Little-known psychedelic found to have a fascinating effect on cognitive flexibility after just a single dose

A new study published in Molecular Psychiatry has revealed that a single dose of the psychedelic drug 2,5-dimethoxy-4-iodoamphetamine (DOI) can lead to long-lasting changes in brain structure and cognitive flexibility in mice. The researchers found that mice treated with DOI became more attuned to previously overlooked cues, allowing them to learn more efficiently from their experiences. These effects appeared to depend on the timing of drug administration and the animals’ experiences after the treatment.

DOI is a synthetic psychedelic from the amphetamine class that acts primarily by activating serotonin receptors in the brain. It is known for inducing long-lasting alterations in perception and has been studied for its ability to promote neuroplasticity, or the brain’s ability to form new connections. But much of this work has focused on the short-term effects immediately following drug administration.

Less is known about how these structural changes in the brain translate into long-term behavioral adaptations, particularly in relation to cognitive flexibility, a key feature of mental health and well-being. Cognitive flexibility is the ability to adapt one’s thinking or behavior in response to new information or changing circumstances, and impairments in this ability are often linked to mental health disorders such as depression, anxiety, and obsessive-compulsive disorder.

“My research interests are about cognitive flexibility in general and its relationship to brain plasticity changes. Many neuropsychiatric conditions share a common symptom of cognitive rigidity, so I wanted to study how enhancing neuroplasticity could unlock a more flexible cognitive state to get a stuck brain unstuck. When I was writing my PhD proposal, the psychedelic hype was just starting to pick up and what attracted me was the idea that I can use these drugs as a tool to induce rapid and enduring neuroplasticity,” explained Merima Šabanović, a postdoctoral associate at the Department of Psychiatry at Weill Cornell Medicine.

“Serotonergic psychedelic compounds have recently emerged as promising treatments for various psychiatric conditions, although the underlying mechanisms remain unclear. It has been suggested that the ability of these compounds to rapidly promote the brain’s capacity to change its structure and function could be the catalyst for broad behavioral shifts, but evidence for a measurable cognitive change is lacking, especially over an extended period post-treatment.”

The study, conducted while Sabanovic was a PhD candidate at the University of Oxford, was carried out on young adult mice to assess the structural and cognitive effects of DOI. The researchers administered a single dose of DOI to the mice and then evaluated their behavior using a complex reversal learning task designed to measure cognitive flexibility. This task required the mice to adapt their behavior based on changing reward patterns, allowing the researchers to see how well the animals could learn from both positive and negative outcomes.

In addition to behavioral testing, the researchers performed brain imaging to assess changes in brain structure following DOI treatment. They used magnetic resonance imaging (MRI) to look for alterations in brain volume, focusing on regions associated with sensory processing and cognitive control. Brain samples were collected from the mice 24 to 36 hours after drug administration to capture the early structural changes, as well as several weeks later to investigate any long-term effects.

The researchers also varied the timing between the drug treatment and the testing to explore whether the post-drug experiences influenced the outcomes. In some cases, the mice were allowed to continue with the learning tasks in the days following the DOI treatment, while in other cases, they were barred from these tasks to see how a lack of post-drug experience would affect their cognitive flexibility.

Šabanović and her colleagues confirmed that a single dose of DOI led to measurable changes in brain structure within just one day. Specifically, they found significant increases in the volume of several brain regions, including sensory and association areas of the cortex, as well as subcortical structures involved in higher-order cognitive processes. These findings align with previous research showing that psychedelics promote rapid growth in dendritic spines and synaptic connections, both of which are markers of neuroplasticity.

However, the most interesting findings emerged when the researchers looked at how DOI affected the mice’s cognitive flexibility in the reversal learning task. Initially, the DOI-treated mice did not show any significant improvements in overall decision-making accuracy compared to the control group. But when the researchers introduced a novel challenge—a sudden change in the reward structure—the DOI-treated mice exhibited a unique learning strategy.

Unlike the control mice, which primarily learned from rewards, the DOI-treated mice began to learn from the absence of rewards, or “reward omissions.” This represents a shift in cognitive strategy, indicating heightened sensitivity to previously overlooked negative feedback.

The researchers also found that these cognitive effects were not immediate but developed over time. Mice that underwent the novel challenge one week after DOI treatment showed significant improvements in their ability to adapt to the new task structure, suggesting that the benefits of DOI on cognitive flexibility require time to manifest.

Interestingly, when the researchers tested the mice just one day after drug treatment, they did not observe these improvements, suggesting that the timing of the post-drug challenge plays a critical role in how the drug influences cognitive flexibility.

The study also showed that the experiences the mice had during the week following DOI treatment were crucial. Mice that were allowed to continue practicing the learning task during this period showed greater improvements in cognitive flexibility, while those that were barred from the task did not exhibit the same level of improvement. In fact, the latter group performed worse than the control group in some cases, suggesting that the cognitive benefits of DOI may depend on ongoing cognitive engagement after the drug is administered.

“In this study, we uncovered that a single moderate dose of psychedelic drug (±)-DOI has long-term effects on how adaptable the mice can be in a complex decision-making task,” Šabanović told PsyPost. “Strikingly, (±)-DOI caused a paradigm shift in the cognitive strategy such that the animals developed a new sensitivity to reward omissions never before seen in mice that we have tested on this task. Usually, the mice ignore the trials where they don’t get a reward, which would be like us learning only from the questions we got right on an exam, and completely ignoring the ones we got wrong. However, the mice that were injected with (±)-DOI beforehand were able to use these previously overlooked cues in the weeks after treatment and perform better at the task as a result.”

“Even though the underlying idea was simple – find the cognitive effects of a single psychedelic treatment days and weeks after the compound had left the system – the approach was risky as complex cognitive tasks in mice demand months of daily training and testing, with no guarantee of findings. We were testing healthy mice after all, there was no deficit to rescue, and mice are actually very good at the task to begin with. So, with there being only a small window for performance to change, we were surprised to see that a single dose of this drug could have such big and unique effects weeks after the treatment.”

“We got lucky in a way to have done our experiments in the order that we did, because we got the ‘good’ positive results first – the change in strategy, and the better adaptability with the one-week gap before the cognitive challenge,” Šabanović explained. “In hindsight, if we had gotten two rounds of negative results, we may have abandoned the project with me rushing to graduate in time. However, we still controlled our initial excitement about a positive result and approached those findings with caution.”

“Instead of jumping to what could be the next ‘big thing’ for the project, we wondered what else could explain our results, specifically whether the one-week gap between drug treatment and the novel challenge was the key. We zeroed in on rigorous, albeit very time-consuming controls to decipher what shaped the behavior we were seeing.”

“Then it turned out that 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,” Šabanović continued. “The crucial concept that kept being the subject of our discussions 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. 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).”

The fact that the cognitive benefits of DOI were only observed after a delay suggests that the full effects of psychedelics on cognitive flexibility may take time to develop. This raises questions about the optimal timing for therapeutic interventions involving psychedelics. Future studies could explore how different intervals between drug administration and cognitive challenges influence the outcomes.

“The link between the rapidly induced neuroplasticity and mood changes seen with psychedelics indeed deserves the attention that the research community has been spending on such studies,” Šabanović said. “But, other drugs can also induce such effects. 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. And while great work is being done studying spines and dendrites, receptors and synapses, the preclinical behaviors we are measuring to translate and study the mechanisms of the transformations observed in the clinic are still limited to short-term effects and reductive antidepressant tests.”

“As we marvel at these striking immediate post-treatment effects and navigate the psychedelic research field that is still young and changeable, have we been overlooking the critical phase when neuronal plasticity truly integrates into the brain and its directing of cognition and behavior? Our work suggests that enduring behavioral changes seem to unfold in a different rhythm, one that demands a greater understanding of downward plasticity and how the context in which these changes transpire shape the effects that we are seeing.”

The study, “Lasting dynamic effects of the psychedelic 2,5-dimethoxy-4-iodoamphetamine ((±)-DOI) on cognitive flexibility,” was authored by Merima Šabanović, Alberto Lazari, Marta Blanco-Pozo, Cristiana Tisca, Mohamed Tachrount, Aurea B. Martins-Bach, Jason P. Lerch, Mark E. Walton, and David M. Bannerman.