A.; Korem, M.; Almog, R.; Galboiz, Y. Vitamin B12, Demyelination, Remyelination and Repair in Multiple Sclerosis. J. Neurol. Sci. 2005, 233, 93–97. [Google Scholar] [CrossRef]
  41. Yoon, J.Y.; Klein, J.P. Subacute Combined Degeneration from Nitrous Oxide Use. N. Engl. J. Med. 2022, 387, 832. [Google Scholar] [CrossRef]
  42. Check, L.; Abdelsayed, N.; Figueroa, G.; Ragunathan, A.; Faris, M. Subacute Combined Degeneration of the Cervical Spine Secondary to Inhaled Nitrous-Oxide-Induced Cobalamin Deficiency. Cureus 2022, 14, e21214. [Google Scholar] [CrossRef]
  43. Narasimhan, P.; Sklar, R.; Murrell, M.; Swanson, R.A.; Sharp, F.R. Methylmalonyl-CoA Mutase Induction by Cerebral Ischemia and Neurotoxicity of the Mitochondrial Toxin Methylmalonic Acid. J. Neurosci. 1996, 16, 7336–7346. [Google Scholar] [CrossRef] [Green Version]
  44. Fernandes, C.G.; Borges, C.G.; Seminotti, B.; Amaral, A.U.; Knebel, L.A.; Eichler, P.; De Oliveira, A.B.; Leipnitz, G.; Wajner, M. Experimental Evidence That Methylmalonic Acid Provokes Oxidative Damage and Compromises Antioxidant Defenses in Nerve Terminal and Striatum of Young Rats. Cell. Mol. Neurobiol. 2011, 31, 775–785. [Google Scholar] [CrossRef] [PubMed]
  45. Okun, J.G.; Hörster, F.; Farkas, L.M.; Feyh, P.; Hinz, A.; Sauer, S.; Hoffmann, G.F.; Unsicker, K.; Mayatepek, E.; Kölker, S. Neurodegeneration in Methylmalonic Aciduria Involves Inhibition of Complex II and the Tricarboxylic Acid Cycle, and Synergistically Acting Excitotoxicity. J. Biol. Chem. 2002, 277, 14674–14680. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  46. Savage, S.; Ma, D. The Neurotoxicity of Nitrous Oxide: The Facts and “Putative” Mechanisms. Brain Sci. 2014, 4, 73–90. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  47. Abushik, P.A.; Niittykoski, M.; Giniatullina, R.; Shakirzyanova, A.; Bart, G.; Fayuk, D.; Sibarov, D.A.; Antonov, S.M.; Giniatullin, R. The Role of NMDA and MGluR5 Receptors in Calcium Mobilization and Neurotoxicity of Homocysteine in Trigeminal and Cortical Neurons and Glial Cells. J. Neurochem. 2014, 129, 264–274. [Google Scholar] [CrossRef]
  48. Oomens, T.; Riezebos, R.K.; Amoroso, G.; Kuipers, R.S. Case Report of an Acute Myocardial Infarction after High-Dose Recreational Nitrous Oxide Use: A Consequence of Hyperhomocysteinaemia? Eur. Heart J. Case Rep. 2021, 5, ytaa557. [Google Scholar] [CrossRef]
  49. Jevtović-Todorović, V.; Todorović, S.M.; Mennerick, S.; Powell, S.; Dikranian, K.; Benshoff, N.; Zorumski, C.F.; Olney, J.W. Nitrous Oxide (Laughing Gas) Is an NMDA Antagonist, Neuroprotectant and Neurotoxin. Nat. Med. 1998, 4, 460–463. [Google Scholar] [CrossRef] [PubMed]
  50. Abraini, J.H.; David, H.N.; Lemaire, M. Potentially Neuroprotective and Therapeutic Properties of Nitrous Oxide and Xenon. Ann. N. Y. Acad. Sci. 2005, 1053, 289–300. [Google Scholar] [CrossRef]
  51. Mohsenzadegan, M.; Kourosh Arami, M.; Oshaghi, M.; Sedigh Maroufi, S. A Review of the Effects of the Anesthetic Gas Nitrous Oxide on the Immune System; a Starting Point for Future Experiences. Immunopharmacol. Immunotoxicol. 2020, 42, 179–186. [Google Scholar] [CrossRef]
  52. Emmanouil, D.E.; Quock, R.M. Advances in Understanding the Actions of Nitrous Oxide. Anesth. Prog. 2007, 54, 9–18. [Google Scholar] [CrossRef] [Green Version]
  53. Malamed, S.F.; Clark, M.S. Nitrous Oxide-Oxygen: A New Look at a Very Old Technique. J. Calif. Dent. Assoc. 2003, 31, 397–403. [Google Scholar]
  54. Balster, R.L.; Cruz, S.L.; Howard, M.O.; Dell, C.A.; Cottler, L.B. Classification of Abused Inhalants. Addiction 2009, 104, 878–882. [Google Scholar] [CrossRef]
  55. APA (American Psychiatric Association). Diagnostic and Statistical Manual of Mental Disorders, 5th ed.; American Psychiatric Publishing: Washington, DC, USA, 2013. [Google Scholar]
  56. Gillman, M.A. Nitrous Oxide, an Opioid Addictive Agent. Review of the Evidence. Am. J. Med. 1986, 81, 97–102. [Google Scholar] [CrossRef]
  57. Gillman, M.A.; Lichtigfeld, F.J. Pharmacology of Psychotropic Analgesic Nitrous Oxide as a Multipotent Opioid Agonist. Int. J. Neurosci. 1994, 76, 5–12. [Google Scholar] [CrossRef]
  58. Zacny, J.P.; Klafta, J.M.; Coalson, D.W.; Marks, S.; Young, C.J.; Klock, P.A.; Toledano, A.Y.; Jordan, N.; Apfelbaum, J.L. The Reinforcing Effects of Brief Exposures to Nitrous Oxide in Healthy Volunteers. Drug Alcohol Depend. 1996, 42, 197–200. [Google Scholar] [CrossRef]
  59. Dohrn, C.S.; Lichtor, J.L.; Coalson, D.W.; Flemming, D.; Zacny, J.P. Reinforcing Effects of Extended Inhalation of a Low Nitrous Oxide Concentration in Humans. Pharmacol. Biochem. Behav. 1993, 46, 927–932. [Google Scholar] [CrossRef]
  60. Fidalgo, M.; Prud’homme, T.; Allio, A.; Bronnec, M.; Bulteau, S.; Jolliet, P.; Victorri-Vigneau, C. Nitrous Oxide: What Do We Know about Its Use Disorder Potential? Results of the French Monitoring Centre for Addiction Network Survey and Literature Review. Subst. Abus. 2019, 40, 33–42. [Google Scholar] [CrossRef]
  61. Ramsay, D.S.; Leroux, B.G.; Rothen, M.; Prall, C.W.; Fiset, L.O.; Woods, S.C. Nitrous Oxide Analgesia in Humans: Acute and Chronic Tolerance. Pain 2005, 114, 19–28. [Google Scholar] [CrossRef] [Green Version]
  62. Ickowicz, S.; Brar, R.; Nolan, S. Case Study: Naltrexone for the Treatment of Nitrous Oxide Use. J. Addict. Med. 2020, 14, e277–e279. [Google Scholar] [CrossRef]
  63. Garg, A.; Sinha, P.; Kumar, P.; Prakash, O. Use of Naltrexone in Ketamine Dependence. Addict. Behav. 2014, 39, 1215–1216. [Google Scholar] [CrossRef]
  64. Ramsay, D.S.; Watson, C.H.; Leroux, B.G.; Prall, C.W.; Kaiyala, K.J. Conditioned Place Aversion and Self-Administration of Nitrous Oxide in Rats. Pharmacol. Biochem. Behav. 2003, 74, 623–633. [Google Scholar] [CrossRef]
  65. Tracy, M.E.; Slavova-Hernandez, G.G.; Shelton, K.L. Assessment of Reinforcement Enhancing Effects of Toluene Vapor and Nitrous Oxide in Intracranial Self-Stimulation. Psychopharmacology 2014, 231, 1339–1350. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  66. Wood, R.W.; Grubman, J.; Weiss, B. Nitrous Oxide Self-Administration by the Squirrel Monkey. J. Pharmacol. Exp. Ther. 1977, 202, 491–499. [Google Scholar] [PubMed]
  67. Rupreht, J.; Ukponmwan, O.E.; Dworacek, B.; Admiraal, P.V.; Dzoljic, M.R. Enkephalinase Inhibition Prevented Tolerance to Nitrous Oxide Analgesia in Rats. Acta Anaesthesiol. Scand. 1984, 28, 617–620. [Google Scholar] [CrossRef] [PubMed]
  68. Dzoljic, M.; Rupreht, J.; Erdmann, W.; Stijnen, T.H.; van Briemen, L.J.; Dzoljic, M.R. Behavioral and Electrophysiological Aspects of Nitrous Oxide Dependence. Brain Res. Bull. 1994, 33, 25–31. [Google Scholar] [CrossRef] [PubMed]
  69. Harper, M.H.; Winter, P.M.; Johnson, B.H.; Koblin, D.D.; Eger IInd, E.I. Withdrawal Convulsions in Mice Following Nitrous Oxide. Anesth. Analg. 1980, 59, 19–21. [Google Scholar] [CrossRef]
  70. Rupreht, J.; Dworacek, B.; Ducardus, R.; Schmitz, P.I.; Dzoljic, M.R. The Involvement of the Central Cholinergic and Endorphinergic Systems in the Nitrous Oxide Withdrawal Syndrome in Mice. Anesthesiology 1983, 58, 524–526. [Google Scholar] [CrossRef]
  71. Milne, B.; Cervenko, F.W.; Jhamandas, K.H. Physical Dependence on Nitrous Oxide in Mice: Resemblance to Alcohol but Not to Opiate Withdrawal. Can. Anaesth. Soc. J. 1981, 28, 46–50. [Google Scholar] [CrossRef] [Green Version]
  72. Dzoljic, M.R.; Haffmans, J.; Rupreht, J.; Adolfs, M.J.P.; Dzoljic, M.M.; Cappendijk, S.L.T. Decrease of Beta-Endorphin in the Brain of Rats Following Nitrous Oxide Withdrawal. Drug Metabol. Drug Interact. 1991, 9, 139–148. [Google Scholar] [CrossRef]
  73. Benturquia, N.; Le Marec, T.; Scherrmann, J.M.; Noble, F. Effects of Nitrous Oxide on Dopamine Release in the Rat Nucleus Accumbens and Expectation of Reward. Neuroscience 2008, 155, 341–344. [Google Scholar] [CrossRef] [Green Version]
  74. Gillman, M.A. Analgesic (Sub Anesthetic) Nitrous Oxide Interacts with the Endogenous Opiod System: A Review of the Evidence. Life Sci. 1986, 39, 1209–1221. [Google Scholar] [CrossRef]
  75. Gillman, M.A.; Lichtigfeld, F.J. Opioid Properties of Psychotropic Analgesic Nitrous Oxide (Laughing Gas). Perspect. Biol. Med. 1994, 38, 125–138. [Google Scholar] [CrossRef] [PubMed]
  76. Maze, M.; Sanders, R.D.; Weimann, J. Biologic Effects of Nitrous Oxide: A Mechanistic and Toxicologic Review. Anesthesiology 2008, 109, 707–722. [Google Scholar] [CrossRef]
  77. Maze, M.; Fujinaga, M. Recent Advances in Understanding the Actions and Toxicity of Nitrous Oxide. Anaesthesia 2000, 55, 311–314. [Google Scholar] [CrossRef]
  78. Smith, D.J.; Bouchal, R.L.; DeSanctis, C.A.; Monroe, P.J.; Amedro, J.B.; Perrotti, J.M.; Crisp, T. Properties of the Interaction between Ketamine and Opiate Binding Sites in Vivo and in Vitro. Neuropharmacology 1987, 26, 1253–1260. [Google Scholar] [CrossRef]
  79. Smith, P.B.; Welch, S.P.; Martin, B.R. Interactions between Δ9-Tetrahydrocannabinol and Kappa Opioids in Mice. J. Pharmacol. Exp. Ther. 1994, 268, 1381–1387. [Google Scholar]
  80. Hynes, M.D.; Berkowitz, B.A. Catecholamine Mechanisms in the Stimulation of Mouse Locomotor Activity by Nitrous Oxide and Morphine. Eur. J. Pharmacol. 1983, 90, 109–114. [Google Scholar] [CrossRef]
  81. Berkowitz, B.A.; Finck, A.D.; Hynes, M.D.; Ngai, S.H. Tolerance to Nitrous Oxide Analgesia in Rats and Mice. Anesthesiology 1979, 51, 309–312. [Google Scholar] [CrossRef]
  82. Emmanouil, D.E.; Dickens, A.S.; Heckert, R.W.; Ohgami, Y.; Chung, E.; Han, S.; Quock, R.M. Nitrous Oxide-Antinociception Is Mediated by Opioid Receptors and Nitric Oxide in the Periaqueductal Gray Region of the Midbrain. Eur. Neuropsychopharmacol. 2008, 18, 194–199. [Google Scholar] [CrossRef] [Green Version]
  83. Quock, R.M.; Kouchich, F.J.; Liang-Fu, T. Influence of Nitrous Oxide upon Regional Brain Levels of Methionine-Enkephalin-like Immunoreactivity in Rats. Brain Res. Bull. 1986, 16, 321–323. [Google Scholar] [CrossRef] [PubMed]
  84. Zuniga, J.R.; Joseph, S.A.; Knigge, K.M. The Effects of Nitrous Oxide on the Central Endogenous Pro-Opiomelanocortin System in the Rat. Brain Res. 1987, 420, 57–65. [Google Scholar] [CrossRef]
  85. Narita, M.; Funada, M.; Suzuki, T. Regulations of Opioid Dependence by Opioid Receptor Types. Pharmacol. Ther. 2001, 89, 1–15. [Google Scholar] [CrossRef] [PubMed]
  86. Tobias, J.D. Tolerance, Withdrawal, and Physical Dependency after Long-Term Sedation and Analgesia of Children in the Pediatric Intensive Care Unit. Crit. Care Med. 2000, 28, 2122–2132. [Google Scholar] [CrossRef] [PubMed]
  87. Kretschmer, B.D. Modulation of the Mesolimbic Dopamine System by Glutamate: Role of NMDA Receptors. J. Neurochem. 1999, 73, 839–848. [Google Scholar] [CrossRef] [PubMed]
  88. Mathé, J.M.; Nomikos, G.G.; Schilström, B.; Svensson, T.H. Non-NMDA Excitatory Amino Acid Receptors in the Ventral Tegmental Area Mediate Systemic Dizocilpine (MK-801) Induced Hyperlocomotion and Dopamine Release in the Nucleus Accumbens. J. Neurosci. Res. 1998, 51, 583–592. [Google Scholar] [CrossRef]
  89. Kegeles, L.S.; Martinez, D.; Kochan, L.D.; Hwang, D.R.; Huang, Y.; Mawlawi, O.; Suckow, R.F.; Van Heertum, R.L.; Laruelle, M. NMDA Antagonist Effects on Striatal Dopamine Release: Positron Emission Tomography Studies in Humans. Synapse 2002, 43, 19–29. [Google Scholar] [CrossRef] [PubMed]
  90. Richardson, K.J.; Shelton, K.L. N-Methyl-D-Aspartate Receptor Channel Blocker-like Discriminative Stimulus Effects of Nitrous Oxide Gas. J. Pharmacol. Exp. Ther. 2015, 352, 156–165. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  91. Izumi, Y.; Hsu, F.-F.; Conway, C.R.; Nagele, P.; Mennerick, S.J.; Zorumski, C.F. Nitrous Oxide, a Rapid Antidepressant, Has Ketamine-like Effects on Excitatory Transmission in the Adult Hippocampus. Biol. Psychiatry 2022, 92, 964–972. [Google Scholar] [CrossRef]
  92. van Amsterdam, J.; van den Brink, W. Nitrous Oxide-Induced Reproductive Risks: Should Recreational Nitrous Oxide Users Worry? J. Psychopharmacol. 2022, 36, 951–955. [Google Scholar] [CrossRef]
Figure 1. The main mechanisms involved in N2O-induced neurotoxicity. Central toxicity arises from the deactivation of the cobalt-ion at the cobalamin (vitamin B12) molecule, which leads to a cascade of neurotoxic effects.
Figure 1. The main mechanisms involved in N2O-induced neurotoxicity. Central toxicity arises from the deactivation of the cobalt-ion at the cobalamin (vitamin B12) molecule, which leads to a cascade of neurotoxic effects.
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Figure 2. The known mechanisms of action of N2O that are involved in abuse and dependence. N2O induces opioid release in the periaqueductal grey area, on the one hand, and it also acts as an N-methyl-D-aspartate (NMDA) receptor antagonist, on the other hand. Via both routes, N2O is able to inhibit gamma-aminobutyric acid (GABA) interneurons, disinhibiting dopamine (DA) release, which can cause symptoms of abuse and dependence.
Figure 2. The known mechanisms of action of N2O that are involved in abuse and dependence. N2O induces opioid release in the periaqueductal grey area, on the one hand, and it also acts as an N-methyl-D-aspartate (NMDA) receptor antagonist, on the other hand. Via both routes, N2O is able to inhibit gamma-aminobutyric acid (GABA) interneurons, disinhibiting dopamine (DA) release, which can cause symptoms of abuse and dependence.
Ijms 23 14747 g002
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Brunt, T.M.; van den Brink, W.; van Amsterdam, J. Mechanisms Involved in the Neurotoxicity and Abuse Liability of Nitrous Oxide: A Narrative Review. Int. J. Mol. Sci. 2022, 23, 14747.

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Brunt TM, van den Brink W, van Amsterdam J. Mechanisms Involved in the Neurotoxicity and Abuse Liability of Nitrous Oxide: A Narrative Review. International Journal of Molecular Sciences. 2022; 23(23):14747.

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Brunt, Tibor M., Wim van den Brink, and Jan van Amsterdam. 2022. "Mechanisms Involved in the Neurotoxicity and Abuse Liability of Nitrous Oxide: A Narrative Review" International Journal of Molecular Sciences 23, no. 23: 14747.

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