The Global Drug Survey 2022 shows a clear increase in the use of nitrous oxide as a recreational drug, particularly during the pandemic (6, 7). Globally, 17 % of young adults report having tried nitrous oxide for recreational purposes and of these 42 % had tried it in the last twelve months (8). Neurological adverse effects with myeloneuropathy, subacute combined degeneration, either with or without associated megaloblastic anaemia, have been reported (7–9). Our patient developed serious nerve injury following overconsumption of nitrous oxide, and he was one of the first of several similar cases we identified with this condition at Oslo University Hospital.
The pathophysiology is not fully known, but the onset of adverse effects can be acute or follow prolonged use. In the short term, nitrous oxide displaces oxygen and can trigger epileptic seizures, arrhythmias, cardiac and respiratory arrest (8, 10). Neurotoxic complications mostly occur with prolonged exposure, usually due to inactivation of vitamin B12 (cobalamin). Nitrous oxide oxidises the cobalt ion in vitamin B12 and impairs conversion of homocysteine to methionine. Without methionine, there is no methylation of myelin, the insulating layer around nerve cells. This leads to demyelination in both the central and peripheral nervous system (8, 10).
Nitrous oxide-induced neuropathy is typically reported in young people in their twenties and notably affects mostly the lower limbs, with symptoms that include varying degrees of unsteadiness, numbness and weakness (11, 12). Reported neurophysiological findings are usually sensorimotor neuropathy with mixed axonal and demyelinating features. The findings can be difficult to differentiate from demyelinating neuropathy (such as Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy), but at a group level neurographic differences have been reported that may be useful in the differential diagnosis (13, 14). However, several cases have also been reported with more striking neurophysiological findings in the form of predominately motor axonal damage in the legs, similar to that seen in axonal variants of Guillain-Barré syndrome (15, 16). This was found in our patient, as well as in other patients who we have examined with nitrous oxide-induced neuropathy.
Nitrous oxide (dinitrogen monoxide, N2O) is itself a weak analgesic and sedative gas that can provide short-term relief during medical procedures, and is most commonly used during childbirth and dental treatment. This medical grade nitrous oxide contains at least 21 % oxygen, and there are strict requirements regarding ventilation and occupational exposure. When inhaled, it produces a feeling of euphoria, which is the origin of its name laughing gas or happy gas and has led to its recreational use. As a party drug, nitrous oxide has been readily available as whipped cream cartridges (whippits), small 8 g cartridges that can be purchased in kitchen supply shops. As demand has increased, online shops have sprung up offering home delivery of larger gas canisters, typically 615 g or 2 kg canisters (17, 18). We would like to emphasise that these gas cartridges and canisters are not the same as medical grade nitrous oxide, since they are not mixed with oxygen and are intended for industrial use or to whip cream. The gas in the canisters is also pressurised and can cause frostbite to the mouth and hands when opened. Therefore, the gas is typically filled into balloons prior to inhalation, earning it the nickname of 'balloons' among young people.
Until recently, nitrous oxide parties have been mostly associated with nightclubs in the Mediterranean, but in recent years its use has become more common in Scandinavia (19–21). In Denmark, the problem has become so great that the police have set an age limit of 18 years for the purchase of nitrous oxide (22). In Norway, it is illegal to sell nitrous oxide as a recreational drug, but it is not considered to be a narcotic. Therefore, the canisters are imported and resold anonymously via certain social media channels.
Since the intoxicating effect is short-acting and does not cause a hangover, many people may believe that nitrous oxide is harmless, but this is a false sense of security. Hallucinations and disorientation occur in 20–30 % of users, while persistent neurological adverse effects have been reported in 4–5 %, usually starting around six months after regular intake (7, 11). People with high intake over time seem to develop more severe disease, which indicates that the nerve damage is dose-related (8, 11). The mean daily dose when used as a recreational drug is approximately 40 g, although it can be as much as 800 g in heavy users (7, 8). The neurotoxic threshold varies between individuals, but in nearly all cases a cumulative total dose over time of about 65 kg will cause the most severe nerve injury requiring hospitalisation (11). It is likely that some people are more susceptible to rapid development of symptoms, including those with pre-existing vitamin B12 deficiency (for example, people with a vegetarian diet, malnutrition or excessive alcohol consumption) (8, 11).
If excessive use of nitrous oxide is suspected, it is recommended that blood levels of vitamin B12 be measured. However, if vitamin B12 levels are normal, methylmalonic acid and homocysteine should be assessed since they may identify functional vitamin B12 deficiency (9, 11). There is no established treatment, but cessation of nitrous oxide and high-dose vitamin B12 injections are recommended initially, after which maintenance treatment with oral supplementation should be considered (8, 10). Several cases indicate that the prognosis is best when treatment is initiated rapidly, but improvement is slow and the condition is not always reversible (8, 10, 11). Since nitrous oxide is still legal in Norway, healthcare professionals must be aware that not all patients will report it when asked about use of recreational drugs. Use of nitrous oxide should be specifically enquired about in cases of suspected acute/subacute neuropathy in young people.