Progress is impossible without change, and those who cannot change their minds cannot change anything. (George Bernard Shaw)

Welcome, fellow curious minds, to the backstage of psychedelic research! Today, let's dive deeper into the intricacies of our recent Molecular Psychiatry paper “Lasting dynamic effects of the psychedelic 2,5-dimethoxy-4-iodoamphetamine ((±)-DOI) on cognitive flexibility”, exploring the ideas that characterized our research journey.

The Psychedelic Hype

In 2019, as I crafted my PhD proposal, psychedelic science was heating its gears as preclinical research started catching up with the human neuroimaging that spearheaded the new psychedelic renaissance. Robin Carhart-Harris and David Nutt published their “tale of two receptors” review [1] two years before, proposing how psychedelics open a “window of plasticity,” increasing the brain’s capacity for change. The stage was set when David Olson’s lab published their report on structural and functional neuroplasticity changes induced by psychedelics [2], the first of many such findings replicable across laboratories and species. My interest lay in brain plasticity in general – curious about the symptoms of cognitive rigidity common to many neuropsychiatric conditions, I wanted to study how enhancing neuroplasticity could unlock a more flexible cognitive state to get a stuck brain unstuck and the allure of their rapid and enduring effects made psychedelics my tool of choice.

The Unseen Depths

The story begins with a paradox that is echoed through psychedelic literature. Rapidly induced neuroplasticity and mood changes indeed demanded close studies, but other drugs can also induce such effects (after all, ketamine was still in its heyday). What is unique to psychedelics is how long these effects last, for months and even years, translating to shifts in personality – something that other drugs very much fail to do. But while great work was being done on spines and dendrites, receptors and synapses, preclinical behaviors measured, aimed to translate and quantify the transformations observed in the clinic, were limited to short-term effects and reductive anti-depressant tests.

The idea was simple – find the cognitive effects of a single psychedelic treatment days and weeks after the compound had left the system. However, the approach was risky as complex cognitive tasks in mice demand weeks of daily training and testing, rain or shine, sick or healthy (the researcher, not the mouse, of course), with no guarantee of findings. We were testing healthy mice after all, there was no deficit to rescue, so there was only a small window for performance to change.

The Journey Begins

 In our first experiment, we aimed to maximize discovery potential by testing both learned and novel adaptability. After a single injection of the psychedelic (±)-DOI outside of the cognitive task, we continued testing the mice on the same set of rules for an additional week. (±)-DOI’s effect was limited: the drug group marginally outperformed the controls, but no significant improvement was noted compared to their pre-treatment performance. However, the groups diverged after a novel cognitive challenge. One week post-treatment, the task rules changed unexpectedly requiring the mice to re-learn the task. (±)-DOI-treated animals recovered their performance faster and uniquely shifted their strategy to include learning from reward omissions – something we and others have never before seen mice able to do in this task!

Unveiling the Plasticity Consolidation: Slow Science, Steady Progress 

The 'Aha!' moment struck when we embraced slow science. Controlling our initial excitement about a positive result and approaching our findings with caution, we wondered whether the one-week gap between drug treatment and the novel challenge was the key. In an era that glorifies swift breakthroughs, we opted for a deliberate, thorough investigation. We focused on rigorous, albeit very time-consuming controls to decipher what shaped the behavior we were seeing. What emerged was a more nuanced understanding of (±)-DOI’s cognitive effects.

The significant effect on novel adaptability did not manifest immediately after treatment, as effects were absent when we tested mice one day after the (±)-DOI injection, nor when the animals were barred from training between drug treatment and the novel rule reversal. The crucial concept that surfaced was consolidation — the slow process through which molecular and neuronal changes transform into enduring alterations in brain circuitry via a pruning process of “downward plasticity” directed by the environment [3]. Earlier cognitive studies of psychedelics focused on the acute or immediate post-acute phase when the drug either did nothing or made performance worse (not surprising considering the profound psychedelic effects on attention and sensory processing). In the excited rush to publish the immediate post-treatment effects, has the field overlooked the critical phase when neuronal plasticity truly integrates into networks directing complex cognition?

The Missing Link

While the field marvels at the immediacy of molecular shifts, enduring behavioral changes seem to unfold in a different rhythm, one that demands patience and a keen eye for the subtle nuances of integration. The time and energy lengthy behavioral experiments require can put a strain on the most motivated researchers, especially if one is plagued by the sense of not doing enough. As a graduate student, I would not have time to delve into causal studies using neural recordings and more technical manipulations –  the experiments that are all the rage when proving oneself in science. Our journey wasn't the flashiest, nor did it race against the clock. Instead, it unfolded at its own pace, revealing the delicate dance between underlying neuronal plasticity processes and the context in which enduring behavioral changes transpire. As we continue to navigate this still-young field, let's remember that sometimes, the most profound discoveries emerge not in the frenzy of the immediate, but in the patient embrace of the slow, steady dance of science.

Works cited

1. Carhart-Harris, R. L., & Nutt, D. J. (2017). Serotonin and brain function: a tale of two receptors. Journal of psychopharmacology, 31(9), 1091-1120.

2. Ly, C., Greb, A. C., Cameron, L. P., Wong, J. M., Barragan, E. V., Wilson, P. C., ... & Olson, D. E. (2018). Psychedelics promote structural and functional neural plasticity. Cell reports, 23(11), 3170-3182.

3. Diniz, C. R. A. F., & Crestani, A. P. (2023). The times they are a-changin’: a proposal on how brain flexibility goes beyond the obvious to include the concepts of “upward” and “downward” to neuroplasticity. Molecular Psychiatry, 28(3), 977-992.

Author note: Poster image was created with the assistance of DALL·E 2.