No Laughing Matter: The Neuroscience of Nitrous Oxide (Galaxy gas, Laughing gas, Whippets)
Gunna's infamous "whippet can on the head," that went viral in 2020.
A Reintroduction
American native rapper “Gunna” has shown to cut against social norms in more ways than one. Whether it is his audacious fashion statements or weight loss transformations, he always seems to be one step ahead of the curve. Most notably, Gunna’s relationship with whippets (nitrous oxide) was an event that led to outright reticulation on social media. He has expressed his frustration for the overwhelming amount of judgment he received for this act in his single “Livin Wild,” stating: “I been getting high inconsistent, but you tryna show me different…Judging me for trying the whippets, I'm tired of the critics.” Despite this large amount of hate, there has been a resurgence of adolescent teens huffing frutti nitrous oxide in the form of “Galaxy Gas.” The array of seemingly harmless flavors makes it an easy selling point to young individuals, but its dangerous side effects on neural structure and neural development are not heavily emphasized. While Gunna may have spearheaded the use of nitrous oxide in everyday life, it is substantially more important to underscore its toxic characteristics. In this article, we will discuss the neurophysiological mechanisms of nitrous oxide (NO, whippets, galaxy gas, laughing gas, etc...) and its negative effect on neuronal health.
We will open our discussion by describing how the inhalation of nitrous oxide ultimately leads to its cognitive effects. One of the most direct ways nitrous oxide interacts with the nervous system is through opioid receptors. While there are many different classes of receptors, all play a major part in various physiological functions such as euphoria, respiratory, depression, and neuroprotection. However, one of the most important functions of nitrous oxide is its effect on the pain modulatory system. The analgesic effects of this drug are the most applicable and are harnessed in many medical practices. (Shenoy and Liu, 2023).
An example of content surrounding Galaxy Gas
So, how does NO cause analgesia? First, some backstory: endogenous opioids are compounds made by your brain (hence the term endogenous) that act on opioid receptors throughout the brain and body. There are many different classes of opioid receptors. Still, as a whole, opioid receptors play a major part in a variety of physiological functions, such as euphoria, respiratory depression, and neuroprotection. Most important, however, is their role in pain modulation, which is most relevant to this article. This is how opioids such as morphine work; they mimic the endogenous opioids that are produced in our bodies (Shenoy and Liu, 2023).
So, why is laughing gas such a common analgesic? One of the ways that nitrous oxide works is by leading to increased opioid peptide release in the periaqueductal gray (PAG), which leads to the activation of pain inhibitory pathways that stop the nociceptive (pain) signals from our peripheral from ascending the spinal cord and being processed. The PAG is a cluster of neurons in our midbrain, and one of its key roles is to modulate pain sensations. Release of the endogenous opioids by this structure, facilitated by nitrous oxide, is crucial for the pain inhibition that we see when this analgesic is used (Fujinaga and Maze, 2002).
Now, the question I’m sure you’ve all been wondering: how does laughing gas, well, make you “laugh?” One of the answers to that question is that nitrous oxide produces anxiolysis (anxiety-reducing) effects. One of the ways that it does this is by modulating the GABAa receptor. Briefly, GABA (Gamma-aminobutyric acid) is our primary inhibitory neurotransmitter. Generally, this leads to reduced brain activity, as GABA is working to decrease neuronal stimulation. So, one of the ways that nitrous oxide works in the brain is to modulate the effects of the GABAa receptor, enhancing GABA signaling. With this increase in inhibitory action and intracellular mechanisms, the brain, overall, is less “active:”, producing anxiolysis as one of its effects (Emmanouil and Quock, 2007). Along with this, and through other mechanisms, we see the effects that attract people to recreationally use nitrous oxide, mainly a feeling of euphoria.
Acutely, the negative effects of nitrous oxide include dizziness, lightheadedness, and headaches, although the feelings of euphoria tend to weigh out these aversive symptoms. However, chronic use of nitrous oxide leads to much more dangerous effects.
Chronic Nitrous Oxide Effects
One negative effect is rapid neuropathy in both cortical regions and the spinal cord which is largely the result of vitamin B12 deficiency. Vitamin B12 is a necessary component in the reaction that forms the myelin sheath (fatty tissue surrounding the axon of the neuron and allows for electrical signals to travel more effectively, ultimately increasing the rate of transmission between neural cells). The presence of myelin maximizes the functionality of our neurons so they may operate in their absolute best condition. As a result of Vitamin B12 insufficiency, the phospholipid layer of the sheath begins to degenerate, resulting in impaired neural communication that decreases overall cognitive function. (Brunt TM et al., 2022)
In addition, repeated use of nitrous oxide also leads to a drastic reduction in motor control. While myelination is important for cognitive ability, it is imperative for physical movement. Motor neurons extend from various parts of the brain and travel to all parts of the body, and myelination ensures that signals from our brain get to our muscles in time to coordinate a response. With this reduction in myelin, meticulous mechanical movement becomes more challenging. Multiple studies looking into chronic nitrous oxide use find restricted movement in both lower and upper limbs along with abnormal electrophysiological signaling (Li, Y. et al., 2021) (Van Amsterdam et al., 2015).
Finally, nitrous oxide is extremely accessible. While “Galaxy Gas” mentions on its website that it is not intended to be inhaled, many states do not require you to have any form of identification to purchase canisters. In addition, things such as whippets and whipped cream canisters are other easy ways teens can get a hold of nitrous oxide. This in conjunction with its addictive and neurodegenerative properties makes it a “slippery slope.”
Gunna was ahead of his time, but at what cost? As a general rule of thumb, if you don't need to inhale it, avoid doing so.
Sources
Emmanouil, D. E., & Quock, R. M. (2007). Advances in Understanding the Actions of Nitrous Oxide. Anesthesia Progress, 54(1), 9-18. https://doi.org/10.2344/0003-3006(2007)54[9:AIUTAO]2.0.CO;2
Fujinaga, M., & Maze, M. (2002). Neurobiology of nitrous oxide-induced antinociceptive effects. Molecular neurobiology, 25(2), 167–189. https://doi.org/10.1385/MN:25:2:167
Shenoy, S.S., Lui, F. (2023). Biochemistry, Endogenous Opiods. StatPearls. https://www.ncbi.nlm.nih.gov/books/NBK532899/
Van Amsterdam, J., Nabben, T., & Van den Brink, W. (2015). Recreational nitrous oxide use: Prevalence and risks. Regulatory Toxicology and Pharmacology, 73(3), 790-796. https://doi.org/10.1016/j.yrtph.2015.10.017
Brunt TM, van den Brink W, van Amsterdam J. Mechanisms Involved in the Neurotoxicity and Abuse Liability of Nitrous Oxide: A Narrative Review. International Journal of Molecular Sciences. 2022; 23(23):14747. https://doi.org/10.3390/ijms232314747
Li, Y., Zhang, X., & Zhao, C. (2021). Electrophysiological characteristics of patients with nitrous oxide abuse. Neurological Research, 43(10), 793–801. https://doi.org/10.1080/01616412.2021.1935101
