Introduction to Nitrous Oxide

While use of this anesthetic in medicine has been widely touted as a safe anesthetic alternative to other more potentially hazardous drugs, there is risk of liver damage and recent studies have shown an increased risk of acute funicular myelosis associated with latent vitamin B12 deficiency caused by extended use of the drug, both medicinally and recreationally.[2]
Nitrous oxide (chemical compound N2O) is a non-flammable, colourless gas with a slightly sweet odour. It is a dissociative drug which was discovered in 1772 and has been in common usage recreationally since the early 1800s.
The psychological effects of nitrous oxide were discovered in 1799 by British chemist and inventor Humphry Davy. When inhaled, nitrous oxide can cause euphoria, sedation, analgesia (pain relief), laughter/giggling, dissociation of the mind from the body, auditive distortions, visual hallucinations (rare) and other phenomena. In 1800, Humphrey Davy started marketing nitrous oxide as a recreational drug. Nitrous oxide was called ‘laughing gas’ and its use became popular at social events, predominantly those of the British upper classes, where it was commonly sold for entertainment. In modern times, nitrous oxide is sometimes used at parties, usually filled into balloons and inhaled from them.
As it's primary medical use is sedative and analgesic, nitrous oxide is used as an anaesthetic in dentistry and sometimes in surgery. Nitrous oxide is also used in the dairy industry, in car racing, in welding and in rocket engines.
Other names for nitrous oxide are: N2O, dinitrogen monoxide, E942, nitrous, laughing gas, NOS, hippie crack, etc.

Using nitrous oxide

Methods of Administration

In order to produce its dissociative effects, nitrous oxide has to be inhaled, usually by mouth.
A common source for nitrous oxide are whippets, which are small canisters that contain pressurized nitrous oxide. These are normally used in special devices for dispensing whipped cream. With a cracker, whippets can be opened and the nitrous oxide released into a balloon, from which it then can be inhaled. Both whippets and crackers can be obtained from several online suppliers and in head shops.

Dispensing nitrous oxide into balloons is done by inserting a whippet into the cracker, slipping the balloon over the end of the cracker, and screwing the cracker so the seal of the whippet is punctured and the balloon is filled with nitrous oxide. This may be repeated with the same balloon in order to fill larger amounts of nitrous oxide into the balloon. The nitrous oxide has to be filled into the balloon first, and not inhaled directly from the cracker (see dangers).
Another common source for nitrous oxide are whipped cream cans. These contain cream and nitrous oxide as a propellant. Whipped cream cans are usually more expensive than whippets, but are used mainly because they are readily available in most places. Nitrous oxide can be inhaled from whipped cream cans by letting them sit vertically with the opening upwards for about 2-3 minutes, then putting the mouth on the opening and pressing on the opening to release the nitrous oxide, which can be inhaled until whipped cream starts to come out of the can. It is also possible to transfer nitrous oxide from a whipped cream can into a balloon, from which it can be inhaled easier.
Nitrous oxide can be administered by connecting a tank of nitrous oxide to a breathing mask, for continuous administration. This method can be quite dangerous, for several reasons: continuous administration of pure nitrous oxide will result in hypoxia or anoxia (lack of oxygen), accidents due to equipment may happen (improper connection between tank and mask, etc.), the tank may run out of nitrous oxide (and the user will have nothing to breathe) and the user may stay under the influence of nitrous oxide for a very long time, which can be dangerous. If this method is used, at least 20% oxygen has to be added to the nitrous oxide and the user has to be under permanent supervision. If pure nitrous oxide (without oxygen) is used by this method, no more than a few inhalations have to be done (maximum one minute). The amount of time spent inhaling can’t be determined by the user (who will most likely lose consciousness), so the presence of a trip sitter is absolutely necessary.

Effects of nitrous oxide

Nitrous oxide can produce the following effects: giggling, euphoria, auditive distortions (flanging of sound), analgesia (pain relief, sometimes numbing), loss of balance, tingling or numbing in extremities, dissociation (detaching from reality, out-of-body experiences) and dream-like states. When nitrous oxide administration is prolonged, the user usually falls unconscious and can experience dreams and visions, out-of-body experiences and sometimes mystical and religious experiences. Altered thought patterns (usually involving strange arrangements of words) are sometimes observed.
Nitrous oxide quickly enters the bloodstream through the alveoli in the lungs. Nitrous oxide is fat soluble, being quickly distributed in the whole body, including synapses in the brain. Nitrous oxide is an uncompetitive NMDA channel blocker, which explains its effects.
The effects of a single inhalation of nitrous oxide start almost instantly, usually a few seconds after inhaling. The effects peak about 10-20 seconds after inhalation, and they diminish as quickly as they began. If nitrous oxide administration is prolonged, the effects reach a plateau about 30-60 seconds after the first breath, and diminish a few seconds after nitrous oxide is no longer administered. Mild sedation, feeling of well-being and sometimes headache (especially with prolonged administration) can be felt up to 30 minutes after coming down.

Combinations with nitrous oxide

Nitrous oxide has gained a reputation of combining very well with most psychoactives.
Combinations with hallucinogenic drugs are usually very intense and should be carried out only by experienced hallucinogen users. 2C-I, 5-MEO-DMT, cannabis, DPT, DXM, ketamine, LSD, Psilocybe mushrooms and Salvia divinorum have been reported to cause intense dissociation with nitrous oxide. Also, in many cases, nitrous oxide in combination with hallucinogens alters the experience of the latter significantly, even after the user comes down from the nitrous oxide.
Combinations of nitrous oxide with methamphetamine and BZP (and possibly other stimulants) are reported to be euphoric and overall pleasant. Combinations with opiates are reported to potentiate the opiate euphoria.

Other uses for nitrous oxide

Nitrous oxide is bacteriostatic (stops bacteria growth), fat soluble and does not leave residues, taste or odor, which makes it useful as an aerosol propellant in the dairy industry. In whipped cream cans, nitrous oxide is held under pressure where it becomes a liquid and mixed with liquid cream. When released from the can, together with the cream, nitrous oxide expands, foaming the cream. Nitrous oxide works similar when used in special whipped cream dispensers.
In car racing, nitrous oxide is usually injected into the intake manifold in order to increase engine power. This is achieved because nitrous oxide supplies more oxygen to the engine than air, allowing the engine to work faster, and because the nitrous oxide expands in the intake manifold, the temperature drops, making a denser charge possible. Nitrous oxide used in car racing is contaminated with sulphur dioxide to discourage human consumption and should not be used recreationally.
Nitrous oxide has been used medically as a mild anaesthetic since 1863, in dentistry, surgery and childbirth. Nitrous oxide has replaced other medically used anaesthetics (chloroform, diethyl ether), which have a higher toxicity. In a medical setting, nitrous oxide is usually administered through a mask with 20% oxygen, to prevent oxygen deprivation. Today, nitrous oxide is used commonly in dentistry, in order to produce analgesia or to calm down anxious patients. Nitrous oxide is also used for analgesia in patients who are or are thought to be allergic to other analgesics (especially children).

Pharmacology of nitrous oxide

Upon inhalation, nitrous oxide diffuses directly into the blood through the alveolar-capillary membranes. N2O has a very low binding affinity for hemoglobin, so it does not combine with hemoglobin and interfere with the transport of O2, making it an excellent anesthetic choice for medicine. The diffusion of nitrous oxide into the blood occurs very rapidly. In one-tenth of the time the blood spends traveling through the alveolar capillaries, the partial pressure of N2O in the blood reaches equilibrium with the partial pressure of N2O outside of the capillary membrane.

When partial pressure equilibrium is achieved, the diffusion gradient for N2O becomes zero, and no more nitrous oxide can enter the blood until more blood circulates through the capillaries. It is for this reason that the uptake of nitrous oxide is limited only by blood flow and not by the diffusion capacity of the N2O.

The N2O gas is carried by the blood to the brain, where interacts with neural receptors to produce its anti-anxiety, analgesic, and euphoric effects. The specific mechanism of action of nitrous oxide in the brain is not fully understood, but it has been shown produce effects by acting on a broad variety of ligand-gated ion channels.

The receptor specific neurological effects of N2O are listed below:

Column 1	Column 2	Column 3	Column 4
Receptor	N2O Action	Effect*	Comments
NMDA	Moderate antagonist	dissociative anesthesia	Brain-body connection, for which NMDA receptors modulate, is mildy dissociated.
nACh (if β2-subunit present)	Moderate antagonist	anesthesia; muscle relaxant	Inhibits acetylcholine from acting on its receptor. Acetylcholine is responsible for activating muscles, therefore inhibiting its receptor produces a muscle relaxant effect.
AMPA	Weak antagonist	anti-convulsant; anti-excitotoxic
Kainate	Weak antagonist	anti-convulsant; anti-excitotoxic
5-HT3	Weak antagonist	anti-nausea; anti-depressent	N2O shares the antagonist mechanism of some anti-nausea drugs
GABAa	Weak agonist	anti-anxiety; sedative; euphoriant; muscle relaxant; slightly hallucinogenic	N2O shares the antagonist mechanism of Muscimol, although much less active. This suggests the action on this receptor contributes to a similar, but weak, sedative, dissociative hallucination.
GABAc	Weak antagonist	anti-convulsant
Glycine	Weak agonist	increases inhibition; anesthesia

*The strength of the effect(s) corresponds with the strength of the agonism/antagonism on the receptor.

Nitrous oxide is also believed to act on the natural opioid system by action on inhibitory neurons. As a result, the inhibitory neurons release endorphins which then act on the μ opioid receptors to produce analgesic effects. Clinical evidence for this is the lack of sedation and analgesia for patients on opiates when administered 50% N2O anesthetic.

Nitrous oxide is clinically administered as an N2O-O2 mix, because under anesthesia the patient cannot breathe independently. A standard N2O cartridge typically contains 8 grams of 100% nitrous oxide gas. Clinically, 100% N2O has been shown to produce anoxia. It should be noted that since nitrous oxide from cartridges is pure, continual inhalations of N2O without sufficient breathing between inhalations will cause oxygen deprivation, potentially leading to brain damage or death.

The metabolism of nitrous oxide is poor in humans, with a rate of only 0.004%, meaning the potency of nitrous oxide exhaled by an individual is almost unchanged.

Chemistry of nitrous oxide

Column 1	Column 2
Systematic (IUPAC) name:	dinitrogen monoxide
Synonyms:	nitrogen oxide, laughing gas, hyponitrous acid anhydride, factitious air
Molecular Formula:	N2O
Molar mass:	44.01 g/mol
CAS Registry Number:	10024-97-2
Melting Point:	-90.81°C
Boiling Point:	-88.46°C @ 760 mmHg
Flash Point:	no data
Solubility:	1 L of the gas dissolves in 1.5 L water at 20°C; freely soluble in sulfuric acid; soluble in alcohol, ether, oils
Additionnal data:	density 1.53 (air = 1)
Notes:	aspect : colorless, non-flamable gas; slightly sweetish odor and taste; very stable, rather inert chemically at room temperature

[1]

Nitrous Oxide is generally prepared by thermal decomposition of ammonium nitrate.

The dangers of nitrous oxide

Short-term dangers of nitrous oxide

Nitrous oxide can produce acute adverse effects in some users, and some of its dissociative effects may represent dangers to the user. Possible adverse effects of nitrous oxide include: nausea (especially when used repeatedly, after a meal, or in combination with alcohol) which can lead to vomiting (can be dangerous to the user, because he/she can fall unconscious on nitrous oxide and choke on his/her vomit) and headaches, during or after the experience. Because nitrous oxide can cause loss of motor control, inhaling it when standing can be dangerous. Nitrous oxide should not be used in any situation in which sudden unconsciousness may be dangerous (standing, driving, operating machinery, etc.). Users should be in a comfortable and safe setting to avoid accidentally inuring themselves. Serious injury and death has resulted from nitrous oxide being inhaled while driving or standing in front of an open window.

Long-term dangers of nitrous oxide

Nitrous oxide interacts with vitamin B12 synthesis in the human body by interfering with the enzyme methionine synthase, depleting the body of vitamin B12. Also, in a scientific study, it was shown that 24 hours of exposure to nitrous oxide caused interferences with DNA synthesis.
When nitrous oxide is used heavily and over an extended period of time, vitamin B12 depletion will probably become a major problem, as it can cause brain and nerve damage. Physical symptoms of vitamin B12 deficiency include: tingling sensation in extremities, paresthesias (no sense of touch and pain), difficulties with motor control (can lead to inability to walk), etc. If a frequent user of nitrous oxide experiences one or more of the above symptoms, it is vital to cease the use immediately and consume healthy amounts of vitamin B12 and other vitamins (especially folic acid). If symptoms persist or get worse, a physician has to be consulted. There are some reported cases of chronic nitrous oxide use resulting in the symptoms mentioned above. However, virtually all of the patients used nitrous oxide excessively, up to 400 whippets each week, over the period of several months.
If nitrous oxide is used frequently (although this is not recommended), consuming supplements containing vitamin B12 and folic acid may reduce the long-term risks of chronic nitrous oxide use.
Heavy use of nitrous oxide can result in lower amounts of lymphocytes of the blood (results in a weakened immune system), reproductive disturbances and hyperhomocysteinemia (a risk factor in vascular disease).
As the effects caused by nitrous oxide are pleasant and very short-lasting, many users desire another dose. Sometimes, this continues until no more nitrous oxide is available to the user. This compulsive use of nitrous oxide can lead to psychological addiction in some users, which can lead to excessive use (dangerous for the reasons stated above) and deterioration of personality.
Prolonged exposure to nitrous oxide has been shown to cause Olney’s Lesions, although the alveolization of certain parts of the brain does not result in further damage as happens with most other dissociative drugs.

Who should not use nitrous oxide

Nitrous oxide should be avoided by pregnant women. High doses of nitrous oxide have been proven to be teratogenic in rodents, and also other conditions caused by chronic use of nitrous oxide (vitamin B12 depletion, hyperhomocysteinemia) can result in a malformed child if the user is pregnant.
Because nitrous oxide tends to diffuse into air-filled spaces in the body (intestines, middle ear, etc.), it may be dangerous when used by persons with middle ear disease, bowel obstruction, pneumothorax, etc. In the case of nitrous oxide in the intestines, it will probably only result in mild gastrointestinal discomfort. Nitrous oxide in the middle ear may cause temporary or permanent hearing loss, which is why nitrous oxide should not be used when one has an ear infection or any other disease in this region. Pneumothorax (collapsed lung, accumulation of air in the pleural cavity) is a medical emergency. Nitrous oxide should not be used for analgesia in such cases, but medical personnel will (hopefully) be aware of the dangers of administering nitrous oxide in these circumstances.

Dangerous or negative interactions with nitrous oxide

Alcohol can increase the likelihood of nausea when combined with nitrous oxide.
Although most other hallucinogens combine well with nitrous oxide, the resulting experience may be too intense for many users, especially those inexperienced with hallucinogens.

Indirect dangers of nitrous oxide

The dangers not directly related to nitrous oxide are mostly present because nitrous oxide is often administered from pressurized containers, without constant oxygen supply, or from sources that may contain contaminants. Also, other compounds like carbon dioxide and nitric oxide may be mistaken for nitrous oxide.
Nitrous oxide is commonly used from tanks or whippets, which contain liquefied nitrous oxide which is under pressure. If nitrous oxide is administered directly from a whippet or tank, the expanding gas will be very cold and is capable of freezing the nose, lips and throat (including vocal cords) of the user. The gas is also under constant pressure and can cause ruptures in lung tissue. Both dangers can be prevented by releasing the nitrous oxide into a balloon before inhalation, so it will warm up and have normal pressure when inhaled.
If nitrous oxide is administered in its pure form, without supplemental oxygen, it can cause hypoxia (low levels of oxygen in the blood). Hypoxia can cause headache, brain damage, and finally death through suffocation. A few breaths of pure nitrous oxide are unlikely to be a problem, but if nitrous oxide is administered through a mask or equivalent, 20% oxygen (by volume) has to be added (2l oxygen for each 8l nitrous oxide). Note that it is not possible to the user to determine whether he/she has enough oxygen, because nitrous oxide does not cause shortness of breath. Hypoxia can also happen if pure nitrous oxide is administered through a garbage bag (can fall over the face) or in a closed room (closet, car or other sealed space).
Different sources of nitrous oxide may contain harmful contaminants. Automotive grade nitrous oxide (NOS, NX) is contamined with sulphur dioxide and should not be inhaled. Food grade nitrous oxide from whippets may contain oily residues, which may be harmful if inhaled. Medical grade nitrous oxide is the highest purity of nitrous oxide available, as it is specifically produced for human consumption.
Nitric acid (NO) should not be confused with nitrous oxide. Nitric oxide is an industrial gas which decomposes lung tissue if inhaled. This can cause irreversible lung damage and death. Containers containing carbon dioxide may be mistaken for whippets containing nitrous oxide, but this is usually quickly noticed by the user, because high concentrations of carbon dioxide rapidly produce shortness of breath, which doesn’t appear with nitrous oxide. Nitrous oxide is colourless and has a slightly sweet taste. Anything that smells strong or has an unusual taste is either contaminated nitrous oxide or not nitrous oxide at all.

Producing nitrous oxide

Industrially, nitrous oxide is usually synthesized by heating ammonium nitrate. Because ammonium nitrate is very explosive, overheating it can detonate it, which has resulted in several huge explosions (even in controlled industrial manufacture). Also, the nitrous oxide obtained by this method is not pure; dangerous contaminants like ammonia, nitric oxide and nitrogen dioxide are also formed. Unless one has professional chemistry equipment, knowledge and legal permission, synthesizing nitrous oxide from ammonium nitrate should not be carried out.
Automotive grade nitrous oxide can be purified, but this subject is quite controversial and is not yet well-documented.

Forms of Nitrous Oxide

Scientific grade nitrous oxide

This is the purest form (99.9%) of nitrous oxide available, but also the hardest to find. It is used in some chemical reactions, when contaminants of any kind can not be tolerated.

Medical grade nitrous oxide

Medical grade (USP) nitrous oxide is 99% pure and intended specifically for human consumption. This form is also hard to obtain (medical suppliers, etc.) and usually controlled. Medical grade nitrous oxide usually are big containers, which contain large amounts of pressurized nitrous oxide.

Food grade nitrous oxide

Food grade nitrous oxide is used in whipped cream cans and whipped cream chargers. It is usually pure enough for human consumption, although many brands of whipped cream chargers have been reported to leave a residue similar to motor oil, which can be potentially harmful to the user. Most recreationally used nitrous oxide is food grade, because it is the easiest to obtain.

Automotive grade nitrous oxide

Automotive grade nitrous oxide is used in car racing. To discourage recreational use of this type of nitrous oxide, it is mixed with sulphur dioxide, which is very unpleasant to inhale and can be harmful to the lungs. Automotive grade nitrous oxide should not be inhaled.

Entonox

Entonox is a mixture of 50% nitrous oxide and 50% oxygen, which is used medically as an anaesthetic to relieve pain during labour, trauma or minor surgeries. It is used more commonly than nitrous oxide with 20% oxygen, mainly because it can be self-administered (the user does not usually lose consciousness, because of the lower concentration of nitrous oxide) and keeps oxygen levels high, so short periods of apnoea will not represent a danger.

The law on Nitrous Oxide

US State Laws

Arizona: Selling nitrous oxide to a minor under 18 years of age is a class 5 felony. Aiding a minor to obtain nitrous oxide is a class 1 misdemeanor.
California: Possessing nitrous oxide for intoxication purposes and being under the influence of nitrous oxide (except when used medically) are misdemeanors.
Connecticut: Selling nitrous oxide to a minor under 18 years of age is punishable by fine.
Florida: Using or possessing nitrous oxide for intoxication purposes is a second-degree misdemeanor. Selling, buying, transferring or possessing more than 16 grams of nitrous oxide for intoxication purposes is a third-degree felony. Possession of Nitrous oxide paraphernalia (devices used to store, transfer or inhale nitrous oxide) is a first-degree misdemeanor.
Georgia: Possession of nitrous oxide (probably medical grade) with intent to distribute is a felony, punishable by 1-3 years in jail and/or a fine not to exceed $5,000. If supply of a minor under 18 years of age is intended, possession with intent to distribute is punishable with 2-6 years in jail and/or a fine not to exceed $10,000. Chemical suppliers are allowed to sale medical grade nitrous oxide only to medical suppliers or licensed practitioners. Nitrous oxide for industrial use has to be mixed with 0.01% sulphur dioxide.
Hawaii: Use as an inhalant of ‘volatile organic solvents’ is unlawful. Nitrous oxide does not fit into this section, not being an organic chemical compound.
Idaho: A minor under 18 years of age who abuses an inhalant (definition includes nitrous oxide) is guilty of a misdemeanor, being punishable with a fine not exceeding $300 and/or 30 days in a ‘juvenile detention facility’.
Illinois: Using inhalants for intoxication purposes and selling inhalants to a minor under 17 years of age is a class C misdemeanor.
Iowa: Buying, selling, possession with intoxication purposes, being under the influence of nitrous oxide (except when used medically) are all considered serious misdemeanors.
Louisiana: Possession and use of nitrous oxide with any other reason than medical, industrial or culinary use is prohibited, being punishable with a fine not exceeding $500 and/or 6 months in jail.
Michigan: Selling devices that contain nitrous oxide or are used to dispense nitrous oxide is a misdemeanor, punishable by not more than 93 days in jail and/or a fine not exceeding $100 (first offense), $500 (second offense) or $2,000 (third and subsequent offenses).
Minnesota: Possessing with intoxication purposes or use of inhalants (including nitrous oxide) are misdemeanors.
New Jersey: Possession of nitrous oxide (probably medical grade) is illegal for anybody except medical personnel, “unless the person obtains a written permit issued by the Department of Health”.
Ohio: Selling nitrous oxide to a person under 21 years of age is illegal. Selling nitrous oxide (to a person over 21 years of age) is illegal if also devices used to inhale nitrous oxide are sold, or if the seller has reason to believe that the nitrous oxide will be inhaled. All sales have to be recorded. All cartridges containing nitrous oxide have to be printed with a note which includes intended use and warning about the presence of ‘dangerous health effects’.
Oregon: Inhalants (including nitrous oxide) are illegal when inhaled. All inhalants have to be marked with the following warning: “Illegal to inhale fumes for purpose of intoxication. Fumes may cause serious injury or death!!”
International law

New Zealand

Selling nitrous oxide for intoxication purposes is a violation of the 1981 Medicines Act. Even food grade nitrous oxide is illegal if the seller knows it is going to be inhaled. This applies to head shops selling whippets (see this case).

United Kingdom

Nitrous oxide is illegal to possess by minors or for intoxication purposes. It is also illegal to sell nitrous oxide to a minor.

The history of Nitrous Oxide

Nitrous oxide was discovered by the British scientist Joseph Priestley, in 1772. The first chemist to undertake further studies on nitrous oxide was Humphrey Davy, who administered nitrous oxide to visitors of the Pneumatic Institute in Bristol, to study its physical effects (1799). He discovered that nitrous oxide causes laughing and called it ‘laughing gas’. In 1800, Humphrey Davy published his work about nitrous oxide, including his own experiences with nitrous oxide. He described nitrous oxide causing analgesia, but this information made it into the medical world only over 40 years later.
After Humphrey Davy discovered its potential for recreational use, he manufactured large quantities of nitrous oxide and introduced it to the public as a recreational drug, being more powerful yet cheaper than alcohol. Nitrous oxide was often sold at parties, carnivals and other social events.
In 1844, the dentist Horace Wells first demonstrated the anaesthetic effects of nitrous oxide, and in 1863, nitrous oxide was introduced in dentistry by Colton, becoming generally accepted in medicine by the year 1880, along with other anaesthetics like diethyl ether and chloroform. The latter two soon replaced nitrous oxide because they were more potent, but their high toxicity caused them to be replaced again by nitrous oxide.

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References

1. ^http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1821130
2. ^N2O-induced acute funicular myelosis in latent vitamin B 12 deficiency

[1]Merck Index, fifteenth edition (2013)