Let’s “Whippit” Away: Nitrous Oxide Misuse and Its Complications

The patient was a 45-year-old man with a history of schizoaffective disorder, inhalant use disorder (in early remission), and alcohol use disorder (in sustained remission) who was referred to our neurology clinic for further evaluation of weakness, 10 months after cessation of severe N₂O misuse. He had used 100 whippits daily for 12 months to cope with anxiety from a breakup and the COVID-19 pandemic. Throughout this period, he denied using other substances, including alcohol. He initially used fewer chargers but gradually increased the number as tolerance developed. His N₂O misuse persisted until he awoke in bed barely able to move his legs. The acute-onset weakness was severe enough to prevent him from working and leaving home. He immediately discontinued using N₂O and left his bed only to receive food deliveries and use the bathroom. Given the extent of his weakness, he ambulated by propping himself up on objects with his arms. Over 1 month, his weakness gradually improved such that he could walk, drive, and return to work. However, because his strength did not fully recover, despite 8 months of abstinence, he sought care from his primary care physician for further evaluation. Laboratory results revealed low vitamin B₁₂ levels (156 pg/mL; normal range 180–914 pg/mL) but normal folate levels (16.0 ng/mL; normal values ≥5.9 ng/mL). He received vitamin B₁₂ supplementation, but his strength only mildly improved over 2 months; therefore, he followed up with his primary care physician. A repeat vitamin B₁₂ test revealed normal levels (289 pg/mL), leading to a neurology referral

Upon presentation to our clinic the following month, the patient’s weakness and altered gait were obvious. He reported tingling in his lower back and feet. He was alert and oriented x4, and his recent and distant memory were intact. His speech was fluent. A physical examination demonstrated lower-extremity weakness in dorsiflexion and eversion bilaterally and mild weakness in inversion on the right side. His reflexes were normal (grade 2+) in his upper extremities and knees but absent in both ankles. Bilateral foot drop, steppage gait, and a positive Romberg test were present. There was a decreased sensation to pinprick in the first interdigital space of each foot. Cranial nerves II to XII were intact, and his finger-to-nose and heel-to-shin testing were normal. The Babinski sign was negative. Given the neurological distribution, there was concern for bilateral peroneal neuropathy versus distal neurological injury in a stocking-glove distribution. The patient was scheduled for a lower-extremity electromyogram and referred to physical therapy. Repeat vitamin B₁₂ testing was ordered. He rescheduled the electromyogram twice, did not present to his follow-up appointment, and was ultimately lost to follow-up. Months later, we learned that he died by suicide.

N₂O induces vitamin B₁₂ deficiency by permanently oxidizing cobalt ions in vitamin B₁₂. Vitamin B₁₂ is a cofactor necessary for the conversion of homocysteine and methylmalonyl coenzyme A to methionine and succinyl coenzyme A, respectively, which are needed for methylation of myelin protein. Demyelination occurs in the central and peripheral nervous systems and can present as subacute combined degeneration (SCD). It should be noted that a normal vitamin B₁₂ level does not necessarily reflect functional vitamin B₁₂. Assessing homocysteine and methylmalonic acid levels, which will be elevated without functional vitamin B₁₂, can more accurately reflect a true deficiency (3, 8). Other proposed etiologies of neurotoxicity include downstream effects of increased reactive oxygen species and prolonged N-methyl-d-aspartate receptor blockade (9).

As noted in other case reports, not all patients with neurological sequelae from N₂O misuse have the typical presentation of SCD. Rather, they have varying distributions of weakness, paresthesia, and imbalance (10). Our patient did not have SCD; he had focal areas of residual weakness, paresthesia, and imbalance, which remained despite vitamin B₁₂ returning to a normal level. Unfortunately, homocysteine or methylmalonic acid levels were not available. The findings from our patient are consistent with those of other patients, suggesting that despite abstinence and treatment of N₂O-induced vitamin B₁₂ deficiency, patients with significant N₂O misuse can experience long-term neurological sequelae. This is especially concerning considering that younger people, who lack fully developed nervous systems, comprise the highest percentage of new misusers (5). Whether sequelae are permanent is yet to be confirmed. Unfortunately, with our patient lost to follow-up, it is unclear whether our recommended physical therapy and additional recovery time would have resulted in the full resolution of symptoms.

Other sequelae of N₂O misuse are medical (dyspnea, wheezing, chest pain, and perioral erythema) and psychiatric (hallucinations, delusions, paranoia, and depression). A systematic review found 29 case reports discussing N₂O as a cause of death, with multiple deaths resulting from asphyxiation due to hypoxia or from arrhythmias. There was one report of suicide after relapse (8). Regarding our patient, it is uncertain to what extent the sequelae contributed to his death by suicide. Both our patient and his family, who informed us of his death, consented to his case being shared so that his passion for science can live on through others learning from his story.

The significant morbidity from N₂O misuse indicates a need for increased awareness. In the Ehirim et al. survey, 79.2% of 101 nonusers in the past 12 months indicated that they would likely try N₂O in the next 3 months, with 93.9% of them reporting that they would be more comfortable experimenting in a social setting (2). Socially, misuse is seen at festivals and clubs (11). One contributing factor may be a lack of awareness of adverse effects. The majority of those surveyed indicated that it was “extremely important” to educate others about the adverse effects. If aware of the risks, some individuals indicated that they would use N₂O in a safer environment (an unenclosed space), inform friends of risks, or not use N₂O altogether (2). Screening for N₂O misuse is especially important given that it is undetected by routine serum and urine tests. Although there is no widely recognized screener specifically for N₂O, the National Institute on Drug Abuse’s tool, Screening to Brief Intervention, screens for N₂O misuse and contains recommendations for clinicians (8, 12).

Providers should also be aware of treatment options. In addition to vitamin B₁₂ repletion and physical therapy, authors of two case reports found reductions in use with oral or intramuscular naltrexone, with one group observing a daily charger consumption decrease of almost 98% after 1 month (13, 14). There is limited evidence for methionine supplementation (10, 15–17).

Given the ease of access, relatively low cost, and short-lived euphoria of N₂O, it is not surprising that it is used by so many to obtain a “legal high.” Furthermore, its popularity is especially alarming considering its prevalence among those without fully developed nervous systems. Given the prevalence of N₂O misuse and its potential dangers, greater emphasis should be placed on screening for and improving psychoeducation about this potentially life-altering substance. With increased awareness, more patients can receive support, evaluation, and treatment to prevent developing the long-term and potentially life-long neurological sequelae experienced by our patient.