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Opinions | Do Mice Hallucinate? Do Humans Head-Twitch?

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In this opinions piece, Mario de la Fuente challenges us to put aside for one moment our anthropocentric assertion that “mice make bad humans” and instead adopt a more murine-centric perspective, in which we might look at psychedelic-induced yawning in humans as something akin to the head-twitch response seen among mice dosed with hallucinogens.

Do Mice Hallucinate?

The human-likeness of the mouse psychedelic experience

We can’t know if animals experience something akin to a psychedelic state, because we simply lack access to the content of their thoughts. Observing their behavior and interactions with the environment is all we can do, which leaves us plenty of latitude for fair speculation.

Mice and rats can identify a feeling, more precisely a distinct internal state, when under the effect of a serotonergic psychedelic. How closely it resembles what humans define as ‘tripping’ is unknown to us, but by differentially pressing levers an animal can inform us that what they were given felt like a psychedelic pulling a serotonergic trigger.

Having worked on psychedelics in mice for quite a few years now, people often wonder what the big deal is about the head twitch response. It works great for identifying psychedelics, but we don’t really know what it means. Head twitch might just be a reflex that psychedelics exacerbate, but could it also reflect an attempt to shake off the unpleasantness of having been administered a psychedelic drug against their will?

At moderate doses, mice under the influence do the usual: eat, sniff, fight, groom, move around. What’s unusual is the sudden transitions from one action to the next, and an apparent lack of continuity: they can initiate a grooming session and stop halfway to stare into infinity, gnaw pellets, suddenly lose interest in food and then start exploring with renewed heed any feature of the only cage they have ever known. To the eyes of the sober, the behavior of a fellow human under the effect of magic mushrooms might appear somewhat erratic, just like those dosed mice. At high doses of psychedelics, mice enter a contemplative state: awake and responsive, but without too much of an interest to engage with their surroundings – something akin to a heroic dose, perhaps?

We suspect our pets dream in their sleep, even if they never told us so. Us humans, meanwhile, can relinquish verbal communication, and yet an observer can pick on someone experiencing very penetrant hallucinations or distortion of perception by their behavior and reactions to the environment. Our capacity as observers makes us great abnormality-detectors, even when we cannot put our finger on what exactly is going on. But, in the case of laboratory animals, we know the cause of such abnormalities beforehand.

The psychedelic experience generators for both humans and mice–our brains–are built with the same blueprints and circuit components. This provides a less anthropomorphizing argument supporting a potential resemblance between the mouse and human psychedelic experience. The recursiveness of the micro- and macro-structures that make up the mammal brain enable the speculation that some degree of similitude could be expected when perturbed by the same psychoactive drug. This is true for stimulants as it is for anesthetics and could be the case for psychedelics as well. Note that while the case is made for a certain degree of resemblance in species with the privilege of a highly developed neocortex, the extent and quality is beyond our understanding.

Non-human mammals do not get to enjoy the paradox of using human language to elaborate on the ineffability of the psychedelic experience, but their cognitive capabilities should be susceptible to the high penetrance of psychedelics’ pharmacological action in whatever it is like to be them. The content and meaning of the psychedelic experience are bound to our capability to engage in abstract thinking, but an animal probably doesn’t need to be familiar with the concept of synesthesia to experience it.

Mice under the effect of psychedelics experience distorted perception; perhaps in modalities different from ours. As prey animals, their senses are tuned to stimuli relevant to their survival priorities. Only they can know what pandemonium of fractalized predators make their guest appearances in the psychedelic mouse show.


The mouse-likeness of the human psychedelic experience

“Mice make bad humans” is a common trope that illustrates quite well the irreconcilable differences between preclinical and clinical research–particularly in neuroscience. If we take a step back from this anthropocentric statement, the truth is that humans also make pretty bad mice.

Unlike mice, humans do not twitch their heads under the effect of psychedelics. But besides making us trip out of this world without moving, psychedelics do other mundane things to us: blood pressure increases, pupils dilate and we yawn. A lot, actually.

Self-reports all over the internet reveal that yawning is integral to the experience occasioned by classical serotonergic psychedelics. It manifests soon after dosing and often does so as an omen of what is about to unfold. The internet echo chambers are prone to perpetuating myths and self-fulfilled prophecies, but yawning is a measurable objective variable, and diligent scientists have confirmed that it is indeed a manifestation worth noting in psilocybin effects booklets (Griffiths et al. 2006, 2016, 2018).

Let’s abandon human solipsism for a minute and take a murine-centric perspective, could yawning be our form of “head twitching”?

Both are naturally present in either species going about their day, but their presentation is unmistakably exacerbated in a situation—having psychedelics in our system–that doesn’t make contextual sense. The yawning buildup is not associated with boredom or somnolence, but it’s there. Mice shake off their heads, although it is unclear what triggers this behavior or what they accomplish with it. We are just as clueless of the actual meaning of either manifestation, but both serve the same apparent purposelessness.

Yawning is not an effect exclusive of psychedelics, neither is head-twitch. We know of several other drugs that can trigger one, the other or both. So even in their limitations, both manifestations share similitude.

There are also some similarities regarding timing and relationship with dose. The larger the amount of the drug, the more frequent the human mouth gaping and the mouse head twitching; especially at the beginning of the trip. Yawning appears to have a premonitory quality as it precedes the peak experience with psilocybin. In mice, head twitching is also an early signature of a classical psychedelic drug’s effect.

What made the mouse head twitch response earn its notoriety is that it manifests as a consequence of the molecular mechanism that enables the psychedelic experience, and the fact that all classical psychedelics induce it. The relationship between human yawning and psychedelics has not been studied with the same systematic industriousness, but self-reports seem to point to a similar generalization: psychedelics users are yawners—in a literal sense.

Mario de la Fuente, PharmD, PhD, is a passionate psychedelic researcher and drug developer. Driven by a fascination for understanding how ordinary chemical matter can elicit such profound effects on the intangible subjective experience, Mario has immersed himself in the complex interaction between the chemistry and neuropharmacology of classic psychedelics and other enigmatic compounds for over a decade. This curiosity has yielded over 30 publications and inventions to this day. He is an Affiliate at the Virginia Commonwealth University and the founder of GONOGO, a consulting firm that supports drug development for neuroscience.