Mice on Acid

To get a legal hallucinogen to market, rodents need to take the first trip.

In the bowels of an animal research facility at Oxford University, mice are stirring in cages. Half of them have been given an injection of saline solution and behave like the docile house pet of your local fifth-grader. The other half have been given DOI, a drug chemically similar to LSD, and are, as the term of art would have it, tripping balls.

What exactly a mouse sees when she’s tripping on DOI—whether the plexiglass walls of her cage begin to melt, or whether the wood chips begin to crawl around like caterpillars—is tied up in the private mysteries of what it’s like to be a mouse. We can’t ask her directly, and, even if we did, her answer probably wouldn’t be of much help.

But the signals that the tectonic plates of a mouse’s reality are shifting beneath her feet are well-documented. Those are the signals that Merima Sabanovic, a neuroscience Ph.D. student at the University of Oxford, has been observing for the past year. The classic response is called, in the imaginative nomenclature of the neuroscientist, the “head-twitch.” What Sabanovic observes is the mouse moving her head from side to side with a certain scientifically telling aplomb. The other signal that the mouse has wandered through the doors of veridical perception into the realm of untethered conception is the “wet-shakes,” which is what your dog does on a summer day to dry off. When your paws extend mere centimeters from your body, there’s only so much somatic recourse you have to fend off the closing in of a foreign reality.

Mice experiments by Sabanovic and her supervisors, David Bannerman and Jason Lerch, are part of a new wave of research into the clinical uses of psychedelic drugs. Humans have been journeying into the hinterlands of psychedelic logic for centuries, primarily for purposes of ritual and other ordeals of cultural significance. Scientific research into the neurological effects of psychedelics began in the middle of last century but was waylaid by bad trips and anti-drug culture warriors. But in the past decade, labs in England and the United States have revived serious research into hallucinogenic drugs and shown they can be useful in treating clinical conditions like depression, disorders resulting from obsessive-compulsions and post-traumatic stress, or even the inevitable face-off between death and patients with terminal illness.

Clinically speaking, one of the ways to think about these conditions—OCD, PTSD, depression—is in terms of rigid behavior, Sabanovic says. Obsessive compulsions are rigid performances of the same behavior over and over again. PTSD is a kind of inflexible openness to intrusion ideas and memories. And depression is a rigid adherence to negative forecasts about the future. So one of the ways that psychedelics could have therapeutic benefits is loosening up these rigid behaviors and unlocking more cognitive flexibility.

Sabanovic and her lab mates are seeking to find long-term neurological effects that would lead to an increase in cognitive flexibility. They are trying to determine whether a psychedelic therapy might work like an antidepressant, particularly an SSRI like Prozac. SSRIs are designed to tune the serotonergic system to the right pitch. Serotonin is one of the brain’s primary neurotransmitters, and the warp and weft of the neural networks that deal in serotonin have an influence on the subjective sensation of well-being and our cognitive functioning in mental systems such as memory. Sabanovic explains that psychedelics are serotonin receptor agonists, with their specific role being to activate a receptor called 5-HT_2A, which mediates subjective experiences. A psychedelic drug upends typical communication among brain cells, the result of which, in perception and behavior, scientists are trying to map.

One big question for Sabanovic is “whether anatomical plasticity can persist weeks after the initial injection,” she says. “We’d like to know whether we can find evidence of long-term improvements in cognitive flexibility as a result of a single dose.” How do the tripping mice help? “The rodent model enables us to control variables which would be difficult or impossible to manipulate in human clinical setting, with things like prior drug exposure, and emotional and environmental context of drug injections,” she says. “If someone walks into a clinic, you don’t know what happened to them earlier that day. It could be anything. With mice, we can control that and study the exact after-effects and way they respond in the long term.”

Sabanovic’s most recent studies have looked at “set and setting.” This is the wisdom that the quality of a trip is affected by what’s going on around the person while she’s under the effect of the drug. When people report having a bad trip, it’s usually due to the negative influence of set and setting. “That’s what I’m trying to incorporate in my studies,” says Sabanovic. “If we manipulate the context, can we manipulate the sensitivity to the drug or its long-term effects?”

Most animal studies of psychedelics have failed to consider the animal’s context at all. In Sabanovic’s studies, the concrete way of measuring these effects is to look at whether “the degree of head twitches is different if you’re in a novel context versus a familiar one.” A drug trip is a disconcerting experience whether you’re a human or mouse, and so researchers might expect that shifting the environment mid-trip causes more subsequent head twitches in the mouse. This would imply a higher level of anxiety, modulated purely by changing the context and not the dosage of the drug. Based on Sabanovic’s preliminary results, this effect appears to hold.

Getting a hallucinogenic drug to market stirs a new brew of challenges. An animal model is needed to pave the way to drug approval. Federal drug administrations are looking for drug efficacy, a clear relation between how much of a drug you give a patient and the behavioral response you get. But the idea of drug efficacy for psychedelics is murky. In fact, the whole pipeline is inverted.

Most drugs work by exacting a neurological shift. Fluoxetine, alias Prozac, works by preventing serotonin from getting sucked back up by the receptors whose job it is to act as a serotonergic Hoover. If you choreograph this dance of neurotransmitters just right, you can mitigate the effects of depression. The potential clinical benefits of psychedelics don’t work by the same kind of mechanism. Their shift isn’t neurological. It’s experiential.

An example of this is the phenomenon of “ego disillusion” in humans. Post-trip, many people—at least those who have gone deep on the good stuff—report having experienced a disintegration of their sense of self. It is a state in which your subjective experience does not depend on a resolute “I” but just sort of becomes incorporated with the world as a whole. The center of gravity drops out from existence. Christof Koch, chief scientist of the Paul Allen Brain Institute in Seattle, recently told me about his own experience with ego disillusion.

“There was no more Christof,” Koch said. “There was just nothing left except this non-self experiencing this icy light of unbearable intensity, and this feeling of terror and ecstasy—both things really combined.” It’s a fundamentally positive experience for most people. It can be valuable indeed for terminally ill patients to experience the cessation of their own existence and feel that everything can seem fine afterward.

The puzzle is how to go to drug administrators and ask them to approve your drug, which, you believe, implodes the illusion of self in humans, based on a bunch of head-twitching, wet-shaking mice, staring up at the mesh sky of their enclosure like it’s a laser show. How would you even provide evidence of that in the brain? It’s not that this experience doesn’t have a neural basis. But you can’t go into the brain and pluck out the experience, just like you can’t identify the neural locus of a particular memory, Inception-style, even though a memory is a neural phenomenon.

For Sabanovic, the puzzle only has the edges in place so far. Perhaps there’s a yet-to-be-found piece, she says, that fills in the picture between the brains of rodents and the experience of humans. Either way, the clinical implications of understanding these experiential shifts, such as ego disillusion, are clear. “It’s hard to grasp what that experience is,” Sabanovic says. “But I think it forces us to shift away from that belief that there’s a drug—there’s a magic pill—that you take every day, and it’ll make you happy. It’ll make you healthy. And it forces us not to look at drug efficacy but rather experience efficacy.”

The problem is that drug administrations don’t speak the language of experience efficacy. They can only understand things in terms of their neurological basis. It’s the long-term deliverable in the vision of neuroscientists like Sabanovic to articulate how all this works in the brain. In the fullness of time, they want to show the FDA a link between drug doses, the tidal changes of neurotransmitters, and the resultant clinical outcomes. But in the meantime, the main thing they have to show is mice doing the waggle dance.

Cody Kommers is a Ph.D. student in experimental psychology at Oxford. He is the host of the Cognitive Revolution podcast. His last article for Nautilus was “We Are All Ancient Mapmakers.” @codykommers

Lead photocollage: Tasnuva Elahi. Original images: torook / Shutterstock; John Williams RUS / Shutterstock