How do depressed rats respond to psychedelics? New data offer insight into the human experience
Despite tricky regulations, research evaluating the antidepressant potential of psychedelics in humans is mushrooming — and the FDA has already approved a nasal spray concoction of the cat tranquilizer ketamine for patients whose depression persists despite conventional therapy.
But scientists still don’t quite fully understand the antidepressant impact of psychedelics on the brain — are the effects purely biological or psychological? A new study looks into the degree and duration of antidepressant effects induced by these drugs — largely branded by governments as illegal hedonistic compounds with no therapeutic potential — in an animal model.
“You really can’t take the brain of a patient and grind it up and extract the genes and look at gene expression and see what’s changed in that brain — the best we have right now is imaging. But that’s still just a window into the black box — to get into the black box, we actually need the brain tissue to be able to analyze,” said Charles Nichols, the director of the study and professor of pharmacology at Louisiana State University (LSU).
“But to get that we have to have a model where the drug works and nobody had yet been able to recapitulate the long term effects or even antidepressants effects to a really convincing level in an animal model.”
Nichols, the son of longtime psychedelic research proponent David Nichols, has been studying the effects of psychedelics in the brain for nearly 25 years. In this study, Nichols and his team compared the impact of a one-time dose of psilocybin (the psychoactive ingredient in magic mushrooms), lysergic acid diethylamide (LSD, or acid as it is fondly known), and ketamine in a rat model for depression.
There are already emerging data suggesting the beneficial effects of psychedelics in humans — apart from the FDA-approved ketamine product, psilocybin is being tested as an antidepressant in a range of trials. Recently, a psychedelic research center was opened at Johns Hopkins.
Data from Nichols’ study — the first direct preclinical comparison of the antidepressant efficacy of ketamine and other psychedelics — showed that both psilocybin and LSD significantly reduces depressive-like behaviors five weeks after a single administration in rats, while only the lowest dose of ketamine evaluated (5 mg/kg) was efficacious in decreasing depressive-like behaviors. In addition, the associated antidepressant-like effects of ketamine were transient compared to psilocybin and LSD-treated rats — and lasted less than two weeks.
“Because there’s so much political discussion tied up into the research, it’s great…this can be a much more data, evidence-based progress towards psychedelic therapies as opposed to a more political grassroots piece,” said Ronan Levy, executive chairman of Toronto-based company Field Trip Psychedelics that is opening up clinics to deliver psychedelic-based psychotherapy.
A WINDOW TO NEW COPING STRATEGIES
In order to see how the “depressed’ rats reacted to the psychedelic compounds, the animals were first put through what is commonly known as a ‘forced swim test’ to measure if they were depressed.
“The short story is you throw them in a bucket of water,” said Meghan Hibicke, the study’s lead author and postdoctoral researcher at LSU Health Sciences Center, Pharmacology and Experimental Therapeutics.
“You see how much they swim versus how much they float. And then you can measure that behavior — so that’s the planning and the passive coping strategy that can be kind of comparable to a depressed person in bed.”
Depressed people find it difficult to get up and brush their teeth — daily functioning is really hard and active, problem-solving is arduous, she said.
“So basically, what makes humans feel bad, makes a rat float, and what makes a human feel better, makes a rat swim … they are just different measures of passive versus active coping strategies — like getting shocked and freezing when you’re human would be a passive coping strategy versus running around and trying to get away.”
Conversely, if you give rats antidepressant medications that have been shown to be effective in humans, the same rats will start to behave more normally. They’ll start swimming in the water and exhibit food-seeking behaviors, Nichols added.
While conducting the study, Nichols and Hibicke were cautious in choosing the doses of the trifecta of psychedelic compounds, relying on literature reviews and consultations with David Nichols to hone in on optimal doses. “If you use too much, the rat is going to be basically super-stoned and it’s not going to be able to perform. And if you don’t use enough, you might not hit a therapeutic level,” Nichols said.
The study findings were significant on two levels. The researchers first accomplished their primary goal of generating a rodent experimental system that could be used to study the molecular, cellular effects with psilocybin as an antidepressant.
“So we now have an animal model, where psilocybin has long-lasting effects after a single dose and we can go and take the (rat) brains out and begin to ask questions on how is it (the drug) changing the brain to do this,” Nichols said.
The second goal was broader — gathering insight into whether the therapeutic benefit is purely psychological or biological.
“What our results have shown is that it’s really kind of neither — that at its core the antidepressant effects are biological because the rat doesn’t really have the existential angst — the same reasons for depression that a human would have. But what we did find was that we could shape the antidepressant effect by the environment that the rat was placed in after the treatment,” Nichols said.
What the rats encountered during their first week after their psychedelic experience either reinforces a coping strategy that was already there, or it taught them a new coping strategy.
“So it seems like psilocybin at least is opening this kind of window where a new coping strategy is learnable which would be really really helpful for people who are suffering from chronic life problems like depression and anxiety and stress and drug addiction or gambling addiction — where there’s a period of time in which, after their psychedelic experience, they can learn a new way to behave under old circumstances or under challenging circumstances,” Hibicke said.
IMPLICATIONS FOR INDUSTRY
What does this mean for the explosion of companies and researchers looking into the therapeutic potential of different psychedelic compounds for a range of conditions?
“Being able to combine our digital health capabilities with the new insights into the biological mechanisms, giving rise to antidepressant-like effects will enhance our ability to identify why some patients may respond better to psilocybin or LSD versus ketamine…further justifying reimbursement for care,” said Shlomi Raz, the chief of Eleusis Benefit Corporation, which sponsored Nichols’ study.
“When you can make predictions that have a high degree of accuracy, the whole perspective on the use of these otherwise costly therapies will begin to change.”
For ATAI Life Sciences — an umbrella entity that is behind companies such as Compass Pathways (which currently has a mid-stage treatment-resistant depression study testing a psilocybin compound) and Perception Neuroscience (which took its ketamine derivative into clinical trials last year) — the study adds more robust evidence supporting the therapeutic use of psychedelics.
Previously, the animal models were largely in mice, Srinivas Rao, ATAI’s chief scientific officer noted. “With rats, you’re just going up the evolutionary ladder a little bit,” he said. “Rats have much more complex behavior than mice — it’s just more brain there.”