Nitrous oxide

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Nitrous oxide
IUPAC name
Dinitrogen monoxide
Other names
Laughing gas, sweet air, protoxide of nitrogen, hyponitrous oxide
3D model (JSmol)
ECHA InfoCard 100.030.017
E number E942 (glazing agents, ...)
PubChem CID
RTECS number
  • QX1350000
UN number 1070 (compressed)
2201 (liquid)
Molar mass 44.013 g/mol
Appearancecolourless gas
Density 1.977 g/L (gas)
Melting point −90.86 °C (−131.55 °F; 182.29 K)
Boiling point −88.48 °C (−127.26 °F; 184.67 K)
1.5 g/L (15 °C)
Solubility soluble in alcohol, ether, sulfuric acid
log P 0.35
Vapor pressure 5150 kPa (20 °C)
−18.9·10−6 cm3/mol
1.000516 (0 °C, 101,325 kPa)
Viscosity 14.90 μPa·s [1]
linear, C∞v
0.166 D
219.96 JK−1mol−1
+82.05 kJmol−1
N01AX13 ( WHO )
  • US: C (Risk not ruled out)
    5 minutes
    Safety data sheet, ICSC 0067
    NFPA 704 (fire diamond)
    Flammability code 0: Will not burn. E.g. waterHealth code 2: Intense or continued but not chronic exposure could cause temporary incapacitation or possible residual injury. E.g. chloroformReactivity code 0: Normally stable, even under fire exposure conditions, and is not reactive with water. E.g. liquid nitrogenSpecial hazard OX: Oxidizer. E.g. potassium perchlorateNitrous oxide
    Flash point Nonflammable
    Related compounds
    Related nitrogen oxides
    Nitric oxide
    Dinitrogen trioxide
    Nitrogen dioxide
    Dinitrogen tetroxide
    Dinitrogen pentoxide
    Related compounds
    Ammonium nitrate
    Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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    Infobox references

    Nitrous oxide, commonly known as laughing gas or nitrous, [2] is a chemical compound, an oxide of nitrogen with the formula N
    . At room temperature, it is a colourless non-flammable gas, with a slight metallic scent and taste. At elevated temperatures, nitrous oxide is a powerful oxidizer similar to molecular oxygen. It is soluble in water.

    Chemical compound Substance composed of multiple elements

    A chemical compound is a chemical substance composed of many identical molecules composed of atoms from more than one element held together by chemical bonds. Two atoms of the same element bonded in a molecule do not form a chemical compound, since this would require two different elements.

    Nitrogen oxide may refer to a binary compound of oxygen and nitrogen, or a mixture of such compounds:

    A chemical formula is a way of presenting information about the chemical proportions of atoms that constitute a particular chemical compound or molecule, using chemical element symbols, numbers, and sometimes also other symbols, such as parentheses, dashes, brackets, commas and plus (+) and minus (−) signs. These are limited to a single typographic line of symbols, which may include subscripts and superscripts. A chemical formula is not a chemical name, and it contains no words. Although a chemical formula may imply certain simple chemical structures, it is not the same as a full chemical structural formula. Chemical formulas can fully specify the structure of only the simplest of molecules and chemical substances, and are generally more limited in power than are chemical names and structural formulas.


    Nitrous oxide has significant medical uses, especially in surgery and dentistry, for its anaesthetic and pain reducing effects. Its colloquial name "laughing gas", coined by Humphry Davy, is due to the euphoric effects upon inhaling it, a property that has led to its recreational use as a dissociative anaesthetic. It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system. [3] It is also used as an oxidiser in rocket propellants, and in motor racing to increase the power output of engines.

    Nitrous oxide (medication) Gas used as anesthetic and for pain relief

    Nitrous oxide, sold under the brand name Entonox among others, is an inhaled gas used as a pain medication and together with other medications for anesthesia. Common uses include during childbirth, following trauma, and as part of end of life care. Onset of effect is typically within half a minute and lasts for about a minute.

    Surgery Medical specialty

    Surgery is a medical specialty that uses operative manual and instrumental techniques on a patient to investigate or treat a pathological condition such as a disease or injury, to help improve bodily function or appearance or to repair unwanted ruptured areas.

    Dentistry branch of medicine

    Dentistry, also known as Dental and Oral Medicine, is a branch of medicine that consists of the study, diagnosis, prevention, and treatment of diseases, disorders, and conditions of the oral cavity, commonly in the dentition but also the oral mucosa, and of adjacent and related structures and tissues, particularly in the maxillofacial area. Although primarily associated with teeth among the general public, the field of dentistry or dental medicine is not limited to teeth but includes other aspects of the craniofacial complex including the temporomandibular joint and other supporting, muscular, lymphatic, nervous, vascular, and anatomical structures.

    Nitrous oxide occurs in small amounts in the atmosphere, but recently has been found to be a major scavenger of stratospheric ozone, with an impact comparable to that of CFCs. It is estimated that 30% of the N
    in the atmosphere is the result of human activity, chiefly agriculture. [4]

    Ozone layer The region of Earths stratosphere that absorbs most of the Suns UV radiation

    The ozone layer or ozone shield is a region of Earth's stratosphere that absorbs most of the Sun's ultraviolet radiation. It contains high concentration of ozone (O3) in relation to other parts of the atmosphere, although still small in relation to other gases in the stratosphere. The ozone layer contains less than 10 parts per million of ozone, while the average ozone concentration in Earth's atmosphere as a whole is about 0.3 parts per million. The ozone layer is mainly found in the lower portion of the stratosphere, from approximately 15 to 35 kilometers (9.3 to 21.7 mi) above Earth, although its thickness varies seasonally and geographically.

    Chlorofluorocarbons (CFCs) and hydrochlorofluorocarbons (HCFCs) are fully or partly halogenated paraffin hydrocarbons that contain only carbon (C), hydrogen (H), chlorine (Cl), and fluorine (F), produced as volatile derivative of methane, ethane, and propane. They are also commonly known by the DuPont brand name Freon.

    Agriculture Cultivation of plants and animals to provide useful products

    Agriculture is the science and art of cultivating plants and livestock. Agriculture was the key development in the rise of sedentary human civilization, whereby farming of domesticated species created food surpluses that enabled people to live in cities. The history of agriculture began thousands of years ago. After gathering wild grains beginning at least 105,000 years ago, nascent farmers began to plant them around 11,500 years ago. Pigs, sheep and cattle were domesticated over 10,000 years ago. Plants were independently cultivated in at least 11 regions of the world. Industrial agriculture based on large-scale monoculture in the twentieth century came to dominate agricultural output, though about 2 billion people still depended on subsistence agriculture into the twenty-first.


    Rocket motors

    Nitrous oxide may be used as an oxidiser in a rocket motor. This is advantageous over other oxidisers in that it is much less toxic, and due to its stability at room temperature is also easier to store and relatively safe to carry on a flight. As a secondary benefit, it may be decomposed readily to form breathing air. Its high density and low storage pressure (when maintained at low temperature) enable it to be highly competitive with stored high-pressure gas systems. [5]

    Oxidizing agent Chemical compound used to oxidize another substance in a chemical reaction

    In chemistry, an oxidizing agent is a substance that has the ability to oxidize other substances — in other words to accept their electrons. Common oxidizing agents are oxygen, hydrogen peroxide and the halogens.

    Rocket pyrokinetic engine used for propulsion; for the incendiary weapon, see Q2037215

    A rocket is a missile, spacecraft, aircraft or other vehicle that obtains thrust from a rocket engine. Rocket engine exhaust is formed entirely from propellant carried within the rocket. Rocket engines work by action and reaction and push rockets forward simply by expelling their exhaust in the opposite direction at high speed, and can therefore work in the vacuum of space.

    In a 1914 patent, American rocket pioneer Robert Goddard suggested nitrous oxide and gasoline as possible propellants for a liquid-fuelled rocket. [6] Nitrous oxide has been the oxidiser of choice in several hybrid rocket designs (using solid fuel with a liquid or gaseous oxidiser). The combination of nitrous oxide with hydroxyl-terminated polybutadiene fuel has been used by SpaceShipOne and others. It also is notably used in amateur and high power rocketry with various plastics as the fuel.

    Hydroxyl-terminated polybutadiene (HTPB) is an oligomer of butadiene terminated at each end with a hydroxyl functional group. It reacts with isocyanates to form polyurethane polymers.

    SpaceShipOne Suborbital air-launched spaceplane

    SpaceShipOne is an experimental air-launched rocket-powered aircraft with sub-orbital spaceflight capability at speeds of up to 900 m/s (3,000 ft/s), using a hybrid rocket motor. The design features a unique "feathering" atmospheric reentry system where the rear half of the wing and the twin tail booms folds 70 degrees upward along a hinge running the length of the wing; increasing drag while remaining stable. SpaceShipOne completed the first manned private spaceflight in 2004. That same year, it won the US$10 million Ansari X Prize and was immediately retired from active service. Its mother ship was named "White Knight". Both craft were developed and flown by Mojave Aerospace Ventures, which was a joint venture between Paul Allen and Scaled Composites, Burt Rutan's aviation company. Allen provided the funding of approximately US$25 million.

    Amateur rocketry hobby in which participants experiment with fuels or custom rocket motors

    Amateur rocketry, sometimes known as experimental rocketry or amateur experimental rocketry, is a hobby in which participants experiment with fuels and make their own rocket motors, launching a wide variety of types and sizes of rockets. Amateur rocketeers have been responsible for significant research into hybrid rocket motors, and have built and flown a variety of solid, liquid, and hybrid propellant motors.

    Nitrous oxide also may be used in a monopropellant rocket. In the presence of a heated catalyst, N
    will decompose exothermically into nitrogen and oxygen, at a temperature of approximately 1,070 °F (577 °C). [7] Because of the large heat release, the catalytic action rapidly becomes secondary, as thermal autodecomposition becomes dominant. In a vacuum thruster, this may provide a monopropellant specific impulse (Isp) of as much as 180 s. While noticeably less than the Isp available from hydrazine thrusters (monopropellant or bipropellant with dinitrogen tetroxide), the decreased toxicity makes nitrous oxide an option worth investigating.

    A monopropellant rocket is a rocket that uses a single chemical as its propellant.

    Specific impulse is a measure of how effectively a rocket uses propellant or a jet engine uses fuel. Specific impulse can be calculated in a variety of different ways with different units. By definition, it is the total impulse delivered per unit of propellant consumed and is dimensionally equivalent to the generated thrust divided by the propellant mass flow rate or weight flow rate. If mass is used as the unit of propellant, then specific impulse has units of velocity. If weight is used instead, then specific impulse has units of time (seconds). Multiplying flow rate by the standard gravity (g0) converts specific impulse from the weight basis to the mass basis.

    Hydrazine A colorless flammable liquid with an ammonia-like odor

    Hydrazine is an inorganic compound with the chemical formula N
    . It is a simple pnictogen hydride, and is a colorless and flammable liquid with an ammonia-like odor.

    Nitrous oxide is said to deflagrate at approximately 600 °C (1,112 °F) at a pressure of 309 psi (21 atmospheres). [8] At 600 psi, for example, the required ignition energy is only 6 joules, whereas N
    at 130 psi a 2,500-joule ignition energy input is insufficient. [9] [10]

    Internal combustion engine

    In vehicle racing, nitrous oxide (often referred to as just "nitrous") allows the engine to burn more fuel by providing more oxygen than air alone, resulting in a more powerful combustion.[ citation needed ] The gas is not flammable at a low pressure/temperature, but it delivers more oxygen than atmospheric air by breaking down at elevated temperatures. Therefore, it often is mixed with another fuel that is easier to deflagrate. Nitrous oxide is a strong oxidising agent, roughly equivalent to hydrogen peroxide, and much stronger than oxygen gas.

    Nitrous oxide is stored as a compressed liquid; the evaporation and expansion of liquid nitrous oxide in the intake manifold causes a large drop in intake charge temperature, resulting in a denser charge, further allowing more air/fuel mixture to enter the cylinder. Sometimes nitrous oxide is injected into (or prior to) the intake manifold, whereas other systems directly inject, right before the cylinder (direct port injection) to increase power.

    The technique was used during World War II by Luftwaffe aircraft with the GM-1 system to boost the power output of aircraft engines. Originally meant to provide the Luftwaffe standard aircraft with superior high-altitude performance, technological considerations limited its use to extremely high altitudes. Accordingly, it was only used by specialised planes such as high-altitude reconnaissance aircraft, high-speed bombers and high-altitude interceptor aircraft. It sometimes could be found on Luftwaffe aircraft also fitted with another engine-boost system, MW 50, a form of water injection for aviation engines that used methanol for its boost capabilities.

    One of the major problems of using nitrous oxide in a reciprocating engine is that it can produce enough power to damage or destroy the engine. Very large power increases are possible, and if the mechanical structure of the engine is not properly reinforced, the engine may be severely damaged, or destroyed, during this kind of operation. It is very important with nitrous oxide augmentation of petrol engines to maintain proper operating temperatures and fuel levels to prevent "pre-ignition", [11] or "detonation" (sometimes referred to as "knock"). Most problems that are associated with nitrous oxide do not come from mechanical failure due to the power increases. Since nitrous oxide allows a much denser charge into the cylinder, it dramatically increases cylinder pressures. The increased pressure and temperature can cause problems such as melting the piston or valves. It also may crack or warp the piston or head and cause pre-ignition due to uneven heating.

    Automotive-grade liquid nitrous oxide differs slightly from medical-grade nitrous oxide. A small amount of sulfur dioxide (SO
    ) is added to prevent substance abuse. [12] Multiple washes through a base (such as sodium hydroxide) can remove this, decreasing the corrosive properties observed when SO
    is further oxidised during combustion into sulfuric acid, making emissions cleaner.[ citation needed ]

    Aerosol propellant

    Food-grade N
2O whippets N2O whippets.jpg
    Food-grade N

    The gas is approved for use as a food additive (E number: E942), specifically as an aerosol spray propellant. Its most common uses in this context are in aerosol whipped cream canisters and cooking sprays.

    The gas is extremely soluble in fatty compounds. In aerosol whipped cream, it is dissolved in the fatty cream until it leaves the can, when it becomes gaseous and thus creates foam. Used in this way, it produces whipped cream which is four times the volume of the liquid, whereas whipping air into cream only produces twice the volume. If air were used as a propellant, oxygen would accelerate rancidification of the butterfat, but nitrous oxide inhibits such degradation. Carbon dioxide cannot be used for whipped cream because it is acidic in water, which would curdle the cream and give it a seltzer-like "sparkling" sensation.

    The whipped cream produced with nitrous oxide is unstable, however, and will return to a more liquid state within half an hour to one hour. [13] Thus, the method is not suitable for decorating food that will not be served immediately.

    During December 2016, some manufacturers reported a shortage of aerosol whipped creams in the United States due to an explosion at the Air Liquide nitrous oxide facility in Florida in late August. With a major facility offline, the disruption caused a shortage resulting in the company diverting the supply of nitrous oxide to medical clients rather than to food manufacturing. The shortage came during the Christmas and holiday season when canned whipped cream use is normally at its highest. [14]

    Similarly, cooking spray, which is made from various types of oils combined with lecithin (an emulsifier), may use nitrous oxide as a propellant. Other propellants used in cooking spray include food-grade alcohol and propane.


    Medical-grade N
2O tanks used in dentistry N2O Medical Tanks.jpg
    Medical-grade N
    tanks used in dentistry

    Nitrous oxide has been used in dentistry and surgery, as an anaesthetic and analgesic, since 1844. [15]

    In the early days, the gas was administered through simple inhalers consisting of a breathing bag made of rubber cloth. [16] Today, the gas is administered in hospitals by means of an automated relative analgesia machine, with an anaesthetic vaporiser and a medical ventilator, that delivers a precisely dosed and breath-actuated flow of nitrous oxide mixed with oxygen in a 2:1 ratio.

    Nitrous oxide is a weak general anaesthetic, and so is generally not used alone in general anaesthesia, but used as a carrier gas (mixed with oxygen) for more powerful general anaesthetic drugs such as sevoflurane or desflurane. It has a minimum alveolar concentration of 105% and a blood/gas partition coefficient of 0.46. The use of nitrous oxide in anaesthesia, however, can increase the risk of postoperative nausea and vomiting. [17] [18] [19]

    Dentists use a simpler machine which only delivers an N
    mixture for the patient to inhale while conscious. The patient is kept conscious throughout the procedure, and retains adequate mental faculties to respond to questions and instructions from the dentist. [20]

    Inhalation of nitrous oxide is used frequently to relieve pain associated with childbirth, trauma, oral surgery and acute coronary syndrome (includes heart attacks). Its use during labour has been shown to be a safe and effective aid for birthing women. [21] Its use for acute coronary syndrome is of unknown benefit. [22]

    In Britain and Canada, Entonox and Nitronox are used commonly by ambulance crews (including unregistered practitioners) as a rapid and highly effective analgesic gas.

    Fifty per cent nitrous oxide can be considered for use by trained non-professional first aid responders in prehospital settings, given the relative ease and safety of administering 50% nitrous oxide as an analgesic. The rapid reversibility of its effect would also prevent it from precluding diagnosis. [23]

    Recreational use

    Aquatint depiction of a laughing gas party in the nineteenth century Doctor and Mrs Syntax, with a party of friends, experimentin Wellcome L0022227.jpg
    Aquatint depiction of a laughing gas party in the nineteenth century
    Whippit remnants of recreational drug use, the Netherlands, 2017 Nitrous oxide whippits used recreationally as a drug by Dutch youngsters near a school, Utrecht, 2017 - 1.jpg
    Whippit remnants of recreational drug use, the Netherlands, 2017

    Recreational inhalation of nitrous oxide, with the purpose of causing euphoria and/or slight hallucinations, began as a phenomenon for the British upper class in 1799, known as "laughing gas parties".

    Starting in the nineteenth century, widespread availability of the gas for medical and culinary purposes allowed the recreational use to expand greatly throughout the world. In the United Kingdom, as of 2014, nitrous oxide was estimated to be used by almost half a million young people at nightspots, festivals and parties. [24] The legality of that use varies greatly from country to country, and even from city to city in some countries.

    Widespread recreational use of the drug throughout the UK was featured in the 2017 Vice documentary Inside The Laughing Gas Black Market, in which journalist Matt Shea met with dealers of the drug who stole it from hospitals, [25] although with nitrous oxide canisters being readily available online, the incidents of hospital theft are expected to be extremely rare.

    A significant issue cited in London's press [26] is the effect of nitrous oxide canister littering, which is highly visible and causes significant complaint from communities. If recreational users in built up areas began to recycle the pure steel canisters after use, some experts believe the stigma attached to the recreational use may dissipate.


    The major safety hazards of nitrous oxide come from the fact that it is a compressed liquefied gas, an asphyxiation risk and a dissociative anaesthetic.

    While relatively non-toxic, nitrous oxide has a number of recognised ill effects on human health, whether through breathing it in or by contact of the liquid with skin or eyes.

    Nitrous oxide is a significant occupational hazard for surgeons, dentists and nurses. Because nitrous oxide is minimally metabolised in humans (with a rate of 0.004%), it retains its potency when exhaled into the room by the patient, and can pose an intoxicating and prolonged exposure hazard to the clinic staff if the room is poorly ventilated. Where nitrous oxide is administered, a continuous-flow fresh-air ventilation system or N
    scavenger system is used to prevent a waste-gas buildup.

    The National Institute for Occupational Safety and Health recommends that workers' exposure to nitrous oxide should be controlled during the administration of anaesthetic gas in medical, dental and veterinary operators. [27] It set a recommended exposure limit (REL) of 25 ppm (46 mg/m3) to escaped anaesthetic. [28]

    Mental and manual impairment

    Exposure to nitrous oxide causes short-term decreases in mental performance, audiovisual ability and manual dexterity. [29] These effects coupled with the induced spatial and temporal disorientation could result in physical harm to the user from environmental hazards. [30]

    Neurotoxicity and neuroprotection

    Like other NMDA antagonists, N
    was suggested to produce neurotoxicity in the form of Olney's lesions in rodents upon prolonged (several hour) exposure. [31] [32] [33] [34] New research has arisen suggesting that Olney's lesions do not occur in humans, however, and similar drugs such as ketamine are now believed not to be acutely neurotoxic. [35] [36] It has been argued that, because N
    has a very short duration under normal circumstances, it is less likely to be neurotoxic than other NMDA antagonists. [37] Indeed, in rodents, short-term exposure results in only mild injury that is rapidly reversible, and neuronal death occurs only after constant and sustained exposure. [31] Nitrous oxide also may cause neurotoxicity after extended exposure because of hypoxia. This is especially true of non-medical formulations such as whipped-cream chargers (also known as "whippets" or "nangs"), [38] which never contain oxygen, since oxygen makes cream rancid. [39]

    Additionally, nitrous oxide depletes vitamin B12 levels. This can cause serious neurotoxicity if the user has preexisting vitamin B12 deficiency. [40]

    Nitrous oxide at 75% by volume reduces ischemia-induced neuronal death induced by occlusion of the middle cerebral artery in rodents, and decreases NMDA-induced Ca2+ influx in neuronal cell cultures, a critical event involved in excitotoxicity. [37]

    Oxygen deprivation

    If pure nitrous oxide is inhaled without oxygen mixed in, this can eventually lead to oxygen deprivation resulting in loss of blood pressure, fainting and even heart attacks. This can occur if the user inhales large quantities continuously, as with a strap-on mask connected to a gas canister. It can also happen if the user engages in excessive breath-holding or uses any other inhalation system that cuts off a supply of fresh air. [41]

    Vitamin B12 deficiency

    Long-term exposure to nitrous oxide may cause vitamin B12 deficiency. It inactivates the cobalamin form of vitamin B12 by oxidation. Symptoms of vitamin B12 deficiency, including sensory neuropathy, myelopathy and encephalopathy, may occur within days or weeks of exposure to nitrous oxide anaesthesia in people with subclinical vitamin B12 deficiency.

    Symptoms are treated with high doses of vitamin B12, but recovery can be slow and incomplete. [42]

    People with normal vitamin B12 levels have stores to make the effects of nitrous oxide insignificant, unless exposure is repeated and prolonged (nitrous oxide abuse). Vitamin B12 levels should be checked in people with risk factors for vitamin B12 deficiency prior to using nitrous oxide anaesthesia. [43]

    Prenatal development

    Several experimental studies in rats indicate that chronic exposure of pregnant females to nitrous oxide may have adverse effects on the developing fetus. [44] [44] [45] [46]

    Chemical/physical risks

    At room temperature (20 °C [68 °F]) the saturated vapour pressure is 50.525 bar, rising up to 72.45 bar at 36.4 °C (97.5 °F)—the critical temperature. The pressure curve is thus unusually sensitive to temperature. [47]

    As with many strong oxidisers, contamination of parts with fuels have been implicated in rocketry accidents, where small quantities of nitrous/fuel mixtures explode due to "water hammer"-like effects (sometimes called "dieseling"—heating due to adiabatic compression of gases can reach decomposition temperatures). [48] Some common building materials such as stainless steel and aluminium can act as fuels with strong oxidisers such as nitrous oxide, as can contaminants that may ignite due to adiabatic compression. [49]

    There also have been incidents where nitrous oxide decomposition in plumbing has led to the explosion of large tanks. [8]

    Mechanism of action

    The pharmacological mechanism of action of N
    in medicine is not fully known. However, it has been shown to directly modulate a broad range of ligand-gated ion channels, and this likely plays a major role in many of its effects. It moderately blocks NMDA and β2-subunit-containing nACh channels, weakly inhibits AMPA, kainate, GABAC and 5-HT3 receptors, and slightly potentiates GABAA and glycine receptors. [50] [51] It also has been shown to activate two-pore-domain K+
    . [52] While N
    affects quite a few ion channels, its anaesthetic, hallucinogenic and euphoriant effects are likely caused predominantly, or fully, via inhibition of NMDA receptor-mediated currents. [50] [53] In addition to its effects on ion channels, N
    may act to imitate nitric oxide (NO) in the central nervous system, and this may be related to its analgesic and anxiolytic properties. [53] Nitrous oxide is 30 to 40 times more soluble than nitrogen.

    The effects of inhaling sub-anaesthetic doses of nitrous oxide have been known to vary, based on several factors, including settings and individual differences; [54] [55] however, from his discussion, Jay (2008) [30] suggests that it has been reliably known to induce the following states and sensations:

    A minority of users also will present with uncontrolled vocalisations and muscular spasms. These effects generally disappear minutes after removal of the nitrous oxide source. [30]

    Euphoric effect

    In rats, N
    stimulates the mesolimbic reward pathway by inducing dopamine release and activating dopaminergic neurons in the ventral tegmental area and nucleus accumbens, presumably through antagonisation of NMDA receptors localised in the system. [56] [57] [58] [59] This action has been implicated in its euphoric effects and, notably, appears to augment its analgesic properties as well. [56] [57] [58] [59]

    It is remarkable, however, that in mice, N
    blocks amphetamine-induced carrier-mediated dopamine release in the nucleus accumbens and behavioural sensitisation, abolishes the conditioned place preference (CPP) of cocaine and morphine, and does not produce reinforcing (or aversive) effects of its own. [60] [61] Effects of CPP of N
    in rats are mixed, consisting of reinforcement, aversion and no change. [62] In contrast, it is a positive reinforcer in squirrel monkeys, [63] and is well known as a drug of abuse in humans. [64] These discrepancies in response to N
    may reflect species variation or methodological differences. [61] In human clinical studies, N
    was found to produce mixed responses, similarly to rats, reflecting high subjective individual variability. [65] [66]

    Anxiolytic effect

    In behavioural tests of anxiety, a low dose of N
    is an effective anxiolytic, and this anti-anxiety effect is associated with enhanced activity of GABAA receptors, as it is partially reversed by benzodiazepine receptor antagonists. Mirroring this, animals that have developed tolerance to the anxiolytic effects of benzodiazepines are partially tolerant to N
    . [67] Indeed, in humans given 30% N
    , benzodiazepine receptor antagonists reduced the subjective reports of feeling "high", but did not alter psychomotor performance, in human clinical studies. [68]

    Analgesic effect

    The analgesic effects of N
    are linked to the interaction between the endogenous opioid system and the descending noradrenergic system. When animals are given morphine chronically, they develop tolerance to its pain-killing effects, and this also renders the animals tolerant to the analgesic effects of N
    . [69] Administration of antibodies that bind and block the activity of some endogenous opioids (not β-endorphin) also block the antinociceptive effects of N
    . [70] Drugs that inhibit the breakdown of endogenous opioids also potentiate the antinociceptive effects of N
    . [70] Several experiments have shown that opioid receptor antagonists applied directly to the brain block the antinociceptive effects of N
    , but these drugs have no effect when injected into the spinal cord.

    Conversely, α2-adrenoceptor antagonists block the pain-reducing effects of N
    when given directly to the spinal cord, but not when applied directly to the brain. [71] Indeed, α2B-adrenoceptor knockout mice or animals depleted in norepinephrine are nearly completely resistant to the antinociceptive effects of N
    . [72] Apparently N
    -induced release of endogenous opioids causes disinhibition of brainstem noradrenergic neurons, which release norepinephrine into the spinal cord and inhibit pain signalling. [73] Exactly how N
    causes the release of endogenous opioid peptides remains uncertain.

    Properties and reactions

    Nitrous oxide is a colourless, non-toxic gas with a faint, sweet odour.

    Nitrous oxide supports combustion by releasing the dipolar bonded oxygen radical, and can thus relight a glowing splint.

    is inert at room temperature and has few reactions. At elevated temperatures, its reactivity increases. For example, nitrous oxide reacts with NaNH
    at 460 K (187 °C) to give NaN

    2 NaNH
    + N
    + NaOH + NH

    The above reaction is the route adopted by the commercial chemical industry to produce azide salts, which are used as detonators. [74]


    The gas was first synthesised in 1772 by English natural philosopher and chemist Joseph Priestley who called it phlogisticated nitrous air (see phlogiston theory) [75] or inflammable nitrous air. [76] Priestley published his discovery in the book Experiments and Observations on Different Kinds of Air (1775), where he described how to produce the preparation of "nitrous air diminished", by heating iron filings dampened with nitric acid. [77]

    Early use

A satirical print from 1830 depicting Humphry Davy administering a dose of laughing gas to a woman Laughing gas Rumford Davy.jpg
    A satirical print from 1830 depicting Humphry Davy administering a dose of laughing gas to a woman

    The first important use of nitrous oxide was made possible by Thomas Beddoes and James Watt, who worked together to publish the book Considerations on the Medical Use and on the Production of Factitious Airs (1794). This book was important for two reasons. First, James Watt had invented a novel machine to produce "Factitious Airs" (i.e. nitrous oxide) and a novel "breathing apparatus" to inhale the gas. Second, the book also presented the new medical theories by Thomas Beddoes, that tuberculosis and other lung diseases could be treated by inhalation of "Factitious Airs". [15]

    Sir Humphry Davy's Researches chemical and philosophical: chiefly concerning nitrous oxide (1800), pages 556 and 557 (right), outlining potential anaesthetic properties of nitrous oxide in relieving pain during surgery Anaesthesia exhibition, 1946 Wellcome M0009908.jpg
    Sir Humphry Davy's Researches chemical and philosophical: chiefly concerning nitrous oxide (1800), pages 556 and 557 (right), outlining potential anaesthetic properties of nitrous oxide in relieving pain during surgery

    The machine to produce "Factitious Airs" had three parts: a furnace to burn the needed material, a vessel with water where the produced gas passed through in a spiral pipe (for impurities to be "washed off"), and finally the gas cylinder with a gasometer where the gas produced, "air", could be tapped into portable air bags (made of airtight oily silk). The breathing apparatus consisted of one of the portable air bags connected with a tube to a mouthpiece. With this new equipment being engineered and produced by 1794, the way was paved for clinical trials,[ clarification needed ] which began in 1798 when Thomas Beddoes established the "Pneumatic Institution for Relieving Diseases by Medical Airs" in Hotwells (Bristol). In the basement of the building, a large-scale machine was producing the gases under the supervision of a young Humphry Davy, who was encouraged to experiment with new gases for patients to inhale. [15] The first important work of Davy was examination of the nitrous oxide, and the publication of his results in the book: Researches, Chemical and Philosophical (1800). In that publication, Davy notes the analgesic effect of nitrous oxide at page 465 and its potential to be used for surgical operations at page 556. [78] Davy coined the name "laughing gas" for nitrous oxide. [79]

    Despite Davy's discovery that inhalation of nitrous oxide could relieve a conscious person from pain, another 44 years elapsed before doctors attempted to use it for anaesthesia. The use of nitrous oxide as a recreational drug at "laughing gas parties", primarily arranged for the British upper class, became an immediate success beginning in 1799. While the effects of the gas generally make the user appear stuporous, dreamy and sedated, some people also "get the giggles" in a state of euphoria, and frequently erupt in laughter. [80]

    One of the earliest commercial producers in the U.S. was George Poe, cousin of the poet Edgar Allan Poe, who also was the first to liquefy the gas. [81]

    Anaesthetic use

    The first time nitrous oxide was used as an anaesthetic drug in the treatment of a patient was when dentist Horace Wells, with assistance by Gardner Quincy Colton and John Mankey Riggs, demonstrated insensitivity to pain from a dental extraction on 11 December 1844. [82] In the following weeks, Wells treated the first 12 to 15 patients with nitrous oxide in Hartford, Connecticut, and, according to his own record, only failed in two cases. [83] In spite of these convincing results having been reported by Wells to the medical society in Boston in December 1844, this new method was not immediately adopted by other dentists. The reason for this was most likely that Wells, in January 1845 at his first public demonstration to the medical faculty in Boston, had been partly unsuccessful, leaving his colleagues doubtful regarding its efficacy and safety. [84] The method did not come into general use until 1863, when Gardner Quincy Colton successfully started to use it in all his "Colton Dental Association" clinics, that he had just established in New Haven and New York City. [15] Over the following three years, Colton and his associates successfully administered nitrous oxide to more than 25,000 patients. [16] Today, nitrous oxide is used in dentistry as an anxiolytic, as an adjunct to local anaesthetic.

    Nitrous oxide was not found to be a strong enough anaesthetic for use in major surgery in hospital settings, however. Instead, diethyl ether, being a stronger and more potent anaesthetic, was demonstrated and accepted for use in October 1846, along with chloroform in 1847. [15] When Joseph Thomas Clover invented the "gas-ether inhaler" in 1876, however, it became a common practice at hospitals to initiate all anaesthetic treatments with a mild flow of nitrous oxide, and then gradually increase the anaesthesia with the stronger ether or chloroform. Clover's gas-ether inhaler was designed to supply the patient with nitrous oxide and ether at the same time, with the exact mixture being controlled by the operator of the device. It remained in use by many hospitals until the 1930s. [16] Although hospitals today use a more advanced anaesthetic machine, these machines still use the same principle launched with Clover's gas-ether inhaler, to initiate the anaesthesia with nitrous oxide, before the administration of a more powerful anaesthetic.

    As a patent medicine

    Colton's popularisation of nitrous oxide led to its adoption by a number of less than reputable quacksalvers, who touted it as a cure for consumption, scrofula, catarrh and other diseases of the blood, throat and lungs. Nitrous oxide treatment was administered and licensed as a patent medicine by the likes of C. L. Blood and Jerome Harris in Boston and Charles E. Barney of Chicago. [85] [86]


    Reviewing various methods of producing nitrous oxide is published. [87]

    Industrial methods

    Nitrous oxide production Nitrous oxide production.png
    Nitrous oxide production

    Nitrous oxide is prepared on an industrial scale by careful heating of ammonium nitrate [87] at about 250 C, which decomposes into nitrous oxide and water vapour. [88]

    → 2 H
    + N

    The addition of various phosphate salts favours formation of a purer gas at slightly lower temperatures. This reaction may be difficult to control, resulting in detonation. [89]

    Laboratory methods

    The decomposition of ammonium nitrate is also a common laboratory method for preparing the gas. Equivalently, it can be obtained by heating a mixture of sodium nitrate and ammonium sulfate: [90]

    2 NaNO
    + (NH
    + 2 N
    + 4 H

    Another method involves the reaction of urea, nitric acid and sulfuric acid: [91]

    2 (NH2)2CO + 2 HNO
    + H
    → 2 N
    + 2 CO
    + (NH4)2SO4 + 2H

    Direct oxidation of ammonia with a manganese dioxide-bismuth oxide catalyst has been reported: [92] cf. Ostwald process.

    2 NH
    + 2 O
    + 3 H

    Hydroxylammonium chloride reacts with sodium nitrite to give nitrous oxide. If the nitrite is added to the hydroxylamine solution, the only remaining by-product is salt water. If the hydroxylamine solution is added to the nitrite solution (nitrite is in excess), however, then toxic higher oxides of nitrogen also are formed:

    Cl + NaNO
    + NaCl + 2 H

    Treating HNO
    with SnCl
    and HCl also has been demonstrated:

    2 HNO
    + 8 HCl + 4 SnCl
    → 5 H
    + 4 SnCl
    + N

    Hyponitrous acid decomposes to N2O and water with a half-life of 16 days at 25 °C at pH 1–3. [93]

    H2N2O2→ H2O + N2O

    Atmospheric occurrence

    Nitrous oxide is a minor component of Earth's atmosphere, currently with a concentration of about 0.330 ppm. [94]

    Emissions by source

    As of 2010, it was estimated that about 29.5 million tonnes of N
    (containing 18.8 million tonnes of nitrogen) were entering the atmosphere each year; of which 64% were natural, and 36% due to human activity. [95] [96]

    Most of the N
    emitted into the atmosphere, from natural and anthropogenic sources, is produced by microorganisms such as bacteria and fungi in soils and oceans. [97] Soils under natural vegetation are an important source of nitrous oxide, accounting for 60% of all naturally produced emissions. Other natural sources include the oceans (35%) and atmospheric chemical reactions (5%). [95]

    Emissions from thawing permafrost are probably higher than previously assumed. [98]

    The main components of anthropogenic emissions are fertilised agricultural soils and livestock manure (42%), runoff and leaching of fertilisers (25%), biomass burning (10%), fossil fuel combustion and industrial processes (10%), biological degradation of other nitrogen-containing atmospheric emissions (9%) and human sewage (5%). [99] [100] [101] [102] [103] Agriculture enhances nitrous oxide production through soil cultivation, the use of nitrogen fertilisers and animal waste handling. These activities stimulate naturally-occurring bacteria to produce more nitrous oxide. Nitrous oxide emissions from soil can be challenging to measure as they vary markedly over time and space, [104] and the majority of a year's emissions may occur when conditions are favorable during "hot moments" [105] [106] and/or at favorable locations known as "hotspots". [107]

    Among industrial emissions, the production of nitric acid and adipic acid are the largest sources of nitrous oxide emissions. The adipic acid emissions specifically arise from the degradation of the nitrolic acid intermediate derived from nitration of cyclohexanone. [99] [108] [109]

    Biological processes

    Natural processes that generate nitrous oxide may be classified as nitrification and denitrification. Specifically, they include:

    These processes are affected by soil chemical and physical properties such as the availability of mineral nitrogen and organic matter, acidity and soil type, as well as climate-related factors such as soil temperature and water content.

    The emission of the gas to the atmosphere is limited greatly by its consumption inside the cells, by a process catalysed by the enzyme nitrous oxide reductase. [110]

    Environmental impact

    Greenhouse effect

    Greenhouse gas trends Major greenhouse gas trends.png
    Greenhouse gas trends

    Nitrous oxide has significant global warming potential as a greenhouse gas. On a per-molecule basis, considered over a 100-year period, nitrous oxide has 298 times the atmospheric heat-trapping ability of carbon dioxide (CO
    ); [111] [112] however, because of its low concentration (less than 1/1,000 of that of CO
    ), [94] its contribution to the greenhouse effect is less than one third that of carbon dioxide, and also less than water vapour and methane. On the other hand, since 38% or more of the N
    entering the atmosphere is the result of human activity, [99] and its concentration has increased 15% since 1750, [94] [113] control of nitrous oxide is considered part of efforts to curb greenhouse gas emissions. [114]

    A 2008 study by Nobel Laureate Paul Crutzen suggests that the amount of nitrous oxide release attributable to agricultural nitrate fertilisers has been seriously underestimated, most of which presumably, would come under soil and oceanic release in the Environmental Protection Agency data. [115]

    Nitrous oxide is released into the atmosphere through agriculture, when farmers add nitrogen-based fertilizers onto the fields, through the breakdown of animal manure. Approximately 79 percent of all nitrous oxide released in the United States came from nitrogen fertilization. Nitrous oxide is also released as a by-product of fossil fuel burning in cars or trucks, though the amount released depends on which fuel was used. It is also emitted through the manufacture of Nitric acid, which is used in the synthesis of nitrogen fertilizers. The production of adipic acid, a precursor to nylon and other synthetic clothing fibres, also releases nitrous oxide. The total amount of nitrous oxide released that is of human origins is about 40 percent. [116]

    Ozone layer depletion

    Nitrous oxide also has been implicated in thinning of the ozone layer. A new study suggests that N
    emission currently is the single most important ozone-depleting substance (ODS) emission and is expected to remain the largest throughout the twenty-first century. [4] [117]


    In the United States, possession of nitrous oxide is legal under federal law and is not subject to DEA purview. [118] It is, however, regulated by the Food and Drug Administration under the Food Drug and Cosmetics Act; prosecution is possible under its "misbranding" clauses, prohibiting the sale or distribution of nitrous oxide for the purpose of human consumption. Many states have laws regulating the possession, sale and distribution of nitrous oxide. Such laws usually ban distribution to minors or limit the amount of nitrous oxide that may be sold without special license.[ citation needed ] For example, in the state of California, possession for recreational use is prohibited and qualifies as a misdemeanour. [119]

    In August 2015, the Council of the London Borough of Lambeth (UK) banned the use of the drug for recreational purposes, making offenders liable to an on-the-spot fine of up to £1,000. [120]

    In New Zealand, the Ministry of Health has warned that nitrous oxide is a prescription medicine, and its sale or possession without a prescription, is an offense under the Medicines Act. [121] This statement would seemingly prohibit all non-medicinal uses of nitrous oxide, although it is implied that only recreational use will be targeted legally.

    In India, transfer of nitrous oxide from bulk cylinders to smaller, more transportable E-type, 1,590-litre-capacity tanks, [122] is legal when the intended use of the gas is for medical anaesthesia.

    See also

    Related Research Articles

    General anaesthetics are often defined as compounds that induce a loss of consciousness in humans or loss of righting reflex in animals. Clinical definitions are also extended to include an induced coma that causes lack of awareness to painful stimuli, sufficient to facilitate surgical applications in clinical and veterinary practice. General anaesthetics do not act as analgesics and should also not be confused with sedatives. General anaesthetics are a structurally diverse group of compounds whose mechanisms encompasses multiple biological targets involved in the control of neuronal pathways. The precise workings are the subject of some debate and ongoing research.

    Inhalant range of chemicals whose volatile vapors or pressurized gases are concentrated and breathed in via the nose or mouth to produce intoxication

    Inhalants are a broad range of household and industrial chemicals whose volatile vapors or pressurized gases can be concentrated and breathed in via the nose or mouth to produce intoxication, in a manner not intended by the manufacturer. They are inhaled at room temperature through volatilization or from a pressurized container, and do not include drugs that are sniffed after burning or heating. For example, amyl nitrite (poppers), nitrous oxide and toluene – a solvent widely used in contact cement, permanent markers, and certain types of glue – are considered inhalants, but smoking tobacco, cannabis, and crack are not, even though these drugs are inhaled as smoke.

    Nitric oxide chemical compound

    Nitric oxide is a colorless gas with the formula NO. It is one of the principal oxides of nitrogen. Nitric oxide is a free radical, i.e., it has an unpaired electron, which is sometimes denoted by a dot in its chemical formula, i.e., ·NO. Nitric oxide is also a heteronuclear diatomic molecule, a historic class that drew researches which spawned early modern theories of chemical bonding.

    Nitrogen dioxide chemical compound

    Nitrogen dioxide is the chemical compound with the formula NO
    . It is one of several nitrogen oxides. NO
    is an intermediate in the industrial synthesis of nitric acid, millions of tons of which are produced each year which is used primarily in the production of fertilizers. At higher temperatures it is a reddish-brown gas that has a characteristic sharp, biting odor and is a prominent air pollutant. Nitrogen dioxide is a paramagnetic, bent molecule with C2v point group symmetry.

    Isoflurane chemical compound

    Isoflurane, sold under the trade name Forane among others, is a general anesthetic. It can be used to start or maintain anesthesia. Often another medication is used to start anesthesia due to airway irritation with isoflurane. It is used by inhalation.

    Sevoflurane Chemical compound

    Sevoflurane is a sweet-smelling, nonflammable, highly fluorinated methyl isopropyl ether used as an inhalational anaesthetic for induction and maintenance of general anesthesia. After desflurane, it is the volatile anesthetic with the fastest onset and offset.

    General anaesthesia

    General anaesthesia or general anesthesia is a medically induced coma with loss of protective reflexes, resulting from the administration of one or more general anaesthetic agents. It is carried out to allow medical procedures that would otherwise be intolerably painful for the patient; or where the nature of the procedure itself precludes the patient being awake.

    Inhalation flow of the respiratory current into an organism

    Inhalation happens when air or other gases enter the lungs.

    Anaesthetic machine medical device used to generate a fresh gas flow for anaesthesia

    An anaesthetic machine or anesthesia machine is a medical device used to generate and mix a fresh gas flow of medical gases and inhalational anaesthetic agents for the purpose of inducing and maintaining anaesthesia.

    Desflurane chemical compound

    Desflurane is a highly fluorinated methyl ethyl ether used for maintenance of general anesthesia. Like halothane, enflurane, and isoflurane, it is a racemic mixture of (R) and (S) optical isomers (enantiomers). Together with sevoflurane, it is gradually replacing isoflurane for human use, except in economically undeveloped areas, where its high cost precludes its use. It has the most rapid onset and offset of the volatile anesthetic drugs used for general anesthesia due to its low solubility in blood.

    Enflurane chemical compound

    Enflurane is a halogenated ether. Developed by Ross Terrell in 1963, it was first used clinically in 1966. It was increasingly used for inhalational anesthesia during the 1970s and 1980s but is no longer in common use.

    Inhalational anesthetic

    An inhalational anesthetic is a chemical compound possessing general anesthetic properties that can be delivered via inhalation. They are administered through a face mask, laryngeal mask airway or tracheal tube connected to an anaesthetic vaporiser and an anaesthetic delivery system. Agents of significant contemporary clinical interest include volatile anaesthetic agents such as isoflurane, sevoflurane and desflurane, as well as certain anaesthetic gases such as nitrous oxide and xenon.

    In atmospheric chemistry, NO
    is a generic term for the nitrogen oxides that are most relevant for air pollution, namely nitric oxide (NO) and nitrogen dioxide. These gases contribute to the formation of smog and acid rain, as well as affecting tropospheric ozone.

    Methoxyflurane chemical compound

    Methoxyflurane, marketed as Penthrox among others, is an inhaled medication primarily used to reduce pain following trauma. It may also be used for short episodes of pain as a result of medical procedures. Onset of pain relief is rapid and of a short duration. Use is only recommended with direct medical supervision.

    Nitrogen dioxide poisoning hazardous chemical exposure

    Nitrogen dioxide poisoning is the illness resulting from the toxic effect of nitrogen dioxide. It usually occurs after the inhalation of the gas beyond the threshold limit value. Nitrogen dioxide is reddish-brown with a very harsh smell at high concentrations, at lower concentrations it is colorless but may still have a harsh odour. Nitrogen dioxide poisoning depends on the duration, frequency, and intensity of exposure. Nitrogen dioxide is an irritant of the mucous membrane linked with another air pollutant that causes pulmonary diseases such as OLD, asthma, chronic obstructive pulmonary disease and sometimes acute exacerbation of COPD and in fatal cases, deaths. Its poor solubility in water enhances its passage and its ability to pass through the moist oral mucosa of the respiratory tract. Like most toxic gases, the dose inhaled determines the toxicity on the respiratory tract. Occupational exposures constitute the highest risk of toxicity and domestic exposure is uncommon. Prolonged exposure to low concentration of the gas may have lethal effects, as can short-term exposure to high concentrations like chlorine gas poisoning. It is one of the major air pollutant capable of causing severe health hazards such as coronary artery disease as well as stroke. Nitrogen dioxide is often released into the environment as a byproduct of fuel combustion but rarely released by spontaneous combustion. Known sources of nitrogen dioxide gas poisoning include automobile exhaust and power stations. The toxicity may also result from non-combustible sources such as the one released from anaerobic fermentation of food grains and anaerobic digestion of biodegradable waste. The World Health Organization (WHO) developed a global recommendation limiting exposures to less than 20 parts per billion for chronic exposure and value less 100 ppb for one hour for acute exposure, using nitrogen dioxide as a marker for other pollutants from fuel combustion. The standards also based on the concentration of nitrogen dioxide that show a significant and profound effects on the function of the pulmonary of asthmatic patients. Historically, some cities in the United States including Chicago and Los Angeles have high levels of nitrogen dioxide but the EPA set a standard values less than 100 ppb for a one-hour exposure and less than 53 ppb for chronic exposure.

    Recreational use of nitrous oxide is the inhalation of nitrous oxide gas for its euphoriant effects.

    Cattle urine patches

    Urine patches in cattle pastures generate large concentrations of the greenhouse gas nitrous oxide through nitrification and denitrification processes in urine-contaminated soils. Over the past few decades, the cattle population has increased more rapidly than the human population. Between the years 2000 and 2050, the cattle population is expected to increase from 1.5 billion to 2.6 billion. When large populations of cattle are packed into pastures, excessive amounts of urine soak into soils. This increases the rate at which nitrification and denitrification occur and produce nitrous oxide. Currently, nitrous oxide is one of the single most important ozone-depleting emissions and is expected to remain the largest throughout the 21st century.

    Inhalation sedation

    Inhalation sedation is a form of conscious sedation where an inhaled drug should:

    1. Depress the central nervous system (CNS) to an extent that allows operative treatment to be carried out with minimal physiological and psychological stress
    2. Modify the patient's state of mind such that communication is maintained and the patient can respond to verbal command
    3. Carry a margin of safety wide enough to render the unintended loss of consciousness and loss of protective reflexes unlikely.


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