Nitrous oxide is a very common inhalational anesthetic. It’s capable of providing analgesia, some anesthesia, and amnesia. Because of its euphoric and hysterical effects, it’s also known as “laughing gas.” Some aspects of its pharmacology are concerning if the drug is used for long periods, whether that’s in recreational or medical settings. As always, there will be more information and links to references on TheDrugClassroom.com which you can find using the link below. Among the potential positive effects are dissociation, euphoria, anxiolysis, mood lift, sedation, analgesia, laughter, and a dream-like state. The negatives can include amnesia, dizziness, nausea, vomiting, and headache.
Some of its benefits in anesthesia are that it generally offers stable cardiorespiratory function, reduces anxiety, offers some pain relief, and doesn’t irritate the respiratory tract. A key part of its widespread medical and recreational use has been its perceived safety. Although the drug is generally quite safe, precautions should be taken. It shouldn’t be used directly from a whipped cream charger or Nitrous Oxide tank. It’s best to use a balloon. The drug should only be inhaled when sitting or laying down. You should never take it in a way that doesn’t let you disconnect from the nitrous source or that deprives you of oxygen. This means, for example, you shouldn’t use a mask. Even opening a container in a small, enclosed area should be avoided. When taken recreationally, the substance can provide a short-lasting euphoric state with reduced or altered perception of your surroundings.
Dream-like hallucinations are sometimes reported and it’s possible to feel depersonalization and derealization. The physical sensations may include feelings of warmth or cold as as well as sensations of body distortion, like stretching, pulling, compression, and disintegration. Its physical euphoria has been reported to enhance orgasm, according to some users. Often there’s an element of amnesia that impairs your memory of the core effect period. Users sometimes become significantly detached from the outside world and even their bodies. This leads to traveling internally in a seemingly location-less or time-less space, which could feel profound. That kind of experience isn’t the most typical response to nitrous oxide.
Most of the perceptual effects involve distortions. Your vision might get blurry and it can be pulsating. Pulsating auditory changes may also occur. Other auditory effects include high pitched sounds, echoes, muffled hearing, and an incorrect sense of distance. Some closed eye visuals can occur, such as patterning. The open eye visuals mainly involve distortions of color and depth. Occasionally there are more complex dream-like hallucinations, such as thinking you’re interacting with a person or someone is touching you. It’s possible to experience confusion, paranoia, and anxiety. Those feelings aren’t the most common response and typically only last for a short period. Sexual effects are sometimes reported, such as increased arousal and sexual feelings. Because of its euphoric and short-lasting nature, there’s typically a big impulse to use the drug again. Another recreational aspect is that it can synergize with drugs like psychedelics, MDMA, and cannabis. Nitrous oxide isn’t a very potent anesthetic. As such, it’s generally used for conscious sedation in cases like dental procedures or labor. It’s frequently an adjunct to local anesthesia in dental cases.
It can also be used in general anesthesia when combined with a more potent inhalational anesthetic or an IV anesthetic. The drug is always administered with oxygen, with the nitrous being at a concentration of 30 to 70%. Nitrous oxide does provide some pain relief and a reduction in anxiety, which can be quite useful. It’s often used in a way that still allows pain to technically be felt, but the pain is much easier to handle. It’s not very good or practical as a single anesthetic. Because of its low solubility in blood, there’s a rapid clearance of the gas. This makes it easy for medical personnel to acutely control what state the patient is in. Nitrous oxide is sometimes administered in the pre-hospital setting, including in areas where opioids aren’t available for emergency medicine. It’s been used in labor since the late 1800s, with the practice becoming more common in the 1900s. The drug allows a woman to maintain consciousness while experiencing analgesia and anxiolysis. Epidural analgesia appears more effective, but Nitrous is often sufficient to meet the demands of a patient. More research should be done on its efficacy and safety in this setting.
Nitrous oxide has also been studied for other potential medical uses. There’s some evidence it could be used similarly to ketamine in the treatment of depression. One study found that it offered antidepressant effects without hallucinations or loss of consciousness. It could potentially be used as a neuroprotectant in ischemic brain injury, although there’s more interest in utilizing Xenon. Some use of the drug for reducing craving and withdrawal symptoms in drug dependence has appeared. It’s primarily been used in alcohol withdrawal, with nitrous being compared to benzodiazepines. Some evidence suggests it might quickly reduce withdrawal symptoms and reduce the need for sedatives. This use has been greatest in South Africa. Nitrous oxide works in a matter of seconds and only lasts for about 2 to 5 minutes. This is why it is continuously administered along with oxygen in medical settings. Once administration ends, the effects quickly end as well. Nitrous oxide is a simple compound made of nitrogen and oxygen which can be described as an oxide of nitrogen.
It’s a colorless gas with a somewhat sweet taste. A few mechanisms for nitrous oxide seem to exist. The primary one is NMDA antagonism. Some of the other possible contributing factors are inhibition of low-voltage activated calcium channels, activation of TREK-1, weak GABA-C antagonism, weak 5-HT3 antagonism, increase in nitric oxide activity, and potentiation of GABA-A receptors. Endogenous opioid peptides might play a role in pain relief. There may be a release of proenkephalin and a rise in metenkephalin.
This leads to activation of descening inhibitory pathways and a modulation of nociception. Variable effects of opioid antagonists have been seen on nitrous oxide’s activity. Nitric oxide plays a possible role in the drug’s action and nitric oxide synthase inhibitors have been shown to inhibit nitrous oxide’s antinociception. An average dose during a session of nitrous oxide use is the equivalent of 1 to 5 chargers or 1 to 5 balloons. The substance should never be used directly from a charger or tank. Joseph Priestley, an English chemist, is believed to have isolated Nitrous oxide for the first time in 1772. It’s may have been prepared before, such as by Joseph Black, but the honor is generally given to Priestley. Priestley and others though it was a highly dangerous substance. It was observed to cause death when mice were placed in a jar of the gas. The first publication about it was in 1776, as part of a volume of Priestley’s Experiments and Observations on Different Kinds of Air. Around the same time, Samuel Mitchill of the US proclaimed Nitrous oxide to be very dangerous. He stated it was the “principle of contagion and capable of producing the most terrible effects when respired by animals.” “If full inspiration of the gaseous azote be made there will be sudden extinction of life.” This view quickly changed.
In 1798, Thomas Beddoes of the Pneumatic Institute made 20-year-old Humphry Davy the Superintendent of the Medical Pneumatic Institution. He quickly got to work investigating nitrous oxide and first took the substance in April 1799. Davy found it could produce brief intoxication with euphoria and distortions of sensation, time, and space. His discoveries were announced to the Nicholson’s Journal in 1799, with Davy writing that he had overturned Mitchill’s hypothesis. Many experiments were conducted by Davy and he also give it to other individuals, including Samuel Taylor Coleridge. An example of people’s response to Nitrous oxide is found in a letter from Robert Southey to Thomas Southey. “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 went on to coin the term “laughing gas.” He published a book that, among other things, mentioned its potential role in medicine in 1800. It was found the substance seemingly alleviated headaches and toothaches. In a practically throwaway statement at the end of the book, Davy said: “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 this statement shouldn’t be understated.
Had Davy and others actually pursued that belief, they could have kickstarted the age of anesthesia. This could have saved people a lot of pain and enabled medical procedures that simply weren’t being done due to the pain issue. Another interesting set of statements from Davy concerned Nitrous oxide’s compulsive nature. “I ought to observe that a desire to breathe the gas is always awakened in me by the sight of a person beathing, or even by that of an air bag or an air holder.” “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.” Important individuals like Astley Cooper, a famous surgeon, soon learned of and experienced nitrous oxide.
Yet the drug failed to move much beyond recreational use for years. Davy’s work began to be discussed in medical and chemistry settings. Nitrous oxide was mentioned in British textbooks in the 1800s to 1820s. Professor Silliman wrote in the American Journal of Science in 1819 that more attention should be given to gases like nitrous oxide. It was brought the attention of the public through demonstrations at the Royal Institution, at private parties, and as part of public entertainment. Its use in England became fairly signifiacant. Public entertainment involving nitrous oxide seemed to kick off around the 1820s and 1830s. Although it’d still be a while before medical use really began, it might have been used to relieve pain after dental extractions as early as 1820 in Paris. It was also considered for other medical uses like relieving asthma. Some poisonings by what was believed to be impure nitrous oxide did occur. There was a bit of use in America.
One account noted that it became “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.” Traveling showmen demonstrated its properties in the US as early as the 1830s. One of those showmen was Samuel Colt, designer of the first mass produced revolver. In 1832, at the age of 18, he toured the East Coast from Canada to Maryland showing nitrous oxide’s effects. Horace Wells, an American dental surgeon, briefly introduced the gas into his medical practice in 1844. He learned about its pain blocking properties during a “Grand Exhibition” organized by Gardner Quincy Colton in Connecticut. On December 10, 1844, Wells noticed that one of the participants in the show inhaled the gas and then injured his leg while staggering around. Yet he didn’t seem notice the pain until the effects wore off. Wells insisted Colton also give him the drug. He didn’t want to just experience Nitrous and instead went a step further, asking for one of his wisdom teeth to be extracted while under the influence of the gas.
The next day, that’s exactly what was done. Wells reported being pain free during the procedure. He proclaimed it was “a new era in tooth pulling.” Wells carried out successful trials of the substance in dental procedures from December 1844 to January 1845. He decided he should present his findings during a demonstration in Boston in January 1845. When he arrived, his work was publicized in daily papers such as the Boston Bee. Those papers also publicized the apparent utility of the gas during dental procedures. Most of the people Wells met in Boston doubted Nitrous oxide’s usefulness. He was allowed to address students at Harvard Medical School sometime in late January. That address was followed by a well-known demonstration elsewhere in Boston on the same evening. In front of students and physicians, Wells failed to fully show Nitrous oxide was useful during a dental procedure.
The patient somewhat cried out and reported pain in the beginning. Some reports claim the patient ended up reporting less pain than usual, but his initial response was enough for many to consider it a failure. Wells attributed the failure to withdrawing the nitrous bag too soon. Some of the spectators reportedly laughed at him. Although he would eventually be recognized by some as the “discoverer of anesthesia,” interest temporarily turned to other anesthetics like ether and chloroform. This was ultimately a tragic story. Wells became ill shortly after the failure in Boston, possibly in connection to a deep sense of humiliation and failure. He tried to get public and official recognition as the discoverer of anesthesia, but was largely unsuccessful. In January 1848, Wells committed suicide by inhaling chloroform and cutting his left femoral artery. Little did he know, just a few weeks earlier the Parisian Medical Society had recognized him as the inventor of anesthesia and made him an honorary member.
Gardner Quincy Colton, the same man who organized the event that introduced Wells to Nitrous oxide’s efficacy, firmly established the use of Nitrous in dentistry in 1863. By the late 1860s, use was fairly widespread. A successful demo in London in 1868 triggered a spread of its use in Europe. The same year, multiple cases of a safer form utilizing both Nitrous oxide and oxygen were published. From the 1860s forward, Nitrous oxide was popularized as an anxiolytic and analgesic tool for procedures like tooth extractions. Prolonged administration wasn’t really reported until around the 1890s. In 1895, Herbert Paterson began giving the gas through the nose in long dental procedures.
Paterson showed this method to others. Though medical use was expanding, nonmedical was still taking place in the mid to late 1800s. William James, a famous philosopher, published accounts of its activity late in the century. The use of nitrous oxide for labor was gaining ground by the 1920s, mainly in the US. All through this time, Nitrous oxide was treated as a basically harmless substance, but things started to shift.
In April 1956, the Lancet published a case series from Bledgam Hospital in Denmark showing megaloblastic bone marrow changes from extended inhalation. Physicians at the hospital thought it could be used for days on end in patients with severe tetanus infections. Two of the first five patients, a 15-year-old boy and a 53-year-old female, died from sepsis following agranulocytosis after the first week. This prompted a trial in two more cases. Both patients showed marked hematological changes on Day 4, and bone-marrow biopsies showed megaloblastic changes. A B12 inactivation report then appeared in 1968. However, this paper largely went unnoticed for about 10 years. When reports began appearing of high miscarriage rates in anesthesia personnel, concerns about occupational exposure increased. Some reports indicated a correlation between working around nitrous oxide and reporting irritability, fatigue, headache, and fetal malformation. Papers detailing nitrous oxide-related neuropathy and myelopathy contributed to occupational exposure concerns and also made people wonder if it should even be used. Neurological problems appeared in a case series in 1978. Most of the patients were dentists and presented with what appeared to be subacute combined degeneration of the spinal cord. The initial symptoms were numbness and tingling in the hands and legs.
And some of them eventually couldn’t walk without assistance. Most of the symptoms slowly declined when use ended, but not all of the symptoms resolved. The same year, an editorial suggested that if nitrous oxide were a new drug, it probably wouldn’t be used. Some usage patterns were affected, but a lot of medical professionals weren’t even aware of these issues. In the 1960s and 70s, there was a rise in recreational use, often among those with access to large amounts of Nitrous oxide, such as dentists and hospital workers. A 1979 paper indicated up to 20% of dental and medical students had experimented with the drug. We learned more about its pharmacology in the 1980s and 1990s. Papers showed it could affect opioid peptides and was an NMDA antagonist. In 2002, a review found it was widely used in labor. Upwards of 50% of women in the UK and 60% of women in Finland were given nitrous oxide. In 2010, the American College of Nurse-Midwives published a statement endorsing the increased availability of nitrous oxide for women in the US. From the 2000s to 2010s, thetre was an apparent decline in the medical use of Nitrous oxide.
At the same time, recreational use was stable or higher. Currently, it’s one of the most common inhalants. There’s been some decline in the use of nitrous oxide in some countries, but use is still significant. Nitrous oxide is unscheduled in the US. Some states, such as California, Florida, and Oregon have laws that prohibit the sale or use of nitrous oxide for recreational purposes. It’s typically uncontrolled in other countries, but there might be some laws pertaining to recreational use. The primary safety concerns are hypoxia and B12 inactivation. Hypoxia is mainly an issue if someone uses Nitrous oxide too much and too quickly, or if they can’t separate from the administration device upon losing consciousness. It’s best to avoid using multiple balloons in quick succession.
Even when you’re hypoxic, you may not feel like you need to breathe or that you’re even being deprived of oxygen. Nitrous oxide is always given with oxygen in medical settings, but that wasn’t always the case, so asphyxia would sometimes occur. Fatalities still rarely occur nowadays from equipment malfunction, inaccurate gas cylinder labeling, and other human error. B12-related concerns are relevant when use is very high or someone is deficient in B12. The substance oxidizes the cobalt core of cobalamin, thereby infringing upon methionine synthase. This inhibition may persist for days and could be cumulative with repeated use. Inhibited methionine synthase raises homocysteine levels and can impair the synthesis of DNA. With the resulting lack of methionine and S-adenosyl methionine, methylation of myelin sheath phospholipids will be impaired.
This diminishes myelin formation, eventually leading to neurological issues. When neurological issues appear, treatment mainly consists of abstinence from nitrous oxide and B12 administration. To prevent these issues, you shouldn’t frequently use the drug and you should keep up your B12 levels. In medical settings, it’s typically fine when used for less than 6 hours. The neurological issues will include things like weakness, clumsiness, numbness, and tingling. It can eventually become difficult to move around. And it’s also possible for there to me memory impairment and mood changes. Neurotoxicity has been mentioned as a possible concern, but it’s not clear how relevant the animal models are to humans. Increases in gas volume or pressure can lead to problems. It is potentially contraindicated, at least in some cases, in bowel, laparoscopic, middle ear, and eye surgery. Caution is advised in neurosurgery. Modern evidence indicates occupational exposure is probably not a concern, especially if there’s proper ventilation and scavenger devices.
Death is very rare with nitrous oxide. Most fatalities have occurred from oxygen deprivation, generally from using a system that doesn’t allow for enough oxygen when someone loses consciousness..