Recreational Use Of Nitrous Oxide Research Articles

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

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.

Intoxication au protoxyde d’azote : des consommations en augmentation aux conséquences lourdes

Recreational use of nitrous oxide has increased significantly in recent years, as hospitalizations related to it. Nitrous oxide abuse leads to neurological and vascular disorders by disturbance of metabolic pathways. Understanding the physiopathology and discovery of efficient biomarkers are currently a key issue in the diagnosis and follow-up of patients.

RECREATIONAL NITROUS OXIDE INHALATION AS AN UNUSUAL CAUSE OF SPONTANEOUS PNEUMOMEDIASTINUM AND PNEUMORRHACHIS SECONDARY TO BAROTRAUMA

RECREATIONAL NITROUS OXIDE INHALATION AS AN UNUSUAL CAUSE OF SPONTANEOUS PNEUMOMEDIASTINUM AND PNEUMORRHACHIS SECONDARY TO BAROTRAUMA

Possible impact of the COVID-19 pandemic on the recreational use of nitrous oxide in the Paris area, France

IntroductionRecreational use of nitrous oxide (N2O) is increasing in Western countries, including France. During the COVID-19 pandemic, some authors warned that recreational N2O use could increase further as the supply of illicit drugs was impacted by various containment measures. MethodsWe retrospectively analyzed N2O exposures reported to the Paris Poison Control Center (France) from 2010/01/01 to 2021/04/15. The Poison Severity Score was used to grade severity. ResultsDuring the study period, 93 cases of N2O recreational exposures were reported (male/female ratio: 1.1; median age: 20.9 years range: [14.8-49.0]). The first case was reported in 2012, 84/93 (90%) and 65/93 (70%) were reported since 2019 and March 17th 2020 (first lockdown in France) respectively. Most of the patients were symptomatic (88/93; 95%) and developed neurological symptoms (78/93; 84%). Among the fourteen patients who developed moderate to severe symptoms, eleven were reported after March 2020. ConclusionDespite a marked increase in recreational N2O exposures during the COVID-19 pandemic, the exact impact of COVID-19 on this increase remains to be determined as it was observed from 2019.

Increasing recreational nitrous oxide use: Should we worry? A narrative review.

Since 2000, the prevalence of recreational nitrous oxide (N2O) use has increased in the Western world. Although N2O is a relatively safe drug, the overall increase in the use of N2O has concomitantly also initiated a modest but important increase in the number of young excessive users. The recent introduction of large 2 kg N2O tanks, allowing high and prolonged dosing, has facilitated this excessive use. This is of 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 vitamin B12 deficiency. The increasing trend of recreational users with N2O-induced neurological damage at emergency departments confirms the urgency of this development. This narrative review describes recent trends in N2O use and misuse, the adverse health effects associated with excessive use and the risk factors of excessive use. Considering the rising trend in N2O use, particularly among young and other vulnerable people, we propose to take legislative action to limit the availability of N2O, and also advocate for better and timely education of non-users, users and medical professionals about the serious side-effects associated with excessive N2O use. It is concluded that the increase in excessive N2O use is of serious concern.

Myeloneuropathy induced by recreational nitrous oxide use with variable exposure levels.

Although several case series have described nitrous-oxide-associated neurological disorders, a comprehensive assessment of exposure characteristics (e.g., time to onset, level of exposure) in substance abusers has not been performed. The aim of this study was to describe the onset patterns of recreational use of nitrous-oxide-induced neurological disorders. All cases of neurological disorders related to nitrous oxide recreational use reported to the Hauts-de-France addictovigilance center between January 2019 and August 2020 were selected. Only cases requiring hospitalization with informative data to perform the nitrous oxide causality assessment were included. A total of 20 cases from five hospitals were included. The male-to-female ratio was 6:1 and the median age was 19years (range 16-34). The neurological presentation (myeloneuropathy 64%, 7/11; sensorimotor neuropathy 36%, 4/11) included for all patients gait disorders due to proprioceptive ataxia and limb hypoesthesia. The median dose used per occasion was 100 cartridges (range 5-960; n=19). The median time from the start of nitrous oxide use to the onset of neurological symptoms was 6months (range 0.7-54; n=16). The cumulative dose was significantly higher in patients with damage to all four limbs than in patients with lower limb symptoms only (p=0.042). A low intermittent exposure may be sufficient to cause neurological damage in some subjects, suggesting that, at the population level, there is no safe exposure to nitrous oxide in recreational settings. The severity of neurological impairment could increase once used at high doses and for prolonged durations of nitrous oxide.

Recreational Nitrous Oxide Use and Associated Factors among Health Profession Students in France.

The first aim of this study was to investigate the recreational use of nitrous oxide (N2O) among health profession students at Montpellier University (France). The second aim was to identify the factors associated with N2O use. All students in medicine, dentistry, pharmacy and midwifery of the Montpellier University were contacted by email to participate in the survey. The students answered directly online by filling out anonymously a questionnaire including demographic information and questions about N2O, illicit drugs and alcohol use. Ethical approval was granted by the ethics committee of the Montpellier University. The sample comprised 593 students (mean age = 22.3 ± 2.6 yr), with 68.6% of females. Lifetime N2O use was reported by 76.6% and frequent alcohol use by 30.5% of the respondents. The lifetime use of cannabis, ‘poppers’, cocaine, ecstasy and LSD was 26.8%, 54.6%, 9.6%, 10.1% and 2.0% respectively. In multivariate analysis, the substances significantly associated with lifetime N2O were alcohol drinking and ‘poppers’ use. With respect to this self-nominated sample, our results indicate that respondents who were alcohol drinkers, were poppers users, follow longer studies, divert medical products for recreational use or were members of a students’ corporation had higher odds of lifetime N2O use.

Alarming increase in poisonings from recreational nitrous oxide use after a change in EU-legislation, inquiries to the Dutch Poisons Information Center.

After the change in EU-legislation in 2014, recreational use of nitrous oxide (N2O) increased in the Netherlands from 2015 onwards. We studied the effect on N2O poisonings during an 11 year period. A retrospective observational study was performed on the incidence rate of N2O poisonings, relative to all recreational drug poisonings reported to the Dutch Poisons Information Center (DPIC) from 2010-2020. Secondary outcomes were the frequency of heavy use, frequent use, co-exposures, and toxicity in 2019 and 2020. 433 N2O poisonings were included. The incidence rate increased exponentially from 0.12% in 2010 to 11% in 2020, with an average monthly rate of 3.8%. In 2019 and 2020, 79% of the patients indicated heavy use, frequent use or both, and 42% used from large cylinders. Chronic toxicity (signs of peripheral neuropathy) was reported in 38% of the patients. The rate of N2O poisonings increased alarmingly in the Netherlands. An increasing proportion of patients reported problematic heavy or frequent use, accompanied by chronic toxicity.

Neurological consequences of recreational nitrous oxide abuse during SARS-CoV-2 pandemic.

IntroductionRecreational use of nitrous oxide (N2O) is a growing practice in France and all around the world and is often associated with neurological complications. We report detailed clinical and paraclinical presentations of 12 patients with combined degeneration of the spinal cord and peripheral neuropathies in relation to N2O consumption, possibly favored by lockdowns due to SARS-CoV-2 pandemic.ResultsWith variable levels of consumption, the 12 patients presented spinal cord and/or peripheral nerve damage, with mostly motor and ataxic symptoms, motor axonal nerve damage, and medullary T2-weighted hyperintensities on MRI. There was a clear improvement in symptoms after vitamin B12 substitution, although some sequelae remained, particularly sensory.DiscussionWe report detailed clinical, electrophysiological, radiological, and biological consequences of N2O abuse in 12 patients. Our data support the clinical and paraclinical observations reported in the literature. The mechanisms of neurological N2O toxicity are still debated. There is currently no precise recommendation on the therapeutic management. The clinical evolution after vitamin B12 substitution seems sufficient but could depend on early management. Effective messages targeting at risk population, but also the health professionals involved, seem crucial as does a better legal framework for this growing practice.

Problematic Use of Nitrous Oxide by Young Moroccan-Dutch Adults.

The recreational use of nitrous oxide (N2O; laughing gas) has largely expanded in recent years. Although incidental use of nitrous oxide hardly causes any health damage, problematic or heavy use of nitrous oxide can lead to serious adverse effects. Amsterdam care centres noticed that Moroccan–Dutch young adults reported neurological symptoms, including severe paralysis, as a result of problematic nitrous oxide use. In this qualitative exploratory study, thirteen young adult Moroccan–Dutch excessive nitrous oxide users were interviewed. The determinants of problematic nitrous oxide use in this ethnic group are discussed, including their low treatment demand with respect to nitrous oxide abuse related medical–psychological problems. Motives for using nitrous oxide are to relieve boredom, to seek out relaxation with friends and to suppress psychosocial stress and negative thoughts. Other motives are depression, discrimination and conflict with friends or parents. The taboo culture surrounding substance use—mistrust, shame and macho culture—frustrates timely medical/psychological treatment of Moroccan–Dutch problematic nitrous oxide users. It is recommended to use influencers in media campaigns with the aim to decrease the risks of heavy nitrous oxide use and improve treatment access. Outreach youth workers can also play an important role in motivating socially isolated users to seek medical and or psychological help.

Associations of socio-demographic characteristics, well-being, school absenteeism, and substance use with recreational nitrous oxide use among adolescents: A cross-sectional study.

PurposeA rapid increase of recreational nitrous oxide use (i.e. laughing gas, N2O) has been reported in several countries, while it has received limited attention in scientific research. We aimed to study the association of socio-demographic characteristics, mental well-being, sickness absence, truancy, and substance use with the frequency of lifetime nitrous oxide use among adolescents.MethodsWe used self-reported questionnaire data of adolescents (N = 555) attending secondary schools to cross-sectionally assess the frequency of nitrous oxide use and potential factors associated with nitrous oxide use, such as gender, mental well-being, and binge drinking. Ordinal logistic regression models were applied with lifetime nitrous oxide use (never, once, ≥ two times) as the outcome variable.ResultsAdolescents were on average 15.6 years old (SD = 0.83, range 14–18), 47.0% were female. In total, 86 (15.6%) adolescents had used nitrous oxide at least once in their life.In the multivariable ordinal regression model, the risk of having a higher category of lifetime nitrous oxide use was associated with a non-Dutch ethnic background (OR = 2.10, 95% CI 1.22; 3.61), attending pre-vocational education (OR = 1.88, 95% CI 1.06; 3.34), a higher score on the scale of externalizing problems (OR = 1.10, 95% CI 1.01; 1.20), binge drinking twice or more in the past four weeks (OR = 2.49, 95% CI 1.25; 4.94), and cannabis use (OR = 1.98, 95% CI 1.03; 3.79).ConclusionsYouth Health Care professionals should be aware of nitrous oxide use in adolescents, especially among adolescents with a non-Dutch ethnic background, lower education levels, externalizing problems, frequent binge drinking, and cannabis use.

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.

Objective: To explore the clinical and imaging characteristics of subacute combined degeneration of the spinal cord (SCD) related to recreational nitrous oxide (N2O) use.Methods: Clinical and imaging data were retrospectively collected from patients with SCD related to recreational N2O use who were diagnosed and treated at Shengjing Hospital of China Medical University from January 2016 to June 2020. The clinical and imaging features of patients with recreational N2O-related SCD were compared with those of patients with N2O-unrelated SCD, who were diagnosed and treated during the same period of time.Results: The study enrolled 50 patients (male/female: 22/28, age: 21.4 ± 4.7 years) with N2O-related SCD and 48 patients (male/female: 27/21, age: 62.0 ± 11.4 years) with SCD unrelated to N2O use. The most common signs/symptoms of the patients in both groups were limb numbness and weakness and unsteady gait, but the incidence of limb weakness, unsteady gait, disorders of urination and defecation, anorexia, reduced deep sensation in lower limbs, ataxia, and positive Babinski sign were lower in the N2O-related SCD group than those in the N2O-unrelated SCD group (P < 0.05). The functional disability rating score of patients in the N2O-related SCD group (median: 3, IQR: 2–5) was also significantly lower than the score in the N2O-unrelated SCD group (median: 5, IQR: 4–7) (P < 0.05). The serum vitamin B12 level was significantly lower in the N2O-unrelated SCD group (median: 96 pg/mL, IQR: 50–170 pg/mL) than the level in the N2O-related SCD group (median: 218 pg/mL, IQR:121–350 pg/mL) (P < 0.05), while both groups had similarly increased levels of homocysteine (P > 0.05). Compared with the N2O-unrelated SCD patients, more patients with N2O-related SCD had abnormal spinal magnetic resonance imaging (MRI) scans (80.0 vs. 64.2%). The patients with N2O-related SCD also had wider spinal lesions on sagittal MRI (5.3 ± 0.8 mm vs. 4.2 ± 1.0 mm), fewer spinal segments with lesions (median: 5, IQR: 4–6 segments vs. median: 6, IQR: 5–7.5 segments), and a higher incidence of the inverted V sign on axial MRI (72.0 vs. 31.2%) (all P < 0.05).Conclusion: The recreational use of N2O has become an important cause of SCD in young patients. Compared with the N2O-unrelated SCD patients, the N2O-related SCD patients had less severe clinical presentations, less obvious decrease in serum VB12 levels, and more obvious MRI changes.

Case report of an acute myocardial infarction after high-dose recreational nitrous oxide use: a consequence of hyperhomocysteinaemia?

BackgroundNitrous oxide (N2O, laughing gas) is increasingly used as a recreational drug and is presumed relatively safe and innocent. It is often being used in combination with other substances, such as cannabis.Case summaryA young adult attended the emergency room because of chest pain after recreational use of very high-dose nitrous oxide in combination with cannabis. Electrocardiography demonstrated ST-elevation in the anterior leads. Coronary angiography showed thrombus in the proximal and thrombotic occlusion of the distal left anterior descending coronary artery for which primary percutaneous coronary intervention was attempted. Thrombus aspiration was unsuccessful and the patient was further treated with a glycoprotein IIb/IIIa in addition to dual platelet therapy. Blood results showed low vitamin B12 and folic acid status with concomitant hyperhomocysteinaemia, a known cause of hypercoagulation. Transthoracic echocardiogram showed a moderately reduced left ventricular ejection fraction (LVEF). Three months later, an improvement in LVEF and no recurrent angina or symptoms of heart failure were noticed.DiscussionWe report a case of acute myocardial infarction secondary to very high-dose nitrous oxide abuse in combination with cannabis and possible hypoxia. We propose that severe hyperhomocysteinaemia secondary to nitrous oxide-induced vitamin B12 deficiency together with the vasoconstrictive effects of cannabis might pose a seriously increased risk for intracoronary, among others, thrombus formation. In conclusion, we contest the safety and innocence of recreational nitrous oxide (ab)use, notably in the context of other factors increasing the risk of coagulation.

Pernicious azotaemia? A case series of subacute combined degeneration of the cord secondary to nitrous oxide abuse

Nitrous oxide abuse is a rare cause of vitamin B12 deficiency and consequent subacute combined degeneration of the spinal cord. Worldwide and Australian statistics indicate that recreational use of nitrous oxide is increasing. We report four cases of females aged 18–24 years presenting with clinical symptoms of subacute combined degeneration of the spinal cord. MRI during admission demonstrated the classic findings of T2 hyperintensity, predominantly within the dorsal columns of the spinal cord, with variable involvement of the lateral corticospinal tracts. These cases highlight the ready availability of nitrous oxide and the fact that heavy prolonged recreational use is occurring in the community. It is important that clinicians in emergency and community settings are alerted to this unusual cause of subacute combined degeneration of the spinal cord because early aggressive vitamin B12 replacement together with behavioural change can reverse this disabling neurological syndrome.

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.

In recent years, there has been a sharp increase in the number of patients with neurological disorders associated with recreational use of nitrous oxide (N2O) in China. Here, we summarize the clinical characteristics of patients with neurological disorders associated with N2O abuse diagnosed in our Hospital. Further, we conducted a literature search on recent cases reported in mainland China to improve the awareness of the outbreak of neurological disorders associated with N2O abuse. We retrospectively collected data of patients diagnosed with neurological disorders associated with recreational use of N2O in Shengjing Hospital of China Medical University from January 2018 to June 2019, and performed a literature search using the "nitrous oxide" and "neurological disorder" as keywords in the Chinese literature databases of WANFANG and CNKI and the English literature databases of Pubmed and Web of Science RESULTS: We enrolled 43 patients (average age: 21.9 ± 3.3years). The main clinical manifestations were weakness and paresthesia in the four extremities and unsteady gait. Further, most patients showed significantly lower levels of serum vitamin B12 (169.4 ± 79.1pg/mL) and increased homocysteine levels (78.1 ± 32.2μmol/L). MRI of the spinal cord showed longitudinal high T2 signal lesions in the dorsal spinal cord in some patients. Moreover, electromyography showed sensory and motor nerve axonal damage combined with demyelination, which was relatively more severe in the lower limbs. There was rapid improvement of the symptoms after treatment with intramuscular injections of vitamin B12 and the overall prognosis was good. The literature search indicated that the number of published papers and related patients showed a rapid annual increase since the first Chinese case reported in 2016 CONCLUSION: Recreational use of N2O is an emerging public health problem in China that needs prompt action from the society and government. Early diagnosis and treatment allow a good overall prognosis.

The Last Laugh – Reversible myeloneuropathy induced by chronic nitrous oxide use

A previously fit and well 19 year old male presents with a progressive ataxic – sensory neuropathy worsening over 2 – 3 weeks. History and investigations revealed extensive recreational use of nitrous oxide resulting in functional B12 deficiency and consequent subacute combined degeneration of the cord. Abstinence and B12 supplementation resulted in a rapid and full neurological recovery. This case report highlights the importance of considering nitrous oxide abuse in the differential diagnosis of atypical neurological symptoms and signs, and emphasizes the possibility of good clinical outcomes with treatment.

WED 011 Subacute combined degeneration of the cord: laugh until you are weak

A 33 year old lady presented to her GP with a 2 week history of numbness affecting her thighs. Routine blood tests revealed normal haemoglobin and folate levels with a borderline B12 concentration of 103 ng/L. Over the subsequent 2 weeks the numbness spread to involve her feet and her hands. Despite commencing cobalamin injections her symptoms continued to progress. She was admitted to hospital 4 weeks after the onset of symptoms with disabling sensory ataxia.All reflexes were either absent or elicited only with reinforcement. Plantars were downgoing. There was impairment of all sensory modalities in a glove-and-stocking distribution, with proprioception accurate at the ankle on the right and the knee on the left. Her gait was broad-based. The remainder of the neurological examination was unremarkable.A full peripheral neuropathy screen revealed no abnormality. An MRI spine showed longitudinally extensive myelitis mainly affecting the dorsal cord extending from C4 to T3. MRI brain and lumbar puncture were pristine.Guided by the MRI findings direct questioning elicited a long history of frequent recreational nitrous oxide use. We review the accumulating literature regarding nitrous oxide-induced subacute combined degeneration of the cord and explore the pathophysiological mechanisms underlying it.

Polydrug abuse associated with nitrous oxide causes death.

The case report by Hirvioja et al. raises some interesting points [1]. Unfortunately, the title is somewhat misleading because it suggests that it was nitrous oxide alone that caused the death and ignores the likelihood, from the data presented, that the death was probably due to the other substances found in the patient's blood as well as the nitrous oxide [1]. As far as I am aware, there is no case in the literature where nitrous oxide alone has caused sudden death during misuse, except when the subject has been asphyxiated because of oxygen lack [2]. I would like to congratulate the authors for not confusing abuse with use, something not always done with enough precision [3]. Indeed, some authors have given the impression that recreational use automatically means abuse [4]. Their paper also highlights the point that pure nitrous oxide abuse is extremely rare and that those who do abuse it do so as part of their polydrug abuse [1, 4]. It is also important to note that although the recreational use of nitrous oxide seems currently to be an increase, the history of the use of nitrous oxide since the late 17th century has been punctuated by cycles of increased and decreased popularity. Furthermore, and in all this time, it has never yet caused the severe problem as found with other drugs such as morphine, heroin, cocaine or the benzodiazepines [4]. However, the statement that ‘Nitrous oxide… is used as an anaesthetic…. during small dental procedures and labour’ is simply wrong. For these indications, nitrous oxide is used at concentrations well below those that could produce unconsciousness and anaesthesia and while the patient is conscious and fully responsive and definitely not anaesthetized [5].

Recreational nitrous oxide use: Prevalence and risks

Nitrous oxide (N2O; laughing gas) is clinically used as a safe anesthetic (dentistry, ambulance, childbirth) and appreciated for its anti-anxiety effect. Since five years, recreational use of N2O is rapidly increasing especially in the dance and festival scene. In the UK, N2O is the second most popular recreational drug after cannabis. In most countries, nitrous oxide is a legal drug that is widely available and cheap. Last month prevalence of use among clubbers and ravers ranges between 40 and almost 80 percent. Following one inhalation, mostly from a balloon, a euphoric, pleasant, joyful, empathogenic and sometimes hallucinogenic effect is rapidly induced (within 10 s) and disappears within some minutes. Recreational N2O use is generally moderate with most users taking less than 10 balloons of N2O per episode and about 80% of the users having less than 10 episodes per year. Side effects of N2O include transient dizziness, dissociation, disorientation, loss of balance, impaired memory and cognition, and weakness in the legs. When intoxicated accidents like tripping and falling may occur. Some fatal accidents have been reported due to due to asphyxia (hypoxia). Heavy or sustained use of N2O inactivates vitamin B12, resulting in a functional vitamin B12 deficiency and initially causing numbness in fingers, which may further progress to peripheral neuropathy and megaloblastic anemia. N2O use does not seem to result in dependence. Considering the generally modest use of N2O and its relative safety, it is not necessary to take legal measures. However, (potential) users should be informed about the risk of vitamin B12-deficiency related neurological and hematological effects associated with heavy use.

Accepting Pain Over Comfort: Resistance to the Use of Anesthesia in the Mid-19th Century

News of the successful use of ether anesthesia on October 16, 1846, spread rapidly through the world. Considered one of the greatest medical discoveries, this triumph over man's cardinal symptom, the symptom most likely to persuade patients to seek medical attention, was praised by physicians and patients alike. Incredibly, this option was not accepted by all, and opposition to the use of anesthesia persisted among some sections of society decades after its introduction. We examine the social and medical factors underlying this resistance.At least seven major objections to the newly introduced anesthetic agents were raised by physicians and patients. Complications of anesthesia, including death, were reported in the press, and many avoided anesthesia to minimize the considerable risk associated with surgery. Modesty prevented female patients from seeking unconsciousness during surgery, where many men would be present. Biblical passages stating that women would bear children in pain were used to discourage them from seeking analgesia during labor. Some medical practitioners believed that pain was beneficial to satisfactory progression of labor and recovery from surgery. Others felt that patient advocacy and participation in decision making during surgery would be lost under the influence of anesthesia. Early recreational use of nitrous oxide and ether, commercialization with patenting of Letheon, and the fighting for credit for the discovery of anesthesia suggested unprofessional behavior and smacked of quackery. Lastly, in certain geographical areas, notably Philadelphia, physicians resisted this Boston-based medical advance, citing unprofessional behavior and profit seeking.Although it appears inconceivable that such a major medical advance would face opposition, a historical examination reveals several logical grounds for the initial societal and medical skepticism.