Nitrous oxide

Nitrous oxide is a very common inhalational anesthetic that offers analgesia, anxiolysis, and sometimes amnesia. It’s a colorless, non-flammable gas with a slightly sweet taste.

Due to its euphoric and hysterical effects, the substance is also called “laughing gas.” It’s been a recreational drug since the late 1700s and is currently one of the most common inhalants.

N2O is also used in the food and automobile industries, such as in whipped cream canisters and as an engine booster.

There are some mechanistic effects that make the gas concerning when large amounts are used.

Nitrous oxide = Laughing gas; Dinitrogen monoxide; Dinitrogen oxide; Factitious air; Entonox

PubChem: 948

Molecular formula: N2O

Molecular weight: 44.013 g/mol

IUPAC: nitrous oxide

Dose

Inhalation

A couple lungfuls is usually adequate to produce effects.

The average amount used during the course of a session is 1-5 cartridges or 1-5 balloons.

Timeline

Inhalation

• Total:  2 – 5 minutes
• Onset: Seconds

Experience Reports

Erowid

Effects

Positive

• Dissociation
• Euphoria
• Sensations of floating, body tingling, warmth, and numbness
• Anxiolysis
• Mood lift
• Analgesia
• Pro-sexual effects
• Laughter & giggling
• Dream-like state

Negative

• Amnesia
• Dizziness
• Nausea
• Vomiting
• Headache

Recreational

The substance offers a short-lasting euphoric state with reduced or altered awareness of your surroundings and a propensity for dream-like hallucinations.

It has a clear dissociative aspect, with users typically becoming somewhat disconnected from their environment. Occasionally a user will significantly detach from the external world and even their body.

Bodily sensations of warmth, cold, tingling, and energy may be present. Sensations of distortion, such as stretching, pulling, and compression, have also been reported. The physical euphoria may be enjoyable and possibly play a role in enhanced orgasm.

Since it only provides effects for a few minutes, a lot of people repeatedly use the drug over a period of 30-60 minutes or even hours. Quick successive use should be avoided.

The drug is usually relaxing and somewhat sedating.

N2O can lead to confusion, paranoia, and anxiety. A Global Drug Survey (GDS) report found 27.8% of users reported hallucinations and 23.9% reported confusion.

Audio distortions are common. Users can report a pulsating “wah-wah” sound along with high-pitched noises, echos, muffled hearing, and an inaccurate sense of distance.

Some visual effects can occur, but they’re normally limited to distortions. Your vision may get blurry and your sense of distance could be impaired. Sometimes a pulsating effect occurs, along with color changes.

The closed eye visuals include colors and patterns.

True hallucinations are less common. When they occur, they’re dream-like and/or delirious and often there’s only an impaired memory of them. The hallucinations could include things like believing your talking with someone or that someone has touched you.

Other effects include depersonalization and derealization.

There’s typically a big impulse/drive to use it again due to its euphoric and short-lasting nature.

It also reportedly synergizes with psychedelics, cannabis, and MDMA. In the case of cannabis and psychedelics, some users report the N2O effect is lengthened.

Sexual

Sexual effects have been reported in medical and recreational settings. It can raise feelings of sexuality and arousal. Orgasm has been been reported, albeit rarely.

An unpublished survey from Stanley Malamed found N2O led to increased sexual feelings, arousal, and sometimes orgasm in some dental hygiene students.

Multiple reports of this being problematic in medical settings have appeared. Occasionally a patient will believe they were inappropriately touched and reports of this kind seem to occur more often among females.

Medical

Nitrous oxide produces a light anesthesia on its own that’s frequently added to an IV anesthetic or another inhalational anesthetic (e.g. halothane). It can reduce the dose requirement for other drugs.

In the case of dental procedures, it may only be added to a local anesthetic.

The substance is not very potent. It has a minimum alveolar concentration (MAC) of 105%, making it a poor drug for general anesthesia. It’s instead used at sub-MAC concentrations for conscious sedation or as an adjunct.

Typically the concentration is 30-70%. It’s recommended the concentration be titrated so that an ideal level of anesthesia is provided without raising the chance of negative effects.

A review of patient records from the University of Southern California School of Dentistry found the typical patient needed 30-40% nitrous oxide.

When used for conscious sedation, the drug helps to reduce pain, can reduce anxiety, and often offers some level of amnesia (more common as the concentration increases). Anxiolysis itself can be quite useful, such as in pediatric settings.

Its low solubility in blood gives it a rapid onset and rapid clearance, with the effects ending shortly after administration ceases. Medical personnel can acutely control what state the patient is in.

Benefits

Nitrous oxide typically offers stable respiration and circulation, is easily breathed, provides some pain relief, is an anxiolytic, has a relatively low cost, and features an amnestic quality.

Usually there’s little effect on cardiovascular activity. One report showed an hour of 60% N2O in healthy volunteers increased heart rate, stroke volume, cardiac output, and blood pressure. Other reports have shown the reverse, possibly from dual cardiovascular-relevant pharmacological actions.

Another report indicated 30% N2O led to a suppression of sympathetic cardiac activity.

Its analgesic, anxiolytic, and amnestic effects can be useful. Some pain may still be felt in certain settings, but it’ll be reduced and less distressing.

Downsides

Some of the downsides are that it can inactivate B12, it’s inadequate on its own for general anesthesia, and there are some pressure/volume changes.

It may raise the risk of arrhythmia when combined with halothane. Otherwise the risk appears to be lower in nitrous oxide anesthesia vs. halothane anesthesia.

There appears to be a small increase in cerebral blood flow and volume, leading to a mild rise in intracranial pressure. Some reports have failed to demonstrate this and it may primarily occur in connection with coadministered drugs. For example, this effect appears to exist more when certain amounts of sevoflurane are also used.

Nitrous oxide might increase cerebral metabolic activity in a regional manner.

Its analgesia is useful during procedures, but it doesn’t last into the postoperative period.

There can also be gas pressure and volume changes in some areas of the body, potentially contraindicating its use depending on the situation.

Pre-hospital setting

Sometimes N2O is used before someone reaches a hospital to manage traumatic pain, such as in acute myocardial infarction. In some areas it is given when opioids aren’t available.

This use has become somewhat common in the UK and Canada.

Labor

Nitrous oxide has been used in labor for well over a century. Although epidural analgesia appears more effective, N2O is often adequate.

The gas offers analgesia and anxiolysis while preserving consciousness.

It’s a useful option since if the patient dislikes the effect, they can easy discontinue it and switch to something else. Women also maintain greater freedom of movement during labor, which can enhance comfortability.

A 2012 Cochrane review indicated there are analgesic effects and there don’t seem to be adverse neonatal effects.

It’s recommended inhalation begins 30 seconds before the start of a contraction.

More studies should be done on its safety and efficacy.

Stanislav Klikovich (Poland) reported this use in 1881 with a 80% N2O/20% oxygen mixture. Equipment for self-administration was introduced by Robert Minnitt in England in 1934.

Other medical uses

Depression

Like other NMDA antagonists, it’s been examined for possible antidepressant effects.

It’s been proposed that it could be used with scopolamine. This is due to scopolamine’s apparent antidepressant effects and because scopolamine has been shown to block potential pathological brain changes from N2O in rats.

Papers

Paper 1

• Randomized, blinded, placebo-controlled trial with 20 patients
• Two sessions, one hour each, one week apart
• 4/10 had a treatment response and 3/10 had full remission at 24 hours.
  • Compared to 1/10 for response and 0/10 for remission in the placebo cases.
• Depressive symptoms significantly improved at 2 hours and 24 hours vs placebo.
  • For some patients, the effect remained until the second use, meaning an impact for a week.
• Hallucinations weren’t reported.

Drug dependence

Effects on withdrawal and craving have been investigated, primarily during alcohol withdrawal.

Some positive results for alcohol withdrawal exist, while other reports have failed to show a notable effect.

When it works, it does so rapidly and may reduce the duration of stay in a treatment center, reduce the time it takes for a patient to enter psychological therapy, and reduce the need for sedatives.

A lot of this work has been done in South Africa since the 1980s, but use has also appeared elsewhere, such as Finland.

Neuroprotection

It appears to have some neuroprotective qualities due to NMDA antagonism, which operates against excitotoxicity. There’s a potential application for the substance in ischemic brain injury.

However, the B12 concerns and effects on cerebral blood flow and metabolism have made people more interested in using xenon.

Chemistry & Pharmacology

Chemistry

Nitrous oxide is a simple compound made of nitrogen and oxygen. It’s a colorless gas with a somewhat sweet taste at room temperature.

Pharmacology

The primary effect seems to be NMDA antagonism. In cultured hippocampal neurons, it had an approximate EC50 of 30-40%. Even at 80%, it was only a partial inhibitor.

A study found N2O could block NMA (racemic NMDA)-induced lesions in rats.

Others mechanisms of unclear importance have been seen.

LVA Ca channels

It’s a weak inhibitor of low-voltage activated (LVA) calcium channels. 80% N2O was shown to cause a 30% depression of LVA currents in rat sensory neurons.

N2O is selective for Cav3.2 LVA. Mutant mice with targeted deletion of Cav3.2 showed diminished N2O analgesia.

TREK-1

Activation of the TREK-1 potassium channel has been seen at clinically relevant concentrations. TREK-1 plays a role in neuronal excitability.

nAChR

Partial inhibition of nicotinic acetylcholine receptors has been reported, with a significant preference for a4b2 over a4b4.

Nitric oxide

It may influence nitric oxide (NO), possibly through affecting nitric oxide synthase. Cyclic GMP (cGMP) activation from NO could play a role in anxiolytic effects.

Microinjection of TRIM (1-[2-(Trifluoromethyl)phenyl]imidazole), a NO synthase inhibitor, into the PAG caused a dose-dependent antagonism of N2O induced antinociception in animals.

N2O was shown to cause a NO-dependent rise in b-endorphin and NO metabolites in rat arcuate nucleus.

GABAA

There’s some evidence of positive modulation at GABAA from N2O. It was found to increase the current flow at a1b2y2.

N2O potentiated the effects of muscimol (a GABAA agonist) in cultured hippocampal neurons.

In mice, flumazenil (benzodiazepine antagonist) and another GABAA competitive antagonist reversed the anxiolytic-like effects of the drug.

Flumazenil reduced ratings of subjective “high” in humans.

Other

Weak antagonism at GABAC and 5-HT3.

Endogenous opioid peptides

A prominent hypothesis for its analgesic effect is that N2O raises opioid peptides (e.g. met-enkephalin), which then inhibit GABA neurons and remove inhibition on descending noradrenergic inhibitory pathways.

This disinhibition of noradrenergic signalling modulates nociception in the spinal cord.

Opioid peptide activity appears to be connected to the periaqueductal gray area (PAG) of the mid brain. PAG plays a role in integrating ascending nociceptive input and descending inhibitory output.

Evidence suggests that of the descending inhibitory pathways that exist, the noradrenergic ones are most important. Nociception is hypothetically modulated at a2 adrenoreceptors in the dorsal horn of the spinal cord.

Opioid antagonists have been found to block its antinociceptive effects in animals, although results in humans have shown naloxone either has no effect, some inhibitory effect, or even a potentiation effect.

EEG

N2O inhalation was found to be connected with changes in full brain, parietal, and frontal level cortical networks.

Losing responsiveness was correlated with decreases in parietal network functional connectivity.

Some, but not all, of the EEG effects are similar to propofol.

History

1768

Joseph Priestley may not have technically been the first to prepare nitrous oxide.

Joseph Black reported the following:

Ammonium nitrate: is the most fusible of the common salts; when the heat is increased it copiously converted into a vapour; the degree of heat sufficient for its fusion is that of boiling water; if exposed to sudden heat (it) undergoes a deflagration…

Either he was discussing something he heard of someone doing or something he did himself.

1772

Priestley (UK) is most deserving of the “discoverer” title in regards to nitrous oxide. He initially called it “dephlogisticated nitrous air” and “nitrous air, diminished.”

He made it by heating ammonium nitrate in the presence of iron filings and then passing the gas through water to remove by-products. It was reported to smell more like regular air than nitrous air.

Dephlogisticated nitrous air is the term by which I first distinguished this species of air, because it admitted a candle to burn in it. (Priestley)

Priestley and other early commenters thought it was highly dangerous to animals and presumably to humans. Mice placed in a jar of N2O exhibited lower activity and eventually death.

Bostock in 1804 wrote an essay in which he said Priestley thought nitrous oxide “was in the highest degree noxious to animals.” He also noted the Society of Dutch Chemists came to the same conclusion.

1776

The first publication about N2O came from Joseph Priestley as part of a volume of his “Experiments and Observations on Different Kinds of Air.”

Pre-1796

Before Davy began his experiments, Samuel Latham Mitchill of the US proclaimed N2O to be highly dangerous.

He stated:

Nitrous oxide was the principle of contagion and capable of producing the most terrible effects when respired by animals in the minutest quantities or even when applied to the skin or a muscle fibre.

And

If full inspiration of the gaseous azote be made there will be sudden extinction of life; and this accordingly accounts for the fact related by Russel and confirmed by other observers, of many persons falling down suddenly, when struck with the contagion of the plague.

Mitchill felt it was toxic and the cause of many diseases.

Beddoes cited Mitchill’s work in 1796.

1798

Thomas Beddoes hired 20-year-old Humphry Davy, a Cornish chemist, to become the Superintendent of the Pneumatic Institution at Clifton in Bristol, England.

Davy first took it in April 1799.

It passed through the bronchia without stimulating the glottis, and produced no uneasy feeling in the lungs.

On April 17, 1799 he inhaled N2O in the presence of Beddoes.

Having previously closed my nostrils and exhausted my lungs, I breathed four quarts of nitrous oxide from and into a silk bag. The first feelings were similar to those produced in the last experiment; but in less than half a minute, the respiration being continued, they diminished gradually, and were succeeded by a sensation analogous to gentle pressure on all muscles, attended by a highly pleasurable thrilling in the chest and extremities. The objects around me became dazzling and my hearing more acute. Towards the last inspirations, the thrilling ceased, the sense of muscular power became greater, and at last an irresistible propensity to action was indulged in; I recollect but indefinitely what followed; I know my motions were various and violent…The next morning the recollections of the effects of the gas were indistinct, and had not remarks written immediately after the experiment recalled them to my mind, I should even have doubted their reality.

Davy quickly announced his discoveries and wrote to the editor of Nicholson’s Journal.

I have this day made a discovery, which, if you please, you may announce in your Physical Journal, namely that the nitrous phosoxyd or gaseous oxyd of azote, is respirable when perfectly freed from nitric phosoxy (nitrous gas). Dr. Mitchill’s theory of contagion is of course completely overturned; the mistake of Priestley and the Dutch chemists probably arose from their having never obtained it pure.

He found it could provide brief intoxication with euphoria and distortions of sensation, time, and space. Feelings of “a slight degree of giddiness,” “a high pleasurable feeling,” and “stamping or laughing” occurred.

Highly positive and potentially even “psychedelic” effects were described in some reports:

I felt a sense of tangible extension highly pleasurable in every limb; my visible impressions were dazzling and apparently magnified, I heard distinctly every sound in the room and was perfectly aware of my situation. By degrees as the pleasurable sensations increased, I lost all connection with external things; trains of vivid visible images rapidly passed through my mind and were connected with words in such a manner, as to produce perceptions perfectly novel. I existed in a world of newly connected and newly modified ideas. I theorised; I imagined that I made discoveries. When I was awakened from this semi-delirious trance by Dr. Kinglake, who took the bag from my mouth, indignation and pride were the first feelings produced by the sight of persons about me. My emotions were enthusiastic and sublime; and for a minute I walked round the room perfectly regardless of what was said to me. As I recovered my former state of mind, I felt an inclination to communicate the discoveries I had made during the experiment. I endeavoured to recall the ideas, they were feeble and indistinct; one collection of terms, however, presented itself; and with the most intense belief and prophetic manner, I exclaimed to Dr. Kinglake “Nothing exists but thought! The Universe is composed of impressions, ideas, pleasures and pains!

Experiments were conducted on himself and others, including Samuel Taylor Coleridge.

Coleridge wrote a letter to Davy describing the effects:

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.

Robert Southey, a poet, wrote to his brother Thomas Southey in July 1799 about the gas.

Davy has actually invented a new pleasure, for which language has no name. Oh Tom! I am going for more this evening; it makes one strong, and so happy!…Tom, I am sure the air in heaven must be this wonder-working gas of delight!

Davy coined the term “laughing gas.”

Some of his experiments were clearly dangerous, but he was determined to fully experience what the drug had to offer.

For example, he “resolved to breathe the gas for such a time and in such quantities as to produce excitement equal in duration and superior in intensity to that occasioned by high intoxication from opium or alcohol.”

On one occasion he tried using it after inhaling hydrogen:

But in this experiment the effects of hydrogen were so debilitating, and the consequent stimulation by nitrous oxide was so great, as to deprive me of sense. After the first three inspirations, I lost all power of standing, and fell on my back, carrying in my lips the mouth piece separated from the cylinder, to the great alarm of Mr. Patrick Dwyer, who was noting the periods of inspiration.

He also mentioned its compulsive nature.

Remarking on his own behavior:

I ought to observe that a desire to breathe the gas is always awakened in me by the sight of a person breathing, or even by that of an air bag or an air holder.

And that of others:

The desire of some individuals acquainted with the pleasures of nitrous oxide for the gas has been so strong as to induce them to breathe with eagerness, the air remaining in the bags after the respiration of others.

1800

Davy published a book that, among other things, mentioned its potential role in medicine. The book was called, “Researches, Chemical and Philosophical; chiefly concerning nitrous oxide, or dephlogisticated nitrous air, and its respiration”

He noted it provided pain relief during a toothache and headache, which led to this statement near the end of the book:

As nitrous oxide in its extensive operation appears capable of destroying physical pain, it may probably be used with advantage during surgical operations in which no great effusion of blood take place.

The significance of that statement shouldn’t be understated. Had Davy and others actually pursued the belief that it may be useful during surgery, the age of anesthesia could have started decades earlier than it did.

In a great historical review from W.D.A Smith in 1965, it was noted that if Davy had researched the gas further, “The Pneumatic Institution could have evolved into the first Anaesthetic Research Institution.”

Because he made that suggestion and didn’t pursue it, more modern commenters have given varying responses.

Most statements simply suggest the full utility of N2O probably didn’t occur to Davy:

These few words, lifted from the unimportant position assigned to them by Davy among a mass of his other deductions, not all of them accurate, have been given much prominence in the history of anaesthesia and it is often implied that Davy was suggesting that nitrous oxide should be used as a general anaesthetic. It is probable, however, that no such idea occurred to him, even though he knew that prolonged inhalation of the gas would produce stupor. If indeed he had conceived the idea of producing surgical anaesthesia by means of nitrous oxide, he would deserve blame rather than praise, in that he, fresh from apprenticeship to a surgeon, made no attempt to follow up this important idea himself or to encourage others to do so. It should, however, be realized . . . that his dominant enthusiasm was chemistry rather than medicine, as was shown by the fact that a year later he resigned his post at the Pneumatic Institution in order to take charge of the chemical laboratory of the newly formed Royal Institution in London. This early promotion resulted in the discontinuance of Davy’s experiments with nitrous oxide. Had he remained in Bristol and taken his medical degree as originally intended, it is more than possible that his genius would have led him to utilize nitrous oxide as a means of producing surgical anaesthesia. [Macintosh and Pratt, 1940]

Having made the suggestion, he dropped the matter and took no further steps to follow it up. From one point of view, why should he? It is not fair to expect it from a pure chemist. What is surprising is that his suggestion was completely ignored by the very people whom it should have interested most; that surgeons should have continued, for nearly fifty years longer, to operate upon screaming, struggling patients in full consciousness. Surely a lasting testimonial to their thickheadedness. [Sykes, 1960]

Cartwright in 1952 was still enthusiastic about Davy’s work.

It is not too much to say that this part of Davy’s book should be read in the original by every anesthetist.

He also gave his perspective on why the anesthesia-related comment didn’t lead anywhere:

But, when we study the facts, it becomes no longer remarkable that Davy’s suggestion of anaesthesia fell on deaf ears. A number of factors conspired together to make the adoption of this idea not only improbable but almost impossible. Of these factors the two most important are, firstly, the outlook of the ordinary eighteenth-century man upon the subject of pain, and secondly the fact that Davy’s idea would have been an entirely new and unheard of thing.

The book refuted Mitchill’s hypothesis. Davy found “nitrous oxide was respirable, and capable of supporting life for a long time than any gas, except atmospheric air and oxygene.”

Bostock in 1804 described how Davy overturned Mitchill’s hypothesis.

The experiment was, however, repeated by Mr. Davy, and he discovered not only that this gas may be respired for a short time without inconvenience, but that the employment of it is succeeded by a singular excitement of the nervous system, which differs from that produced by alcohol and opium, in not inducing a subsequent state of exhaustion. Mr. Davy also proved, that it is absorbed by the blood in considerable quantity.

1800 – 1850

A lot of people were introduced to nitrous oxide, including high-profile individuals, after Davy’s book was published.

Astley Cooper, an important surgeon, experienced it during a meeting of the Askesian Society in either February or March of 1800.

William Allen was also present at that meeting. He discussed his experience in his diary.

Present Astley Cooper, Bradley, Fox and others. We all breathed gaseous oxide of azote. It took a surprising effect upon me, abolishing completely, at first, all sensation: then I had the idea of being carried violently upward in a dark cavern with only a few glimmering lights. The company said that my eyes were fixed, face purple, veins in the forehead very large, apoplectic stertor, etc. They were all much alarmed, but I suffered no pain and in a short time came to myself.

The Askesian Society experiments may have been triggered by one of Davy’s communications about N2O to Nicholson’s Journal. In his third communication, he mentioned how it was prepared for respiration.

Astley Cooper wouldn’t have been aware of Davy’s suggestion that it could be used in surgery.

Many reviews of Davy’s book were published, some of which were very favorable. Though they all seemed to leave out the surgical application comment and often didn’t discuss Davy’s mention of pain relief.

Of the many singular and highly interesting particulars contained in the volume now before us, no proper analysis could be given within the limits of our periodical publication. For most of these, therefore, we must refer the chemical reader to the original work, which demonstrates, in a remarkable degree, the industry and genius of the author, whose enthusiasm for the discovery of truth, has led him, with a perseverance almost without example, to undergo very great sufferings, and even to run the risk, on many occasions, of immediate death. And we have no doubt, that the intelligent reader, after careful perusal of his experiments, will give him due credit for his meritorious exertions. [Annals of Medicine, 1800]

Discussion in medical and chemistry settings

Davy’s work began to be discussed by students, physicians, teachers, and others in the areas of medicine and chemistry.

It was brought to the attention of the public via scientific demonstrations at the Royal Institution, at private parties, through public entertainment, and in non-medical literature.

Humphry Davy joined the Royal Institution in 1801 and gave a short course of lectures after his arrival.

During a concluding lecture on June 20, he offered to let people use the gas after the lecture was done.

An opportunity was given to such as wished it, to breathe some of nitrous oxide . . . Mr. Grosvenor Bedford, Mr. Stodart, and Mr. Underwood, breathed the gas; and the effects it produced, especially on the last, were truly wonderful. He experienced so much pleasure from breathing it, that he lost all sense to everything else, and the breathing bag could only be taken from him at last by force.

One June 23, Davy reported “a select party met at the Institution to try the effects of the gaseous oxide.” It appears nitrous oxide quickly became an attraction at the Royal Institution.

The same “Stodart,” whose full name was James Stodart, published his experiences with N2O in a letter to Nicholson’s Journal in 1802.

He said he “prepared and breathed the gas at different times, and the effects were always pleasurable.” An interesting analgesic effect was described at one point. Stodart said it quickly relieved pain in his face and head one day, with a single use getting rid of the pain for the rest of the day. When his pain returned, he used N2O again before bedtime and awoke pain-free.

A chemistry lecture from Thomas Charles Hope as early as 1800 discussed N2O, as evidenced from a note made by John Lee.

The gaseous oxide of azote—It consists of azotic and oxygen gas—Dr. Mitchell supposes this gas to be the contagion of all diseases—Mr. Davy has discovered its very singular properties—When inhaled it gives highly pleasurable sensations of the most extatic kind —The account given by Dr. Beddoes Jan 18th is perhaps exaggerated

Babington and Allen’s printed syllabus from 1802 mentioned nitrous oxide’s effects and properties. It was at least used in Guy’s and St. Thomas’ hospitals.

Notes from George Hickman in 1806 described Davy’s work and also featured a sketch of an apparatus that’d be used to prepare the gas.

This gas had been thought to be irrespirable but Davy has proved that it may: when respired it produces the most curious sensation.

It should not be exhibited to hysterical persons it has been known to produce ill effects–tho in the common number of persons it produces only temporary effects.

Its properties were mentioned in British chemistry textbooks from the 1800s to 1820s.

it does not prove fatal because, when received into the lungs, it is mixed and diluted with the atmospherical air present in that organ. [Henry, 1815]

There were six references to N2O in the Lancet between October 1823 and 1844.

Professor Benjamin Silliman wrote in 1819 in the American Journal of Science that more attention should be given to the medical uses of gases, including N2O.

Should the revival of the experiments on the respiration of oxygen gas appear to be desired, it would not be difficult to simplify the apparatus and operations so as to bring them within the reach of an intelligent person, even although ignorant of chemistry. This interesting class of experiments ought to be resumed, not with the spirit of quackery nor of extravagant expectation, but with the sobriety of philosophical research; and it is more than probable that the nitrous oxide, which is now little more than the subject of merriment and wonder, if properly diluted and discreetly applied, would be productive of valuable effects.

Bostock had a physiology textbook in 1826 that mentioned it:

Of gases, which although not capable of supporting life are still respirable, the one that is least injurious to the system appears to be nitrous oxide.

There was also some early discussion beyond the UK. In Black’s Lectures on the Elements of Chemistry, Robinson is said to have referred to experiments by Priestley and Davy while in Amsterdam, with Robinson stating:

Its effects when breathed for some time, are very wonderful, and were first discovered, I believe, by Mr. Davy. To those who are not hurt by the sight of folly, they are also very amusing.

Recreational use

Medical use largely didn’t exist during the first decades of nitrous oxide’s public use. Instead, it was taken as a recreational drug.

One of the few suggestions of medical use appeared in a fictional Doctor Syntax book in 1820. In “Doctor Syntax in Search of the Grotesque,” a women complains of a bad tooth, visits a dentist, has the tooth extracted, and is then offered N2O to soothe the pain. This was set in Paris, France.

Another Doctor Syntax book, “The Tour of Doctor Syntax through London,” described a visit to the London Institution during which N2O was demonstrated. The book mentioned the gas providing a “sweet delirium” and a “laughing fit.”

Public entertainment

Use for public entertainment really seemed to begin around the 1820s and 1830s. Sometimes people would use N2O on stage and act out their intoxication.

A playbill for a show at London’s Adelphi Theatre in 1824 mentioned M. Henry demonstrating nitrous oxide and offering it to “any of the Audience who may chuse to inhale it.”

Schoenbein, a German naturalist, witnessed a demonstration at the Adelphi Theatre during a visit to England. The visit doesn’t have a clear date, but it was around 1824 to 1826.

In some of the smaller theatres, physical and chemical experiments are sometimes made, more for the entertainment than for the edification of the audience, and I once saw such a performance. It was at the Adelphi Theatre and they wanted to demonstrate the very odd properties and the physiological effects of the laughing gas.

When the curtain was raised, you could see on the stage, in a wide semicircle, a dozen or more large caoutchouc bladders with shining metal taps, filled with the laughing gas. The “Expenmentator” appeared in a simple dress suit, and made a short opening speech in which he described the properties of the gas, and its preparation, in a way which would have done credit to a professor of chemistry. At the end of his lecture he asked for someone from the audience to come on the stage and to inhale from one of the bladders. A tall daring fellow jumped over the orchestra and on to the stage, and grabbed one of the bladders. But the audience didn’t like him and greeted him with cries of “Off! Off!” At first he did not comply, but when the cries grew louder he went away. A second candidate appeared, but he too was shouted off. When the third met with the same undignified reception, the “Experimentator” interceded and asked the audience firmly but politely not to be so fickle and to let the show go on. This appeal had the desired effect and they proceeded. The volunteer—sitting in a chair—put the tap to his mouth, compressed his nose, and inhaled the laughing gas while the “Experimentator” held the bladder. The tap was then closed while the subject breathed out through the nose. The tap was opened again, the nose compressed, and some more gas inhaled through the mouth. He continued in this way until the bag was emptied. Now the “Experimentator retired; but the “luft-trunken” man remained sitting in his chair for a few minutes, while he stared straight ahead, holding his nose. You can imagine how this comical posture sent the audience into roars of laughter which increased when the intoxicated man leapt smartly from his chair and then made astonishing bounds all over the stage.

When the audience had had its fill and the man had sobered up, a voice called out: “All nonsense and humbug!” “All nonsense and humbug!” echoed immediately from hundreds of throats. “No! No!” came the emphatic reply. When the protests continued, the “Expenmentator” appeared’and shouted at the top of his voice: “Ladies and Gentlemen”. When he obtained a hearing he assured the audience that the experiment was genuine, and he invited the man who had first voiced his doubts to try the experiment himself. The man responded with alacrity and displayed his incredulity by demanding to empty the largest bladder. His request was immediately complied with, and the effect of the gas upon the disbeliever was so great that he beat around him like a madman and assaulted the “Experimentator”. This performance confirmed the sceptics in their doubts and brought forth fresh demonstrations of disbelief.

Schoenbein also mentioned that use was more widespread in England than anywhere else. Because of its effects, he believed people might adopt it as an alternative to alcohol.

My chemical readers may be interested to know that this gas is nowhere inhaled more often than in England, because its marvellous effects were first discovered in this country by Sir Humphry Davy. Once when I stayed in the country with a friend, who was an amateur chemical experimenter, we discussed laughing gas and decided to make a good supply of it ourselves. One fine afternoon, a large party met in the garden to inhale the intoxicating gas in the open air. Some young men inhaled it first, and they all showed undoubted signs of wellbeing and pleasure. When another man of more mature age had his doubts, he decided to take a large quantity of the gas for himself. After breathing a lot of gas, he began to dance and devastate the adjoining flower-bed in his ecstasy—to the delight of his audience. Maybe it will become the custom for us to inhale laughing gas at the end of a dinner party, instead of drinking champagne, and in that event there would be no shortage of gas factories.

Overall, there are signs that nitrous oxide was pretty frequently used in England, but the average person probably didn’t know its effects in the 1820s and 1830s.

A handbill from 1845 talked about its acute compulsive effect.

Those who inhale the Gas once are always anxious to inhale it a second time.

Read (1947) also determined use was notable in England based on a contemporary description:

Judging from the contemporary writer Fievee, the inhalation of “exhilarating” or “laughing” gas became a vogue . . . for in his Lettres sur I’Angleterre he condemned the practice as a national vice of the English!

From what I can tell, the work from Fievee that was referenced can be found here.

Some problems with its use also seemed to occur, such as apparent poisonings from novice-prepared nitrous oxide. Stanley (1842) said three young men tried preparing it on their own. One of them convulsed and took a while to recover. Although this could conceivably have come from N2O, it was suggested they may have overheated the ammonium nitrate.

Early use in America

Many people were introduced to nitrous oxide through the work of travelling showmen as early as the 1830s.

Like in England, use was also likely taking place before then in universities.

Ashurst (1897) in recalling a time earlier in the 1800s wrote:

[It was] the custom of some of our medical schools–at the University of Pennsylvania, for one–for students to breathe “laughing gas”, as it was then called, for a diversion.

Interest in the gas may have come from Philadelphia. Barton wrote a paper in 1808 called entitled, “Dissertation on the Chymical Properties and Exhilarating Effects of Nitrous Oxide.”

But the account which he (Davy) gave of its operation was generally derided as extravagant and imaginary. Few believed it. The description was supposed to have proceeded from a warmed and highly excited mind…In the United States the chymists partook of the prevalent skepticism as to the alleged properties of the gas.

Barton also wrote about its apparent pain relieving effects, which he encountered when using it after hitting his head.

I am decidedly of opinion with Mr. Davy, that this gas has the power of removing intense physical pain.

Barton expressed an interest in bringing N2O to the attention of more physicians.

One of the travelling showmen who demonstrated the gas was Samuel Colt, who would later enable the mass production of the revolver.

In 1832, when Colt was only 18, he toured the East Coast from Canada to Maryland showing nitrous oxide’s effects.

One of the advertisements, titled “Nitrous Oxide Gas For Ladies and Gentlement,” appeared in Portland in October 1832.

Dr. S. Coult respectfully informs the Ladies and Gentlemen of Portland and vicinity, that he will administer the NITROUS OXIDE, or Exhilarating Gas, on Monday evening at the City Hall. Exhibition to commence at 7 o’clock precisely. The peculiar effects of this singular compound upon the animal system, was first noticed by the English Chemist, Sir Humphry Davy. He observed that when inhaled into the lungs it produced the most astonishing effects upon the nervous system; that some individuals were disposed to laugh, sing, and dance; others, to recitation and declamation, and that the greater number had an irresistible propensity to muscular exertion, such as wrestling, boxing, etc., with numerous fantastic feats. In short, the sensations produced by it are highly pleasurable, and are not followed by debility. . . . Dr. G. has exhibited the extraordinary powers of the gas in many cities of the United States, to audiences composed of Ladies and Gentlemen of the first respectability—and many Ladies have inhaled the gas at select Exhibitions. Those Ladies who may be anxious of witnessing the Exhibition, in this city, may be assured, that the City Hall embraces every accommodation for their comfort, and that not a shadow of impropriety attends the Exhibition,, to shock the most modest. He will attend, on reasonable terms, to any applications for private Exhibitions to select parties of Ladies and Gentlemen.

Medical use

A couple mentions of it being tested for medical applications appeared in the 1820s and 1830s.

Curtis (1829) mentioned giving it to a patient with severe asthma attacks. The patient reported feeling much better.

Another individual suffering from wheezing and difficulty breathing whenever they had a cold was said to have been cured by nitrous oxide.

Hudson (1832) suggested it could be used as a stimulant in cases of cholera. This was on the grounds that the state of excitement wouldn’t be followed by sedation. There’s no record of it ever being used around this time in that way.

Back and Morgan (1834) at Guy’s Hospital reported trying to allay severe spasms in a young man suffering from hydrophobia. The spasms only increased, however, with the use of nitrous oxide.

Bigelow (1848) said a patient had her breast removed under N2O gas that was given through a valve mouthpiece and a flexible tube.

After several inspirations the patient’s lips and the most vascular part of the tumour began to assume a purple colour. She remained quiet, however, and in a short time was evidently insensible.

1844 – 1848

Horace Wells, an American dentist, visited an entertainment show at Union Hall in Hartford, Connecticut on December 10, 1844. He was traveling with his wife, Elizabeth.

The show was advertised as a “grand exhibition” and was organized by Gardner Quincy Colton.

During the event, Wells noticed one of the men, Samuel Cooley, inhaled the gas and then injured his leg while staggering around. Despite the injury, he didn’t notice the pain until the N2O wore off.

Based on what he saw, Wells thought it may be a useful analgesic. He asked Colton to give him N2O during a wisdom tooth extraction the following day.

Colton served as the anesthesiologist and another dentist, Dr. John Riggs, extracted the tooth.

Wells reported being unaware of the procedure and experiencing no pain. He proclaimed it was “a new era in tooth pulling.”

After this experience, he carried out 12-15 successful trials of N2O during dental procedures in Connecticut between December 1844 and January 1845.

He decided he should demonstrate its efficacy elsewhere and decided to visit Boston rather than New York, which was his other option.

Wells traveled to Boston in January 1845.

Around the time he arrived, nitrous oxide was publicized in multiple local papers. The Boston Bee reported:

A dentist in Hartford, (Conn.) has adopted the use of nitrous oxide gas, in teeth pulling. It is said that after taking this gas the patient feels no pain.

Posts in the Boston Evening Transcript advertised Wells’ upcoming demo of N2O and requested that local dentists provide patients for Wells to work with.

Most of the people he interacted with in Boston doubted the gas’ efficacy, but he was allowed to address students at Harvard Medical School (Massachusetts Medical School).

He talked to students following a lecture from John Collins Warren, a famous surgeon. The students went into an adjoining room and may have been given N2O by Wells.

The same evening, Wells went elsewhere in Boston to carry out his demonstration. Although it’s often said he was at Massachusetts General Hospital, the evidence doesn’t support that. Rather, it appears the event was at Quincy Hall, Phoenix Hall, or Boylston Hall.

Wells tried to show its efficacy in front of quite a few students and physicians during a dental extraction.

Unfortunately, the patient initially cried out and reported pain. However, it is said he eventually reported the pain was “not as much as usually attends the operation.”

Another account said there was an initial complaint from the patient, but when the patient awoke, he reported no pain at all.

Wells attributed this result to withdrawing the bag too soon.

Some of the spectators completely dismissed the effects and may have even “laughed and hissed.”

For a while, interest turned to ether and chloroform instead. Though Wells would eventually be recognized by some as the “discoverer of anesthesia.”

Shortly after the Boston incident, Wells became physically and psychologically ill, possibly in connection to a deep sense of humiliation and failure.

The excitement of this adventure immediately brought on an illness, from which I did not recover for many months; being thus obliged to relinquish, entirely, my professional business.

Wells tried to get public and official recognition for his status as the discoverer of anesthesia, but he largely failed.

In January 1848, Wells threw sulfuric acid on two women in New York City while under the influence of chloroform. He was arrested and committed to prison in The Tombs (The NY Halls of Justice and House of Detention in Manhattan.)

He committed suicide on January 23, 1848 by inhaling chloroform and cutting his left femoral artery.

Wells died unaware that just a few weeks earlier the Paris Society of Medicine had recognized him as the inventor of anesthesia and made him an honorary member.

1863

The same Gardner Quincy Colton who introduced Wells to the gas was able to firmly establish its use in dentistry.

1867

Colton reported widespread use by the late 1860s.

1868

A successful demo at the Dental Hospital in London by Dr. Evans, a doctor from Paris, triggered a spread of its use.

The same year, Andrew published accounts of multiple cases where N2O was being used in combination with oxygen, making its administration safer.

1860s onward

Nitrous oxide was promoted around North America and Europe.

It was popularized as an anxiolytic and analgesic tool for procedures like tooth extractions. The drug expanded into other fields as well, notably obstetrics and surgery.

Dr. C A Brackett in 1875 reported putting a women under N2O for 30 minutes so that Dr. Squier could remove breast cancer. Brackett called it a “grand success.”

1890s

Prolonged administration wasn’t really reported until around the 1890s.

Herbert Paterson in 1895 began giving N2O through the nose in prolonged dental cases. Paterson also went around the UK showing how prolonged nasal N2O could be used in dentistry.

Late 1800s

Nonmedical use was still taking place. For example, William James published accounts of its use and viewed it as a potentially useful and interesting substance.

In 1882, he stated:

I strongly urge others to repeat the experiment, which with pure gas is short and harmless enough. The effects will of course vary with the individual, just as they vary in the same individual from time to time; but it is probable that in the former case, as in the latter, a generic resemblance will obtain. With me, as with every other person of whom I have heard, the keynote of the experience is the tremendously exiting sense of an intense metaphysical illumination. Truth lies open to the view in depth beneath depth of almost blinding evidence. The mind sees all logical relations of being with an apparant subtlety and instantaniety to which its normal consciousness offers no parallel; only as sobriety returns, the feeling of insight fades, and one is left staring vacantly at a few disjointed words and phrases, as one stares at a cadaverous-looking snowpeak from which sunset glow has just fled, or at a black cinder left by an extinguished brand.

More statements from James are available on Erowid.

1912

While N2O+O2 was being used, it wasn’t popular yet in the UK.

Teter reported giving a demo of it at Guy’s and Chaldicott/Page tried to popularize it, but interest wasn’t significant.

1917

H. Edmund G. Boyle of St. Bartholomew’s Hospital read a paper before the Medical Society of London. The paper was called, “Experiences of the Use of Nitrous Oxide and Oxygen with Rebreathing in Military Surgery.”

Soon after the publication of that paper, he was contacted by the UK’s War Office, which wanted several machines that would allow N2O to be used in military surgeries.

Boyle was asked to review the machines and approve them “for use at the front.”

After the war, N2O+O2 and ether became more common. Boyle reported it was his routine combo for abdominal operations in the 1930s.

Boyle also said people in the US were using the N2O+O2 gas for childbirth. He tried to get people in the UK to do the same, but it took a while to catch on.

He described alarming experiments being carried out by E.I. McKesson in Toledo, Ohio. McKesson demoed for Boyle a practice called “secondary saturation” that would be used to produce relaxation.

Boyle described it as an “alarming sight.” McKesson would give N2O until the pupils widely dilated and the patient’s color was grey, with the patient looking like “death.” He then returned oxygen to the lungs and the patient’s color would return.

Boyle was glad to have seen the demo, but the method was “not one that I am prepared to teach to students.”

1956

Beliefs about nitrous oxide’s safety started to change by the mid-1900s.

The Lancet published a case series by Lassen in April 1956. That series described megaloblastic bone marrow changes from extended inhalation of N2O by patients at Bledgam Hospital in Copenhagen, Denmark.

Physicians at Bledgam suggested in 1954 that general anesthesia with nitrous oxide could be provided to patients with severe tetanus infections.

Of the first five patients, two died from sepsis following agranulocytosis after the first week. They were a 15-year-old male and 53-year-old female.

Records from Bledgam also showed that in patients with similar conditions, N2O administration was the only common factor.

This prompted a trial in two more patients. Both showed marked hematological changes by Day 4 and bone marrow biopsies showed megaloblastic changes.

When N2O was discontinued, the hematological abnormalities went away in 3-4 days.

More cases were published after the Lancet paper.

1950s – 1980s

Other reports built upon the megaloblastic issues reported by Lassen.

It was found that megaloblastic changes would occur after 24-36 hours of exposure, but not within 1 or 6 hours.

Evidence suggested critically ill people were more susceptible to N2O-related issues in shorter periods of time than other patients.

In 1968, a B12 inactivation reported appeared. It was found N2O oxidized the cobalt core of cobalamin, making it inactive for the purpose of methionine synthase. This paper largely went unnoticed by anesthetists and hematologists for years.

Amess (1978) reported that 24 hours of N2O interfered with DNA synthesis. This was accurately associated with B12 issues.

Deacon (1978) reported rapid inhibition of methionine synthase in rats.

The first reports of neuropathy and myelopathy came from Layzer. Initially Layzer reported 3 recreational cases involving two dentists and a hospital technician. They developed problems after using N2O several times per week for months. Some of the symptoms were numbness in the extremities, hypoactive reflexes, and an “electric shock sensation traveling upward from the feet after flexion of the neck.”

Layzer reported a larger case series demonstrating what appeared to be subacute combined degeneration of the spinal cord in 15 people.

Medical professionals began to come to different conclusions about how to proceed.

A 1978 editorial suggested N2O probably wouldn’t be used if it were a new drug. Others said the advantages still outweighed the disadvantages.

Saidman (1985) presented a case in favor of N2O that noted the inhibition of methionine synthase wasn’t correlated with clinical effects during typical N2O use.

Occupational exposure concerns

Vaisman (1967), a Russian anesthetist, reported a 58% abortion rate in anesthesia personnel exposed to gases including nitrous oxide. This triggered a line of research and concern about the safety of employees.

Vaisman also reported a correlation between N2O occupational exposure and irritability, fatigue, headache, nausea, and fetal malformation.

Bruce (1974) reported that slight exposure among personnel could impair audiovisual capabilities. However, all attempts to replicate this finding failed and the researchers retracted their conclusions.

1979

There was an apparent rise in recreational use, especially among dental/medical personnel, in the 1960s and 1970s.

A 1979 paper indicated up to 20% of dental and medical students had experimented with it.

1980s

It was reported to be very common in US dental procedures, with ~25% of US dentists reportedly utilizing conscious sedation.

1980s – 1990s

We learned more about its pharmacology.

Multiple groups found N2O could trigger a rise in opioid peptide, mainly met-enkephalin, concentrations in rat brain. Some research also suggested a rise in b-endorphin.

Research in the 1990s found it was an NMDA antagonist.

2000

The National Survey on Drug Use and Health found N2O was the most common inhalant among 16 and 17-year-olds.

2002

A review found nitrous oxide use during labor was very common in some countries. 50 – 75% of women in the UK and 60% of women in Finland were using it. Use was also high in Australia and New Zealand.

2003

A paper from Auckland University found 12% of first-year students reported using the drug for recreational purposes.

2000s – 2010s

There was an apparent decline in use due to concerns about its safety and doubts about its efficacy relative to alternatives.

One report found it was used in 33% of operations in the US in 2009, but that fell to 21% in 2011.

At the same time, recreational use was stable or higher.

2010

The American College of Nurse-Midwives published a statement endorsing greater availability of N2O for women going through labor.

2013-2014

A survey in England and Wales found N2O was more popular than cocaine, ecstasy/MDMA, or ketamine among 16 to 24-year-olds.

2017

It’s one of the most common inhalants in the US and other countries.

For decades there have been arguments about how much N2O should be used in medical settings. Those debates are still taking place.

Many hospitals have stopped using the gas since the 2000s due to safety concerns and the ability of short-acting and potentially better tolerated drugs.

Legal Status

US (as of March 2017)

Unscheduled

States where there are controls if it’s sold/used for recreational purposes: California, Florida, and Oregon.

Other countries (list may not be complete)

A lot of countries don’t have any specific laws covering N2O, but some do have laws pertaining to recreational use.

Recreational use/sale isn’t allowed in: New Zealand, UK.

Safety

The primary concerns with nitrous oxide are B12 inactivation and hypoxia.

Other general precautions are that you should be sitting or laying down when using it and it’s best to use it from a balloon.

Hypoxia

N2O balloons shouldn’t be used in quick succession and very large balloons are best avoided. Take breaks (preferably longer than 10-20 minutes) in between balloons so that you can deeply breathe regular air. You should also breathe in deeply before using N2O.

Never use N2O in a way that doesn’t let you separate from the N2O source. This means you shouldn’t use a mask, for example.

Don’t hold your breath too long. Holding for more than 30-60 seconds doesn’t seem to be wise.

You generally won’t experience shortness of breath or feeling like you need to breathe even when you experience oxygen deprivation from N2O.

A short period of slight hypoxia generally won’t be an issue for people, but it could potentially raise the chance of seizure and cardiac arrhythmia in some users.

In medical settings, one of the concerns is diffusion hypoxia. This is caused by the rapid outward diffusion of N2O from pulmonary blood, which lowers the concentration of other gases in the lunges. With the oxygen concentration diluted, oxygen transfer across the alveolus can be affected, leading to hypoxia.

Diffusion hypoxia is of minimal relevance for most people, though it could be relevant in pulmonary disease. It can be avoided by only giving oxygen for a period of minutes during the post-N2O washout.

Nowadays N2O is always combined with O2 in medical settings, so hypoxia largely isn’t a concern like it used to be. However, there are occasionally problems due to equipment malfunction, cross-connection of the N2O and O2 lines, inaccurate gas cylinder labeling, or other human error.

B12

B12 inactivation is mainly an issue with prolonged administration, frequent recreational use, or the administration of N2O in someone with B12 deficiency.

Nitrous oxide leads to rapid oxidation (possibly through free radicals) of cobalamin’s cobalt from the monovalent to the trivalent form, which is inactive for the purpose of methionine synthase, which B12 is a coenzyme of.

Here are some of the problems with that action:

• Reduced conversion of homocysteine to methionine, thereby raising homocysteine levels.
• Impeded methionine and S-adenosyl methionine synthesis
  • This prevents methylation of myelin sheath phospholipids, eventually contributing to myelopathy.
• Infringed transmethylation of levomefolic acid to homocysteine, which would normally produce tetrahydrofolate  and methionine.

Higher homocysteine levels could be linked to endothelial dysfunction and prothrombotic effects, but the usually transient effect of N2O shouldn’t be an issue.

This inhibition can seemingly persists for days and therefore exposure more than every few days likely has a cumulative effect.

Some people may initially be asymptomatic, but these problems develop into subacute combined degeneration of the spinal cord.

The symptoms include limb weakness, numbness, ataxia, clumsiness, tingling, and imbalance.

Psychological issues like personality changes, mood disorders, psychosis, and hallucinations can occur.

It can take a bit of time for the problems to become obvious.

Mild megaloblastic changes can appear after 12 hours of administration, with the issues increasing by 24 hours.

Agranulocytosis can eventually develop in severe cases, raising the chance of infection.

Testing

B12 levels may be decreased, but they can also be within the reference limits.

Looking at homocysteine is a better marker.

An MRI may also show spinal cord abnormalities consistent with subacute combined degeneration.

Treatment

The main treatments are abstinence from N2O and the administration of B12.

Methionine may also be useful.

Treatment will generally be effective, but sometimes symptoms persist for 6-12 months or longer.

Prevention

Limit your exposure and make sure you have a good B12 intake.

Even B12 supplementation won’t prevent issues, however, if your N2O use is significant enough.

Papers

Paper 1

• Monkeys exposed to 15% N2O developed subacute combined degeneration in two months, with progressive ataxia.
• Their spinal cords showed degeneration of myelin sheaths and axis cylinders.
• It would take 5 years of a B12 deficient diet to produce the same changes.

Paper 2

• Plasma methionine and S-adenosyl methionine did not decline with 3 hours of N2O.

Paper 3

• Plasma methionine declined 15-25% with 8 to 24 hours of N2O.

Other issues

Frostbite

N2O cannot be taken directly from a container as the gas near the outlet of a tank, for example, can be as low as -55°C (-131°F).

There are reports of recreational use leading to severe tissue damage as well as of accidents leading to injury in occupational settings.

Some examples include:

• The inadvertent leakage of a small amount of liquid nitrous oxide from a valve stem instantly froze the thenar space of an anesthetist’s left hand.
• An anesthesiologist opened a nitrous oxide cylinder and sustaineda direct blast of N2O to his left palm, resulting in frostbite.
• A man tried to recreationally use nitrous oxide by placing his lips directly over the cylinder.
  • His lips froze to the valve block.
  • This led to frostbite of the lips, mouth, tongue, and palate.

Case

Case 1

• 54-year-old male
• Took nitrous oxide directly from a cylinder
• When he became disoriented, the gas hit his left check for an indefinite period of time.
• Presented to ED 12 hours later
  • Edema in his left check
• Admitted to burn center to manage fourth-degree frostbite
• There was complete necrosis of the skin of his cheek
  • The skin eventually separated and left a granulating wound.
• Skin grafting was refused, so the wound healed with a hypertrophic scar.

Neuroxoticity

Short-term exposure has been shown to cause pathological changes in the posterior cingulate and retrosplenial cortex of rats.

The concentration for those changes is about the max concentration used in human anesthesia.

Diazepam, pentobarbital, and scopolamine have been shown to block neurotoxicity in animal models.

Although the potential for neurotoxicity has been shown in animal models, its existence in humans hasn’t been demonstrated. McGregor (2008) reported there was no clear effect on neurological measures when given intraoperatively in response to intracranial aneurysm. It was concluded there was no current evidence to categorically avoid N2O in patients at risk for ischemic brain injury.

Some evidence suggests neurotoxicity could arise from high homocysteine or oxidative stress.

Animals studies showed cell death with prolonged exposure and reversible vacuolation with shorter exposure.

Malignant hyperthermia

This is a very rare response and N2O isn’t contraindicated in patients with malignant hyperthermia.

However, there was one case of the gas triggering the issue:

Case

• 11-year-old female
• Needed general anesthesia
• Because father died from hyperthermia during a surgical procedure, she was given a specific anesthetic that wasn’t a volatile agent or depolarizing muscle relaxant.
• Anesthesia with thiopental and N2O
  • Within 12 minutes, temperature was up 1-2°C
  • Procedure was terminated, followed by cold blankets and dexamethasone.
• Anesthesia attempted again
  • Only with N2O and O2
  • Temperature again began to rise and attempt was cancelled.
  • Body temperature stabilizied without active treatment.

Gas volume and pressure changes

Because nitrous oxide diffuses into body cavities much faster than nitrogen leaves the cavities, a rise in pressure or volume can occur.

Rise in volume:

• Pleural cavity
• Peritoneal cavity
• Bowel

Rise in pressure

• Cranium
• Middle ear
• Eye

Potentially contraindicated

• During or after eye surgery that involve intraocular gas.
  • Due to increase in the size of the bubble.
  • This could raise intraocular pressure and cause vision problems.
• Bowel, laparoscopic, middle ear, and eye surgery
• Caution advised in neurosurgery
• Closing the abdomen after surgery could be more difficult from increased bowel volume.

Occupational exposure

N2O exposure doesn’t seem to be an issue for employees as long as there is proper ventilation and scavenger devices.

Fatalities

Death is very rare and usually comes from oxygen deprivation.

Fatality cases

Case 1

• 25-year-old male
• Dead lying on floor in front of TV with his face covered by a modified gas mask.
  • Whipped cream pump was loaded with N2O cartridge and attached to a plastic bag and the mask.

Case 2

• 35-year-old male
• Found dead in his living room with pornographic videotape playing
• Face covered by a gas mask connected to a gas cylinder marked “N2O”

Case 3

• 59-year-old male
• Found dead in a locked apartment
• Body was seated in a chair and face attached to an anesthetic machine and mask
• Appeared to be using N2O in an autoerotic manner
• It appeared he was using around 95% nitrous oxide and 5% oxygen
• No fail-safe mechanism meant he lost consciousness and died from hypoxia from N2O, with a contributing factor of coronary artery disease.

Case 4

• 38-year-old male
• Dead on the floor in an operating theater
• Wearing an anesthetic face mask that was firmly fastened and connected to a nitrous oxide outlet pipe.
• Determined to be a suicide based on past medical history that included a nervous breakdown and suicide attempt.

Case 5

• 32-year-old male
• Lifeless in hospital storage area
• Found laying on floor with a plastic face mask covering his nose and mouth, connected to nitrous oxide
• Cause of death ruled asphyxia due to N2O inhalation

Problematic responses

Problem cases

Case 1

• 8-month-old male
• 6 days pre-admission
  • Underwent laparoscopic orchiopexy with isoflurane and nitrous oxide for 80 minutes.
• Family history of anemia that resolved with cobalamin injections in mother.
• Hospitalized for fever, lethargy, and athetoid movements.
• Noted to be pale, listless, and febrile.
• Hypotonia, decreased alertness, motor tremor, and athetoid movements.
• Shown to have profound cobalamin deficiency.
• Also megaloblastosis and pancytopenia
• Within 48 hours of IM hydroxycobalamin, had increased alertness and decreased athetosis.
• 4 months later, still highly delayed in development.

Case 2

• 30 year old male
• History of intermittent N2O use.
• New onset of psychotic symptoms a few days after inhaling N2O for over 10 hours
• Described having demons in his head, also paranoia regarding himself and safety of family.
• Family said he had become rude and verbally aggressive.
• Evaluation
  • Alert, emotionally labile, easily angered, smiled inappropriately.
  • Followed commands inconsistently.
  • Easily distractable and paranoid about his safety.
• B12 level was low at 148 ng/L
• But functional measures of cobalamin activity were very low
  • Markedly elevated homocysteine and methylmalonic acid
• Treatment
  • IV thiamine, oral folic acid, IM cobalamin 1000 ug, and antipsychotic
• Three days later
  • Mental status was back to baseline and no reccurence of symptoms for several months at follow-up

Case 3

• 21-year-old male
• For pain treatment associated with extensive perineal abscess, he was given a 50:50 mixture of nitrous oxide from doctors.
• Eventually using around 1280 liters of N2O mixture per week
• District nurses became concerned about the amount of N2O exposure and complained to hospital pain team.
• Man had progressive severe difficulity in walking for six weeks
• GP referred him to a neurologist, who diagnosed him with a spinal cord disorder and admitted him to hospital.
• He couldn’t hold a cup or put on his glasses, due to severe lack of coordination. Also inability to stand independently due to severe ataxia.
• Diagnosed with dorsal column spinal syndrome (probably subacute combined degeneration) and given B12
• B12 level was low at 269 ng/L, but not excessively low.
• MRI showed long lesion of the dorsal column, typical of subacute combined degeneration
• Injections of B12 then continued with aftercare
• At 3 month follow-up he had no gait ataxia and normal hand function, was also independent with walking.

Case 4

• 28-year-old male
• Admitted to N2O abuse for 2 years, using bulbs used for making whipped cream.
• • Took it directly from whipped cream dispenser
  • Taking up to 80 bulbs per day
• First noticed symptoms 1 week pre-presentation and worsened in 2 days prior to presentation
• Saw his GP who referred him to ED
• Presented
  • Bilateral numbness and weakness in both lower limbs
  • Had difficulty walking and maintaining balance.
• Decreased proprioception in both feet and decreased vibration sense to the level of both knees.
• Tests
  • B12 at 184 ng/L
• Diagnosis of polyneuropathy secondary to N2O abuse
• Given B12, receiving around 7 B12 injections IM over a 3 month period

Case 5

• 31-year-old male
• Had been using nitrous oxide since 15, with average of once per month.
• For past two years, reportedly using 500 to 750 cartridges in balloons during 5 to 6 hour sessions, frequency of 2-3x per week.
• Several month history
  • Imbalance, limb weakness, and numbness and tingling from the toes to the waist and in the hands and forearms.
• Sought medical attention after awakening with complete numbness from the nipples to the toes.
• Presented
  • Vibration sensation diminished in the feet and ankles.
  • Ataxia, Lhermitte sign, and an equivocal Romberg sign.
  • B12 – 127 ng/L, a bit low
• MR examination showed changes of the cervical sign in the posterior columns bilaterally.
• Treated with B12 injections

Case 6

• 50-year-old female with very limited vegetarian diet and presumed preexisting B12 defiency
• Received isoflurane and nitrous oxide for two hours
• 4 weeks after operation
  • Rapidly developed increasing unsteadiness of gait and sensory impairment of her legs.
• 6 weeks after operation
  • Unable to walk and was readmitted to hospital.
• Lab results showed macrocytic anemia and low B12, with normal folate concentrations.
• Diagnosis of subacute combined degeneration of the spinal cord secondary to B12 deficiency.
• Injections of B12 provided
• After five months
  • Much improved, able to walk on crutches
  • But still a variety of impairments such as with position and vibration sense

Case 7

• 27-year-old female
• Chronic N2O use for 3 years, average of 100-200 chargers per day on 3-4 days per week.
• Also ended up using B12 as well after reading about recommendation online.
• No use for past 10 days and also no B12 due to running out for past 10 days.
• Worsening lower extremity weakness for about 10 days, multiple falls, and “pins and needles”
• Presented to ED
  • Abdominal pain and inability to urinate for 12 hours
  • Decreased vibration sensation and reduced proprioception in both lower extremities.
  • Positive Romberg’s test
  • Unable to balance without support
  • Results from MRI indicative of subacute combined degeneration
  • B12 of 683 pg/mL normal
  • Normal homocysteine and elevated methylmalonic acid
• Treated with B12, but no follow-up

Case 8

• 35-year-old male
• Daily use of N2O, about 100 cannisters
• Presented to ED
  • Complaining of disorientation, worsening subjective weakness, and developing flexion contractures of the fingers, urinary urgency, and loss of balance.
• Exam showed positive Babinski sign, brisk reflexes in all four limbs, diminished sensation in a stocking and glove distribution, and ataxia.
• B12 level was normal
• MRI showed increased T2 signal in dorsal columns
• Deemed to likely be N2O-releated myeloneuropathy
• High-dose B12 as treatment

Case 9

• 16-year-old female
• Frequently used N2O for three months
• Week before admission
  • Progressive ascending numbness over all four extremities
  • Numbness began in hands and reached the elbows, and moved from the ankles to the knees.
  • Difficulty holding things and an unsteady gait over 4 days
• Admission
  • Sensory ataxia, positive Romberg test, unable to perform tandem gait.
  • Low-normal B12 of 219.6 ng/L
• Mild polyneuropathy shown
• MRI showed T2 hyperintensity in the central and dorsal spinal cord section.
• Patient received B12
  • After one month, the sensory ataxia and numbness in feet and hands improved.

Case 10

• 22-year-old male
• Had been using cannabis relatively minimally (1 joint per week) for five years and N2O starting two years earlier
  • N2O had increased significantly, reaching up to 100 cartridges daily in the past 9 months
• Brought to ED after altercation at apartment building
• Shouted about being followed and claimed he was in danger.
• His behavior had declined over the past 6 months.
• Man believed the police were tracking him and that he had the powers of telepathy and mind control
• At psychiatric unit
  • Two verbal outbursts necessitating antipsychotic medication
• Denied hallucinations
• Tests
  • B12 was low at 144 ng/L
  • High homocysteine and high methylmalonic acid
• B12 given intramuscularly

Case 11

• 20-year-old female
• Admitted to N2O use
• Experienced bilateral paresthesia of the lower extremities for 3 weeks pre-admission
• Numbness ascended to the trunk and then she had difficulty walking, followed by numbness in the hands and associated back pain.
• MRI findings consistent with demyelination of the dorsal regions of the spinal column and demyelination around the central canal.
• Nerve conduction study pointed to demyelinating polyneuropathy
• B12 low at 126 ng/L and methylmalonic acid was high

Case 12

• 59-year-old male
• Anesthesia
  • Given midazolam and then fentanyl, N2O, and halothane
• Fine during operation and postoperative period
  • Discharged after 4 days
• Fine at 8 and 15-day follow-ups
• On 20th postoperative day
  • Patient returned
  • Had reported progressive weakness and dizziness over past 3 days and noted by wife to be “nervous and shaky”
• Motor exam showed very mild symmetrical weakness in the extremities
• Symptoms progressed daily, increasing hand pain, weakness, parasthesia, and an unsteady gait
  • Lost position sense in extremities and became mildly confused
• Within 10 days of onset
  • Unable to walk even with assistance
• B12 level showed 75 ng/L, which was below normal range
• Diagnosis of subacute combined degeneration of the spinal cord secondary to B12 deficiency
• Condition slowly improved with weekly injections of B12
  • Able to stand and fully move within 3-4 weeks
  • Mental status and other neurologic symptoms also improved
  • Fully resolved in 6-8 weeks without recurrence while receiving B12

Case 13

• 33-year-old
• No psychiatric history
• Inhaled N2O daily for nearly 4 weeks before admission
• Presented with bizarre behavior and delusions
  • Thought he was part of NASA experiment and was serving as an “interface” between humans and machines.
  • Felt compelled and controlled to destroy furniture and break a window at his home.
  • Rode his bike into a moving vehicle because his mind told him to.
  • Actions were part of his “training”
  • Also said he was told he had a second wife and would need to kill his current wife
• Initially denied drug use
  • Then admitted to excessive use of nitrous oxide
• No motor or sensory deficits
• No gait difficulties
• B12 was low-normal at 202 ng/L
• MMA was high as 1078 nmol/L and homocysteine was high as 48.4 mol/L
• Given B12 every day for a week
• Discharged, continued taking B12 every week for a month
• 2 weeks after presented to hospital
  • Delusion started resolving and he felt better

Case 14

• 39-year-old male
• Using nitrous oxide for 10-15 months to facilitate his creativity
• Went to ED
  • Reported 2 weeks of progressive difficulty with walking
  • Gait shown to be unsteady and a positive Romberg test
  • Unable to walk without assistance
• Low B12 at 217 ng/L
• Treated with B12 and folic acid daily for 2 weeks
• Follow-up 14 days later
  • Gait was dramatically improved as was the rest of his neurologic exam

Case 15

• 24-year-old male
• Friend brought him to ED
  • Said he had been using nitrous oxide for several year without issue
  • But use had increased significantly and rapidly in the past 2 weeks
    • Went from a few cannisters per month and 240 per day
• Reported to ED
  • Numbness and tingling in hands and feet for 2 weeks
  • Said symptoms were worsening
  • Beginning to have trouble walking due to lack of balance and “dragging” his feet
  • Hands were becoming “clumsy”
• Reported forgetfulness for 2 weeks
• Exam
  • Sensation to light touch was decreased and proprioception was diminished in toes and feet
  • Romberg test showed poor balance, but not falling.
• B12 was low-normal at 312 ng/L
• High MMA at 49.17 umol/L and homocysteine at 39.9 umol/L
• Given B12 in ED and then daily
  • Discharged on third day, but without change in his symptoms.
• Lost to follow-up

Case 16

• 28-year-old male
• Inhaling N2O began 4-6 months prior
• Use gradually increased to most evenings per week for about 2 hours
• Use increased a lot during the 2 weeks before presentation
  • Probably using the drug most hours of the day
• 6 days before admission
  • Family found him confused and disoriented in apartment
  • Had several hundred N2O cannisters littered about
  • Taken to ED but discharged
• Then stated with family
  • Was sleeping excessively
  • Had crying and agitation
  • Inappropriate behavior like exposing his genitals
  • Visual hallucinations when looking at computer screen
  • Confusion
  • Complained about feeling guilty but couldn’t explain this clearly
• Presented to hospital after inappropriate and confused behavior
  • Difficulty in concentration, recall, and calculations.
  • Gait ataxia
• B12 at 383 ng/L
• Given haloperidol for two days
• Had continued improvement and was discharged after 15 days with basically normal cognition, affect, and no hallucinations or delusions.
• Normal on discharge and during five month follow-up

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