Dangers of Nitrous Oxide

For some common sense (you'd think) warnings about nitrous use, see Nitrous Dos & Don'ts.

Nitrous is a drug and like any drug can be emotionally habit-forming. While there is no physiological addition to nitrous, it can lend itself to compulsive use. This danger was known as early as the 1840s as seen in this handbill for a nitrous demonstration which reads: "Those who inhale the Gas once, are always anxious to inhale it the second time." Because of its short duration, nitrous lends itself to bingeing in an attempt to stay high or to recapture fleeting glimpses into otherness.

Another issue with the short duration of a nitrous trip (or perhaps just cheapness) is reuse the nitrous. This is done by exhaling into someone else's mouth, or by exhaling into a bag or balloon for reinhalation. Reuse reduces the available oxygen while increasing carbon dioxide and makes hypoxia (oxygen deprivation) more likely. Deaths involving nitrous oxide are very rare, but almost always involve putting a bag over the head or opening a tank in a sealed space such as a car.

It should be pointed out that in the dentist's office one never receives 100% nitrous. Instead you breathe a mix of nitrous and oxygen -- generally 70% N2O to 30% oxygen. This is equivalent to the amount of oxygen in room air -- but the nitrogen has been replaced by nitrous oxide.

Nitrous does not kill brain cells, but lack of oxygen does.

The primary physiological dangers of nitrous inhalation are:

There is also evidence of long term risks for dentists and others who receive a continuous low level exposure.

Oxygen Deprivation

"Occasionally, certain anesthetic agents become misused drugs. Nitrous oxide is an example. A gas of low anesthetic potency, it is incapable of inducing deep levels of anesthesia if an adequate oxygen concentration is maintained. Nitrous oxide induces a state of behavioral disinhibition, analgesia, and euphoria. One of the problems occasionally encountered when nitrous oxide is used for recreational purposes is that, unless the compound is administered with at least 20 percent oxygen, hypoxia (decreased oxygen content of the blood) can be induced. But in order to achieve high enough concentrations of nitrous oxide to get a good behavioral effect, concentrations of 50 percent or greater must be inhaled. If such concentrations are mixed with room air, inhaled oxygen concentrations drop to low levels and the hypoxia may result in irreversible brain damage."

Robert M. Julien

Frostbite and Motor Control

"Physicians and dentists have long considered nitrous oxide to be a safe pharmacological agent. Nevertheless, there is some evidence that excessive or prolonged use of it can damage the bone marrow and nervous system by interfering with the action of vitamin B-12. Moreover its use in non-medical settings presents several hazards that users should keep in mind. Breathing it directly from pressurized tanks is dangerous for two reasons. First, gas flowing from such tanks is very cold -- cold enough to cause frostbite of noses, lips and (most serious) vocal cords. Being anesthetized, a user may be unaware of such injuries until too late. Second, because nitrous oxide does not support life, it should be mixed with oxygen if it is to be breathed for more than a few minutes. At private parties, oxygen tanks are rarely supplied, and people have died of asphyxiation by breathing straight nitrous oxide through face masks. One way to avoid these dangers is to fill balloons from tanks and breathe from the balloons."

"Further, nitrous oxide rapidly leads to complete loss of motor control, and anyone who breathes it while standing will soon reel about and fall down. Therefore, it is unwise to try the gas unless one is in a comfortable sitting or lying position. Serious injuries have resulted from people inhaling laughing gas while standing in front of open windows, when driving cars or when operating machinery. Others have been badly hurt by accidentally pulling heavy tanks of nitrous oxide over onto themselves while intoxicated."

"People who breathe nitrous oxide for more than a few minutes at a time may experience nausea, especially if they have just eaten. They may also feel hung over for some time after. Addiction to nitrous oxide is a real possibility. Addicts may suffer serious mood and personality changes in addition to the bone marrow and nervous system damage already mentioned."

Weil & Rosen

Chronic Overuse of Nitrous

"This 36-year old electrical engineer came to the emergency room complaining that he was unable to walk. Symptoms had begun 4 days earlier with 'pins and neeedles' in both feet that gradually worsened and ascended to involve the knees and the fingertips. With worsening of the paresthesias (no sense of touch or pain) he noted difficulty in maintaining proper control of the movements of his arms and hands and trouble in walking. He also reported the sensation of electric shocks through his back and legs upon flexion of the neck. He denied bladder or bowel impairment but he had been unable to have an erection for the past week. His past medical history was unremarkable except for occasional abuse of alcohol in the past. However he denied any drinking of alcohol for the past 8 months.

For recreational purposes he had inhaled two to three boxes of nitrous oxide, each box containing 24 cartridges, practically every day for the past six months.

When first seen his general physical examination was completely unremarkable. The neurological examination showed hyperesthesia and hyperalgesia in the lower extremities up to the knees. He had severe bilateral sensory dystaxia and could only stand with support.

Intramuscular B12 injections were started and during the following days his hematological status improved, (-apart from neurological symptoms, the functional B12 deficiency caused by N2O also produces megaloblastic anemia,- ed.) although his neurological condition continued to deteriorate. The paresthesias ascended to the nipples and he developed fecal and urinary incontinence.

Four weeks later he began to improve and four months after the onset of the symptoms, and his last use of nitrous oxide he could walk with some hesitation and had completely regained bowel and bladder control and sexual function..."

Stacey et al

More Overuse of Nitrous

"This 32 year old woman was admitted to the neurology service for inability to walk and paresthesias in her limbs and trunk. Her symptoms began 3 weeks prior to admission with a 'tingling' sensation in the soles of her feet, trunk and hands. Her gait became progressively less steady and the day prior to admission she had an episode of urinary incontinence. Her past medical history was significant for bulimia and occasional intranasal use of cocaine.

For the previous 3 months she had inhaled nitrous oxide for recreational purposes, up to 200 cartridges a day, three to four times a week.

Stacey et al

Folic Acid and B Vitamin Deficiencies

For the really health conscious among you (a contradiction in terms?) if you "must" do nitrous for a longer period be sure to take high doses of folic acid (is also depleted from your body as a result of functional B12 deficiency) and vitamin B12. (No injury NOT guaranteed, but it might help)

Also, but less well known, the state of B12 deficiency caused by regular use of nitrous oxide produces hyperhomocysteinemia, an accumulation in the blood of the amino acid homocysteine. Hyperhomocysteinemia is a risk factor for vascular disease of all sorts. Furthermore, hyperhomocysteinemia, B12 deficiency and folic acid deficiency early in pregnancy all increase the risk of getting a child with a neural tube defect (spina bifida and anencephaly, childeren with no brains or open spinal cord). If you are a woman, planning to get pregnant or just "at risk of getting pregnant", nitrous is a bad idea.

B12 and Other Issues

There have been reports of immunological and reproductive disturbances in professionals who are chronically exposed to nitrous oxide. The immunological disturbances are documented by Peric et al (1991) _Anaethesia_ 46: 531-7. Apparently anaesthetic personnel had been complaining about weakness and recurrent infections and decreased peripheral blood leukocyte counts has been found. The operating rooms were found to be improperly ventilated, causing nitrous oxide and halothane (another anaesthetic) to remain in the air. Even after a 3-4 week holiday, some personnel has decreased B lymphocytes and increased red cell count, haemoglobin concentration and haematocrit and other disturbances. I don't have a reference handy for the reproductive disturbances, but the study basically found that women who were chronically exposed to nitrous had difficulty becoming pregnant. It should be noted that these health effects are the result of CHRONIC exposure; a single balloon at a Dead show (or a single visit to the dentist) is unlikely to be a problem for a healthy individual.

Aside from its psychopharmacological actions, nitrous oxide has one other (known) significant metabolic action: it interacts with vitamin B12. This was first reported in an in vitro study in 1968, but didn't really receive notice from anaesthesiologists until ten years later (because medline didn't exist yet :-) ). In 1978, however, Amess et al showed that 24 h of nitrous oxide administration caused interference with DNA synthesis in humans. Since then, the interaction between nitrous oxide and B12 has been better characterized.

Basically, 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. Nitrous oxide converts the cobalt from the monovalent form to the bivalent form. As a result, methionine synthase activity is inhibited. Recovery is believed to require absorption of new unoxidized B12 (and synthesis of new apoenzyme).

Humans seem to be far more resistant to complications from this than rodents. I don't have the energy to go through the various published studies at this point, so I will quote from Nunn's "Clinical Aspects of the Interaction Between Nitrous Oxide and Vitamin B12" (1987), _Br. J. Anaesth._ 59: 3-13.

It seems likely that in man, in contrast to the rat, exposure of less than 30 minutes will not cause any measurable change in methionine synthase activity. In combination with a wealth of clinical experience, this suggests that there is no special hazard for short exposures to nitrous oxide. There is a variable response to exposures lasting between 30 minutes and 2 h. However, it now seems likely that exposures of more than 2 h are likely to cause interference with hepatic methionine synthase activity. The paucity of human data makes it more difficult to say how long an exposure is required to cause significant interference with DNA synthesis. It is likely that there will be considerable individual variation and results obtained in healthy patients cannot be extrapolated to the patient who is seriously ill. Nevertheless, it seems likely that, once methionine synthase activity is inhibited, it will remain so for days.

With respect to repeated exposures to nitrous, be aware that this effect can build up (Nunn gives "intervals of less than 3 days" as a cut-off).

Mandatory nitrous horror story: Layzer (in (1978) "Myeloneuropathy after prolonged exposure to nitrous oxide," _Lancet_ 2:1227) reports a case of 15 people who had been inhaling nitrous oxide for long periods of time and developed a condition resembling subacute combined degeneration of the cord, whatever that means.

I would suggest that the following types of people in particular avoid exposure to significant amounts of nitrous:

  • Pregnant women: since nitrous oxide is a known teratogen in rodents, acting by depleting folates and partially reversible by oral folinic acid, we can expect a similar syndrome in humans.
  • Vegans who don't take B12 supplements: although documented cases of vegans with B12 deficiencies are scarce, theories on nutrition indicate that vegans are unlikely to get as much B12 as other groups of people.

Nausea, Gut, Ear Pain

N2O does not combine with haemoglobin, but is carried free in the blood and excreted unchanged through the lungs. The risk of hypoxia comes not from any interaction between N2O and O2 in the blood or brain, but from simply not inhaling oxygen often enough. The vast majority of deaths from N2O abuse have been through stupidity (tying a plastic bag full of N2O round the head, letting off a tank in a airtight place, that sort of thing). There have been a few cases of malignant hyperthermia (raised body temperature),and this is considered a potentially serious threat to those with the genetic requirement (check out your family history - look for deaths during surgery, both minor and major).

There are 4 stages of general anaesthesia. The first is drowsiness, confusion and analgesia. The second stage involves excitement, euphoria, spontaneous muscle movements, hallucinations (auditory and visual). The third stage is loss of consciousness, and the fourth stage is heading into coma, where the patient stops breathing. Anaesthetists generally aim for the upper levels of stage three, which is why some people 'wake up' during the operation - they've drifted up into stage two. From personal experience, I think that recreational use of inhalational anaesthetics (N2O and ether) induce stage 2 and sometimes stage 3, depending on the pattern of use.

General Anaesthetics can give nausea and vomiting as a side effect, the risk of this is increased if you have been drinking alcohol. Not only is this a bit unpleasant but there is a risk of inhaling your own vomit if you are a bit confused or temporarily unconscious.

Reverse tolerance has been reported in the literature, and this seems to be confirmed by my own personal experiences. Reverse tolerance is getting more intense or prolonged feelings with the same or lower quantities of a drug. Most psychoactive substances don't work this way, I don't know why N2O does. As all traces of the gas are excreted from the body within an hour after cessation of use, it's not due to fat stores being reintroduced to the blood (as can happen with marijuana).

Nitrous oxide will dissolve out of blood into air filled spaces eg the intestines, the middle ear. N2O in the gut will just give you a gut pain, but if you have ever had middle ear disease, or damaged ear drums, you could be in for permanent hearing loss. There are also some cases of transient hearing loss, but I don't know much about this.