Nitrous Oxide: A Gas With Mystical, Antidepressant, and Addiction Potential

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The Gaseous Path to Mysticism

The English chemist Joseph Priestly first synthesised nitrous oxide in 1772. Another English chemist, Humphry Davy, experimented with the gas and published his findings in his work Researches, Chemical and Philosophical (1800). Therein, he noted the analgesic effects of the chemical, as well as its psychoactive effects. Davy coined the term ‘laughing gas’. Despite Davy discovering it could relieve patients of their pain, it wasn’t applied as an anaesthetic by doctors for another 44 years.

At the end of the 18th century, owing to its psychoactive effects, the British upper class started to use nitrous oxide recreationally at ‘laughing gas parties’. While some experienced effects like stupor, sedation, and dreaminess, others would ‘get the giggles’ in their euphoric state and often erupt into laughter. This giggling and uncontrollable laughter occurs with classic psychedelics too. The English poet Robert Southey had the following to say about his nitrous oxide experience:

Oh Tom! such a gas has Davy discovered! Oh Tom! I have had some. It made me laugh & tingle in every toe and finger tip. 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 so strong & so happy! So gloriously happy! & without any after debility but instead of it increased strength & activity of mind & body — oh excellent air bag. Tom I am sure the air in heaven must be this wonder working gas of delight.

Another English poet, Samuel Taylor Coleridge, also spoke highly of the gas:

I felt a highly pleasurable sensation of warmth over my whole frame, resembling that which I remember once to have experienced after returning from a walk in the snow into a warm room. The only motion which I felt inclined to make, was that of laughing at those who were looking at me.

Like psychedelics, nitrous oxide also has the potential to induce profound mystical states. The philosopher William James’s ideas on the mystical experience – published in The Varieties of Religious Experience (1902) – were born out of his nitrous oxide self-experiments. He, as well as the philosophers Paul Benjamin Blood and Xenon Clark, found a gaseous path to mysticism: a way of gaining metaphysical insights through the inhalation of sufficient doses of nitrous oxide. James’s gaseous revelations and conclusions included the following (recorded immediately after the experience or upon later reflection): “Reconciliation of opposites”, “Good and evil reconciled in a laugh!”, “Thought deeper than speech!”, pluralism (“there are various ‘points of view’”), and the idea that religious experiences have important long-term consequences whether or not they are veridical. These are just a handful of examples.

James and other famous nitrous oxide self-experimenters landed on a mysticism without dogma: a chemically-inspired mysticism not attached to any specific religion. Blood also subscribed to this pluralistic view. James was seeking to discover mystical insight – novel insight – rather than solidify pre-existing beliefs and creeds.

Nonetheless, James found that his mystical insights disappeared as the effects of nitrous oxide wore off, and he judged the words he wrote down in the aftermath to be “tattered fragments” that were “meaningless drivel”. Some of these so-called mystical insights, which seem typical of nonsensical drug-fuelled insights, include “What’s mistake but a kind of take?”, “What’s nausea but a kind of -ausea?”, and “Sober, drunk, -unk”.

In any case, the emotional reaction seen in other mystical experiences was present. James reported experiencing “astonishment” and the “strongest emotion” he had ever felt, and he wrote down while on the drug,

Oh my God, oh God, oh God!

Psychonauts have also discovered that nitrous oxide can induce mystical experiences, although it can be challenging to achieve this with the gas alone; typically, psychonauts will inhale the gas while already tripping. This can reliably lead to profound mystical states, although those curious should be wary: inhaling nitrous oxide can lead to unexpectedly intense psychedelic experiences. One must proceed with caution, with the knowledge that psychedelics and nitrous oxide work synergistically together (i.e. they intensify each other’s effects).

The Use of Nitrous Oxide in the Treatment of Depression

Nitrous oxide is most commonly associated with a short-lived high, and it’s not really considered to be worthy of consideration beyond that. The history of its use as a mystical aid challenges this view, but so does a growing body of research into its potential mental health applications. Medically, nitrous oxide is administered in operating rooms and dental practices as an anaesthetic. But as a 2018 paper published in the Journal of Clinical Psychopharmacology states, it has also “shown early promise as a rapidly acting antidepressant in patients with treatment-resistant major depression.” This novel treatment is appealing because, unlike other novel drug treatments like ketamine and psychedelics, the psychoactive effects are both less intense and shorter-lasting.

A 2021 phase 2 clinical trial published in Translational Medicine explored the use of nitrous oxide for treatment-resistant depression (which affects around one-third of those with depression). Similar trials in the past had used a 50% nitrous oxide concentration, but adverse effects may occur at this concentration, including nausea, vomiting, and headaches. This 2021 study involved a 25% concentration, which the researchers discovered had comparable efficacy in treating depressive symptoms but with significantly fewer adverse effects. Lead study author Peter Nagele said:

This investigation was motivated by observations from research on ketamine and depression. Like nitrous oxide, ketamine is an anesthetic, and there has been promising work using ketamine at a sub-anesthetic dose for treating depression. We wondered if our past concentration of 50% had been too high. Maybe by lowering the dose, we could find the ‘Goldilocks spot’ that would maximize clinical benefit and minimize negative side effects.

While nitrous oxide is known for its euphoric and laughter-inducing effects, in the study above, patients who received low doses of the gas actually fell asleep. “They’re not getting high or euphoric, they get sedated,” Nagele said. He added:

[W]e need acceptance by the larger medical community for this to become a treatment that’s actually available to patients in the real world. Most psychiatrists are not familiar with nitrous oxide or how to administer it, so we’ll have to show the community how to deliver this treatment safely and effectively. I think there will be a lot of interest in getting this into clinical practice.

A 2022 study on the efficacy and safety of nitrous oxide in the treatment of treatment-resistant depression, conducted in China, revealed similar promising results. Published in Psychiatry Research, the researchers found that a single inhalation of 50% nitrous oxide effectively alleviates depression, although benefits lasted for no longer than one week, and patients receiving nitrous oxide experienced significantly more adverse effects (lasting no longer than 24 hours) than the placebo group. Nonetheless, the study authors deem nitrous oxide a safe treatment for patients with treatment-resistant depression.

(It can appear that the duration of sustained benefits is related to the duration of the drug’s effects: the effects of ketamine and its benefits outlast those of nitrous oxide, and those of psilocybin outlast those of ketamine. However, another short-lasting drug, DMT, can produce sustained remission from depression for several months, so we cannot simply tie the duration of mental health benefits to the duration of drug effects. Other factors are involved in long-term efficacy, although researchers are still investigating which factors are the most important.)

Nagele and other researchers argued in an article in The Lancet why nitrous oxide deserves greater attention as a novel mental health treatment:

Like ketamine, nitrous oxide (laughing gas) is an N-methyl-D-aspartate-receptor antagonist. The similarity between the presumed mechanism of action of nitrous oxide and ketamine supports the possible effectiveness of nitrous oxide as a rapid-onset antidepressant. Although promising as a treatment, ketamine can have considerable undesirable side-effects such as confusion, dissociation, other psychomimetic effects, and substance abuse potential. Unlike ketamine, nitrous oxide has an excellent safety profile in major surgery, obstetrics, dentistry, and emergency care.

However, we should be careful not to confuse rapid antidepressant effects with a ‘cure’ or ‘fix’ for depression. Due to its benefits being short-lived, Nagele and others write, “The hope is that nitrous oxide can provide rapid onset of antidepressant effect during the time whereby the therapeutic benefit of any newly commenced traditional antidepressant or non-pharmacological therapy has its delayed effect.”

In any case, promising research on the mental health application of nitrous oxide continues to grow. Nitrous oxide can reduce suicidal ideation in treatment-resistant depression (also observed in ketamine therapy), which means it could potentially be a life-saving intervention. Patients experiencing suicidal ideation are typically screened out of clinical trials, treatments, and retreats involving classic psychedelics, and many psychotherapists may refuse (or stop) sessions if a client reports having suicidal thoughts. In the UK, those feeling suicidal can be eligible for state-funded treatment, but they can end up on long waiting lists, which means help can come too late. It is, therefore, critically important to identify – and make available – novel safe and effective treatments for depression featuring suicidality.

A 2024 systematic review and meta-analysis of the use of nitrous oxide in the treatment of major depressive disorder and treatment-resistant depression found (in a clinical context):

• Nitrous oxide has a fast-acting antidepressant effect.
• Nitrous oxide can alleviate symptoms in depression with a high risk of suicide.
• Nitrous oxide antidepressant effect lasts 2 weeks, peaks in 24 h.
• Nitrous oxide has fewer serious side effects than ketamine.
• Nitrous oxide does not seem to develop dependence in its users, unlike ketamine.

The Risks of Nitrous Oxide

While the study above concluded that nitrous oxide does not seem to develop dependence in users, its use in a recreational, uncontrolled context can reveal a different story. Abuse of, and addiction to, nitrous oxide is possible. The drug’s short-lasting high often leads users to binge on nitrous oxide. For some users, if this acts as a form of escapism and self-medication, addiction can develop.

The addictive potential of nitrous oxide was highlighted in the documentary Stevo-O: Demise and Rise (2009), which shows the Jackass star’s descent into a serious addiction to the drug (he was heavily drinking and abusing cocaine at the same time). As a result of this poly-drug abuse, he developed psychosis, which involved hearing the voices of ‘angels’ and ‘demons’. This drug-induced psychosis led to his continued belief in alternate dimensions. At the height of his addiction, he went through 600 nitrous oxide canisters in 24 hours, and he was high on cocaine and laughing gas for three days in a row, not sleeping, which resulted in visual, auditory, and tactile hallucinations. In 2008, fellow Jackass stars staged an intervention for Stevo-O, and he was involuntarily sectioned to a psychiatric hospital. He has since led a life of sobriety, staying abstinent from all drugs.

Davy also succumbed to a life-threatening addiction to nitrous oxide. It didn’t take long before he started using the drug outside laboratory conditions. He would sit alone in the dark and inhale huge amounts of the gas. He developed cravings for it, confessing that “the desire to breathe the gas is awakened in me by the sight of a person breathing, or even by that of an airbag or air-holder.” Gavin Butler writes in a piece for Vice, “Towards the end of 1799 Humphry went so far as to construct an “air-tight breathing box” in which he could sit for hours on end, inhaling as much nitrous as he could before losing consciousness and having even more intense, “sublime,” and “vivid” experiences. He almost died in this chamber on more than one occasion.”

Nitrous appears to have an abuse/addiction potential not seen in classic psychedelics, so users should be aware of this. One of the major risks of heavy or prolonged use of nitrous oxide is B12 deficiency, which can result in neurotoxicity, typically manifesting as myelopathy (injury to the spinal cord) or myelneuropathy (damage to the spinal cord and peripheral nerves of the lower limbs). Vitamin B12 depletion in the body following intake of nitrous oxide is concerning because it is rapid, chemically irreversible, and can last up to three days. B12 deficiency, which can result from daily use of nitrous oxide, can also lead to megaloblastic anemia (the development of large blood cells that crowd out healthy cells).

Nevertheless, Nagele et al. (2018) state, “Despite the potential seriousness, the incidence of this side effect is very low, and probably also mitigated by the fact that in the United States flour is enriched with folic acid and vitamin B12.” They add:

[N]itrous oxide has minimal addiction potential. Its abused form is often referred to as “whippits”, as nitrous oxide is the gas within whipped cream canisters. The main difference between nitrous oxide abuse and its medical use is, when abused, nitrous oxide is inhaled at a 100% concentration without oxygen. Inhaling any pure gas other than oxygen may cause asphyxiation, particularly when taken with other CNS depressants.

In light of this, users should avoid using nitrous oxide, particularly in large amounts or chronically, in combination with benzodiazepines, opioids, and barbiturates. I have also written about the potential dangers of using nitrous oxide in combination with ketamine. In a clinical context, at least, many of the potential risks of laughing gas are mitigated. As Nagele et al. (2018) stress:

There are several misconceptions about nitrous oxide administration in a medical setting. First, very few, if any, patients get euphoric or “high” after a standard 1-hour inhalation of 50% nitrous oxide. The typical response is sleepiness and mild sedation. Most patients are easily arousable and able to communicate with the treatment team. Second, while nitrous oxide does inactivate vitamin B12, this is of very little clinical relevance after a single nitrous oxide administration. Third, recovery time is very short. Typically, patients are completely recovered within 10 minutes and are able to operate a motor vehicle. While in clinical trial settings, more extensive vital sign monitors are used to increase the sensitivity of detecting adverse events, in dental practice, nitrous oxide is administered without any mandatory vital sign monitors.

In summary, users should be cautious about chasing the peak of the nitrous oxide high through chronic use, perhaps in an attempt to cling to the mystical insight they gained and lost, or in search of a revelation they thought they were close to having during a previous high. While nitrous oxide can offer genuine mystical experiences, particularly when combined with other drugs (e.g. MDMA, ketamine, and psychedelics), these combinations can present new physical and psycholoigcal risks. However, some of these combinations could perhaps be approached safely. And their potential to produce intense experiences is not to be trivialised. They could offer effective routes towards profoundly interesting and transformative states of mind.

The narrative around nitrous oxide in the medical community is also starting to change. A growing body of research means we can longer dismiss nitrous oxide as a mere party drug, offering no benefits and only risks. It may start to be respected as a novel mental health treatment alongside ketamine, one which offers unique advantages.

Sam Woolfe | Community Blogger at Chemical Collective | www.samwoolfe.com

Sam is one of our community bloggers here at Chemical Collective. If you’re interested in joining our blogging team and getting paid to write about subjects you’re passionate about, please reach out to David via email at blog@chemical-collective.com