# First episode of catatonia followed by a psychotic episode related to chronic nitrous oxide use: A case report

Tanguy Taillefer de Laportalière, Maximilien Redon, Anne Roussin, Estelle Willemet, Etienne Very, Jean Olivier, Maryse Lapeyre-mestre

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Tanguy Taillefer de Laportalière, Maximilien Redon, Anne Roussin, Estelle Willemet, Etienne Very, et al.. First episode of catatonia followed by a psychotic episode related to chronic nitrous oxide use: A case report. Drug and Alcohol Review, 2025, 44 (3), pp.908-912. 10.1111/dar.14012. hal-05524735

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# First episode of catatonia followed by a psychotic episode related to chronic nitrous oxide use: A case report

Tanguy Taillefer de Laportalière<fnref n="1" /> ID | Maximilien Redon<fnref n="2" /> | Anne Roussin<fnref n="3" /> |
Estelle Willemet<fnref n="2" /> | Etienne Very<fnref n="4" />,<fnref n="5" /> | Jean Olivier<fnref n="2" /> | Maryse Lapeyre-Mestre<fnref n="3" />

## Correspondence

Tanguy Taillefer de Laportalière,
Department of Pharmacy, Toulouse
University Hospital, Hôpital Paule de
Viguier, 330 Avenue de Grande Bretagne,
Toulouse 31300, France.

Email: tailleferdelaportaliere.t@chu-toulouse.fr

## Abstract

**Introduction:** Nitrous oxide is widely used for recreational purposes, leading to constantly increasing cases of severe use disorder. Although the scope of the deleterious consequences of nitrous oxide use is relatively well described for neurological and thromboembolic-related complications, this is not the case in the psychiatric field.

**Case Presentation:** We report the case of a 20-year-old woman who developed nitrous oxide-induced peripheral neuropathy. The patient had a history of frequent nitrous oxide use. One year later, she presented with catatonia linked to nitrous oxide use, associated with vitamin B12 deficiency and hyperhomocysteinaemia, with no apparent psychiatric causes. Nine months after the catatonic episode, she experienced a psychotic episode linked to long-term nitrous oxide use.

**Discussion and Conclusion:** To the best of our knowledge, this is the first report describing a cascade of neurologic and psychiatric complications of chronic use of nitrous oxide. Hyperhomocysteinemia caused by nitrous oxide consumption could explain the occurrence of such events. Homocysteine, methylmalonic acid, and active vitamin B12 are key biomarkers to determine the involvement of nitrous oxide in psychiatric symptoms.

## KEYWORDS

catatonia, nitrous oxide, substance-related disorders

## 1 | INTRODUCTION

Nitrous oxide (N₂O) is a central nervous system depressant gas used for its euphoric and mind-altering effects, with recreational use recently increasing worldwide [1, 2]. In 2016, Kaar et al. highlighted a global increase in the use of N₂O in recent years. Their study revealed a variable yet significant lifetime prevalence of N₂O use across different countries: 29% in the USA, 39% in the UK, 23% in Australia, and 27% in New Zealand [3]. In France, the first warning emerged in late 2019 with reports of

neurological damage (peripheral neuropathies, combined spinal cord degeneration) in young patients with N₂O use disorders characterised by heavy, continuous consumption outside a recreational context, craving and ongoing use despite negative consequences [4]. Rapidly, the number of addictovigilance reports increased, with 2.8 times more cases in 2020–2021 [2]. The massive intake, initially of several small ~8 g cartridges, then of larger “smartwhip” canisters, gradually spread in the European Union, with neurotoxic effects as the first reported symptoms of this new substance use disorder [5]. In response to rising

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

© 2025 The Author(s). *Drug and Alcohol Review* published by John Wiley & Sons Australia, Ltd on behalf of Australasian Professional Society on Alcohol and other Drugs.

<footnote n="1">¹Department of Pharmacy, Toulouse University Hospital, Toulouse, France</footnote>

<footnote n="2">²Department of Emergency, Crisis and Liaison Psychiatry, Toulouse University Hospital, Toulouse, France</footnote>

<footnote n="3">³Department of Medical and Clinical Pharmacology, Addictovigilance Centre, Toulouse University Hospital, University of Toulouse, Toulouse, France</footnote>

<footnote n="4">⁴Department of Psychiatry, Psychotherapy, and Art Therapy, Toulouse University Hospital, Toulouse, France</footnote>

<footnote n="5">⁵ToNIC, Toulouse NeuroImaging Center, Université de Toulouse, Inserm, UPS, Toulouse, France</footnote>
nitrous oxide use, several countries have enacted restric-
tions. In the United Kingdom, possession for non-
legitimate use has been banned since 2023 [6].

Since January 2024, French law has banned the sale of
more than 10 N₂O cartridges to individuals, expanding
2021 regulations limiting access for minors and restricting
quantities sold [7, 8]. These serious outcomes are related to
N₂O binding to the cobalt ion of vitamin B12 (cobalamin),
which serves as a cofactor for the enzymes methionine
synthase and methylmalonyl-CoA mutase [9]. Methionine
synthase catalyses the remethylation of homocysteine to
methionine using 5-methyltetrahydrofolate as the methyl
donor. The products (methionine and tetrahydrofolate) par-
ticipate in the active methionine and folate pathways [9].
The methionine synthase inhibition by inactivation of vita-
min B12 by N₂O results in hyperhomocysteinemia and an
increase in blood 5-methyltetrahydrofolate concentration
along with myelinisation alterations (decrease of methio-
nine) and changes in DNA synthesis (decrease of tetrahy-
drofolate). Although vitamin B12 has been found to be
reduced in some cases of heavy N₂O use, this is not always
true [10]. Several authors underlined that homocysteine
and methylmalonic acid are better biomarkers of N₂O dele-
terious exposure [9–11]. Serious N₂O-related arterial and
venous thromboembolic complications have been reported,
potentially related to the accumulation of homocysteine,
although the exact mechanism remains unclear [12, 13].
Other complications related to vitamin B12-associated met-
abolic disturbances and the effect of N₂O may be expected,
including those identified in the occupational context. A
review identified 91 cases of N₂O-related harm, with 80%
being neurological and 20% involving psychiatric manifes-
tations [14]. We describe the first case of catatonia in the
context of heavy and prolonged N₂O use.

2 | CASE DESCRIPTION

In July 2022, a 20-year-old woman (body mass index of
22 kg/m², history of depressive syndrome, migraine attacks,
chronic use of N₂O and no long-term medication) was
admitted to the hospital's emergency room for neurological
symptoms diagnosed as N₂O-induced peripheral neuropa-
thy, with normal vitamin B12 (236 pg/mL [normal 197-
771 pg/mL]), and hyperhomocysteinemia (91.1 µmol/L
[normal <15 µmol/L]). No psychiatric symptoms were
found. She consumed approximately two to three 650 g bot-
tles three times a week (estimated total per week: 4800 g).
The patient was discharged from the emergency ward with
a prescription for intramuscular vitamin B12 supplementa-
tion (to improve compliance) and a follow-up visit, which
she ultimately did not attend. A few weeks before this
event, the day after a heavy consumption of N₂O, she

consulted her general practitioner (GP) for unilateral right-
sided deafness, which resolved after a few days of corticoste-
roid therapy.

In July 2023, she presented to her GP again with
4 days of anorexia, psychomotor retardation and insom-
nia, for which the GP prescribed oxazepam 10 mg/day.
One day later, she became mute and was transferred to
the emergency ward. Blood pressure, heart rate and oxy-
gen saturation were normal on arrival. The neurological
examination found a conscious patient without any ocu-
lomotor or sensory deficit. Cardiological, pulmonary and
gastrointestinal examinations were normal. A non-
injected computed tomography scan did not find any sign
of stroke and was considered normal. The psychiatric
evaluation identified six typical symptoms of catatonia
according to DSM V: stupor, mutism, catalepsy, negativ-
ism, posturing and echopraxia. The Bush-Francis Catato-
nia Rating Scale score was 19/69 (three points for
immobility/stupor, three for mutism, three for staring,
two for posturing/catalepsy, one for rigidity, one for neg-
ativism, three for withdrawal and three for ambiten-
dency). Blood exams reported vitamin B12 deficiency
(72 pg/mL) and hyperhomocysteinemia (58.7 µmol/L).
All other results were normal (haemoglobin, ionograms,
serum calcium and ammonia, C-reactive protein, lipid,
copper, thyroid-stimulating hormone, liver enzymes and
renal function, folate), apart from hypokalaemia
(3.3 mmol/L [3.4-4.5 mmol/L]) and decreased bicarbon-
ate (18 mmol/L [22-29 mmol/L]). Serologies for syphilis,
human immunodeficiency virus, hepatitis B and C virus
were all negative. The patient received 100 mg of intrave-
nous hydroxyzine instead of lorazepam due to a logistical
error and refused all other treatments. Symptoms sponta-
neously improved in 24 h, without any sign of catatonia,
except for negativism. The patient was discharged home
against medical advice with instructions to stop using
N₂O, a proposal for addiction follow-up, and increased
monitoring by her GP. Her family later confirmed that
she continued to consume one to two canisters per week.

In April 2024, the patient exhibited a sudden change
in behaviour after the recreational use of N₂O. Her family
reported a decreased need for sleep, incoherent speech,
emotional instability (going from laughter to tears) and
undirected hyperactivity. Her family took her to a psychi-
tric emergency department where the psychiatrist noted
psycho-behavioural disorganisation with a bizarre behav-
iour, disorganised speech and morbid rationalism. She
presented with delusions of persecution and megaloma-
nia (interpretative and intuitive mechanisms), with total
adherence to the delusion and intense emotional involve-
ment. Her mood was high, with familiarity and playful-
ness. There was no marked psychomotor acceleration,
suicidal thoughts or heteroaggressive impulses. No
neurologic symptoms were found. In view of the serious clinical consequences and the denial of the psychiatric disorders, she was admitted to psychiatric care without consent. Treatment with risperidone 2 mg was initiated that evening. The following day, there was favourable development with coherent and fluent speech. The patient was euthymic, without suicidal or morbid thoughts and without sleep or appetite disturbances. There were no delusional or disorganised elements, no psychomotor acceleration and no mood elevation. The patient and her family confirmed the absence of other substance use. A diagnosis of acute pharmacologically-induced psychotic episodes was made. The involuntary status was withdrawn, and the patient was discharged against medical advice with arrangements for psychiatric and addiction follow-up.

### 3 | DISCUSSION

To the best of our knowledge, we describe here the first published case of catatonia related to chronic use of $N_2O$, preceded by an episode of peripheral neuropathy and followed by a psychotic episode in the context of persistent use. Only one recent publication mentions catatonia as a potential complication without going into detail [15]. Even if all other neurological aetiologies (epilepsy, encephalitis, encephalopathy) were not definitively eliminated due to discharge against medical advice, these causes do not seem compatible with the lack of clinical worsening and a spontaneous recovery within 24 h, with $N_2O$ use ceasing during hospitalisation. Other causes, such as calcium metabolism (phosphorus, vitamin D and parathyroid hormone), vitamins B1 and B6, were not investigated due to early discharge. However, the patient's family confirmed a sustained $N_2O$ consumption in the weeks before the catatonic and psychotic episodes, and all investigations performed during the second hospitalisation were normal. Furthermore, the persistent hyperhomocysteinemia over time and the rapid recovery after $N_2O$ withdrawal support its suspected role [9–11].

Pharmacological hypotheses for $N_2O$'s mechanism of action (GABAergic activation, NMDA glutamate receptor inhibition) do not explain its potential role in catatonia [16]. In the case of catatonia associated with vitamin B12 deficiency, the reversibility of catatonic symptoms by administration of vitamin B12 supports an indirect relationship [17, 18]. Catatonia may occur even with moderately decreased vitamin B12 levels (between 150 and 200 pg/mL) [19]. Both vitamin B12 deficiency and inactivation result in an increase in homocysteinemia, which plays a major role in the onset of catatonia. Accumulation of homocysteine can lead to neurotoxicity by causing

cellular damage due to oxidative stress, mitochondrial dysfunction and depletion of the myelin layer [9, 19]. In addition, homocysteine acts as an NMDA glutamate receptor agonist and this pathway is directly involved in its neurotoxicity [20, 21]. Since memantine (an NMDA receptor antagonist) may be used in case of failure of benzodiazepines for the treatment of catatonia, hyperhomocysteinemia may induce catatonia through activation of the NMDA glutamate receptor [22]. Finally, substance withdrawal (alcohol, benzodiazepines, etc.) is a possible cause of catatonia [22].

This case is remarkable for the cascade of neurological and psychiatric symptoms. Despite recommendations to discontinue $N_2O$, the patient's ongoing use led to increasingly severe manifestations. The mechanisms behind the neuropathy are known. Regarding unilateral deafness, we lack information for better characterisation; main causes are typically infectious, autoimmune, or traumatic. Neurological damage affecting auditory sensory transmission from $N_2O$ cannot be ruled out. The psychotic episode's rapid resolution after hospitalisation with only 2 mg of risperidone strongly suggests pharmacopsychosis. Several psychiatric complications from non-medical $N_2O$ use have been reported elsewhere, including hallucinations, delusions and mood disturbances [14, 23]. The exact role of $N_2O$ in these conditions is not fully established. Several hypotheses have been put forth by authors who have described psychotic disorders associated with B12 deficiency and hyperhomocysteinemia. These include direct nerve damage similar to neuropathy or increased dopaminergic transmission via NMDA receptors due to $N_2O$ [24, 25].

Non-medical $N_2O$ use remains a public health problem with major clinical consequences on a very young and vulnerable target population (adolescents and young adults). When $N_2O$ use is suspected, the most frequent clinical presentations are neurological disorders [14]. Severe psychiatric complications are related to $N_2O$ use, with worsening in cases of persistent use. This case report, with the escalation of symptoms, first neurologic symptoms, then resolutive catatonia followed by a subsequent psychotic episode, highlights the wide range of potential neuropsychiatric complications. Moreover, unlike other substance use disorders, recreational use of $N_2O$ is not predominantly male, with a proportion of women suffering complications unusually high, suggesting the need for close monitoring of young females who report non-medical $N_2O$ use, particularly given physiological vulnerabilities [26]. This case underscores the necessity of close monitoring (on the addictive, nutritional, neurological and psychiatric levels) and treatment for patients who use $N_2O$ for extra-medical purposes, emphasising the importance of regularly inquiring about
<figure><img src="image_3.png" /></figure>

substance use with both the patient and their family, as no urinary or blood tests are available. Clinicians should also be aware of the relevant biological markers to measure when there is suspicion of N₂O use, namely homocysteine, methylmalonic acid and active vitamin B12 [9–11]. This case also highlights the urgent need to regulate N₂O use in France and globally.

The patient gave her consent to publish the case. This case was reported to the French addictovigilance system (ANSM French Medicine Agency) in agreement with a French law related to mandatory reporting of any serious end/or unexpected case of recreational non-medical use, hazardous use or dependence to any psychoactive substance.

## AUTHOR CONTRIBUTIONS

All author certifies that their contribution to this work meets the standards of the International Committee of Medical Journal Editors.

## FUNDING INFORMATION

No funding was associated with the project.

## CONFLICT OF INTEREST STATEMENT

The authors have no conflicts of interest to declare.

## DATA AVAILABILITY STATEMENT

Data available on request from the authors.

## ORCID

Tanguy Taillefer de Laportalière ID https://orcid.org/0000-0002-0173-6437

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**How to cite this article:** Taillefer de Laportalière T, Redon M, Roussin A, Willemet E, Very E, Olivier J, et al. First episode of catatonia followed by a psychotic episode related to chronic nitrous oxide use: A case report. Drug Alcohol Rev. 2025;44(3):908–12. https://doi.org/10.1111/dar.14012