John, a 15-year-old boy, was at a party with friends. One of his friends pulled out a box of small ‘whippit’ canisters. John tried these several times over the last few months and exclaimed to his friends, “These are great fun; you should give it a go!”
He showed them how to put laughing gas into balloons and inhale it. The party went on for a few hours, and the balloons seemed to never end.
As John headed home after the party, he felt a little uneasy. The following day he still didn’t feel quite right; his arms and legs felt tingly, and he had difficulty walking. His older brother brings him to their local emergency department.
This article focuses on the use of nitrous oxide in the recreational setting and the harmful side-effects seen in the clinical setting due to prolonged abuse.
Nitrous Oxide (dinitrogen oxide, N2O) is commonly referred to as Laughing Gas, Hippy crack, whippits, Nitrous or NOS. It is a colourless gas. Since its discovery as a compound in the 18th century, it has had many uses in medicine and engineering. Its use and abuse are becoming increasingly prevalent among young adults and adolescents as an inhaled anxiolytic.
Historical use of nitrous oxide
N2O’s use as a recreational relaxant spans from the Victorian aristocracy in the 18th century to the modern day. After Joseph Priestley’s discovery in 1772, the great chemist Humphry Davy began experimenting with its psychoactive properties. The use of nitrous oxide as a factitious air had [previously been described by Thomas Beddoes and James Watt (he of the steam engine)
The recreational use of nitrous oxide
A misperceived “safe high” is obtained with the help of gas cartridges that are designed to prolong shelf life and as a whipping agent in whipped cream dispensers. The gas is extracted from small cartridges (mainly 8g whippits), using a ‘cracker’ device, and is inhaled from balloons or whipped cream dispensers. N2O can also be extracted from larger cylinders by directly inflating a balloon without an extractor device. Inhalation of N2O is often called ‘Nanging’, and allegedly induces a fleeting sensation of relaxation or euphoria.
Whippit bulbs hold roughly 10 ml of liquid N2O. This equates to around 4L of gas in a normobaric setting.
The European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) has reported its use to be “a growing concern for Europe”, partly due to growing popularity due to ease of accessibility, low cost and perceived safety.
Recreational use of N2O has become more prevalent in the EU over the last decade, partly due to the increasing availability of the gas itself and the components required and partly through legislation changes. In July 2014, the European Court of Justice declared that “products without apparent therapeutic effect cannot be classified as medicines.” In countries like the Netherlands, sales of nitrous oxide canisters and their components are regulated under the Commodities Act, leaving the processes required for recreational use challenging to prosecute. With decreasing legal repercussions observed in the EU, the availability of larger nitrous oxide cylinders has facilitated heavier use.
In 2016, nitrous oxide was declared a “psychoactive substance” and came under the auspices of the UK Psychoactive Substance Act 2016. If someone is deemed in possession of N2O with the intent to supply, they could receive a prison sentence of up to 6 months. In 2018, the data on N2O consumption in the UK was reviewed. Consumption by adults (aged 16-59) in England and Wales rose from 2% of the population to 2.3%.
How does nitrous work?
Due to the chemical compounds’ broad array of effects at a pharmacological level, N2O’s mechanism of action is poorly understood. A wide variety of ligand-gated ion channels are thought to be involved:
- Dopamine a2-adrenergic receptors (analgesic)
- GABAa receptors (anxiolytic)
- NMDA receptor-mediated currents (anaesthetic)
- AMPA, Kainate, GABAc, 5-HT3 receptors & nACh channels (mixed effect)
Side-effects of recreational use
The perceived safe high and short-lived euphoric dissociation may lead to sessions where participants may inhale upwards of 100 canisters or, using larger NOS containers, high volumes of N2O directly from individual balloons.
Initial effects of inhalation of N2O include:
- Euphoria
- Dissociation
- Hallucination
- Temporary loss of motor control
- Analgesia
- Intoxication
N2O is stored in liquid form in steel cylinders, and direct exposure to the body causes a significant hazard. The temperature of the jet stream exiting the cylinders is as low as -55°C, leading to frostbite and burn injuries. These burns may appear superficial but can rapidly develop into mid or deep-dermal burns.
Before the 1950s, the use of nitrous oxide in industry and recreation was deemed a reasonably safe practice. However, in 1956, Lassen et al. showed that prolonged exposure led to megaloblastic changes in the bone marrow. Long-term recreational use of N2O can lead to irreversible neurological damage.
Recreational use of nitrous oxide has led to increased presentations due to both acute toxicity and long-term sequelae.
Nitrous oxide can render vitamin B12 inactive through oxidation of the cobalt ion. As vitamin B12 has a major role in maintaining myelination of the spinal cord through methylation, nitrous exposure can lead to demyelination in both the central and peripheral nervous systems.
The most common myelopathy is ‘subacute combined degeneration of the spinal cord’ (SACDC). It occurs due to the functional inactivation of Vitamin B12 and predominantly affects the dorsal and lateral columns of the spinal cord.
Dorsal column: impaired vibration sense, proprioception and tactile discrimination
Lateral corticospinal tract: spasticity, weakness, hyperreflexia
Common neurological presentations include:
- Ataxia
- Sensory deficits
- Paraesthesia
- Weakness
- Gait disturbance
- If severe: spasticity +/- paraplegia
Differential diagnoses to consider include:
- Nutritional (folic acid/copper) deficiency
- Medication-induced
- Small bowel disease (coeliac/IBD/lymphoma)
- CNS demyelination
- Pancreatic disease
- Neoplastic
- In an acute setting: consider ischaemic spinal cord syndrome
Investigations
Once nitrous oxide use is in the differential, how should we investigate further?
If suspecting nitrous oxide-induced neuropathy, one should always consider the differential diagnoses. A detailed clinical history is essential for assessment and a thorough clinical examination. In chronic B12/folate deficiency, a blood film will often show megaloblasts alongside macrocytic anaemia.
Patients with physiological B12 deficiency may have a B12 level within the normal range – nitrous oxide inactivates B12 and may not decrease levels.
A common way of accurately measuring physiological B12 deficiency is by measuring homocysteine (> 15 micromol/L) and methylmalonic acid (>270nmol/L). These are both precursors to vitamin B12 in cobalamin metabolism. Serum levels may be elevated due to an inability to react with oxidised B12.
Treatment of N2O-related neuropathies
The main goal of treatment of SACD and other neuropathies due to chronic N2O abuse is focused on supplementation with vitamin B12 and stopping ongoing damage.
Hydroxocobalamin can be given orally or parenterally.
1000 mcg IM once weekly for 1 month, before transitioning to oral supplements.
Treatment targets and response can be measured with regular homocysteine and methylmalonic acid assessment.
References
Qudsiya, Z. and De Jesus, O., 2020. Subacute combined degeneration of the spinal cord.
Wuebbles DJ. Nitrous oxide: no laughing matter. Science. 2009 Oct 2;326(5949):56-7.
