Xenon is a gas refined from the Earth’s atmosphere by cooling air to cryogenic temperatures and then boiling off the different components. It’s rare – air only contains about 0.087 parts per million by volume. This makes it expensive – a 25 litre tank will cost you around two thousand dollars.
Xenon has a variety of industrial applications, including arc lamps and the excimer lasers used in semiconductor photolithography. It also has a curious medical application. Xenon works as an inhalational anaesthetic much like nitrous oxide, and it is sometimes used for babies and small children when the risks of using more traditional anaesthetics make it worth the high cost.
This is surprising, because xenon is a noble gas. This means that it is chemically inert and should not react with other elements. Nevertheless, it does function as an anaesthetic – and even has a reputation for its recreational qualities. Due to its scarcity and expense, not many people have tried it, and this also contributes to its reputation as an exotic substance.
The journalist and documentarian Hamilton Morris filmed an episode of his show Hamilton’s Pharmacopeia about xenon. He reported profound hedonic effects:
“Pulsations of euphoria. I feel a euphoric… I feel it in every region of my body. The extremities especially, the fingers and toes. It’s very good. I feel tremendous euphoria.”
Xenon itself is not classified as an illegal substance – though it is not approved by the FDA for general consumer supply. My friend Raj was investigating xenon for its theraputic potential, and offered to arrange a session for me and my collaborator Ethan so we could analyse its effects. That’s what this writeup is about – but before I write about xenon’s phenomenology, I’d like to discuss its pharmacology.
I’ll provide some context. The NMDA receptor is one of several receptor molecules responsible for excitatory neurotransmission in the brain. It’s a complex protein which lives on the surface of the neuron, and when the neurotransmitter glutamate binds to it, it opens up – allowing ions to flow into the neuron. However, other molecules – like ketamine and nitrous oxide – might also bind to the receptor in a way that prevents it from opening. Such molecules are known as NMDA receptor antagonists.
We looked at the effects of xenon on NMDA-activated currents in cultured hippocampal neurons. We found that 80% xenon, which will maintain surgical anaesthesia, reduced NMDA-activated currents by about 60%, with no significant change in the NMDA EC50 value or Hill coefficient. This non-competitive inhibition indicates that xenon should strongly inhibit neural transmission, despite the high glutamate concentrations in synaptic clefts.
If xenon exerts its effects by inhibiting NMDA receptors, then this explains some important features of its pharmacological profile, particularly as NMDA receptor antagonists can relieve pain and cause amnesia, which are features of xenon anaesthesia. Like nitrous oxide (‘laughing gas’), which may also act, at least partly, on NMDA receptors, xenon can induce a state of euphoria. Other neuronal targets for xenon may emerge, but its powerful inhibition of the NMDA receptor is likely to be instrumental in the anaesthetic and analgesic effects of this ‘inert’ gas.
The NMDA receptor also requires the presence of glycine before it can be activated by glutamate, and additional research suggests that xenon works by occupying the glycine binding site on the NMDA receptor. This is supported by evidence that xenon is more effective when glycine levels are low, and molecular modelling suggests that inert gases despite being only weakly interacting can still occupy nonpolar cavities within receptor proteins.
However, perhaps things are not so simple as this basic key-and-lock, molecule-and-receptor model. The theoretical mechanisms of anaesthesia deserve particular attention in consciousness research – as after all, anaesthesia is how we switch consciousness off – so I found myself reading a few more papers on the proposed mechanisms of xenon. One in particular began with a lively description of the state of play in anaesthesia research. From Electron spin changes during general anesthesia in Drosophila (Turin et al., 2014):
General anesthesia is both indispensable and fascinating. Millions of surgical procedures are performed each year, most of which would be unthinkable if general anaesthetics did not exist. However, although the first clinical anesthesia with diethyl ether was reported over 160 years ago, the mechanism by which the same general anaesthetics act on animals as far apart in evolution as paramecia and man – and even plants – is still unclear. In 2005, general anaesthesia was included in a Science list of major unsolved problems in the august company of cancer, quantum gravity, and high temperature superconductivity. Today, general anaesthesia remains an intellectual challenge and arguably, one of the few experimental inroads to consciousness.
The mystery of general anaesthesia resides in a uniquely baffling structure-activity relationship: the range of compounds capable of acting as general anaesthetics makes no pharmacological sense. Adrien Albert called it “biological activity unrelated to structure”. In number of atoms, the simplest of the general anaesthetics is xenon, a monoatomic noble gas, and the most complex is alfaxalone, a 56-atom steroid, spanning a 35-fold range in molecular volume. In between is a host of molecules of widely different structures: nitrous oxide, halogenated compounds (sulfur hexafluoride, chloroform, halothane, etc.), strained alkanes (cyclopropane), phenols (propofol), ethers (diethyl ether and sevoflurane), amides (urethane), sulfones (tetronal), pyrimidines (barbiturates), etc. If one adds gases, like dioxygen and nitrogen, that cause narcosis under pressure and volatile solvents used as inhalational recreational drugs, the list is longer still. What property can all these molecules possibly have in common that causes general anaesthesia?
A selection of general anaesthetics. Note the lack of any visible structure-activity relationship. From Spintronics in Neuroscience by Luca Turin, on YouTube.
While the protein binding hypothesis provides a plausible mechanism for xenon’s anaesthetic effects, it doesn’t fully explain a curious pattern observed across all anaesthetics. The Meyer-Overton correlation, first described by Hans Horst Meyer in 1899 and then by Charles Ernest Overton in 1901, reveals that the potency of anaesthetic agents correlates remarkably well with their solubility in olive oil, regardless of their chemical structure.
The Meyer-Overton correlation for anaesthetics. From Wikipedia.
The Turin paper continues:
A partial answer has been known for nearly a century. General anaesthetics are lipid-soluble, and their potency, regardless of structure, is approximately proportional to lipid solubility, a relationship known as the Meyer–Overton rule. This relationship implies, surprisingly in light of their diverse structures, that, after they have arrived at their destination, all general anaesthetics are equally effective. Accordingly, because general anaesthetics dissolve in the oily core of the lipid bilayer, they were long thought to perturb the featureless dielectric in which ion channels, receptors, and pumps are embedded, although an action on proteins could never be ruled out.
The lipid bilayer expansion hypothesis for anaesthetics, proposing that anaesthetics disrupt the lipid bilayer structure of the cell membrane. From Wikipedia.
Xenon participates in this correlation much the same as other anaesthetics, suggesting it shares their mechanism of action. This creates a paradox: If anaesthetics act through specific protein binding effects as per the Franks-Lieb hypothesis, how can such structurally diverse molecules all produce similar effects with potencies that correlate precisely with their lipid solubility as per the Meyer-Overton hypothesis?
While a reconciliation between the two theories discussed remains elusive – there’s a third, much weirder theory I’d like to discuss.
Abstract: The question of what generates conscious experience has mesmerized thinkers since the dawn of humanity, yet its origins remain a mystery. The topic of consciousness has gained traction in recent years, thanks to the development of large language models that now arguably pass the Turing test, an operational test for intelligence. However, intelligence and consciousness are not related in obvious ways, as anyone who suffers from a bad toothache can attest – pain generates intense feelings and absorbs all our conscious awareness, yet nothing particularly intelligent is going on.
In the hard sciences, this topic is frequently met with skepticism because, to date, no protocol to measure the content or intensity of conscious experiences in an observer-independent manner has been agreed upon. Here, we present a novel proposal: Conscious experience arises whenever a quantum mechanical superposition forms.
They propose a series of quantum biology experiments, one of which entails coupling two qubitsQ1 and Q2 via a candidate biological substrate B:
If we then find that it is possible to mediate entanglement between Q1 and Q2 via the system B, then we can conclude that B requires a quantum mechanical description. This paradigm is rather flexible, as different coupling schemes and different substrates B can be investigated. For instance, B could be a microtubule, a receptor protein such as rhodopsin, a single nerve cell or even a brain organoid.
In order to narrow down the space of candidate biological substrates, Neven’s team wishes to conduct a series of preliminary experiments – one of which has already been performed, involving testing the anaesthetic potency of different xenon isotopes in mice. These isotopes differ only by the number of neutrons in their atomic nuclei, which in principle should not have any significant influence on any chemical reactions – but check out the results:
As Neven et al. conclude – if different xenon isotopes have different anaesthetic potencies, this implies that quantum effects must be implicated in anaesthesia:
Intriguingly, the work of Li et al. on the anesthetic effects of xenon isotopes shows that the potency of the two isotopes with half-integer nuclear spin (129Xe and 131Xe, spin of 1/2 and 3/2, respectively) is about 30% less than the potency of the two isotopes with zero nuclear spin (132Xe and 134Xe).
This difference, if confirmed, cannot be explained by differences in the outer electron shells (there are none) and is unlikely to be caused by differences in atomic mass (<1% difference between 131Xe and 132Xe). If true, the results suggest that some of the effects of xenon on consciousness may be mediated by nuclear spins, quantum systems amenable to superposition.
It is suggestive that the half-integer spin isotopes were the ones with reduced anesthetic potency. The non-zero spin may act as a qubit contributing to the formation of larger superpositions, which, according to our conjecture, would be correlated with a richer conscious experience counteracting the anesthetic effect.
Neven’s team plans to replicate this finding, with fruit flies and then brain organoids – at the time of writing, I believe the fruit fly study should have already been completed. In the meantime, they consider an entertaining prospect, one which appeals to my sensibilities:
Before achieving brain–quantum computer coupling, let us consider a simpler question: can volunteers given sub-anesthetic doses distinguish different xenon isotopes, say, by their differential psychedelic properties?
Specific isotopes may be purchased from NUKEM Isotopes GmbH in Germany. Price upon request.
Learning that xenon was going to be used to demonstrate how anaesthesia could be mediated by quantum effects only made me more excited to try it – even if we wouldn’t have access to specific isotopes. What should I expect? In between pulsations of euphoria, would I spontaneously experience some profound insight into the quantum nature of consciousness?
Both myself and my fellow qualia researcher Ethan were visiting the Bay Area when Raj offered to facilitate an evaluation of xenon, and we arranged to meet up at a group house in Berkeley one Friday afternoon.
Our tank of xenon.
We asked the supplier for details about our xenon’s isotope ratios, and they replied:
The xenon we have is full-spectrum, not stripped of any isotopes.
If you sum up the ratios of even and odd numbered atomic mass numbers, you get the ratio of the less potent half-integer spin isotopes to the more potent zero spin isotopes. This is around 47.6% to 52.4%. Lacking a mass spectrometer to separate the isotopes, we weren’t going to become isotope connoisseurs any time soon – but I figured it was interesting to know this nonetheless.
Me and Ethan had agreed not to discuss anything until afterwards, so as to avoid priming one another – but he hadn’t arrived yet anyway, so I went first. We measured out a four litre balloon, and then I laid down in the darkness of the cosy backyard den, put on the obligatory Steve Roach as low-entropy background music, and made myself comfortable. I was ready to go down the x-hole.
We used a water displacement method to gauge the volume of the balloons as we filled them.
I started my field recorder before I took the hit, and gave my assessment immediately afterwards – the experience still fresh in my mind and my voice still deep from the dense gas. The following transcript is an accurate description of what I experienced:
Cube Flipper:pitch-shifted gurgling and laughter
Cube Flipper: There was nothing about this experience which was perceptually distinguishable from nitrous. That is the end of my report. That is the entirety of my report.
Raj: Huh.
Cube Flipper: Don’t tell anyone else I said that, I would be interested to see whether Ethan says roughly the same thing.
Raj: Yeah I think it was more similar to nitrous than I expected but I found the headspace a bit better and a bit less painful.
Cube Flipper:Mmm.
Cube Flipper: It was pretty good though, I mean there’s nothing wrong with nitrous.
Cube Flipper: By the same, I mean the same sort of – okay, let’s like decrease the amount of damping in your somatic field all at once and – basically as soon as you do that there’s sort of a buzzing and a roar that spreads everywhere, like you can sort of feel ripples moving throughout your body, and it’s like you would expect from nitrous – a perception starts in one place and it spreads elsewhere and it has room to bounce off one side and move back up and it feels very wave mechanic-esque.
Cube Flipper: Oh, gutted… I was sort of expecting something like the 5-MeO-DMT equivalent of nitrous. Alright, cease recording—
How underwhelming. Sample size one, but I found that xenon was largely the same as nitrous oxide – just two orders of magnitude more expensive.
A year beforehand, I’d taken it upon myself to spend some time experimenting with nitrous oxide, so I was relatively familiar with its phenomenology. I rode my bicycle down to The Twilight Zone in Oakland to pick up a tank – a weird detail I recall is that the lady working the counter had recently been assaulted while getting out of her car, and she threw in a can of pepper spray for free. I then spent a couple of days holed up in my apartment testing how nitrous interacted with a variety of activities – but mostly just lying on my bed and listening to music.
I posted a thread about these experiences, if you’d like to read about it. In summary, I tend to find that the typical nitrous trip is a mostly non-visual, tactile affair – which follows a consistent trajectory:
Immediately after inhaling, there is a sudden decrease of damping in the somatic field. This abrupt release of tension causes a large amount of waves to start bouncing around, reflecting off the inside of the three-dimensional body map.
As the initial harshness settles out, the wave spectrum becomes more harmonious. Over time, chop turns into swell, until the wave medium is mostly still once again.
There’s several additional details I’d like to note about the phenomenal wave dynamics of nitrous oxide:
The overall experience is more harmonious when you maintain a symmetric posture and don’t move around too much. This is very similar to DMT.
The waves are mostly linear, which is to say that they generally pass right through each other without interacting too much. This is very different to DMT.
Attention can be used to focus the waves. For instance, I can put my attention on a point on my forehead until the wave function’s amplitude distribution is entirely concentrated in that one spot.
The experience responds positively to particular emotions, which cause the waves to harmonise in novel and unexpected ways.
In the case of xenon, owing to our limited supply I didn’t get to experiment with these dynamics too thoroughly. Regardless, I still feel comfortable claiming that the dynamics were very similar, though I felt that the normally harsh waves on the nitrous come up were somewhat more euphoric in the case of xenon.
Later on, me and Ethan compared our experiences, and he confirmed with me that he too found the xenon to be mostly the same as nitrous – aside from the slightly more comfortable come up. I remain unsure whether the purity or quality of common head shop nitrous could account for this difference in harshness. Raj also predicts that the difference will be more pronounced if using a rebreather. If so, I’d want to test the rebreather with nitrous as well.
As with nitrous, I didn’t have to wait long for everything to settle out, and soon I was ready to go again. Here’s the transcript, from immediately afterwards:
Cube Flipper:Uhmmmm-hmmm.
Cube Flipper: Well the headfuck has the exact same flavour as nitrous.
Cube Flipper: Nitrous will take questions about epistemic uncertainty and basically mock you with them. I know that much.
Cube Flipper: That is not exactly what happened here. This is much weaker than that. I’ve had some pretty wacky times with nitrous and this is pretty basic by comparison. The question in this case is: is it possible to tell this apart from something else.
As I mentioned earlier, nitrous can do curious things to any emotions that one bring into the experience. I’ll do my best to explain the nitrous headspace, which I feel is very similar to xenon’s.
My archetypal nitrous experience is as follows. If my mood is harbouring an ironic bent, this may unfold thematically into a general feeling that I’m being pranked in some fashion. At the extrema, this is like the feeling of being the butt of some great cosmic joke, a joke which oscillates horrendously between the highest and lowest octaves of joke-space as I experience its every incarnation from the most sophisticated to the most lowbrow and droll – a joke whose punchline forever remains obscure.
Nothing so intense happened here, but the xenon was certainly doing strange things with my lingering feelings of uncertainty from the first trip – can we really tell xenon apart from nitrous?
Afterwards, Raj discussed his xenon practice with me, reporting that he found the xenon headspace quite useful for doing Internal Family Systems work which wasn’t manageable sober. The impression I gathered was that he has figured out how to use the xenon to channel his emotions into a compassionate experience amenable to productive self-therapy. It actually sounded quite wholesome, compared to this trite cosmic joke attractor I’m prone to stumbling into myself.
When we compared notes, Ethan confirmed that he also found that the xenon headspace was similar to that of nitrous.
This felt like a reasonable place to wrap things up. I did not have any further conclusions to draw from this experience. It was Friday afternoon, and there was a party to go to – and so we went our mutual ways.
This is the section of the review where what I normally do is challenge myself to put what I understand of the pharmacology next to what I understand of the phenomenology and try to make some original claims about how the two relate to one another.
This time around I’m not sure quite what to say. Given the phenomenological similarities we observed between xenon and nitrous oxide, I’d be very surprised if whatever they might be doing wasn’t also very similar – be it classical or quantum. However, there wasn’t anything about this experience which bore even an aesthetic resemblance to quantum effects like superposition – as is sometimes reported with 5-MeO-DMT – not that pure aesthetics necessarily tells you anything about the physical or ontological status of the waves in question. At the very least, I think what I felt could easily be described using simple nonlinear wave dynamics, similar to those discussed in the electrostatic brain post:
Simulation of low and high frequency electromagnetic waves in a variable-permittivity medium, created by Bijan Fakhri for qri.org. These bear an aesthetic similarity to the somatic waves I experienced on xenon and nitrous oxide, though there are significant qualitative differences I’d need more time to analyse.
My default assumption is that set and setting effects could be partially accountable for xenon’s euphoric reputation. Nitrous is cheap, often regarded as a low-class drug, and is frequently consumed in casual or social settings. By comparison, xenon is expensive, and carries the kind of elite status that I expect inclines its users towards treating it with the kind of reverence normally reserved for other exotic substances like DMT.
I’d expect that taking a high level of care and intention with one’s xenon experience could lead to significantly more euphoria than one would expect from your average nitrous session, but with similar practices it might be possible to achieve a comparable level of euphoria using nitrous oxide at a fraction of the cost.
However, any further claims I’d like to make about their similarities are directly contradicted by the one questionnaire study I was able to find comparing their subjective effects. From The effects of subanaesthetic concentrations of xenon in volunteers (Bedi et al., 2002):
Individual subjects’ visual analogue scores (mm) for the subjective sensations shown, just before loss of response to verbal command, when breathing either xenon or nitrous oxide. (n = 10 in the xenon group. n = 9 in the nitrous oxide group).
All subjects reported a subjective difference between study agents, with eight subjects stating a preference for xenon; one was indifferent to each gas and one subject felt less well following administration of xenon.
Subjects reported feeling significantly drowsier, more pleasant, less nauseous and safer breathing xenon than nitrous oxide (p = 0.016, 0.04, 0.008 and 0.016, respectively).
The fact that participants reported feeling notably safer while using xenon seems particularly noteworthy in the context of Raj’s xenon-assisted therapy experimentation.
Now, it’s possible that relative dosage is a factor here – how does one decide what an equivalent dose of xenon and nitrous oxide are? In this study, the questionnaire results were taken from right before the following condition was met:
When the subject no longer responded to a loud verbal command, i.e. when the responsive component of the Observer’s Assessment of Alertness/Sedation score changed from 3 to 2, the circuit was flushed with oxygen and the subject was allowed to awaken.
I’m not sure how this should compare with a four litre xenon or nitrous balloon, so it’s likely that the recreational doses we used were quite different, and that the divergent phenomenology only becomes pronounced at a higher dosage. Raj seemed confident that we’d find more interesting phenomenology if using a rebreather – but until we can try this, my conservative recommendation is that anyone who wants to give xenon special attention should take as their null hypothesis the prospect that it might not be so special after all.
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