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

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).

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