Ketamine and Nitrous Oxide: Synergistic But Potentially Harmful

Among psychonauts, drug combinations are sought out, experimented with, and appreciated due to their potential to modulate or intensify psychedelic states, and perhaps introduce novel states of mind not yet experienced. But with these potential rewards – new mental realms explored – can come greater risks. Unexpected effects and intensity can carry a psychological risk (of emotional distress) while drugs in combination can involve an array of physical risks (ranging from injury to toxicity). 

There are all kinds of ‘flips’ when it comes to psychedelic drug combinations: the ‘candy flip’ (MDMA and LSD), ‘hippie flip’ (MDMA and psilocybin), ‘kitty flip’ (MDMA and ketamine), and ‘nexus flip’ (MDMA and 2C-B). These all involve MDMA, but other sorts of combinations are possible. One that is enjoyed by many psychonauts is the combination of ketamine (K, ket) and nitrous oxide (N20, laughing gas, hippie crack, whippits, nangs, nos). This combination doesn’t have an official name – an associated ‘flip’ – but I have come across someone suggesting it as the ‘Steve-O flip’ (named after the eponymous Jackass star, based on his heavy use of ketamine and nitrous oxide as an addict). 

Ketamine and nitrous are a synergistic combination (in both a technical and preferential sense): the combined effect is greater than the sum of the effects seen when each drug is given alone and many users find that the two drugs pair well with each other – subjective effects are felt to be enhanced and not simply intensified. But there some research indicates that this combination carries a heightened risk of neurotoxicity. 

This post will first describe the experience of the ketamine and nitrous combination, which I will call the ‘dissos flip’ – ‘dissos’ being an alternative name for dissociatives, since ‘Steve-O flip’ may carry some connotations of drug abuse and one could argue it makes light of Steve-O’s serious addiction to both substances. Next, I’ll dig into the limited research on the risks of this drug combination and offer some harm-reduction advice.

Both ketamine and nitrous oxide are dissociative drugs, meaning that they both produce distortions of sight and sound and feelings of detachment – or dissociation – from the environment and/or self. Other types of dissociative drugs include phencyclidine (PCP), which ketamine is actually an analogue of, as well as dextromethorphan (DXM), which is found in over-the-counter cough medicines, and Salvia divinorum, or salvia, which produces an intense, short-lasting visionary experience, somewhat like DMT.

Both ketamine and nitrous oxide also have the potential to induce mystical experiences, which are classically framed as featuring a unitive state (a feeling of becoming unified – or one – with everything, which includes ego loss), profound joy, ineffability (being unable to adequately describe the experience), transcendence of space and time, a sense of sacredness or the holy, and noetic quality (a feeling of gaining deep insight). However, ketamine (in high enough doses) by itself is more likely to induce mystical states than nitrous oxide on its own (although the philosopher and psychologist William James certainly achieved such states with the latter drug).

Since ketamine and nitrous oxide are both dissociatives, combining them can have a synergistic effect, in both senses of the term ‘synergistic’ outlined earlier: more intense effects and more desirable effects. However, because of this synergy, users should be aware that the combination may lead to an unexpected intensity, duration, and state of mind. One may become more dissociated (from one’s sense of self and environment), more likely to have an out-of-body experience (OBE), and trip for longer than if using each drug on its own. As the Redditor u/blondeboy1900 writes in a post titled ‘Ketamine and Nitrous - Just wow.’:

Prior to this experience, I had only done nitrous while on acid. I really enjoyed this combination but it didn't feel particularly psychedelic or trippy. The nitrous simply gave me this really pleasant body rush where my whole body went numb for a minute and music sounded so vibrant and delicious. Don't get me wrong, nitrous and acid is a great combo, but it has never felt particularly overwhelming to me.

But on ketamine, N2O was a totally different experience. I did a whip-it at the peak of 100mg Ketamine and I was blown away. It added a whole new dimension to the dissociation of the K. It was like being dissociated while being dissociated, a trip within a trip. A total mind fuck. Nitrous should not be under-estimated as a psychedelic enhancer.

Furthermore, because of the potentiation of effects resulting from this combination, one may become more incapacitated, which can be risky if having the experience alone (so without the attention of someone who can look after your physical safety). The experience may also be especially distressing, and come with some physical dangers, if done in an uncontrolled and chaotic setting like a rave or festival. In contrast, when done in a quiet and comfortable setting where you have the freedom to relax into the experience, one may enjoy profound feelings of bliss and other mystical effects.

There are many accounts of people achieving surprisingly intense states of mind when ‘dissos flipping’. For example, in one Reddit post titled ‘Finding god by accident doing nitrous on k’, the Redditor u/Meathippie writes, “I apparently didn’t know / forgot about the synergy between these things.” He adds, “I knew the answer to everything, like something was showing me something. It’s nothing I can capture in words…it’s closer to what I heard dmt was like until I tried and never “broke through”...I wish I could bring back the “knowing” like lighting in a bottle, but it can’t be expressed in words and is slippery.”

Here we can clearly see the noetic quality of mystical experiences – that sense of strong conviction in gaining important knowledge, which then reliably slips away as the experience fades. (I call the feeling of understanding everything – as the user above experienced – the total noetic experience.) We see ineffability too in this trip report – the inability to capture the experience in words. Another Redditor, u/cyode, replied to the post with his love for the combination, saying: "I go into oblivion...totally mind blowing every time it happens. Very similar feelings to breaking through on DMT for sure, but like a different route to the same place where the “knowing” is just so damn strong!"

In response to u/cyode, u/Meathippie says: "Such a smoother, easier, and less scary ride to get there than dmt, less emotional as well…" So, in some sense, dissos flipping may be considered a kind of spiritual cheat code – a way to achieve a DMT-like breakthrough or full-blown mystical experience without the commitment of taking a strong dose of a longer-lasting psychedelic or without the speed, turbulence, or fear associated with DMT or other intense, short-acting visionary experiences like those induced by salvia and 5-MeO-DMT.

In another Reddit post on the combination, from someone wanting to know what the experience is like, the Redditor u/homelesssawyer responded, “Quickest way to meet god”. Another Redditor, u/gratefulwhomps, said: "They go together like peanut butter and jelly." u/apieceofcourgette said: "It's straight euphoria whilst forgetting who you are for a bit. With other responses including: "This is the way to the source, whatever that may be from your perspective." and, "Best out of body experience, found myself and met god."

On the other hand, overwhelm is possible. As u/gamelollamp stresses: "Cheat code to out of body experience- have seen people put that shit down and not touch it again though so be careful."

In the post from u/blondeboy1900 mentioned earlier, u/codedinblood said: "Nitrous on any high dose disso is fucking legendary. It gives me ego death every time."

But of course, while ego dissolution can feel liberating and blissful, it can also be a frightening experience, so it’s important to keep this possible effect in mind before trying the combination.

A Reddit post from u/Nolo_85 titled ‘Full breakthrough on Ketamine combined with Nitrous oxide (NOS)’ speaks to the ‘spiritual cheat code’ potential of this combination:

All sound went buzzing, fractals everywhere and energy getting pumped, then the fractals want to shatter became maximum and extreme high buzzing sound..I was getting the feeling of my consciousness was getting launched. It was really scary but then I became aware, this is what I have read about and tried a few times with DMT. I can break through if I let go now.. and..and so I had to let go..

My mind went launching out of my body on warpspeed and ended up what felt like the source of creation. I went into a tonic state, think my eyes went REM. Consciousness became one with everything and all. At that moment I also knew everything there was to know. What real reality was. It was insane. I can't remember most now but at that moment i knew..

There it was like everything was made out of light, energy and fractals. It's actually undescribable. Dont remember how I came back exactly.... I tried to reach this with DMT but never worked. This however.. Most profound experience I ever had.

I want to mention that this breakthrough is probably not for the faint of heart. If i did not know about it I probably wouldn't have let go because I think it could also be terrifying. Like if you are dying maybe.

The philosopher Chris Letheby argues that psychedelic-induced mystical experiences may be therapeutic “not primarily because they change people’s beliefs about the ultimate nature of reality, but because they enable people to revise their self-conceptions in healthier ways, changing how they see themselves and how they relate to their own minds and lives.”

There is not much research available on the effects of combining ketamine and nitrous oxide, not to mention a dearth of trip reports (reflected in the lack of a common, widely used name for its combination, and a lack of resources online about it). However, one paper from 2000 published in the British Journal of Pharmacology finds the combination may be risky. It is titled ‘Ketamine potentiates cerebrocortical damage induced by the common anaesthetic agent nitrous oxide in adult rats’. 

Each drug on its own, at clinically relevant doses (they’re both used in anaesthesia), has the potential to induce psychotomimetic (psychotic-like) reactions in humans and to cause neurotoxicity (disruption to, or death, of nerve cells in the brain) in rats. This is because they’re both antagonists of N-methyl-D-aspartate (NMDA) glutamate receptors, which means they block or dampen the activity of these receptors. Ketamine and nitrous oxide induce psychoactive effects through this binding, in contrast to the classic psychedelics, whose effects are mediated by activity at the serotonin 5-HT2A receptors. In contrast to the classic psychedelics, nevertheless, NMDA antagonists have long been known to have neurotoxic effects.

The 2000 study notes:

Because drug combinations used in clinical anaesthesia sometimes include both ketamine and N2O, we undertook experiments to evaluate whether augmented neurotoxicity results from their combined use.

The design of the experiment was as follows:

Ketamine and N2O were administered alone or in combination by various dosing regimens to adult female rats for a duration of 3 h and the severity of cerebrocortical neurotoxic changes was quantified histologically. Because GABA agonists are known to protect against the psychotomimetic and neurotoxic effects of NMDA antagonists, we also evaluated whether the combined neurotoxicity of ketamine+N2O can be prevented by certain commonly used GABA agonists.

The researchers found the following results:

When ketamine and N2O were used in combination the neurotoxic reaction was enhanced to a degree much greater than can be explained by simple additivity. The apparent synergistic interaction was particularly striking when low doses of the agents were combined, the degree of toxic synergism at higher doses being masked by a ceiling effect. GABA agonists protected against ketamine/N2O neurotoxicity.

Yet the enhanced neurotoxicity seen in rat brains in this study does not mean the same necessarily applies to humans. The researchers state, “Whether such pathomorphological changes do occur in humans as a result of combined exposure to N2O and ketamine is unknown, but it is well known that a significant percentage of patients following surgical anaesthesia manifest mental disturbances referred to variously as ‘acute organic brain syndrome', ‘delirium' or ‘toxic psychosis'.” They add, “While a toxic psychosis in a small percentage of patients is currently viewed as an acceptable risk associated with any major surgical procedure in which general anaesthesia is used, it warrants consideration that the frequency of such reactions might be reduced if the anaesthetic protocol avoids heavy use of either N2O or ketamine and totally avoids use of the two agents together.”

What is crucial to emphasise here, however, is that this study, as well as other studies on the neurotoxicity of ketamine and nitrous oxide, are looking at anaesthetic doses of the drugs, whereas recreational or psychonautical use involves subanesthetic doses. The researchers did find that low doses of the two drugs caused a severe neurotoxic reaction in the rat cerebral cortex that was not seen when the drugs were administered on their own. But these were, nonetheless, low anaesthetic doses, and so still higher than subanaesthetic doses. The researchers state that:

When a non-toxic dose (20 mg kg−1 i.p.) of ketamine (equivalent to 3 mg kg−1 i.m. in humans)...was supplemented with a non-toxic concentration (50 vol%) of N2O (equivalent to 35 vol% N2O in humans)...it caused a more severe neurotoxic reaction than was produced by any dose of ketamine by itself. While interspecies comparisons do not provide a precise basis for risk evaluation, it is important to recognize that the doses of these agents used in our rat experiments, when converted into human dose equivalents, are well within the range of doses often used in human anaesthesia (ketamine is used in human anaesthesia at a dose of 5–10 mg kg−1 i.m., and N2O in concentrations up to 75 vol%).

It is possible that combining both drugs in subanesthetic doses would be riskier from a neurotoxicity standpoint than using each drug alone, but research would need to establish this. Studies have shown that daily high-dose ketamine use in substance use disorder (SUD) has clear neurotoxic effects, so in the context of ketamine abuse, adding in nitrous can be even more detrimental. If both drugs are used together in moderate doses, infrequently or rarely, then this may not have a neurotoxic effect; but again, we need research to identify the short-, medium-, and long-term risks of such a combination. The researchers in the 2000 study suggest that acute psychosis seen in patients administered both ketamine and nitrous oxide may indicate co-occurring neurotoxicity. Thus, if dissos flipping does not result in an acute psychotic reaction, this could mean that neurotoxicity is not occurring (but once again, we lack evidence to make any conclusion about this).

Based on the trip reports included above, as well as personal experience with dissos flipping, you may want to pursue this drug combination. As a potentially easy shortcut to a spiritual experience, which you can be finished with in a matter of minutes, it is highly appealing. On the other hand, by quickly and intensely altering a ketamine experience (ketamine is typically taken first, then nitrous), dissos flipping may result in a challenging experience, which may include a frightening ego dissolution experience, panic, overwhelm, and even a psychotic-like reaction. 

Since such a reaction is short-lived, the chance of ongoing emotional difficulties (long after the experience ends) may be lower than a longer-lasting bad trip on LSD, psilocybin mushrooms, or ayahuasca, but this does not mean there is no risk of persistent difficulties (as evidenced by the people who have experienced worsened mental health after an experience with a short-lasting compound like DMT or 5-MeO-DMT). I have not personally come across any reports, however, describing similar difficulties after a particularly intense ketamine and nitrous experience.

In addition, dissos flipping can cause strong time dilation, with the experience feeling like it’s lasting hours, years, or even an eternity. While you may be gone for only a minute in real time, subjectively, time may lose meaning altogether (recall the transcendence of time and space feature of mystical states references earlier) or it may feel neverending. You may completely forget who you are, what you are, where you are, that you have a body, or that you’ve taken a drug. So if you’re thinking of inhaling nitrous while on a strong dose of ketamine, you should be prepared for the possibility of an intense OBE (making you experience yourself as consciousness without a body) or mystical experience. Experienced psychonauts may more readily accept such effects. If you do find yourself in a state of struggle or overwhelm when trying this combination, it’s important to know how to navigate the experience.

Finally, with respect to the potentially neurotoxic effect of dissos flipping, it’s not yet clear if subanaesthetic doses in combination have such an effect. Nonetheless, if you want to avoid that as a potential risk, then it may be best to avoid this drug combination completely, at least until more evidence emerges. Otherwise, you might feel more comfortable using only moderate doses of each drug, which could minimise the risk of potential harm. 

If avoiding dissos flipping or only using moderate doses in combination makes you feel like you’re missing out on a quick and short-lived spiritual experience, combining a classic psychedelic with nitrous is always a possibility, and seemingly a much safer one. However, even with this combination, one should be aware that nitrous oxide itself carries risks. As a 2015 paper states:

Side effects of N2O include transient dizziness, dissociation, disorientation, loss of balance, impaired memory and cognition, and weakness in the legs. When intoxicated accidents like tripping and falling may occur. Some fatal accidents have been reported due to due to asphyxia (hypoxia). Heavy or sustained use of N2O inactivates vitamin B12, resulting in a functional vitamin B12 deficiency and initially causing numbness in fingers, which may further progress to peripheral neuropathy and megaloblastic anemia.

When used safely, with harm reduction practices in mind, adding nitrous oxide to a psychedelic experience can feel profoundly enlightening. Whether the ‘insights’ had during the experience are real and not just illusory is up for debate (see my previous post on metaphysical insights induced by psychedelics). They are typically impossible to remember. Yet even those who have such a deeply noetic experience come away thinking there is only a powerful sense of insight, rather than something with actual content or meaning. But this is a subject for another and much more in-depth discussion.

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