Authors
Sally Turner
Published
August 30, 2024
What is nitrous oxide?
Discovered in 1722 by Dr Joseph Priestley, nitrous oxide (N2O) is now an essential medicine and a popular recreational drug.
Nitrous oxide is simply structured, with just two nitrogen atoms and one oxygen atom. It is an analgesic, anxiolytic, a sub-anaesthetic, and a recreational substance. It is used in medicine, dentistry, rocket science, motor racing, agriculture, and catering.
N2O is the third most used recreational drug in England and Wales[i, (a)] with nearly 9% of young adults using it at least once in their lifetime[i]. Most often, it is consumed via distributing the slightly sweet-tasting contents of gas canisters (either a ‘whippit’ that contains 8g of nitrous oxide or cylinders that contain up to 670g of the gas), into a balloon, which the consumer then inhales. In a medical context, nitrous oxide is typically balanced with Oxygen in a 50:50 up to 70:30 preparation.
What does nitrous oxide do, and how does it do it?
Nitrous oxide envelopes consumers in a brief but intense euphoric haze of dizziness, delirium, and giggles. Shortly after inhalation, consumers can sometimes experience acute cognitive difficulties, temporary motor control impairment, tingling in the limbs, sound distortion, and hallucinations. The effect wears off after a few minutes and full conscious is restored.
 | “The atmosphere of the highest of all possible heavens must be comprised of this gas. It made me laugh and tingle… it made one strong and so happy, so gloriously happy” (Robert Southey ~1799) |
For a drug with so many uses, our knowledge of how it works is relatively limited. We know that nitrous oxide has a multitude of effects that all seem to be modulated by different neuronal pathways or a combination of different pathways.
The euphoria, giggling, and hallucinations that can occur following nitrous oxide consumption are likely due to how it affects dopaminergic and glutamatergic neurotransmission (via inhibition of glutamate receptor N-methyl-D-aspartate/NMDA)[ii].
Analgesic drugs typically target opioid receptors in the midbrain[iii]. Nitrous oxide targets the opioid and norepinephrine neuronal systems. The interactions between these systems, alongside NMDA inhibition, likely explains nitrous oxide’s analgesic effects[iv, v, vi]. Nitrous oxide is also an anxiolytic; probably due to NMDA and gamma-aminobutyric acid (GABA) inhibition[vii]. The sub-anaesthetic qualities of N2O are likely down to how nitrous oxide imitates nitric oxide in the central nervous system[vii].
Importantly, nitrous oxide influences serotonergic neurotransmission, glycine, and activates K+ channels[vii]. However, how nitrous oxide affects these, and whether or not that impacts the psychological and physiological experiences induced by N2O, is currently unknown.
Recreational uses of nitrous oxide
Dubbed ‘hippy crack’ by misinformed tabloid journalists, nitrous oxide is far removed from crack cocaine, within its chemical structure, its harm potential, its legality, and its uses.
“Laughing gas parties” were a staple of Victorian nightlife in Britain. Scientific genius, Dr Humphrey Davy, frequently described the enjoyment him and his friends shared during such parties. Davy later conducted the first clinical trial of nitrous oxide in 1799.
Since then, the UK has the highest prevalence of nitrous oxide use across the world[viii]. Hearing the hissing of a whippet being cracked and balloons being filled with the gas has become a frequent occurrence for ravers and clubbers worldwide[ii]. Given that the night-time economy is synonymous with recreational use of nitrous oxide, it is unsurprising that 2/3 of consumers are below 24-years-old[vii].
Medicinal uses of nitrous oxide
Nitrous oxide also harbours a myriad of medicinal uses. If you have ever given birth, had a tooth extracted, or experienced a painful medical procedure, you are probably aware of how much relief you experienced when your clinician asks you to inhale a gas: that gas was likely nitrous oxide mixture[b]. Supportive data of nitrous oxide’s medicinal uses from the last 200 years warranted the WHO classifying nitrous oxide as an “essential” medicine[xv].
Nitrous oxide quickly and effectively relieves pain and can reduce anxiety[ix, x, xi]. Pain induced from cancer, labour, colonoscopies, biopsies, intravenous procedures, ophthalmologic procedures, and dental procedures, has shown to be responsive to nitrous oxide.[xii] One study suggested that at the right doses, nitrous oxide is as effective at relieving pain as morphine[xiii].
N2O’s painkilling and anaesthetic properties make it a useful tool for conscious patients undergoing painful clinical procedures, which is likely why it is the most commonly used sub-anaesthetic worldwide[xii, xiv]. Emerging preclinical and clinical research also suggests that nitrous oxide could also be an effective treatment for depression[xvi], alcohol withdrawal (in alcohol-dependent patients)[xvii], and Post-Traumatic Stress Disorder[xviii], although more supportive evidence is needed.
Is nitrous oxide harmful?
For UK-based consumers from 2023, the potential harms from using nitrous oxide are now three-fold: health, legal, and societal.
Serious health consequences from nitrous oxide are rare: in the last 20 years, 56 deaths in England and Wales involved nitrous oxide, in both medical and non-medical settings[i]. Excessive use may result in oxygen deprivation which can lead to heart attacks and, in some instances, can be fatal. Using N2O alongside other drugs in the same session also appears to increase the risk of adverse health outcomes and has occasionally been associated with respiratory depression and lung damage[xix, xxii]. Most nitrous-oxide related deaths, however, have been associated with excessive and/or risky N2O consumption[vii, xix].
As nitrous oxide can sometimes impair motor control and drop blood pressure, accidents and fainting can occur, which can cause additional consequences. Panic attacks and anxiety-related conditions have also been reported, although these seem rare and are likely restricted to those who consume nitrous oxide excessively[xix, xx, xxi].
N2O comes out of canisters and whippets at sub-zero temperatures (~-40°C), which risks consumers getting frostbite on exposed skin. This is more likely for those who dispense their nitrous oxide from cannisters, rather than whippets, although the risk is still present for whippet-users.
Heavy and prolonged use[v] of N2O has been associated with a variety of secondary health harms due to the neurotoxicity that it can cause. Such harms include cardiovascular problems[xix], neurological impairments[xxiii], cognitive impairments[xxiv], and vitamin B12 deficiency[xxv].
Recently, cylinders containing up to 670g of nitrous oxide have become easily available in the market (Fastgas, Smartwhipp, Cream Deluxe, Greatwhip). They contain roughly 75x the amount of gas in standard whippits. Cylinder use makes it easier to consume nitrous oxide in large amounts and there has been a link to higher prevalence of side effects[xxvi].
Intensive use (10–20 balloons or more daily) can lead to vitamin B12 defficiency causing serious neurological complications such as myelopathy and generalized demyelinating polyneuropathy[xxvii]. These complications are usually reversible and can generally be resolved through vitamin B12 supplementation (injections), but the neurological recovery may be retarded of even incomplete if patients continue to use nitrous oxide[xxvii].
When used chronically over an extended period of time, nitrous oxide may also affect DNA synthesis[xxviii], however, more research that examines the duration of time within which this can occur, is urgently needed.
Vitamin B12 deficiency is associated with similar levels of neurological and cognitive impairment that chronic use of nitrous oxide is[xix, xxix, xxx]. The risk and severity of neurotoxicity is greater in individuals with existing vitamin B12 deficiency. This makes it difficult to be certain about whether nitrous oxide or untreated vitamin B12 deficiency, or both, cause the health consequences that are often associated with chronic use of nitrous oxide.
Additionally, individuals of Asian ethnicities are disproportionately affected by nitrous-oxide-related neurological impairment; the exact reason for this is unknown[xxx]. However, nitrous oxide consumers, particularly those of Asian ethnicities or those with an existing or potential vitamin B12 deficiency, should approach nitrous oxide with extra caution.
Some evidence suggests a link between nitrous oxide and experiencing a psychotic episode[xix, xxxi]. However, the prevalence of this, and the confounding effect of vitamin B12 deficiency in studied samples, make it hard to estimate whether nitrous oxide causally increases this risk[xxix].
It is unknown whether nitrous oxide can cause dependence. Current evidence suggests it is rare, but possible[xxxii]. The psychokinetic properties of nitrous oxide make it highly unlikely that physical dependence could occur.
 | In 2023, and against expert advice and evidence provided by Drug Science and other professionals, the UK Government announced nitrous oxide will be classified under the Misuse of Drugs Act, 1971, citing reasons of littering and environmental concerns[vii]. |
Nitrous oxide, when used as an agricultural tool, can produce catastrophic environmental harms. This damage does not extend to its uses as a recreational or medicinal drug[vii]. Nitrous oxide and drug policy experts have stated that an abundance of unintended consequences is likely to occur as a result of nitrous oxide’s reclassification.
“I can’t see the enforcement approach doing anything positive… increasing risky behaviour [and] criminalising young people, which is far more dangerous than nitrous [oxide] anyway” -Steve Rolles, Transform Drug Policy Foundation (2022)
Currently, nitrous oxide supply and distribution are largely maintained by friends and family of consumers[vii]. This reduces potential contact between consumers and criminal gangs; consumers, therefore, are less likely to become victims of exploitative drug distribution chains. This is likely to change following the re-classification of nitrous oxide.
Professor Nutt has estimated that if just 10% of current nitrous oxide consumers in the UK were penalised for possession and usage, this would more than double the UK prison population in an already stretched justice system. It is likely that consumers (not suppliers) would avoid prison, and judges would instead, opt for community-based sentences. Such community-based justice, ironically, is associated with interpersonal harms that increase the risk and severity of drug use[xxxiii].
Take home message
Nitrous oxide has been a popular substance for hundreds of years and is now an essential medicine. Despite scattered evidence, serious health harms of nitrous oxide seem rare, and restricted to heavy use. Further research that examines causal associations between nitrous oxide and its potential harms, is urgently needed. Nitrous oxide carries some of the least risk of all drugs, however, the legal consequences of using nitrous oxide now risk subjugating almost a tenth of the UK’s younger generation to punitive harms.
Footnotes
[a] The ONS does not classify alcohol nor tobacco as drugs, and therefore, these estimations exclude both substances.
[b] Nitrous oxide, typically mixed with oxygen in 1:1 preparations, is used in 76% of births (CQC, 2021), and 94% of tooth extractions (Li et al., 2023)
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