The increasing recreational use of nitrous oxide: history revisited

Nitrous oxide (N ₂ O) is used in the food industry as a mixing and foaming agent (E942) in the production of whipped cream, ^1,2 and as a fuel booster in the motor industry. ³ It is also a familiar agent in obstetric, dental, emergency, and anaesthetic practice, where use is made of its analgesic and anaesthetic properties. However, nitrous oxide was used recreationally long before its medical potential was realized. Joseph Priestly is accredited with first synthesizing the gas in 1772, ³ and by the late 18th century inhalation of nitrous oxide became a popular public entertainment. ⁴ The gas became a fashionable addition to British high-society parties in the early 1800s thanks to its euphoric and relaxant properties, which led chemist Humphrey Davy to coin the term ‘laughing gas’. ³

Although the routine use of nitrous oxide in anaesthesia is declining in both the UK ⁵ and internationally, ⁶ there has been a recent resurgence of recreational use of the gas. Its presence is now commonplace at festivals and university parties, ⁴ with a surprisingly high 7.6% of 16- to 24-yr-olds responding to the 2013/14 Crime Survey for England and Wales reporting nitrous oxide use in the preceding year. ² This is a greater proportion than had used cocaine, ecstasy, or ketamine. ⁴ Despite this, it is our impression that many anaesthetists and emergency department doctors are unaware of the scale of nitrous oxide use in the community.

The product is freely available from catering outlets, street vendors, and even via home-delivery service through the Internet or mobile vans advertising nitrous oxide for sale in UK cities. For recreational use, nitrous oxide is commonly sold in prefilled balloons (at point of use) or small pressurized metal canisters (Fig.  1 ) designed for the food industry. A standard catering canister containing 8 g of nitrous oxide in a volume of 10 cm ³ can be bought for as little as £2, ⁷ and produces the equivalent of ∼8 litres of nitrous oxide gas at standard temperature and pressure. ⁸ The pressurized gas is released into balloons using either a puncturing device, called a charger, or equipment designed to produce whipped cream. ^2,8 Once a user inhales from a balloon, the partial pressure of nitrous oxide increases in the lungs and subsequently in the bloodstream, producing the desired neurological effects.

Fig 1

Nitrous oxide canisters (Image source: pakete©123RF.com).

An ideal agent for recreational use?

The first time I inspired the nitrous oxide, I felt a highly pleasurable sensation of warmth over my whole frame … . The only motion which I felt inclined to make, was that of laughing at those who were looking at me. My eyes felt distended, and towards the last, my heart beat as if it were leaping up and down. On removing the mouth-piece, the whole sensation went off almost immediately.

Samuel Taylor Coleridge, poet, letter to Sir Humphrey Davy, 1799 ⁹

Nitrous oxide fulfils many of the desirable properties of an ideal agent for the food industry in that it is non-flammable, bacteriostatic, colourless, tasteless, and odourless. ¹ It also has properties that attract recreational drug users. It is legal, cheap, readily available, and undetectable on routine drug screens. It has a very rapid onset of action, such that the physiological effects (behavioural disinhibition, analgesia, and euphoria) begin within seconds of inhaling the gas. Its rapid offset of action and lack of hangover effect mean that the user may safely resume normal activities within a short time of exposure. As one university student described the experience: ‘it came on fast and totally wipes you out … and in five minutes you are ready to do your homework.’ ⁸

The gas produces minimal cardiorespiratory disturbance in fit patients and is rapidly and completely eliminated from the body after exposure, so is generally considered to be safe. ¹⁰ However, it may pose significant risks in certain population groups, and with particular methods of administration. There were 17 deaths related to nitrous oxide misuse reported between 2006 and 2012. ⁴ The true figure could be much higher, with intoxication falsely attributed to other drugs.

Dangers of recreational nitrous oxide use

Nitrous oxide has a number of specific adverse effects of relevance to patient selection for general anaesthesia involving the agent, ^11,12 but also poses risks to fit subjects engaged in recreational use.

High concentrations of inhaled nitrous oxide constitute a hypoxic inspired mixture. The dangers of such mixtures in the dental chair will be familiar to older generations of anaesthetists, and contributed to the Department of Health banning general anaesthesia by non-anaesthetists outside the hospital setting. ¹³ The likelihood and severity of resultant hypoxaemia will depend on the effectiveness of nitrous oxide delivery, air entrainment, depth of respiration, and breath-holding to alter washout of nitrogen, oxygen, and carbon dioxide from the lungs. Such hypoxaemia should be well tolerated by a fit person but could give rise to seizures, arrhythmias, or even respiratory or cardiac arrest in patients with epilepsy, cardiac disease, or other co-morbidities, especially if combined with other centrally acting or arrhythmogenic drugs.

Vomiting in patients who are obtunded by co-ingestion of other drugs carries an aspiration risk, and the disorientation and loss of motor control caused by nitrous oxide can result in trauma, particularly if used while driving or operating machinery. Although there is said to be no physiological addiction, like any drug, nitrous oxide can be habit forming, with the associated financial and social implications. ¹ A handbill from 1845 advertising a public demonstration of the effects of laughing gas proclaimed ‘those who inhale the Gas once are always anxious to inhale it a second time.’ ¹

Problems from chronic use

Chronic or intensive nitrous oxide abuse carries serious risks. Nitrous oxide interferes with DNA synthesis during even relatively short exposures, ¹¹ by directly inhibiting the enzyme methionine synthetase and inactivating its cofactor, vitamin B ₁₂ , resulting in reduced synthesis of methionine and tetrahydrofolate. A few hours of exposure can cause megaloblastic changes in the bone marrow, and days of exposure can cause agranulocytosis. ^11,12 The likelihood of vitamin B ₁₂ inactivation is increased in individuals abusing the gas in poorly ventilated environments and in those with pre-existing low vitamin concentrations, such as vegans or those with pernicious anaemia. Habitual abuse inhibits the synthesis of new methionine synthetase.

Chronic vitamin B ₁₂ inactivation can present with symptoms ranging from mild paraesthesiae ¹² to a neurological condition resembling subacute degeneration of the cord. ^11,14,15 Impairment of methylation of myelin sheath proteins results in axonal loss, causing myelopathy and peripheral neuropathy. Instances linked to chronic or intensive nitrous oxide abuse have presented with ascending or intermittent distal numbness, ataxia, impaired proprioception, and reduced grip strength. ^15,16 Investigations in these patients have revealed increased mean cell volume despite normal haemoglobin concentrations, low or low-normal vitamin B ₁₂ concentrations, high homocysteine (methionine precursor) concentrations, and long segmental hyperintensity changes in the posterior columns on magnetic resonance imaging. ¹⁵ Some of these patients have been treated successfully with vitamin B ₁₂ and folate supplementation alongside cessation of nitrous oxide use, but others have suffered permanent neuronal damage. ^15,16

In addition to neurological symptoms, functional vitamin B ₁₂ deficiency causes megaloblastic anaemia, skin hyperpigmentation, and vascular disease from hyperhomocysteinaemia, and is teratogenic. ^1,12,17

Problems from unregulated methods of administration

In medical practice, nitrous oxide is available as a piped supply of pure gas, which is delivered to the patient via a breathing circuit with a controlled supply of oxygen to avoid hypoxic mixtures, or as Entonox, a 50:50 mixture of N ₂ O and oxygen, which is delivered to the patient via tubing containing a demand valve. ¹¹ The demand valve forms a crucial inherent safety feature in that the patient must be capable of exerting sufficient inspiratory effort to release any Entonox from the supply, such that no further Entonox can be released to a patient obtunded by hypoxia. In this scenario, the rapid offset of action of the gas means that consciousness is rapidly restored, and breathing room air reverses the hypoxia.

In recreational use of nitrous oxide, inhaling the gas from a balloon has similar safety features. Air, and therefore oxygen, may be entrained alongside the gas on inhalation, and if the user is rendered hypoxic and loses consciousness, manual grip on the balloon will fail, propelling the balloon away. Assuming the airway remains patent, hypoxic drive will cause the user to start to breathe room air again, reversing the hypoxia. Permanent harm could occur if the user is obtunded with other drugs, or aspirates vomit, or is prone to seizures or cardiac dysrhythmias in the presence of hypoxia.

More dangerous effects have been recorded when alternative methods of nitrous oxide administration have been used. Some users dispense the nitrous oxide canisters into whipped cream dispensers (‘whippets’) and inhale the gas directly from the nozzle. The lack of a reducing valve means that this inhaled gas is under considerable pressure, and instances of pneumomediastinum and subcutaneous emphysema have been attributed to intra-alveolar rupture from this practice. ¹⁸

Through lack of available equipment, or through seeking to achieve higher concentrations of inspired gas, users may breathe nitrous oxide directly from canisters. When a compressed gas expands rapidly, it undergoes significant cooling as a result of adiabatic change of state (this is the physical principle underlying the mechanism of the cryoprobe used in therapeutic rapid freezing of tissues). ¹⁹ There is further cooling as a result of loss of latent heat of vaporization. ¹² The anaesthetic effects of the gas may make users initially unaware of the tissue damage being caused by inhalation of such cold gas or freezing of metal components of the delivery system, and frostbite of the mouth, nose and vocal cords is a recognized complication. ^1,8,12,20

The rapid offset of effects may cause abusers of the gas to explore methods of continuous inhalation of higher concentrations to enhance and prolong the effects, such as rebreathing in an enclosed container, such as a bag over the head, or opening cylinders in a small enclosed space, such as a car. This increases the ratio of N ₂ O to oxygen. Once there is significantly less than 20% oxygen in the inhaled gas, there is potential for irreversible hypoxic brain damage or death by asphyxiation. ^1,8 Simulations have confirmed the dangerous hypoxic environment that can be created inadvertently. When a standard 8 g nitrous oxide canister is punctured in an enclosed bag, such as that which has been found tied over the head of a fatality from nitrous oxide abuse, the percentage of nitrous oxide rapidly increases to 59%, while the oxygen concentrations decrease to 13% in 10 s, and only 10% within a minute. ⁸ Adding the effects of respiration within this enclosed environment would reduce the available oxygen even further as oxygen is used. At 50% inspired nitrous oxide, the normal response to hypoxia is blunted, making death from asphyxia even more likely. ⁸

Problems from unregulated manufacture and storage

Industrial manufacture of nitrous oxide involves heating ammonium nitrate to 250°C and then removing impurities, such as NH ₃ , N ₂ , NO, NO ₂ , and HNO ₃ , by passage through a series of washers and scrubbers. ^11,12 Unregulated manufacturing of the gas for recreational abuse is likely to have less stringent quality-control processes, and resultant inhaled impurities can cause harm. ²¹ Deaths have been reported after contamination of nitrous oxide balloons with butane, ⁷ and older anaesthetists will have learnt about patient fatalities in the UK in 1966 reported in a special BJA editorial. ²²

Improper storage of the gas also creates the potential for harm. Nitrous oxide for medical use is stored in cylinders below its critical temperature, so it exists as a vapour above a volume of nitrous oxide in its liquid phase. ¹² These cylinders are intentionally under-filled to accommodate increases in pressure as the vapour phase expands. Overfilling of the cylinders and storage above the critical temperature carries an explosion risk. ¹¹

Regulation of nitrous oxide

Nitrous oxide is not a controlled drug and therefore not subject to the Misuse of Drugs Act 1971. ² The large cylinders of nitrous oxide seen in hospitals are classed as medicinal products, and supplying or administering these without MHRA (Medicines and Healthcare products Regulatory Agency) authorization is a criminal offence under the Human Medicines Regulations 2012. However, the small canisters designed for the catering industry are not classed as medicinal products and therefore not subject to this Act. ²

Until very recently, it was not illegal to sell or possess nitrous oxide, given its legitimate uses. Possession of nitrous oxide with the intent to inhale is a misdemeanour in most states in the USA, ¹ and in the UK the Intoxicating Substances (Supply) Act 1985 prohibits the sale, to those under the age of 18 yr, of substances which the seller has reason to believe may be inhaled for the purposes of intoxication. ²³ Similar to glue, petrol, knives, and other legal substances that may cause harm through misuse, regulation of sale of this gas to adults is fraught with difficulty. In recognition of the resurgence of the recreational use of nitrous oxide and the difficulties in restricting its availability, the Advisory Council on the Misuse of Drugs recently issued public health safety advice and recommendations to the Government, local councils, and the Department of Health to increase awareness of this issue. ²⁴ In response to this, in May this year, the Home Office released new legislation, the Psychoactive Substances Bill 2015, ²⁵ which makes it an offence to ‘produce or supply any substance intended for human consumption that is capable of producing a psychoactive effect.’ Although medicinal nitrous oxide is exempt from this legislation, it does give the police and local authorities new powers to enforce civil sanctions against the supply of nitrous oxide for recreational use. It remains to be seen how effective such legislation will be, with the danger that resulting covert manufacture may lead to unforeseen consequences, such as increased concentrations of dangerous impurities in supplied nitrous oxide gas, while restrictions on supply of canisters and balloons may shift recreational abuse toward the more hazardous larger cylinders and airtight bags. ¹⁰

Relevance to anaesthetists and other medical professionals

Perceptions of relative safety of usage coupled with cheapness and ease of procurement of this gas make it an increasing public health issue.

Patients who suffer complications of acute nitrous oxide abuse (e.g. hypoxia, aspiration, cardiac arrthythmias, seizures, trauma, pneumomediastinum) may present to the emergency department, and recreational abuse should be considered as a differential diagnosis in these patients.

Chronic nitrous oxide abuse should be considered in the differential diagnosis of patients presenting with atypical neurological symptoms and signs, particularly where these resemble subacute degeneration of the cord. ¹⁵

With increasing popularity of this recreational drug, particularly among young adults, consideration should be given to counselling pregnant women against the teratogenic risks of chronic nitrous oxide use, alongside advice about other drugs, tobacco, and alcohol.

Increasing usage and documented complications of this gas may give insight into further potential hazards of medical use and exposure in health-care workers.

In conclusion, in most people, inhalation of nitrous oxide gas from balloons produces little or no adverse effect. However, intense or chronic abuse can cause permanent neurological damage, while rebreathing in an enclosed space can cause hypoxia and asphyxial death. Fatalities can also occur through contaminated supplies, or through trauma or aspiration, particularly when co-ingested with other drugs or alcohol. There should be increasing awareness among the clinical staff of the various presentations and dangers of this increasingly popular drug of abuse.

Authors' contributions

Co-wrote the manuscript: G.R., A.B.

Declaration of interest

A.B. is on the editorial board of British Journal of Anaesthesia and Journal of the Intensive Care Society .