The Global Drug Survey 2019, which was conducted in more than 30 countries, revealed that nitrous oxide (N₂O) was the 10th most popular substance among the studied population (1). N₂O abuse for recreation is increasingly popular among Chinese adolescents and young adults, which leads to neurological and psychiatric complications (2). Subacute combined degeneration and peripheral neuropathy are identified as the most common neurological manifestations (3, 4). However, psychiatric and cognitive impairments caused by N₂O abuse have not received much attention, and only case reports have been reported in the literature (5, 6).

Numerous studies have demonstrated significant mental health and behavioral comorbidities among patients who are inhalant abusers. Inhalant abusers are more likely to have an episode of major depression (7) and suicidality (8) and are at an increased risk of drug abuse problems in future (9). Functional imaging has proven to be very sensitive in detecting cerebral blood flow and metabolism derangement early in the course of drug addiction (10). This work focuses on single-photon emission computed tomography (SPECT) findings in patients with neuropsychiatric symptoms caused by N₂O abuse.

N₂O is colloquially known as “hippy crack” or “laughing gas.” It is increasingly taken for recreational purposes for its euphoric and relaxing effects and hallucinogenic properties. The abuse of N₂O is a significant public health concern, which predominantly affects adolescents. Although the subacute combined degeneration of the spinal cord and peripheral neuropathy caused by N₂O abuse are gradually concerned as the most common neurological damage (3, 4), psychiatric symptoms and cognitive dysfunction caused by N₂O abuse have not received much attention (11, 12). All the patients enrolled in this study consumed large amounts of N₂O for a long time before the onset of neuropsychiatric symptoms. Their psychiatric symptoms included emotional symptoms (e.g., mania, depression, anxiety, and fear), psychotic symptoms (hallucinations and delusions), personality changes, and impulsive and aggressive behavior, in line with previous reports (13). The anxiety depression factor score was the highest in the BPRS score, which was consistent with the HAMD and HAMA scores, suggesting that the patients must have symptoms of anxiety and depression. Thinking factors (e.g., disorder of concept, exaggeration, hallucinations, and abnormal thinking content) have high factor scores, indicating that patients with positive psychotic symptoms are prominent, and affect self-awareness and ability to work and study. The lack of vitality factor scores in the BPRS scores indicates that in addition to the positive symptoms, negative symptoms are also more prominent. This is not reported in previous studies. The relationship between negative symptoms and long-term prognosis and brain function needs further follow-up.

Of the 16 patients, 15 patients and their families complained of unresponsiveness and decreased memory, and seven of them had a MoCA score < 26, indicating that there was a decline in cognitive function (e.g., memory loss, inattention, and executive function decline). Both psychiatric symptoms and cognitive dysfunction result in the decline of work and life abilities.

Chronic N₂O poisoning is related to the interference of vitamin B12, inactivates methionine synthase, interferes with myelin anabolic metabolism, and also results in the accumulation of homocysteine (14). High levels of homocysteine cause oxidative stress and mitochondrial dysfunction, leading to nerve demyelination (15). Homocysteine activates N-methyl-D-aspartate receptors on neuronal cell membranes and induces calcium ions to flow into neurons and mitochondrial calcium overload, eventually leading to neuronal necrosis and apoptosis (16). Of the 16 patients. 11 patients in this study had elevated serum homocysteine levels and only four of them had decreased levels of vitamin B12, which may be related to the nine patients who had self-medicated with methylcobalamin before their visit to our department. This result suggests that elevated serum levels of homocysteine is a more sensitive indicator than decreased serum levels of vitamin B12 for diagnosis (14).

Although the brain MRI of the patients enrolled in this study showed that the brain structure was normal, rCBF changes were different in different brain regions in this study. Local decreased or increased blood perfusion was observed in several brain regions, rather than diffuse decreased blood perfusion. The main findings were hypoperfusion in the frontal lobe and the temporal lobe, which is in accordance with the clinical manifestations of mental behavior abnormalities and cognitive functional decline caused by N₂O abuse.

Similar to ketamine, N₂O, as an NMDAR antagonist, can reduce the signaling of excitatory glutamate neurons, change the structure and function of hippocampal synapses, and cause learning and memory disorders. Short-term N₂O exposure can cause reversible vacuolation of neurons, while long-term abuse can lead to neuron death (17). Psychiatric symptoms and cognitive decline in these patients may be dominated by this injury mechanism. Therefore, it is worth further studying the changes in neurotransmitters caused by N₂O abuse and how they affect the learning and memory functions of adolescents.

In the treatment of patients with neuropsychiatric symptoms caused by N₂O abuse, in addition to supplying vitamin B12 for nerve repair, we should also perform neuropsychological testing in time to strengthen interventions for mental symptoms and enhance patient compliance, which will not only improve the prognosis of patients but also help prevent relapse (18).

Previous studies have shown that N₂O abuse may induce manic relapse in patients with mood disorders (19). The occurrence of psychiatric symptoms observed in this study is consistent with the clinical characteristics of substance-induced mental disorders, which indicate that N₂O abuse can induce mental disorders. Future studies should expand the sample size to further explore the pathogenesis and disease characteristics of N₂O-induced mental disorders.

As most of the patients reported initiation of N₂O use in late adolescence or early adulthood, which involves risks to their still developing brain (20), education about N₂O abuse is necessary to prevent impaired brain development. Follow-up and further investigation of the possible effects of N₂O on brain development in young people will lead to meaningful prevention strategies.

The limitation of our study is the small sample size. We will continue to collect cases and expand the sample size to further explore the pathogenesis of N₂O-induced neuropsychiatric damage.

This was the first study to demonstrate the obvious effect of N₂O abuse on CBF in patients with neuropsychiatric symptoms. CBF perfusion imaging is helpful in detecting the changes in rCBF in patients with N₂O abuse, thus indicating changes in local brain functional activity in an early stage.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.

The study involving human participants was approved by the Medical Ethics Committee of China–Japan Friendship Hospital. The trial number is: 2018-34-K25. Written informed consent was obtained from all the participants or his/her parents/legal representatives (for participant under 18 years old).

FL and CT: have full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. LW, FL, and CT: study concept and design and study supervision. LW, QW, MD, and XD: acquisition of data. CT, RW, and ZL: neuropsychological rating. WH: magnetic resonance imaging. LY and YZ: SPECT/CT imaging. LW, QW, and FL: analysis and interpretation of data. LW and FL: drafting of the manuscript. LW: funding acquisition. All authors critical revision of the manuscript for important intellectual content. All authors read and approved the final manuscript.

This study was supported by research grants from the First Hospital of Tsinghua, University Pilot Funds (LH-02).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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