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Abstract

Nitrous oxide is a widely used analgesic agent, used also in combination with anaesthetics during surgery. Recent research has raised concerns about possible neurotoxicity of nitrous oxide, particularly in the developing brain. Nitrous oxide is an N-methyl-d-aspartate (NMDA)-antagonist drug, similar in nature to ketamine, another anaesthetic agent. It has been linked to post-operative cardiovascular problems in clinical studies. It is also widely known that exposure to nitrous oxide during surgery results in elevated homocysteine levels in many patients, but very little work has investigated the long term effect of these increased homocysteine levels. Now research in rodent models has found that homocysteine can be linked to neuronal death and possibly even cognitive deficits. This review aims to examine the current knowledge of mechanisms of action of nitrous oxide, and to describe some pathways by which it may have neurotoxic effects.

Keywords: nitrous oxide, neurotoxicity, homocysteine, NMDA antagonist

1. Introduction

Nitrous oxide (N ₂O) has been used alone or in combination with other agents to produce analgesia and anaesthesia for over 150 years [ 1]. It shows anaesthetic properties at very high concentrations, with a minimum alveolar concentration needed to produce anaesthesia in 50% of subjects (MAC) of 104% [ 2]. To reach near this level without compromising oxygenation, hyperbaric conditions are necessary which are impractical in a surgical setting. During the 1940s however, doctors began administering N ₂O in combination with a number of other non-volatile anaesthetic agents to allow for lower N ₂O concentrations to be used [ 1]. Nowadays, nitrous oxide is still used in combination with various anaesthetic agents such as isoflurane and ketamine for anaesthetic sparing, to allow lower concentrations of volatile or non-gaseous anaesthetics to be used [ 3, 4].

Nitrous oxide is also commonly administered in a 50:50 mixture with oxygen to give analgesia during labour as it has no effect on awareness, and can be self-administered by the mother allowing for more personalised pain relief during contractions. In recent years, however, the safety and efficacy of nitrous oxide has been questioned [ 5, 6]. While many studies show adverse effects of nitrous oxide anaesthesia, there is still no general consensus as to whether N ₂O is dangerous enough to warrant discontinuation as an anaesthetic or analgesic [ 7]. This review article aims to summarise the current evidence for toxicity of nitrous oxide. However, with the limited clinical data presently available on nitrous oxide toxicity it is, as of yet, too soon to draw conclusions.

2. Neurotoxicity

It has been documented through a series of clinical studies that nitrous oxide administration is associated with post-operative cardiac problems [ 6, 8]. Further evidence is now mounting which implies nitrous oxide may also cause neurotoxicity. Often, neurological damage may not have overt symptoms and vulnerable patients, such as the elderly, may experience cognitive changes which may go unnoticed. It is often the most vulnerable patients exposed to anaesthetic agents, so one must be sure that the stress of surgery is not exacerbated by the anaesthetic agent which should be providing relief.

Many of the neurotoxic effects of nitrous oxide are dependent on exposure at a certain age or developmental stage. Extensive research indicates that the main periods of vulnerability to nitrous oxide neurotoxicity are during the perinatal period and again in the aged brain. The foundation work has mostly been carried out in rat models but more recent research work has extended into non-human primate models. In rats, perinatal development extends to postnatal day (PND) 7, juvenile rats are classed PND 22-28, adolescence begins around PND 30-35 while adulthood is reached at PND 60 [ 9]. This demonstrates the rapid development of rats in comparisons to primates and humans.

2.1. Perinatal Brain

Rat neurodevelopment is confined to a short period directly after birth, from postnatal day (PND) 0 to PND 7. This roughly translates to a period spanning the third trimester of pregnancy to approximately the 6th month of age in humans [ 10]. During this period there is a massive increase in programmed cell death as excess neurons are cleared and synapses of remaining neurons are strengthened, known as synaptogenesis. As can be seen in , rats exposed to N ₂O in combination with other clinical anaesthetics during this period have a consistent, excessive increase in apoptosis in various brain regions, most notably the retrosplenial cortex (RSC) and thalamus [ 11]. It was also found that these animals have long term impairment of cognitive function [ 12, 13]. It has been shown that at PND 7 in rats there is peak N-methyl-d-aspartate (NMDA) receptor expression in the developing brain, which may explain the increased sensitivity to N ₂O [ 14, 15]. This period is approximately equivalent to 20-22 weeks in humans.

Table 1

Using non-human primates, these models can be taken a step closer to clinical relevance, achieving that which would not be ethical or feasible in a human study. No current studies have looked at N ₂O alone, but one study assessed neurotoxicity after a N ₂O/isoflurane mixed anaesthesia protocol in PND 5 or 6 rhesus monkeys [ 23]. Similar to rodent models, there was widespread cell death in the young monkeys, but interestingly they found a different pattern of distribution in comparison to rodent models. While rodents usually had cell death in the posterior cingulate and retrosplenial cortex (PC-RSC) and thalamus [ 11, 14], this study found widespread apoptosis in the temporal gyrus, hippocampus and frontal cortex [ 23]. The primate study also found evidence of both necrotic and apoptotic cell death occurring, as opposed to simply apoptotic in the rat. Other studies involving administration of ketamine, another NMDA antagonist anaesthetic, to PND 3-6 rhesus monkeys demonstrated similar patterns of cell death and cognitive dysfunction as rodent models [ 24, 25, 26]. These studies also found that by PND 35, the neurotoxic effects of ketamine were no longer present.

Loepke et al. [ 27] undertook a review of all general anaesthetics administered to children in the perinatal period and found a wide range of variability in neurotoxic potential of anaesthetic agents. Nitrous oxide itself had not been subjected to any clinical trials but it was reported that in utero or perinatal exposure to N ₂O was correlated with short term neurological problems such as resistance to smiles and increased muscle tone [ 28]. This indicates that further research into the effects of N ₂O on infants should be undertaken, considering how popular N ₂ O is as an induction agent and anaesthetic.

2.2. Aged Brain

A study by Noguchi et al. [ 29] compared a range of different aged rats, from PND 20-60, and discovered that at PND 30, MK801 started producing NMDA antagonist toxicity, with PND 60 rats having the highest level of cell death. This indicates that once past the early vulnerable stages after birth, juvenile rats are not as susceptible to the neurotoxic effects of NMDA antagonists, while adolescents are less vulnerable than adults. A number of rodent studies found that N ₂O administration alone or in combination with other anaesthetic agents produced cognitive deficits in aged mice (18-20 months old) [ 20, 21, 22]. As shown in , all studies from this lab used the radial arm maze (RAM) to test cognitive function, which is known to involve hippocampal and cortical memory circuits. One interesting study found that older rats were more susceptible to N ₂O in combination with ketamine than younger (6 month old) rats [ 19]. They hypothesised that this was due to reduced hepatic function in older rats, which resulted in slower clearance of ketamine from the body. This highlights the fact that N ₂ O may not always be reliably compared to ketamine or other non-inhalational anaesthetics, due to their different metabolisation processes.

There is also a trend, as seen in , that in adult rats, high concentrations of N ₂O given under hyperbaric conditions can result in neurotoxicity [ 31], however due to the fact that these concentrations are unfeasible in a clinical setting, this may not be altogether relevant except to help understand the toxic potential of N ₂O. Together, these results infer that there is a period, beginning in the weeks just after birth, extending until adulthood, where rats appear to have a less severe reaction to NMDA antagonist toxicity, except at clinically irrelevant concentrations. This may be due to changes in the brain during this period, where there is a high level of development but less programmed cell death. In line with these findings, Yon et al. [ 16] showed that between PND7 and PND14, rats become desensitized to the damage induced by an isoflurane/N ₂ O/midazolam cocktail, and showed a significant increase in expression of Bcl-XL, an anti-apoptotic protein. Clearly, this warrants further study.

Table 2

3. Molecular Mechanisms of Action

Despite widespread use for many years, the mechanisms by which nitrous oxide achieves its anaesthetic and analgesic properties have still not fully been elucidated. It has been suggested that opioid receptors are responsible for the analgesic properties of nitrous oxide. Research revealed that administration of Nalaxone, an opioid reverse agonist, inhibits the analgesic effects of nitrous oxide [ 37]. It is well known that there are a range of opioid receptors so it is difficult to pinpoint one specific receptor as being responsible. Work done on the abdominal muscles of mice found that the endogenous ligand for the κ-opioid receptor, dynorphin, may be the mediator of N ₂O antinociception [ 38, 39]. However, both the µ- and ε-opioid receptors were found to have involvement in the rat hot plate test, which involves more peripheral nerves [ 40]. A study in the guinea-pig brain served to compare binding by nitrous oxide to opioid receptors in the brain and discovered N ₂O acts differently on µ- and κ-opioid receptors. µ-receptors were competitively inhibited by N ₂O while κ-receptors were non-competitively bound [ 41]. Another mechanism of analgesia appears to be via indirect T-type calcium channel inhibition by N ₂O [ 42]. This shows there is a high level of variance in how nitrous oxide modulates receptor activity to produce its analgesic effects.

For a drug to have an anaesthetic effect it must decrease excitatory output or increase inhibitory signals to result in a net loss of neuronal activation. In terms of nitrous oxide anaesthesia, the glutamatergic N-methyl-d-aspartate (NMDA) receptors have been implicated as a major site of action. NMDA receptors are the natural receptors for endogenous glutamate and are excitatory in nature. In this way nitrous oxide, as an NMDA antagonist, may inhibit excitatory signalling in the CNS. At the simplest neurological level, it was found that NMDA receptors were necessary for the behavioural effects of N ₂O in the nematode Caenorhabditis elegans, while volatile anaesthetics such as isoflurane or halothane had another, unspecified mechanism of action [ 43]. While we cannot directly translate findings in this organism to rodents or humans, NMDA receptors are a highly conserved structure through phyla, allowing for some level of comparison. Jevtovic-Todorovic et al. [ 30] looked at the mechanistic similarities between N ₂O and other NMDA receptor antagonists in an in vivo rodent model to discover that N ₂O acted via NMDA receptor antagonism. N ₂O was found to produce neurotoxicity, afford neuroprotection, and induce blockade of NMDA currents, as well as work in the same age-dependent manner as other NMDA receptor antagonists such as MK801. It also provides the same sort of dissociative anaesthesia as ketamine, an NMDA receptor antagonist, overall suggesting that N ₂ O likely works through this receptor.

Further work has revealed that N ₂O also has some actions on the two-pore domain TREK-1 potassium channel [ 44]. This channel functions as a leak channel to release potassium from the cell, stabilising the resting membrane potential in neurons [ 45]. Previously, it has been shown that TREK-1 channels are important for anaesthesia and knockout mice for the channel are resistant to volatile anaesthetics [ 46]. TREK-1 has also been found to be important in various types of pain perception [ 47]. This ion channel could then be a factor in both the anaesthetic and analgesic actions of N ₂ O.

4. Mechanisms of Neurotoxicity

There are various mechanisms which are responsible for its neurotoxic effects, such as NMDA antagonism, enzyme inhibition and alteration of cerebral blood flow. Different brain conditions have different vulnerabilities to each form of toxicity, with neonatal brains more susceptible to NMDA antagonism, vitamin B ₁₂ deficient patients more prone to homocysteine mediated problems and the damaged brain often more vulnerable to changes in cerebral blood flow. Because of this, there is a wide range of patients to whom N ₂O may have some form of toxicity, with different groups being at greater risks than others. In this way it is extremely important to understand all the needs of a patient before giving nitrous oxide. The danger arises when nitrous oxide is given during dental procedures or as emergency analgesia, e.g., en route to hospital, where underlying problems such as vitamin B ₁₂ deficiencies may be undetected. One case study details a patient who presented with weakness in her lower limbs as well as peripheral numbness [ 36]. MRI scans showed abnormalities on the cervical spinal cord consistent with small lesions. The patient was found to be deficient in vitamin B ₁₂ and had been exposed to nitrous oxide for dental surgeries 2-3 months previously. Following 10 months of vitamin B ₁₂ injections the symptoms had abated, yet this could have been avoided altogether if nitrous oxide had been avoided for this patient. This highlights the need to fully elucidate nitrous oxide mechanisms of toxicity, so that clinicians can make informed decisions regarding N ₂O use. This case is reflected in further case reports involving patients with no prior N ₂O abuse experiencing myelopathies following N ₂O anaesthesia [ 48], as well as patients with a history of N ₂O abuse [ 49, 50, 51, 52].

4.1. NMDA Antagonism

NMDA receptors are excitatory receptors in the body which respond to the endogenous agonist glutamate. NMDA antagonists are known to have both protective and toxic effects depending on their activation. As glutamate is an excitatory neuromodulator, excessive release, for example after traumatic brain injury, can lead to excitotoxicity due to high influx of Ca ²⁺ into neurons. In this way, NMDA antagonists can provide protection against excitotoxic damage [ 30, 53]. This was shown in a rat model of middle cerebral artery occlusion (MCAO), where 75% N ₂O provided a reduction in cortical, but not striatal, infarcts [ 54]. This was associated with increased performance in motor coordination tasks compared to MCAO animals with no treatment [ 55]. While this might suggest some use for N ₂O as a treatment for stroke due to its NMDA antagonist features, it has also been shown that N ₂O has the ability to inactivate tissue plasminogen activator (tPA), as well as increase haemorhage and blood-brain barrier dysfunction [ 56]. This would preclude its use for stroke as the NMDA antagonist benefits are outweighed by the negative effects.

If administered to the naïve brain, however, N ₂O has the ability to cause neurotoxicity itself. N ₂O has been shown to induce cell death in neurons after prolonged exposure, and shorter term exposure also leads to a more reversible vacuolisation [ 30, 31]. Another potent NMDA antagonist, MK-801 [ 57], like nitrous oxide, leads to antagonism and thus reduction of signal from excitatory glutamatergic neurons. Despite showing anti-convulsive actions [ 58], it has not been introduced clinically due to the finding it can form lesions in the brain [ 59]. It has also been found to alter the structure and function of hippocampal synapses [ 60]. Jevtovic-Todorovic et al. [ 30] used MK-801 in a comparative study to investigate the possibility that N ₂O was a NMDA antagonist, with N ₂O showing identical physiological outcomes to MK-801. They found that both drugs induce a similar age-dependent toxicity in older rats. They also discovered that administration of GABAergic or muscarinic agents was successful in reversing the vacuolisation of neurons after N ₂O or MK-801 administration [ 30]. N ₂O is not as potent an antagonist as MK-801 but there appear to be numerous similarities between the two drugs in terms of toxicity. Similar to N ₂O, another NMDA receptor antagonist, ketamine, is often used as an anaesthetic agent. Ketamine is also coming under scrutiny since it was discovered that, like N ₂O, it has the ability to induce reversible or irreversible vacuolisation of neurons [ 19, 25]. Ketamine has also been implicated in causing neuronal cell death by increasing NMDA NR1 subunit expression, leading to increased cytosolic calcium and increased cell death. However, this was after prolonged (24 h) expression and there is little evidence of this mechanism being involved in N ₂ O neurotoxicity.

The neurotoxic actions of NMDA antagonists have been attributed to modulation of GABAergic inhibition of various neuronal pathways. The PC/RSC has been associated with learning and memory, as well as pain and awareness. Studies have found that NMDA antagonist administration can result in increased acetylcholine (ACh) release in the PC/RSC as well as the septohippocampal pathway, also involved in learning and memory [ 61, 62]. Normally, NMDA receptors on GABAergic neurons act as an upregulating mechanism to ensure constant inhibitory GABA release. GABA acts upon receptors on cholinergic neurons in the PC/RSC such that ACh release is tonically inhibited. NMDA antagonists release this GABAergic inhibition of cholinergic neurons, allowing ACh release for as long as the NMDA receptor is antagonised. Both studies suggested that NMDA antagonists act not at the region where ACh release is recorded, but instead at some separate site, with GABAergic projections between both sites. In the case of the PC/RSC this was shown to be the basal ganglia [ 62], while for the hippocampus it appears to be the medial septum. These findings have been extended to show increased ACh release in the cerebral cortex of rats exposed for 1 h with 75% N ₂O [ 63]. The area postrema is one of the major centres involved in emesis and can be stimulated by acetylcholine [ 64]. This increased cholinergic output has been postulated to underlie the increased nausea and vomiting often accompanying N ₂O administration. It has yet to be studied if N ₂ O can have similar effects on other pathways.

The group led by John Olney [ 65], who has carried out a mass of work in this field, has referred to this NMDA hypofunction as a cause of complex excitotoxicity. Antagonism of NMDA receptors on GABAergic neurons can release other pathways from the inhibitory control of GABA. These other pathways are usually excitatory in nature, such as the cholinergic pathway investigated above [ 62]. This excitatory disinhibition has now been implicated in a range of disorders such as schizophrenia and Alzheimer's disease [ 66, 67, 68, 69]. While N ₂ O most likely does not have as severe an effect as MK801 or ketamine due to its shorter duration of action, it is nevertheless important to consider how these changes in learning and memory centres may affect the very young or old brain.

4.2. Homocysteine Imbalance

One side effect of N ₂O which may mediate its toxic effects is indirect inactivation of methionine synthase, an important enzyme in the remethylation pathway converting homocysteine to methionine. Nitrous oxide irreversibly binds to the cobalt atom in vitamin B ₁₂, also known as cobalamin, via mechanisms which are not well understood. This leads to oxidation of the enzyme [ 70], eventually causing inactivation of vitamin B ₁₂. Vitamin B ₁₂ is an essential cofactor for methionine synthase so inactivation leads to a loss of function of the enzyme. In the normal methionine cycle, methionine is converted to homocysteine (Hcy) via the intermediary molecules S-adenosyl-methionine (SAM) and S-adenosyl-homocysteine (SAH). From here, homocysteine can either be irreversibly converted to cystathione (eventually becoming glutathione) via the trans-sulfuration pathway, or reversibly converted back to methionine by methionine synthase. Homocysteine, a sulphur-containing amino acid, does not appear to have any inherent function in the body except as a part of this methionine pathway. However, it is known to have various toxic effects in the body so any accumulation can be detrimental. A randomised double-blind study into the effects of anaesthesia post-surgery found that N ₂O administration was associated with higher rates of heart attack, even with patients having non-cardiac surgeries [ 8]. Homocysteine has been associated with a high rate of cardiac problems [ 71, 72] and patients are found to have elevated homocysteine levels post-surgery [ 73, 74]. This cardiovascular dysfunction appears to be regulated by increasing coagulation and endothelial adhesion, promoting atherosclerosis, as well as altering vascular responses to certain molecules such as argenine via oxidative mechanisms [ 75].

Recent interest in homocysteine has revealed multiple pathways by which it causes neurotoxicity at a cellular and cognitive level. Homocysteine has been shown to act as an agonist on the glutamate binding site on NMDA receptors, having an opposing effect to N ₂O (see ). While this might suggest that N ₂O may counteract homocysteine excitotoxicity, in reality N ₂O is cleared from the system very quickly following cessation of anaesthesia, while homocysteine is known to stay elevated in humans serum for days. In adolescents, homocysteine levels return to baseline between 12 and 24 h [ 74], while in adults this post-exposure increase is still high at 24 h [ 73] and continued elevation has been noted for up to one week [ 76, 77]. Lipton et al. [ 78] also report on the dual actions on the NMDA receptor that homocysteine can have. As well as being an agonist, Hcy can also act as a partial antagonist on the glycine binding site of the NMDA receptor. While this might imply that the two binding sites for Hcy would cancel each other out, one being excitatory and one inhibiting the excitatory potential, the reality is more complex, particularly in a brain injury setting. During brain damage such as stroke or traumatic brain injury, glycine levels in the brain become elevated and will overpower the partial homocysteine binding on the NMDA receptor, leading to an elevated excitatory output. Adding to this the agonistic effect of homocysteine on the glutamate binding site, this achieves an even higher level of excitotoxic damage [ 78].

It is known that methionine synthase inactivation is very fast in rats as compared with humans, with a half-time in rats of 5.4 min vs. 40 min in humans when exposed to 50% N ₂O [ 32] (See ). However, 40 min is still well within the time frame of human exposure during surgery so this should not be taken lightly. Often, these increases in homocysteine may not reach detrimental levels in normal patients, but patients at high risk for hyperhomocysteinemia (HHcy; classed as Hcy levels > 15 µmol/L) could be severely affected if given N ₂O anaesthesia. There are numerous risk factors for HHcy such as Alzheimer's disease [ 79], vitamin B ₁₂ deficiency [ 80], MTHFR gene mutation [ 81], age and gender [ 82]. One striking example of this is a case report involving a young child (3 months old) with an MTHFR gene mutation, leading to an MTHFR enzyme deficiency [ 35]. This enzyme is important in the remethylation pathway and deficiencies have been linked to HHcy. This particular patient was administered 60% N ₂O on two occasions during surgery, and within 3 weeks after surgery was admitted to hospital suffering from seizures. Less than 2 months post-surgery the patient had died and was found to have severe lesions in the brain, as well as nerve demyelination. At such a young age it is probable that the brain was extremely sensitive to molecular changes and the rapid and extreme increase in homocysteine levels appears to have been involved in the patient's death. This again highlights the need for clinicians to be vigilant in ensuring their patients are not at risk if exposed to N ₂O. It also showcases the range of physiological parameters which are important to be aware of before administering N ₂O, which dentists and paramedics, who routinely use N ₂ O as an analgesic and anxiolytic, do not normally have access to.

4.3. Reactive Oxygen Species and Mitochondrial Dysfunction

A range of molecules involved in apoptotic mechanisms in neurons have been found associated with increased homocysteine levels. One of homocysteine's main mechanisms of cellular damage is oxidative stress, which involves the formation of reactive oxygen species (ROS). ROS are strongly involved in apoptosis and cell death so any increase in levels will be detrimental. It was discovered that NMDA receptor activation leads to production of O ₂*− free radicals in cerebellar granular cells [ 83], peroxyinitryte (ONOO −) in the midbrain [ 84] and various ROS in the forebrain [ 85, 86]. Since homocysteine can act as an NMDA agonist this may cause increases in ROS. Increased intracellular Ca ²⁺ following NMDA receptor activation may account for the increased ROS, whilst ROS can themselves cause a rise in intracellular Ca ²⁺ [ 87, 88]. As seen in , this increased Ca ²⁺ can lead to disturbances in mitochondrial function, resulting in the production of ROS [ 85, 89]. This mitochondrial dysfunction may be a major pathway involved in homocysteine mediated neurotoxicity. It is interesting to note that oxidative stress and mitochondrial ROS formation play a role in Alzheimer's disease (AD) pathogenesis [ 90], and it has been shown that high plasma homocysteine is a reliable biomarker for AD [ 91], although there is no clear consensus as to any causal relationship [ 92]. AD treatments which act as NMDA antagonists (e.g., memantine) have been shown to reduce homocysteine mediated neurodegeneration [ 93]. This implies a common underlying mechanism between the two and highlights the damage that can result from homocysteine overload in the brain.

Increased intra-mitochondrial Ca ²⁺ also induces formation of mitochondrial permeability transition pores (MPTP), which allows release of cytochrome C from the mitochondria. Cytochrome C can then bind with APAF (Apoptotic Protease Activating Factor) to form an apoptosome, leading to downstream activation of caspase 3, resulting in apoptosis and cell death [ 94]. It has been shown that the vacuolisation resulting from N ₂O exposure is in fact massive swelling of mitochondria [ 31]. Drugs increasing mitochondrial membrane stability have been shown to be protective against the neurotoxic effects of N ₂O when combined with midazolam and isoflurane [ 95]. This membrane stabilisation was associated with improved cognition in rats tested [ 95].

4.4. In Combination with Other Anaesthetics

While N ₂O induced anaesthesia may not show convincing evidence of danger to some, it is also prudent to assess the toxicity of N ₂O in combination with clinically relevant anaesthetic agents to more closely mimic real world scenarios. There are a series of papers which combine N ₂O with isoflurane which consistently show an increase in neuroapoptosis when the two are combined over either agent alone [ 17, 20, 96]. These findings have even been replicated in a non-human primate model, the rhesus monkey [ 23]. It appears that this neurotoxicity is correlated with age; younger animals are susceptible to increased neurodegeneration with isoflurane addition, while adults are less prone to neuronal damage [ 18, 23]. This may be related to the dual function of GABAergic neurons. In young animals, GABAergic neurons are excitatory in nature for a short period postpartum, while in older animals they take on their normal inhibitory function [ 97]. This may mean that alongside N ₂O induced excitotoxicity, isoflurane, a GABA receptor agonist, can induce extra excitotoxicity, while in adults isoflurane may counteract the excitotoxicity. This excitatory GABAergic action is also found in humans in the few weeks after birth [ 98], which would suggest that this same enhancement of N ₂ O excitotoxicity by isoflurane or any GABA agonist could be present in humans.

5. Strategies to Minimize Toxicity of N₂O

The primary concern in medicine is to cause no harm; therefore it would not be possible to perform procedures without anaesthesia. The stress and damage caused by this would be greater than any deleterious side effects from N ₂O anaesthesia. However, although N ₂ O has been used for over a century, it should not be excluded from examination, and if similar or better alternatives are available, they should perhaps be utilised.

A number of possible adjuncts have been put forward. Xenon, another gaseous anaesthetic agent, has been found to be neuroprotective in comparison with other anaesthetics, including N ₂O [ 13] and has already begun clinical trials for neonates at risk for hypoxic brain damage (CoolXenon2-ISRCTN75602528; Toby Xe-ISRCTN08886155). Melatonin also shows neuroprotective promise when combined with anaesthetics [ 18]. This may be even more relevant for N ₂O due to the proven effect of melatonin in decreasing homocysteine mediated neurotoxicity in animal studies [ 99, 100].

In terms of possible replacements, a few studies have looked at remifentanil, a fast acting opioid analgesic. Due to its speed of recovery, it has been suggested as a replacement for N ₂O in neurosurgery, as it does not adversely affect cerebral blood flow, unlike N ₂O [ 101]. Remifentanil has also been suggested as a labour analgesic agent if administered intravenously [ 102].

6. Conclusions

At the moment, it is premature to suggest that N ₂O should be discontinued as an anaesthetic agent. However, the growing body of evidence does support the theory that N ₂O has some neurotoxic effects and these results should not be taken lightly. Nitrous oxide is regularly used for neonatal surgery and, as shown, this is a high risk period for neurodevelopment. It is difficult to assess the long term cognitive outcomes in humans, but rat studies suggest long term developmental issues such as memory impairment. Nitrous oxide is also often used in elderly or brain damaged patients and it is clear from numerous studies, such as the ENIGMA trial, that N ₂O is not as harmless as some might believe. It is important that further molecular work be carried out to determine the pathways by which N ₂O has its toxic effects, as these pathways may reveal areas for drug development to replace or work alongside N ₂ O to mitigate its neurotoxic effects. It would also be advisable to carry out further studies on non-human primates to determine any differences between rodent studies. At the moment, from rodent studies, we can only make educated assumptions on what might occur in humans. Non-human primates can help bridge this gap in knowledge without compromising patient safety in clinical trials.

Acknowledgments

The work was supported by a grant (1958) from Action Medical Research, West Sussex, UK.

Conflicts of Interest

The authors declare no conflict of interest.

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86. Dugan L.L., Sensi S.L., Canzoniero L.M., Handran S.D., Rothman S.M., Lin T.S., Goldberg M.P., Choi D.W. Mitochondrial production of reactive oxygen species in cortical neurons following exposure to N-methyl-d-aspartate. J. Neurosci. 1995;15:6377-6388.

93. Zieminska E., Lazarewicz J.W. Excitotoxic neuronal injury in chronic homocysteine neurotoxicity studied in vitro: The role of NMDA and group I metabotropic glutamate receptors. Acta Neurobiol. Exp. 2006;66:301-309.

94. Camello-Almaraz C., Gomez-Pinilla P.J., Pozo M.J., Camello P.J. Mitochondrial reactive oxygen species and Ca ²⁺ signaling. Am. J. Physiol. Cell Physiol. 2006;291:C1082-C1088. doi: 10.1152/ajpcell.00217.2006.

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The Neurotoxicity of Nitrous Oxide: The Facts and "Putative" Mechanisms

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Nitrous oxide is a widely used analgesic agent, used also in combination with anaesthetics during surgery. Recent research has raised concerns about possible neurotoxicity of nitrous oxide, particularly in the developing brain. Nitrous oxide is an N-methyl-d-aspartate (NMDA)-antagonist drug, similar in nature to ketamine, another anaesthetic agent.

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What are inhalants?

Although other substances that are misused can be inhaled, the term inhalants refers to the various substances that people typically take only by inhaling. These substances include:

solvents (liquids that become gas at room temperature)

aerosol sprays

gases

nitrites (prescription medicines for chest pain)

Inhalants are various products easily bought and found in the home or workplace-such as spray paints, markers, glues, and cleaning fluids. They contain dangerous substances that have psychoactive (mind-altering) properties when inhaled. People don't typically think of these products as drugs because they're not intended for getting high, but some people use them for that purpose. When these substances are used for getting high, they are called inhalants. Inhalants are mostly used by young kids and teens and are the only class of substance used more by younger than by older teens.

How do people use inhalants?

People who use inhalants breathe in the fumes through their nose or mouth, usually by sniffing, snorting, bagging, or huffing. It's called different names depending on the substance and equipment they use. For more information, read NIDA's Research Report on Inhalants.

Although the high that inhalants produce usually lasts just a few minutes, people often try to make it last by continuing to inhale again and again over several hours.

Products Used as Inhalants

Solvents

industrial or household products, including:

paint thinners or removers

dry-cleaning fluids

gasoline

lighter fluid

art or office supply solvents, including:

correction fluids

felt-tip marker fluid

electronic contact cleaners

glue

Aerosols

household aerosol items, including:

spray paints

hair or deodorant sprays

aerosol computer cleaning products

vegetable oil sprays

Gases

found in household or commercial products, including:

butane lighters

propane tanks

whipped cream aerosols or dispensers (whippets)

used as anesthesia (to make patients lose sensation during surgery/procedures), including:

Nitrites
How do inhalants affect the brain?

Most inhalants affect the central nervous system and slow down brain activity. Short-term effects are similar to alcohol and include:

slurred or distorted speech

lack of coordination (control of body movement)

euphoria (feeling high)

dizziness

People may also feel light-headed or have hallucinations (images/sensations that seem real but aren't) or delusions (false beliefs). With repeated inhalations, many people feel less self-conscious and less in control. Some may start vomiting, feel drowsy for several hours, or have a headache that lasts a while.

Unlike other types of inhalants, nitrites, which are often prescribed to treat chest pain, are misused in order to improve sexual pleasure by expanding and relaxing blood vessels.

What are the other health effects of inhalants?

Long-term effects of inhalant use may include:

liver and kidney damage

hearing loss

bone marrow damage

loss of coordination and limb spasms (from nerve damage)

delayed behavioral development (from brain problems)

brain damage (from cut-off oxygen flow to the brain)

In addition, because nitrites are misused for sexual pleasure and performance, they can lead to unsafe sexual practices or other risky behavior. This increases the chance of getting or spreading infectious diseases such as HIV/AIDS or hepatitis.

Read more about drug use and HIV/AIDS in Drug Use and Viral Infections (HIV, Hepatitus) DrugFacts. Read more about drug use and hepatitis at our webpage about viral hepatitis.

Can a person overdose on inhalants?

Yes, a person can overdose on inhalants. An overdose occurs when a person uses too much of a drug and has a toxic reaction that results in serious, harmful symptoms or death.

These symptoms can cause seizures and coma. They can even be deadly. Many solvents and aerosol sprays are highly concentrated, meaning they contain a large amount of chemicals with a lot of active ingredients. Sniffing these products can cause the heart to stop within minutes. This condition, known as sudden sniffing death, can happen to otherwise healthy young people the first time they use an inhalant. Using inhalants with a paper or plastic bag or in a closed area may cause death from suffocation (being unable to breathe).

How can an inhalant overdose be treated?

Because inhalant overdose can lead to seizures or cause the heart to stop, first responders and emergency room doctors try to treat the overdose by treating these conditions. They will try to stop the seizure or restart the heart.

Can inhalants cause addiction, a form of substance use disorder?

Although it's not very common, repeated use of inhalants can lead to addiction, a form of substance use disorder (SUD). An SUD develops when continued use of the drug causes issues, such as health problems and failure to meet responsibilities at work, school, or home. An SUD can range from mild to severe, the most severe form being addiction.

Those who try to quit inhalants may have withdrawal symptoms that include:

How can people get treatment for addiction to inhalants?

Some people seeking treatment for use of inhalants have found behavioral therapy to be helpful:

Cognitive-behavioral therapy helps patients recognize, avoid, and cope with the situations in which they are most likely to use drugs.

Motivational incentives uses vouchers or small cash rewards for positive behaviors such as staying drug-free.

More research is needed to identify the most effective treatment options for addiction to inhalants.

Points to Remember

Although other substances that are misused can be inhaled, the term inhalants refers to the various substances that people typically take only by inhaling.

Inhalants are various products easily bought and found in the home or workplace-such as spray paints, markers, glues, and cleaning fluids. They contain dangerous substances that have psychoactive (mind-altering) properties when inhaled.

People who use inhalants breathe them in through the mouth (huffing) or nose.

Most inhalants affect the central nervous system and slow down brain activity.

Short-term health effects include slurred or distorted speech, lack of coordination, euphoria (feeling high), dizziness, and hallucinations.

Long-term health effects may include liver and kidney damage, loss of coordination and limb spasms, delayed behavioral development, and brain damage.

A person can overdose on inhalants. Because inhalant overdose can lead to seizures or cause the heart to stop, first responders and emergency room doctors try to stop the seizure or restart the heart.

Although it's not very common, repeated use of inhalants can lead to addiction, a form of substance use disorder. Withdrawal symptoms include nausea, sweating, problems sleeping, and mood changes.

Some people seeking treatment for use of inhalants have found behavioral therapy to be helpful.

Learn More

For more information about inhalants, visit our:

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Inhalants DrugFacts | National Institute on Drug Abuse

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Although other substances that are misused can be inhaled, the term inhalants refers to the various substances that people typically take only by inhaling. These substances include: solvents (liquids that become gas at room temperature) aerosol sprays gases nitrites (prescription medicines for chest pain) Inhalants are various products easily bought and found in the home or workplace-such as spray paints, markers, glues, and cleaning fluids.

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Nitrous oxide belongs to a class of recreational drugs known as inhalants. Inhalants can be dangerous because they can be commonly found in substances in the home or workplace. Because inhalants are often contained in substances which are readily at hand, many people may not realize they are dangerous or easily abused. Inhalants may also be abused more often by younger people-children and adolescents.

The National Institute on Drug Abuse (NIDA) explains that inhalants are the only class of substance abused more by younger than by older teens. Inhalants are one of the only classes of drugs that are rarely administered by any other method than inhalation.

What Is Nitrous Oxide?

Nitrous Oxide is a colorless, nonflammable gas with a sweet smell. It is commonly called "laughing gas" and may be used by dentists or doctors during procedures or surgeries. MedScape states that nitrous oxide has other uses. It is used in non-medical ways, such as in the car racing industry and for food processing.

NIDA states that, of the gasses abused through inhalation, nitrous oxide is the most commonly abused as it is found in many household products. These may include whipped cream cans, products used for car racing, such as those that boost octane levels, and other aerosol cans.

Understanding Nitrous Oxide Abuse

Because of the variety of uses for nitrous oxide, it is readily available, which makes it a high risk potential for abuse. As it is a gaseous substance, nitrous oxide is abused through inhalation, commonly called "huffing." Inhalant abuse or huffing refers to intentionally breathing in the vapors of a substance for the purpose of getting "high."

Side Effects Of Nitrous Oxide Abuse

As is true with abuse of many inhalants, nitrous oxide abuse can cause staggering effects to health, both short-term and long-term.
Short-term effects of nitrous oxide may include:

delusions

dizziness

headache

drowsiness

euphoria

feeling of lightheadedness

hallucinations

lack of coordination

slurred speech

L ong-term effects of nitrous oxide may include:

brain damage

bone marrow damage

heart damage

kidney damage

liver damage

lung damage

hypoxia: a condition that occurs when there is not sufficient oxygen reaching a person's tissues

vitamin B12 deficiency-which may lead to nerve damage

Can People Become Addicted To Nitrous Oxide?

It's rare to form an addiction to inhalants, but it can happen. This may be in part because nitrous oxide, like many inhalants, can be extremely dangerous to abuse multiple times. As Drug Free World reports, those who abuse inhalants may experience overwhelming urges to keep abusing them. When attempting to stop abuse, or when a person no longer has access to the inhalant, he or she may also experience withdrawal symptoms.

Signs Of Nitrous Oxide Addiction

Two of the largest signs of any addiction are forming a tolerance to the substance (needing more of the substance to achieve the same effect) and experiencing withdrawal when not taking it. Other signs of addiction can include withdrawing from friends and family, not participating in activities which would normally be important to a person, or engaging in risky behavior to obtain or abuse the substance. Some of the common withdrawal symptoms associated with nitrous oxide are:

Risks Of Nitrous Oxide Addiction

One of the biggest dangers of nitrous oxide abuse and addiction is that many people are unaware of the risks associated with it, especially young people. As the National Inhalant Prevention Coalition (NIPC) explains, "many parents are in the dark regarding the popularity and dangers of inhalant use."

It tends to be younger people who are most at risk. Inhalants are inexpensive, easy to obtain, and may provide one of the easiest ways to get high. The NIPC reports that inhalants are one of the most commonly abused substances in the country; they are as highly abused as marijuana, and perhaps much more dangerous.

Inhalants are dangerous because they produce the same effect as anesthetics: they slow body function. As with many substances, the degree of effect of inhalants depends on the person taking them. A person may experience impaired function, lack of or lowered inhibition, or even faint (lose consciousness).

Perhaps one of the biggest risks associated with inhalant abuse and addiction is a condition called Sudden Sniffing Death Syndrome. The NIPC explains this means: "the user can die the 1st, 10th or 100th time he or she uses an inhalant."

Who Is At Risk Of Nitrous Oxide Addiction?

No one is exempt from the risk of addiction. That is why prevention of abuse is so important. However, nitrous oxide abuse and subsequent addiction are most common among adolescents, especially younger teens. The NIPC reports that one in five students entering the eighth grade will have abused inhalants. Further, "statistics show that young, white males have the highest usage rates" as do Hispanic and American Indian populations.

Nitrous Oxide Addiction Treatment

While early prevention is perhaps the surest method to avoid abuse and addiction, treatment may be necessary for those already addicted to nitrous oxide. However, when you realize a person is addicted, it is important to remain calm, especially if you come to this realization while the person is high.

People who are high on inhalants and become agitated may experience hallucinations, have violent outbursts, or, in extreme cases, undergo heart dysfunction which can be fatal. Treatment can begin after a person receives necessary medical care, if needed.

Inpatient rehab centers can provide professional support and care. For some, addiction may require more than outpatient counseling. Rehab centers can make that difference, and we at RehabCenter.net can connect you with some of the most effective rehab facilities. Addicted individuals may require medication, behavioral therapy, group or individual counseling, or other treatment methods. Some, all, or a combination of these methods are available at our rehab centers.

Over one million people abused inhalants for the purpose of getting high in the United States in 2016 alone. With youth affected most by nitrous oxide abuse and addiction, prevention is key to help dissuade youth from suffering some of the more severe long-term effects of abuse or overdose. Contact us today to learn more about our rehab centers, speak with our experts, and to be connected with resources.
For More Information Related to "Nitrous Oxide Abuse And Addiction" Be Sure To Check Out These Additional Resources From RehabCenter.net: Sources
Drug Free World- Are Inhalants Addictive?
MedScape- Nitrous Oxide Administration
National Inhalant Prevention Coalition- About Inhalants
National Institute On Drug Abuse- DrugFacts: Inhalants
National Institute On Drug Abuse- What Are Inhalants?

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Of the gases abused through inhalation, nitrous oxide is the most commonly abused as it is found in many household products. Because of the variety of uses for nitrous oxide, it is readily available, which makes it a high risk potential for abuse.

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Abstract

The direct and indirect effects of nitrous oxide (N ₂O) on the nociceptive responses of lumbar dorsal horn neurons, and the indirect effects on midbrain reticular formation (MRF) neurons and thalamic neurons were determined in goats anaesthetized with isoflurane. The technique used enabled the differential delivery of N ₂O to either the torso or the cerebral circulation, thus allowing assessment of the direct spinal and indirect brain effects of N ₂O. Systemic delivery of N ₂O appeared to have divergent effects, facilitating (4/11) or depressing (7/11) the responses of dorsal horn neurons. Such divergent effects were also observed when N ₂O was differentially delivered to the circulation in the torso (i.e. the spinal cord). Likewise, MRF and thalamic responses to noxious stimulation were variably affected by administration of N ₂O to the torso, with some cells facilitated (7/13 MRF neurons, 3/8 thalamic neurons) and others depressed (6/13 MRF neurons, 5/8 thalamic neurons). It appears that N ₂O has variable effects on the caprine CNS. The facilitatory action of N ₂ O might partially explain why it is a relatively weak anaesthetic.

depression dorsal horn facilitation goats midbrain neurons nitrous oxide nociception spinal cord site of action thalamus

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REFERENCES

1. Antognini, J.F. and Kien, N.D., 1994. A method for preferential delivery of volatile anesthetics to the in situ goat brain. Anesthesiology, 80, 1148-1154

2. Antognini, J.F., Saadi, J., Wang, X.W., Carstens, E. and Piercy, M., 2001. Propofol action in both spinal cord and brain blunts electroencephalographic responses to noxious stimulation in goats. Sleep, (in press).

3. Gyulai, F.E., Firestone, L.L., Mintun, M.A. and Winter, P.M., 1996. In vivo imaging of human limbic responses to nitrous oxide inhalation. Anesthesia and Analgesia, 83, 291-298

4. Jinks, S., Antognini, J.F., Carstens, E., Buzin, V. and Simons, C., 1999. Isoflurane can indirectly depress lumbar dorsal horn activity in the goat via action within the brain. British Journal of Anaesthesia, 82, 244-249

5. Zar, J.H., 1999. Biostatistical Analysis, 4th edn, (Prentice-Hall, Upper Saddle River, NJ), 136-139

© Kluwer Academic Publishers 2001

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Variable Effects of Nitrous Oxide at Multiple Levels of the Central Nervous System in Goats

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The direct and indirect effects of nitrous oxide (N 2O) on the nociceptive responses of lumbar dorsal horn neurons, and the indirect effects on midbrain reticular formation (MRF) neurons and thalamic neurons were determined in goats anaesthetized with isoflurane.

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Nitrous oxide (often referred to as laughing gas, whippets, cartridges, hippy crack, N2O, or nangs) is a gas inhalant used medically and recreationally as an anesthetic agent. It is often believed that the effects of nitrous, which include euphoria, sound distortion, and minor to strong hallucinations, is caused by oxygen deprivation to the brain. This is a common misconception.

Nitrous oxide on its own has low potency and many consider it an inert, benign gas that has little if any influence on vital physiologic functions (though this is not true when nitrous oxide is combined with other anesthetics, sedatives, or opioids). This is why it can be used safely as an anesthetic for minor dental and medical procedures. This is not to suggest, however, that nitrous oxide use is completely safe; all drug use comes with risks.

Review of scientific literature on the effects of nitrous oxide shows no evidence that the gas decreases oxygen flow to the brain, nor that it kills brain cells. The mechanisms of action, or how the effects of nitrous are caused, are unknown. The leading theory is that it likely involves an interaction with the endogenous opioid system because it is abolished by administration of the opioid antagonist, naloxone. The strongest evidence suggests that nitrous oxide stimulates release of enkephalins , which bind to opioid receptors that trigger descending noradrenergic pathways, a mechanism of pain modulation.

There is no scientific data to support the theory that nitrous oxide reduces oxygen flow to the brain, causing the dream-like, euphoric state often obtained by inhaling the gas. In fact, Erowid states that effects of nitrous on the central nervous system include " cerebral vasodilation and increased cerebral blood flow "-meaning increased oxygen flow to the brain. Principal adverse effects include nausea, vomiting, dizziness, increased respiratory rate, and hypotension (low blood pressure). Chronic exposure to the gas can cause damage to bone marrow and the nervous system by interfering with the actions of vitamin B-12.

The claims floating around the internet that nitrous oxide restricts oxygen flow to the brain are not substantiated by science or fact. It is the spreading of misinformation such as this that perpetuates the stigma associated with drugs and drug use. Always do your own research about a substance before ingesting (or in this case, inhaling). For more information on nitrous oxide and harm reduction practices, click here.

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No, Nitrous Does Not Deprive Your Brain of Oxygen | DanceSafe

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Nitrous oxide (often referred to as laughing gas, whippets, cartridges, hippy crack, N2O, or nangs) is a gas inhalant used medically and recreationally as an anesthetic agent. It is often believed that the effects of nitrous, which include euphoria, sound distortion, and minor to strong hallucinations, is caused by oxygen deprivation to the brain.

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Adolescent Rehab Louisiana - Drug Abuse Treatment Centers Louisiana

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Most people know nitrous oxide as laughing gas, but it's more commonly known as whip-its on the drug scene. Whip-its abuse is on the rise among teens. The Substance Abuse and Mental Health Services Administration reports that more than 12 million people in the U.S. have tried whip-its at least once. It is debatable as to whether nitrous oxide is addictive and can lead to the need for teen rehab, but inhaling it is very dangerous.

Nitrous oxide can easily be obtained from head shops. The gas is sold in canisters, and teens often use it to fill up balloons, which can be sold at parties.

An even easier way for teens to get their hands on nitrous oxide, and the root of the name whip-its, is from whipped cream canisters. These canisters have a cartridge of compressed nitrous oxide inside from which teens can inhale the gas. That means parents can have an easy-access drug sitting in their refrigerator.

Nitrous oxide might not be on the same level as street drugs like cocaine and heroin, but it is extremely dangerous. It is commonly used in dentist offices, but in these cases the dentist mixes the gas with oxygen and administers it through a mask. When kids inhale nitrous oxide from a canister or a balloon, they are not getting the oxygen that the dentist supplies. The more they inhale, the less oxygen they consume, causing a condition known as hypoxia.

Hypoxia is when the whole body or a part of the body is deprived of oxygen. In the case of whip-its, the brain can become severely deprived of oxygen, which can cause brain and nerve damage and can result in death.

Teens who abuse nitrous oxide might end up in rehab, but if they abuse nitrous oxide regularly they face something that is perhaps even more severe. Over time, nerve damage can occur, causing something known as peripheral neuropathy. This is when the nerves experience a tingling feeling or numbness. Other dangerous side effects from the abuse of nitrous oxide include vomiting, with the risk of breathing the vomit into their lungs, seizures and cardiac arrest.

It is also important to keep in mind that there are many who people who believe that nitrous oxide is addictive and can lead to teen drug rehab. Unfortunately, it is a real possibility that by the time a teen admits to a problem with whip-its, he or she might have already severely damaged his or her nervous system.

In the end, parents and teens must understand that dangerous drugs aren't just the illicit street drugs everyone knows about. Even those drugs that seem the tamest can cause severe damage and death, so know your facts about whip-its.
About the Author

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The Dangers of Whip-Its (Nitrous Oxide) - Adolescent Rehab Louisiana - Drug Abuse Treatment Centers Louisiana

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Most people know nitrous oxide as laughing gas, but it's more commonly known as whip-its on the drug scene. Whip-its abuse is on the rise among teens. The Substance Abuse and Mental Health Services Administration reports that more than 12 million people in the U.S. have tried whip-its at least once.

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I feel very sorry for this poor man, but equally we must all take responsibility for our actions. Plastic carrier bags are a vital feature of the tramp-chic look I've been going with this season, and to be fair, the one I'm currently carrying my laptop around in reads "plastic bags can be dangerous: to avoid suffocation keep this bag away from babies and children."

Is there anything else to worry about with hippie crack? All drugs carry risks, and it is only by clarifying those risks that we can decide how to manage them. Luckily the Medicines and Healthcare Regulatory Authority has put out a press release, which has manifested itself mostly under headlines suggesting nitrous is "no laughing matter".

The MHRA says: "Whilst the inhalation of nitrous oxide may be perceived by some as harmless activity, there are a number of health risks associated with its inhalation. The 'rush' users experience is caused by starving the brain of oxygen. This can cause the user to collapse and injure themselves when falling."

To be effective in public health policy it is generally considered that your message must be credible. I suspect most hippie crack users will already have experimented with holding their breath, and will rightly conclude that their transcendent experience on nitrous is a drug effect; and that it's an anaesthetic used in hospitals, and in childbirth, so the effect is probably not caused by starving the brain of oxygen; and that the MHRA, of all reputable bodies, is talking nonsense.

In fact, the pharmacology of nitrous oxide is fascinating, and a window on to how we deduce what drugs do in the brain. It seems to work on the NMDA neurotransmitter system, and on the opioid system. Animal models suggested that it might increase the release of opiate molecules made by your own body. To test whether opiates were responsible for the effects on humans, researchers gave nitrous to people in pain, and then gave an opiate receptor blocker, to see if the analgesic effect was reversed, or changed: the analgesic effect was, but the subjective sensations of being "high" were not, even at high doses, suggesting that this aspect of its effect must be mediated by a different neurotransmitter system. It seems likely that these effects are mediated by the NMDA system, perhaps similarly to ketamine.

Are there any real dangers with nitrous oxide? Well it's fairly safe overall, and I suppose you could risk manage the "falling over" thing by "sitting down", but it has been studied closely for a long time - on account of its widespread medical use, and the worry about chronic low dose exposure for dentists and people who work in operating theatres - and it turns out that it does have a major side effect: it selectively oxidises the folate, or vitamin B12, in your body. Vitamin B12 is needed for a process called methylation, involved in making DNA among other things, and without it you have a tough time making new cells.

There are cases in the literature of people overexposed to nitrous becoming dangerously B12 deficient, but it seems clear that the effects are reversed simply by giving high dose vitamin B12.

This may be rather trendy and "harm reduction" of me, but if I was going to put out a press release on hippie crack, I would advise against using it, but I wouldn't shoot down my credibility with primary school assertions about its mode of action on the brain. I would state the risks clearly, and if I thought the risks from, perhaps, folate deficiency were significant and worrying, I might also mention the harm reduction strategies available, and start monitoring outcomes.

· Please send your examples of bad science to bad.science@theguardian.com
Topics

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Ben Goldacre: Nitrous oxide starves the brain of oxygen? Don't make me laugh

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I feel very sorry for this poor man, but equally we must all take responsibility for our actions. Plastic carrier bags are a vital feature of the tramp-chic look I've been going with this season, and to be fair, the one I'm currently carrying my laptop around in reads "plastic bags can be dangerous: to avoid suffocation keep this bag away from babies and children."

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Information on how it works in the body, its effects, risks and addictive potential (and how you can reduce them), and its potential medical uses

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Nitrous oxide, commonly known as "laughing gas," has been used in anesthesiology practice since the 1800s, but the way it works to create altered states is not well understood. In a study published this week in Clinical Neurophysiology, MIT researchers reveal some key brainwave changes among patients receiving the drug.

For a period of about three minutes after the administration of nitrous oxide at anesthetic doses, electroencephalogram (EEG) recordings show large-amplitude slow-delta waves, a powerful pattern of electrical firing that sweeps across the front of the brain as slowly as once every 10 seconds.

This frequency is characteristic of our deepest sleep, but the waves induced by nitrous oxide are twice as large as - and seemingly more powerful than - the ones seen in slumber. "We literally watched it and marveled, because it was totally unexpected," says Emery Brown, the Edward Hood Taplin Professor of Medical Engineering at MIT and an anesthesiologist at Massachusetts General Hospital (MGH). "Nitrous oxide has control over the brain in ways no other drug does."

Brown was joined in the research by co-authors Kara Pavone, Oluwaseun Akeju, Aaron Sampson, Kelly Ling, and Patrick Purdon, all of MGH.

The discovery came after Brown began recording EEG readings from all of his anesthesiology patients, starting in 2012. A sticker with six electrodes is placed on the forehead to measure voltage fluctuations resulting from the collective effect of neurons communicating in the brain. This EEG signal feeds into a computer that records it and displays the data as waves on a monitor in the operating room. The technique is safe and noninvasive.

When family doctors explain anesthesia, they sometimes describe it as "putting a patient to sleep," using the metaphor of our closest experiential comparison. But sleep is nothing like anesthesia; it is a natural physiological state of decreased arousal during which the brain cycles naturally between rapid eye movement (REM) and non-REM states approximately every 90 minutes. Someone can easily be awakened from even the deepest stages of sleep.

Anesthesia, by comparison, is a drug-induced, reversible coma during which a patient is unconscious, cannot remember, feels no pain, and does not move - yet is physiologically stable. This state of coma remains as long as the flow of drugs is maintained, and patients awake from anesthesia with the sensation that no time has passed.

Nitrous oxide is commonly administered at the tail end of surgery, to keep a patient unconscious while more potent ether anesthetics clear from his or her system, or is administered along with the ether anesthetics throughout an operation to reduce the doses of the latter.

Brown says that anesthesiologists should use an EEG to monitor the brain states of their patients under anesthesia - which could make better anesthetic dosing decisions possible and alleviate concerns about awareness under anesthesia. "It's hard to imagine that in 2015 you can just anecdotally observe this," Brown says.

He speculates that if the pure, powerful slow waves produced by nitrous oxide could somehow be maintained at a steady state - as opposed to disappearing in mere minutes - then nitrous oxide might be used as a potent anesthetic from which rapid recovery would be possible.

It remains a mystery why these large, slow waves only continue for around three minutes, despite continuous administration of nitrous oxide. Brown says there appears to be a sort of rapid habituation or desensitization process at work.

He postulates that nitrous oxide may block signals from the brainstem that would otherwise maintain wakefulness. When certain receptors in the thalamus and cortex are not bound by nitrous oxide, these brain regions normally receive excitatory signals from arousal centers lower in the brain. Without those signals, loss of consciousness occurs, marked by slow waves. "If you see slow EEG oscillations, think of something having happened to the brainstem," Brown says.

"It is worth pointing out that nitrous oxide has been shown previously to affect these low-frequency oscillations, but by causing a decrease rather than an increase," says neurobiologist David Liley of Swinburne University of Technology in Australia, who was not involved in the research.

Previous research has largely explored lower doses of nitrous oxide - levels at which it is considered a sedative, inducing faster beta oscillations in the brain, which are indicative of relaxation but not loss of consciousness. "The nice thing about Emery's study is that they could use high concentrations at high flow rates, which if used alone in healthy, initially conscious volunteers would cause way too much nausea and vomiting," Liley says.

Brown and his team are now systematically studying the EEG signatures and behavioral effects of all of the principal anesthetics and anesthetic combinations.

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Uncovering the mechanism of our oldest anesthetic

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Nitrous oxide, commonly known as "laughing gas," has been used in anesthesiology practice since the 1800s, but the way it works to create altered states is not well understood. In a study published this week in Clinical Neurophysiology, MIT researchers reveal some key brainwave changes among patients receiving the drug.

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Effect of Nitrous Oxide on Neurologic and Neuropsychological Function after Intracranial Aneurysm Surgery

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Assistant Professor, Department of Anesthesiology, Mayo Clinic College of Medicine. Current position: Clinical Associate Professor, Department of Anesthesiology, Stanford University School of Medicine, Stanford, California. † Professor, ‡ Assistant Professor, Department of Anesthesiology, ‡‡ Assistant Professor, Department of Biostatistics, Mayo Clinic College of Medicine, Rochester, Minnesota. § Associate Professor, ...