To what extent is nitrous oxide safe to consume?
Disclaimer: I do not condone recreational use of nitrous oxide. This article is not medical advice and should not be taken as such.
Nitrous oxide is a naturally occuring oxide of nitrogen with the molecular formula N2O. Nitrous oxide was first used as a dental anaesthetic in 1844 by Horace Wells. Since then, it has become the most widely used weak inhalational anaesthetic in the world. As with many psychoactive substances, its strict use in medicinal scenarios created the temptation for its use as a recreational drug. As nitrous oxide is quite common (it can be found in whipped cream canisters) and widely considered fairly harmless, for a long time it remained an accessible and inexpensive ‘legal high’. Recently however, it was made illegal in the UK to ‘tackle anti-social behaviour’. This piece aims to explore the effects nitrous oxide has on the human body from its psychoactive properties, to potential neurotoxicity and addiction.
To understand the dangers the use of a drug poses, one must first understand its mechanism of action. Nitrous oxide is known to cause euphoria, dizziness, numbing of pain, sound distortion, tingling in limbs, and occasionally light hallucinations.The suggested mechanisms of action include stimulation of dopamine circuits leading to euphoria, stimulation of opioid receptors leading to the release of norepinephrine, which provides the analgesic effect, activation of GABA A receptors leading to an anti-anxiety effect, and alterations in brain blood flow. The exact mechanism of action is not known in full detail, nevertheless, the hypothesis of opioid receptor stimulating has been shown to be true as the administration of Nalaxone, an opioid reverse agonist, lead to the mitigation of nitrous oxide effects. Nitrous oxide appears to have different interactions with different opioid receptors, binding to μ-receptors as a competitive inhibitor and non-competitively to κ-receptors. This gives nitrous oxide the ability to act as both an opioid receptor agonist and antagonist. Its agonistic effect appears to be stronger however, judging from its analgesic properties. Another proposed mechanism for its analgesic effects is the inhibition of T-type calcium ion channels which leads to blood vessel dilation and a decrease in blood pressure. Moving on from analgesic effects, to achieve an anaesthetic effect, a drug must either decrease the brain’s excitatory output or increase inhibitory signals to result in an overall decrease in neural activity. The major receptor implicated in the anaesthetic effects of nitrous oxide is the glutamatergic N-methyl-D-aspartate (NMDA) receptor. NMDA receptors are a major excitatory receptor in the brain, and hence nitrous oxide acts as an NMDA receptor antagonist. NMDA receptors are also involved in synaptic plasticity and are believed to play a crucial role in memory formation (more about this later). By binding to and inhibiting NMDA receptors, nitrous oxide greatly reduces excitatory signalling in the central nervous system. NMDA receptors have been shown to be essential for the behavioural effects of nitrous oxide in roundworms. Although this finding cannot be directly projected onto humans, the NMDA receptor gene is highly conserved through phylla, so some conclusions can still likely be drawn. Moreover, nitrous oxide has also been shown to affect two-pore domain TREK-1 potassium channels. TREK-1 potassium channels function as leak channels and allow potassium ions to leave nerve cells to maintain resting membrane potential in neurons. These ion channels are present in both excitable and non-excitable cells, and have been linked with anaesthesia and pain perception. Hence, it is not too far-fetched to propose that these channels play a role in the anaesthetic and analgesic effects of nitrous oxide. Furthermore, there have been links made between nitrous oxide use and stimulation of dopamine circuits, triggering the brain’s reward pathways and leading to a feeling of euphoria. Lastly, nitrous oxide is thought to stimulate GABA A receptors, a type of important inhibitory receptor which, when stimulated, reduces the excitability of a neuron, leading to an anti-anxiety effect, similar to the effect felt after alcohol consumption.
Many medicines have side effects but nitrous oxide is fairly safe, right? Well, despite its reputation and its wide use in medical procedures, it may have a negative impact on the body after all. Firstly, there is a consensus in the scientific community that regular use of nitrous oxide can lead to vitamin B12 deficiency. Nitrous oxide creates this deficiency by oxidising the cobalt atom in vitamin B12. Vitamin B12 is used as a cofactor by two enzymes: methionine synthase and L-methylmalonyl-CoA mutase. Methionine synthase catalyses the conversion of homocysteine to the essential amino acid methionine. Methionine is required for general protein synthesis and in particular for the formation of S-adenosylmethionine. S-adenosylmethionine is a universal methyl donor for nearly 100 different substrates, including DNA, RNA, proteins, and lipids. Myelin proteins are an essential group of proteins that depend on S-adenosylmethionine for methylation. If myelin protein methylation is not conducted and maintained, demyelination of neurons in the central and peripheral nervous systems begins to occur. Demyelination of neurons leads to slow/poor action potential transduction and can lead to common symptoms of nitrous oxide induced nerve damage, such as numbness, tingling or weakness in limbs. S-adenosylmethionine has also been shown to be involved in the maintenance of cell membranes, as well as the production and breaking down of neurotransmitters such as dopamine, serotonin and melatonin. Another, perhaps more important, function of S-adenosylmethionine is epigenetic control of gene expression as well as DNA maintenance and repair. L-methylmalonyl-CoA is also crucial to the body, being an important intermediate in the synthesis of succinyl-CoA, it is essential for the correct function of the citric acid cycle. The citric acid cycle allows the body to generate ATP, NADH and FADH2, all of which play essential roles in aerobic respiration and the generation of energy via the electron transport chain in mitochondria. With too little L-methylmalonyl-CoA in the body, energy demands may not be met, leading to weakness or more severe problems. Another form of toxicity attributed to nitrous oxide comes as a result of homocysteine imbalance. With a deficiency in vitamin B12 and impaired conversion of homocysteine to methionine, homocysteine can accumulate in the body. High levels of homocysteine have been linked with higher risks of cardiac problems. The reasons for this cardiovascular dysfunction appear to be increased coagulation and endothelial adhesion promoting atherosclerosis, as well as altered vascular responses to certain molecules via oxidative mechanisms. Homocysteine has also been shown to act as an agonist of the NMDA receptor, having an opposite effect to nitrous oxide. Although this may not seem too harmful, while nitrous oxide is cleared from the body very quickly, homocysteine can remain elevated for days and may cause excitotoxic damage, especially after nitrous oxide anaesthesia is used in treatment of brain injuries. Moreover, increased homocysteine levels have been associated with involvement in apoptotic mechanisms. It is thought that the binding of homocysteine to NMDA receptors and acting as an agonist can cause generation of reactive oxygen species such as O2•− radicals. Such reactive oxygen species are strongly linked with apoptosis and cell death, so a strong increase in the levels of these species can be detrimental. Furthermore, reactive oxygen species can cause increases in intracellular Ca2+ ion concentrations, which can lead to disturbances in mitochondrial function. Increased intra-mitochondrial Ca2+ concentrations induce the formation of mitochondrial permeability transition pores, which allow the release of cytochrome C from mitochondria. Not only does this reduce the rates of oxidative phosphorylation, but cytochrome C can then go on to bind with apoptotic protease activating factor to form an apoptosome, leading to the downstream activation of caspase 3, and resulting in apoptosis. Similar oxidative stress leading to the formation of reactive oxygen species in mitochondria has been shown to play a role in Alzheimer’s disease and high plasma homocysteine was identified as a reliable biomarker for Alzheimer’s disease, although there is no general consensus on any relationship between the two. Lastly, the inhibition of NMDA receptors by nitrous oxide for prolonged periods of time has been shown to slightly impair memory formation. Despite there being evidence for many negative effects of nitrous oxide consumption on the brain, most of these effects are only observed on a significant scale either after prolonged or regular exposure to the gas. From this, one may conclude that in low concentrations and limited exposure, nitrous oxide is fairly harmless and its use as an anaesthetic is justified in many scenarios.
Having analysed the toxicity of nitrous oxide, one should consider the aspect of addictiveness as is the main problem with many light social drugs. Unlike many other drugs, nitrous oxide doesn’t appear to exhibit properties which can lead to a physical dependence. This means that even after regular nitrous oxide use and a sudden decision to quit, a person will not experience physical withdrawal symptoms, which makes breaking the habit much easier. Nevertheless, it is possible to create a psychological dependency on nitrous oxide as the brain’s reward circuits are stimulated when the gas is inhaled, leading to cravings of achieving the same high. That being said, nitrous oxide is not considered addictive, especially in comparison with substances like nicotine, alcohol and cannabis.
Apart from the toxicity of the drug itself, there are other safety concerns to be taken into account if nitrous oxide were to be used recreationally. Firstly, one must concern oneself, like with any substance, with the purity of the product. One should never consume automotive-grade nitrous oxide as it contains sulphur dioxide which is both unpleasant and harmful to inhale. Secondly, one should ensure to only consume nitrous oxide in open air or a large space — one should never attempt to fill a small space (like a car or a plastic bag over one’s head) with the gas as that can lead to oxygen starvation and suffocation. Finally, one must not consume nitrous oxide while standing up, especially above solid ground, because the commonplace effect of dizziness produced by the gas may create a falling hazard. Perhaps the safest way to consume the gas would be to consume medical grade or filtered nitrous oxide from a balloon, lying down on a soft surface, with a responsible, sober individual beside oneself.
In conclusion, nitrous oxide is a gas with analgesic and anaesthetic properties. It is fairly safe to consume, if pure and in a low concentration. However, regular or prolonged consumption can often yield significant toxicity, causing severe problems such as nerve damage. Nitrous oxide can cause weak psychological dependencies, but no physical dependencies. Despite the relative safety of the gas, from 2001–2020, there were 56 deaths in England and Wales with nitrous oxide mentioned on the death certificate. The fact that this figure includes deaths in medical settings and deaths caused by avoidable hazards, such as suffocation and/or falling, should be taken into account. Nevertheless, for optimal safety one should refrain from consumption of all recreational drugs, including nitrous oxide, especially with it recently being made illegal in the UK. If nitrous oxide were to be consumed, however, one would need to be aware of avoiding common hazards such as suffocation and falling, by consuming the gas from a balloon and lying down on a soft surface. The purity of the gas would also have to be ensured either by obtaining medical grade nitrous oxide or filtering the gas thoroughly.
References:
British Broadcasting Corporation, B. (2023) What is nitrous oxide and why is it being banned?, BBC News. Available at: https://www.bbc.co.uk/news/health-67346032 (Accessed: 17 November 2023).
Calderón-Ospina, C.A. and Nava-Mesa, M.O. (2020) B vitamins in the nervous system: Current knowledge of the biochemical modes of action and synergies of thiamine, pyridoxine, and Cobalamin, CNS neuroscience & therapeutics. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6930825/#:~:text=Thus%2C%20vitamin%20B12%20is%20especially,thereby%20facilitating%20fast%20conduction%20velocity. (Accessed: 17 November 2023).
Edigin, E., Ajiboye, O. and Nathani, A. (2019) Nitrous oxide-induced B12 deficiency presenting with myeloneuropathy, Cureus. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777927/#:~:text=Nitrous%20oxide%20interferes%20with%20vitamin,and%20thymidine%20during%20DNA%20synthesis. (Accessed: 17 November 2023).
Encyclopedia of Human Nutrition, E. (2013) Methylmalonyl-COA, Methylmalonyl-CoA — an overview | ScienceDirect Topics. Available at: https://www.sciencedirect.com/topics/agricultural-and-biological-sciences/methylmalonyl-coa#:~:text=The%20adenosylcobalamin%2Ddependent%20enzyme%20methylmalonyl,is%20produced%20by%20rumen%20microflora). (Accessed: 17 November 2023).
Hospital, L.T. (2022) Oxide (NOZ) and its effects on the body: Whippets drug, Laguna Treatment Hospital. Available at: https://lagunatreatment.com/drug-abuse/nitrous-oxide/ (Accessed: 17 November 2023).
Loenen, W.A.M. (2018) S-Adenosylmethionine Metabolism and Aging, S-Adenosylmethionine. Available at: https://www.sciencedirect.com/topics/agricultural-and-biological-sciences/s-adenosylmethionine (Accessed: 17 November 2023).
MA;, G. (1986) Nitrous oxide, an opioid addictive agent. review of the evidence, The American journal of medicine. Available at: https://pubmed.ncbi.nlm.nih.gov/3014879/ (Accessed: 17 November 2023).
National Institute of Health, N. (2022) Office of dietary supplements — vitamin B12, NIH Office of Dietary Supplements. Available at: https://ods.od.nih.gov/factsheets/VitaminB12-HealthProfessional/#:~:text=Vitamin%20B12%20is%20required%20for,1%2D3%2C5%5D. (Accessed: 17 November 2023).
Savage, S. and Ma, D. (2014) The neurotoxicity of nitrous oxide: The facts and ‘putative’ mechanisms, Brain sciences. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4066238/ (Accessed: 17 November 2023).
Science, D. (2022) Nitrous oxide (laughing gas) — everything you need to know — drug science, drugscience.org.uk. Available at: https://www.drugscience.org.uk/drug-information/nitrous-oxide/#1614731714218-19bf1003-2a6c (Accessed: 17 November 2023).
Sinai, M. (2023) S-adenosylmethionine, Mount Sinai Health System. Available at: https://www.mountsinai.org/health-library/supplement/s-adenosylmethionine#:~:text=S%2DAdenosylmethionine%20(SAMe)%20is,serotonin%2C%20melatonin%2C%20and%20dopamine. (Accessed: 17 November 2023).
Thompson, A.G. et al. (2015) Whippits, nitrous oxide and the dangers of legal highs, Practical neurology. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4453489/ (Accessed: 17 November 2023).
University College London, U. (2022) Nitrous oxide could disrupt formation of traumatic memories, UCL News. Available at: https://www.ucl.ac.uk/news/2016/mar/nitrous-oxide-could-disrupt-formation-traumatic-memories (Accessed: 17 November 2023).
