Effects of nitrous oxide on the body

8g canister of nitrous oxide

Nitrous oxide (N₂O) is a dissociative that can cause analgesia, euphoria, dizziness, flanging of sound, and, in some cases, slight hallucinations and mild aphrodisiac effect.

This drug is often mislabeled as an 'inhalant', implying it bears a relation to substances such as glue, gasoline, or aerosol sprays.

During the 19th century, William James and many contemporaries found that inhalation of nitrous oxide resulted in a powerful spiritual and mystical experience for the user. James claimed to experience the fusing of dichotomies into a unity and a revelation of ultimate truth during the inhalation of nitrous oxide. Memory of this experience, however, quickly faded and any attempt to communicate was difficult at best. James described a man who, when under the influence of the gas, claimed to know the secret of the universe.

The drug currently (as of 2005) enjoys moderate popularity in some countries. It was often sold at Grateful Dead and Phish concerts. One slang term for the drug is Hippie Crack; this term implies commentary on the typical user of the substances as well as purported similarities between its psychological addiction potential or the short-lived duration of its effects and similar properties of "crack" cocaine.

The recreational use of nitrous oxide is restricted in many districts of the United States. In California, for instance, inhalation of nitrous oxide "for the purpose of causing euphoria, or for the purpose of changing in any manner one’s mental processes," is a criminal offense under its criminal code (Cal. Pen. Code, Sec. 381b). In many other countries, this substance is legal. Small N₂O cartriges, used to make whipped cream, are available to buy by anyone.

Since nitrous oxide can cause dizziness, dissociation, and temporary loss of motor control, it is unsafe to inhale while standing up. Inhalation directly from a tank poses serious health risks, as it can cause frostbite since the gas is very cold when released. For those reasons, most recreational users will discharge the gas into a balloon or whipped cream dispenser before inhaling.

Nitrouse oxide can be habit-forming, mainly because of its short-lived effect (generally from 1 - 5 minutes in recreational doses) and ease of access. Death can result if it is inhaled in such a way that not enough oxygen is breathed in. While the pure gas is not toxic, long-term use in very large quantities has been associated with dangerous symptoms similar to vitamin B12 deficiency: anemia due to reduced hemopoiesis, neuropathy, tinnitus, and numbness in extremities. Pregnant women should not use nitrous oxide, because chronic use is also teratogenic and foetotoxic.

Medicine

Nitrous oxide is a weak general anesthetic, and is generally not used alone in anaesthesia. However, it has a very low short-term toxicity and is an excellent analgesic, so a 50/50 mixture of nitrous oxide and oxygen ("gas and air", supplied under the trade name Entonox) is commonly used during childbirth, for dental procedures, and in emergency medicine.

In general anesthesia it is often used in an 2:1 ratio with oxygen in addition to more powerful general anaesthetic agents such as sevoflurane or desflurane. Its lower solubility in blood means it has a very rapid onset and offset.

It has a MAC of 105% and a blood:gas partition coefficient of 0.46. Less than 0.004% is metabolised in humans.

Nitrous oxide is liquid at approximately 760 psi (5.2 MPa) at room temperature, and is usually stored and shipped as a self-pressurized liquid.

Toxicity

Use of nitrous oxide for prolonged periods of three or more hours, can result in the depletion of Vitamin B12. B12 is a bound coenzyme of methionine synthase and has a tetrapyrrole rings with a monovalent Cobalt at the center. The cobalt functions as a methyl carrier in a transmethylation reaction. In high concentrations, over many hours, nitrous oxide can convert the Cobalt from the monovalent form to the bivalent form. With lowered levels of monovalent B12, the body's production of the enzyme methionine synthase is reduced, resulting in lowered levels of methionine, the starting amino acid for all proteins synthesized in humans. Once the available monovalent B12 is depleted, methionine synthase production can only continue in the presence of fresh B12, such as from sub-lingual B12 supplements.

Legality

Under United States federal law, possession of nitrous oxide is legal and is not subject to DEA purview. It is, however, regulated by the Food and Drug Administration under the Food Drug and Cosmetics Act. Prosecution is possible under its "misbranding" clauses, prohibiting the sale or distribution of nitrous oxide for the purpose of human consumption (the recreational drug use market). Given the necessity of proving intent of either buyer or seller in this case, though, such prosecution are rare.

Many states have laws regulating the possession, sale, and distribution of nitrous oxide;[1] but these are normally limited to either banning distribution to minors, or to setting an upper limit for the amount of nitrous oxide that may be sold without special license, rather than banning possession or distribution completely. In most jurisdictions, like at the federal level, sale or distribution for the purpose of human consumption is illegal.

In all jurisdictions, however, such distribution, possession, and use are legal even though intended for human consumption, when done under the supervision and diretion of licensed medical professional such as a physician or dentist.

Nitrous oxide injection systems for automobiles are usually legal, although some localities require certified system components. There have been reported instances of police officers arresting drivers of vehicles equipped with N₂O injection systems on the grounds that he or she intends to inhale it, although such auto-grade N₂O is often mixed with about 100 ppm sulfur dioxide, making inhalation noxious or even fatal.

Sanctioning bodies in motor sport have banned the material in some classes; in 1976, NASCAR disqualified many drivers for nitrous oxide; in June 1998, the NHRA suspended Pro Stock driver Jerry Eckman and car owner Bill Orndorff for a year, stripped the team of all points, and imposed a fine for violations. The team closed down shortly after the suspension.

Neuropharmacology

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Nitrous oxide shares many pharmacological similarities with other inhaled anesthetics, but there are a number of differences.

Nitrous oxide is relatively non-polar, has a low molecular weight, and high lipid solubility. As a result it can quickly diffuse into phospholipid cell membranes.

Like many classical anesthetics, the exact mechanisms of action is still open to some conjecture. It inhibits the NMDA receptor at partial pressures similar to those used in general anaesthesia (Jevtovic-Todorovic et al., 1998; Mennerick et al., 1998; Yamakura & Harris, 2000). The evidence on the effect of N₂O on GABA-A currents is mixed, but tends to show a lower potency potentiation (Dzoljic & Van Duijn, 1998; Mennerick et al., 1998; Yamakura & Harris, 2000). N₂O, like other volatile anesthetics, activates twin-pore potassium channels, albeit weakly. These channels are largely responsible for keeping neurons at the resting (unexcited) potential (Gruss et al., 2004). Unlike many anesthetics, however, N₂O does not seem to affect calcium channels (Mennerick et al., 1998).

Unlike most general anesthetics, N₂O appears to affect the GABA receptor. In many behavioral tests of anxiety, a low dose of N₂O is a successful anxiolytic. This anti-anxiety effect is partially reversed by benzodiazepine receptor antagonists. Mirroring this, animals which have developed tolerance to the anxiolytic effects of benzodiazepines are partially tolerant to nitrous oxide (Czech & Green, 1992; Emmanouil et al., 1994; Quock et al., 1992). Indeed, in humans given 30% N₂O, benzodiazepine receptor antagonists reduced the subjective reports of feeling “high”, but did not alter psycho-motor performance (Zacny et al., 1995).

The effects of N₂O seem linked to the interaction between the endogenous opioid system and the descending noradrenergic system. When animals are given morphine chronically they develop tolerance to its antinociceptive (pain killing) effects; this also renders the animals tolerant to the antinociceptive effects of N₂O (Berkowitz et al., 1979). Administration of antibodies which bind and block the activity of some endogenous opioids (not beta-endorphin), also block the antinociceptive effects of N₂O (Branda et al., 2000; Cahill et al., 2000). Drugs which inhibit the breakdown of endogenous opioids also potentiate the antinociceptive effects of N₂O (Branda et al., 2000). Several experiments have shown that opioid receptor antagonists applied directly to the brain block the antinociceptive effects of N₂O, but these drugs have no effect when injected into the spinal cord. Conversely, alpha-adrenoreceptor antagonists block the antinociceptive effects of N₂O when given directly to the spinal cord, but not when applied directly to the brain (Fang et al., 1997; Guo et al., 1999; Guo et al., 1996). Indeed, alpha2B-adrenoreceptor knockout mice or animals depleted in noradrenaline are nearly completely resistant to the antinociceptive effects of N₂O (Sawamura et al., 2000; Zhang et al., 1999). It seems N₂O-induced release of endogenous opioids causes disinhibition of brain stem noradrenergic neurons, which release norepinephrine into the spinal cord and inhibit pain signaling (Maze, M. and M. Fujinaga, 2000). Exactly how N₂O causes the release of opioids is still uncertain.

N₂O seems to induce its effects through antagonism on NMDA receptors, GABA-A receptor potentiation and potassium channel activation, as well as having a benzodiazepine-like effect and stimulating endogenous opioid receptors.

Laughing gas in movies and fiction

Laughing Gas (movie)
Laughing Gas (novel)
Laughing Gas is one of the main weapons used by the Batman villain, The Joker; but unrealistically he uses a concoction which is shown as being green and lethal.
To experience a "high", the dentist character (Steve Martin) in the musical film version of Little Shop of Horrors dies from the inhalation of laughing gas.
In the television program Hey Arnold!, Helga Pataki calls Arnold while on laughing gas and confesses her love for him. When she realizes what she did, she sneaks into his house and tries to get the answering machine tape which the confession is recorded in.
Two of the main characters in the American re-make of the film Taxi get trapped in a room filled with laughing gas.
The main character of Zodiac, Sangamon Taylor, uses it as a drug, and even came up with Sangamon's Principle to explain why it should be used over other drugs.
In Black Sheep, the two main protagonists borrow a police car and its nitrous oxide boosters leak after hitting a pothole, intoxicating the two.
In the Munsters episode where Herman sneaks into the hospital to visit Eddie after hours, Herman is given laughing gas by the staff. Lily thinks that he was out drinking.
In the Problem Child 3: Junior in Love the dentist used laughing gas to hibernate Junior.
In the movies Fast and the Furious and 2 Fast 2 Furious, nitrous oxide is largely used in most of cars.
In the film Mission: Impossible II, emergency oxygen masks are deployed on a commercial airliner, but instead they provide not oxygen but nitrous oxide, rendering the passengers and pilot unconscious.
In The Pink Panther Strikes Again, Inspector Clouseau, disguised as a dentist, administers laughing gas to Dreyfus (and to himself) and proceeds to remove the wrong tooth.
In the film Final Destination 2, Tim Carpenter is nearly killed when he is accidentally administered a constant stream of pure nitrous oxide at a dentist's office. In the dentist's absence, a toy from a mobile above the chair falls into Tim's mouth forcing him either to breathe the pure nitrous oxide or choke.
An episode of The Fresh Prince of Bel Air shows Will and Carlton in a dentist's office with William Shatner and the valve on a nitrous oxide tank comes loose. The three become extremely intoxicated and later show the hangover symptoms.
In the animated series GI Joe, laughing gas was commonly used to torture prisoners of Cobra, most often by the Dreadnoks. The torture was unrealistic to actual laughing gas, in that the Cobra laughing gas made its victims laugh so hard they soon were in pain and, in at least one episode, the gas appeared to tickle its victims when coming into contact with skin; as the series's authors were not willing to show a real torture technique which people might copy.
Nitrous oxide use is portrayed in the movie Kids.
Nitrous oxide is used by characters in the movie Bio-Dome.
Nitrous oxide is used by several characters in the movie Tank Girl.
In the 1998 movie Lethal Weapon 4, Mel Gibson, Danny Glover, Chris Rock use laughing gas as a 'Truth drug' on Kim Chan in a dentist's office which slowly fills with laughing gas, causing all present to reveal unintended truths to each other while uncontrollably laughing.
"Laughing Gas" is the name of a poem by Beat poet Allen Ginsberg.
Laughing Gas is also used in A Night At The Roxbury.
In The Road Warrior, nitrous oxide is used to speed the Lord Humungus's vehicle.
In Saved by the Bell, Dustin Diamond's character, Screech, is peer pressured into getting nitrous oxide for a party, but brings helium by mistake.
In Novocaine (film) (2001) Steve Martin's character, Dr. Frank Sangster (a dentist), administered nitrous oxide to a young boy.

Laughing gas as a sexual fetish

In recent years, a number of adult sites and groups have appeared on the internet, which cater to various medical fetishes. There have been a number of Yahoo and MSN groups that cater to laughing gas as a sexual fetish exclusively or attach it to the larger fetishes of dental, medical or sleeping gas fetishes. The oldest and longest running website devoted to the fetish of laughing gas, exclusively, is The Laughing Gas Zone, which started out as a Yahoo adult group in 1997 and later became a website devoted to "fantasy" laughing gas mixed with the fetish of tickling. The site disclaimer states that it does not condone the actual use of laughing gas and further states that it promotes "healthy" fantasy based scenarios, rather than the real thing.

References

BERKOWITZ, B.A., FINCK, A.D., HYNES, M.D. & NGAI, S.H. (1979). Tolerance to nitrous oxide analgesia in rats and mice. Anesthesiology, 51, 309-12.
BRANDA, E.M., RAMZA, J.T., CAHILL, F.J., TSENG, L.F. & QUOCK, R.M. (2000). Role of brain dynorphin in nitrous oxide antinociception in mice. Pharmacol Biochem Behav, 65, 217-21.
CAHILL, F.J., ELLENBERGER, E.A., MUELLER, J.L., TSENG, L.F. & QUOCK, R.M. (2000). Antagonism of nitrous oxide antinociception in mice by intrathecally administered antisera to endogenous opioid peptides. J Biomed Sci, 7, 299-303.
CZECH, D.A. & GREEN, D.A. (1992). Anxiolytic effects of nitrous oxide in mice in the light-dark and holeboard exploratory tests. Psychopharmacology (Berl), 109, 315-20.
DZOLJIC, M. & VAN DUIJN, B. (1998). Nitrous oxide-induced enhancement of gamma-aminobutyric acidA-mediated chloride currents in acutely dissociated hippocampal neurons. Anesthesiology, 88, 473-80.
EMMANOUIL, D.E., JOHNSON, C.H. & QUOCK, R.M. (1994). Nitrous oxide anxiolytic effect in mice in the elevated plus maze: mediation by benzodiazepine receptors. Psychopharmacology (Berl), 115, 167-72.
FANG, F., GUO, T.Z., DAVIES, M.F. & MAZE, M. (1997). Opiate receptors in the periaqueductal gray mediate analgesic effect of nitrous oxide in rats. Eur J Pharmacol, 336, 137-41.
GRUSS, M., BUSHELL, T.J., BRIGHT, D.P., LIEB, W.R., MATHIE, A. & FRANKS, N.P. (2004). Two-pore-domain K+ channels are a novel target for the anesthetic gases xenon, nitrous oxide, and cyclopropane. Mol Pharmacol, 65, 443-52.
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GUO, T.Z., POREE, L., GOLDEN, W., STEIN, J., FUJINAGA, M. & MAZE, M. (1996). Antinociceptive response to nitrous oxide is mediated by supraspinal opiate and spinal alpha 2 adrenergic receptors in the rat. Anesthesiology, 85, 846-52.
JEVTOVIC-TODOROVIC, V., TODOROVIC, S.M., MENNERICK, S., POWELL, S., DIKRANIAN, K., BENSHOFF, N., ZORUMSKI, C.F. & OLNEY, J.W. (1998). Nitrous oxide (laughing gas) is an NMDA antagonist, neuroprotectant and neurotoxin. Nat Med, 4, 460-3.
MENNERICK, S., JEVTOVIC-TODOROVIC, V., TODOROVIC, S.M., SHEN, W., OLNEY, J.W. & ZORUMSKI, C.F. (1998). Effect of nitrous oxide on excitatory and inhibitory synaptic transmission in hippocampal cultures. J Neurosci, 18, 9716-26.
QUOCK, R.M., EMMANOUIL, D.E., VAUGHN, L.K. & PRUHS, R.J. (1992). Benzodiazepine receptor mediation of behavioral effects of nitrous oxide in mice. Psychopharmacology (Berl), 107, 310-4.
SAWAMURA, S., KINGERY, W.S., DAVIES, M.F., AGASHE, G.S., CLARK, J.D., KOBILKA, B.K., HASHIMOTO, T. & MAZE, M. (2000). Antinociceptive action of nitrous oxide is mediated by stimulation of noradrenergic neurons in the brainstem and activation of [alpha]2B adrenoceptors. J Neurosci, 20, 9242-51.
YAMAKURA, T. & HARRIS, R.A. (2000). Effects of gaseous anesthetics nitrous oxide and xenon on ligand-gated ion channels. Comparison with isoflurane and ethanol. Anesthesiology, 93, 1095-101.
ZACNY, J.P., YAJNIK, S., COALSON, D., LICHTOR, J.L., APFELBAUM, J.L., RUPANI, G., YOUNG, C., THAPAR, P. & KLAFTA, J. (1995). Flumazenil may attenuate some subjective effects of nitrous oxide in humans: a preliminary report. Pharmacol Biochem Behav, 51, 815-9.
ZHANG, C., DAVIES, M.F., GUO, T.Z. & MAZE, M. (1999). The analgesic action of nitrous oxide is dependent on the release of norepinephrine in the dorsal horn of the spinal cord. Anesthesiology, 91, 1401-7

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