Single DMT dose treats stress-induced depression more effectively than Prozac in mice

Leão and Lima da Cruz performing a DMT purification procedure. Credit: Lima da Cruz et al.

Psychedelics are psychoactive substances that trigger unusual mental states, also referred to as “trips,” altering the perceptions, thoughts, and emotions of those taking them and typically inducing hallucinations. Over the past few decades, some mental health researchers have been investigating the possible benefits of these substances for the treatment of various psychiatric disorders, particularly major depressive disorder (MDD).

MDD is the most severe form of depression, characterized by persistent and intense feelings of sadness and hopelessness, disrupted sleep or eating patterns, and a loss of interest in daily activities. MDD is currently treated primarily with antidepressants, such as selective serotonin re-uptake inhibitors (SSRIs), pharmaceutical drugs that block the reabsorption of the neurotransmitter serotonin into nerve cells.

Researchers at the Brain Institute (ICe) of Universidade Federal do Rio Grande do Norte recently carried out a study involving mice aimed at evaluating the possible antidepressant effects of the psychedelic compound N,N-dimethyltryptamine (DMT), which is extracted from various plants found in the Amazon forest in South America and in other tropical regions.

This study was performed in collaboration with Thiago C. Moulin’s group at the Department of Pharmaceutical Biosciences of Uppsala University in Sweden.

The team’s findings, published in Translational Psychiatry, showed that a single dose of DMT was more effective in treating depression-like symptoms in mice than 30 days of treatment with a commonly prescribed SSRI.

“The current landscape of psychedelic research is characterized by a rush to clinical trials, often moving forward before we have a profound understanding of the underlying cellular mechanisms,” Richardson N. Leão, senior author of the paper, told Medical Xpress.

“This mirrors the history of classic antidepressants like SSRIs, which were widely adopted despite significant gaps in our knowledge of how they function at the cellular level.

“Furthermore, most animal research on N,N-dimethyltryptamine (DMT) has relied on models primarily focused on anxiety. While these studies are valuable, they often fail to capture the complex behavioral and cognitive disruptions, such as anhedonia (the inability to feel pleasure) and cognitive deficits, that are hallmark symptoms of MDD.”

“Jurema” samples, the DMT source in Ayahuasca found in Brazil. Credit: Lima da Cruz et al.

Testing the effects of DMT on a mouse model of depression

Leão’s lab at Universidade Federal do Rio Grande do Norte has been investigating the effects of psychedelics on the brain at a cellular level for over a decade now. A key goal of his recent study was to systematically evaluate the effects of pure DMT on a mouse model of depression, known as the unpredictable chronic mild stress (UCMS) paradigm.

“We also wanted to explore how DMT affects the birth and integration of new neurons in the hippocampus, testing the ‘neurogenic hypothesis’ of depression,” said Rafael Lima, leading author and postdoctoral fellow researcher at Brain Institute.

“Another key question in the field is whether the ‘awake psychedelic experience’ (the ‘trip’) is necessary for therapeutic effects. We sought to provide initial evidence by testing if DMT remains effective when administered under anesthesia. By addressing these questions, we hope to provide a more stable scientific foundation for the development of fast-acting, next-generation antidepressants.”

To assess the effects of DMT on the brain and behavior of mice, the researchers used a combination of behavioral tests and cellular tracking techniques. The tests they performed primarily focused on two symptoms of depression, namely a loss of pleasure (anhedonia) and cognitive decline.

“We didn’t just look at simple anxiety; we used the UCMS protocol,” explained Leão. “For eight weeks, mice were exposed to various mild but frustrating stressors—such as changing their light cycles, tilting their cages, or dampening their bedding—at unpredictable times. This accurately replicates the persistent ‘wear and tear’ that leads to depression in humans.”

This prolonged exposure to mild stressors ultimately led to the emergence of some behaviors that closely resemble those observed in humans diagnosed with MDD. Once the animals started showing the first signs of depression, the researchers administered a single dose (30 mg/kg) of pure DMT.

Other mice were administered either a placebo pill or the SSRI fluoxetine, commonly known by the brand name Prozac, daily for a period of 30 days. To evaluate the effects of the three interventions, the researchers performed a series of tests, namely a reward, memory maze, and an anesthesia test.

“As part of the reward test, we gave the mice a choice between plain water and sugar water,” explained Leão. “Depressed mice typically lose interest in the ‘treat,’ but we measured if DMT could restore their natural drive to seek out pleasure. Secondly, we tested the mice in a memory maze. Using a radial arm maze, we tested ‘pattern separation’—the ability to distinguish between similar locations. This is a high-level brain function that often fails during depression.”

The third test carried out by the researchers, dubbed the anesthesia test, was aimed at determining whether DMT could still ease stress-induced depression in mice if it was administered while the animals were under general anesthesia, specifically isoflurane. This means that the mice would be unconscious and would not experience a “psychedelic trip” and the altered perceptions associated with it.

“A part of our study involved a ‘genetic tagging’ system (DCX-Cre),” said Leão. “This allowed us to literally light up new neurons born in the hippocampus, the brain’s center for mood and memory, under a microscope. We counted these new neurons and looked at where they went.

“Stress often causes new neurons to get ‘lost’ and plug into the wrong circuits in an aberrant manner that will ultimately lead to apoptosis, wasting the resources and time invested in those new neurons.”

To investigate the effects of DMT at a cellular level, the researchers used high-resolution imaging techniques. These techniques allowed them to determine whether DMT guided new cells to properly integrate brain circuits, essentially prompting the brain to create new connections.

Main results of the team’s experiments

Interestingly, the researchers found that a single dose of DMT reversed several symptoms of depression in the examined mice. Notably, the psychedelic compound was found to be more effective than a 30-day course of fluoxetine in alleviating anhedonia and cognitive impairments.

“Beyond just ‘creating’ new neurons, our study is the first to show that DMT actively reduces ectopic integration,” said Leão. “This means it helps adult born neurons from the dentate gyrus to plug into the correct ‘slots’ in the hippocampal circuit, allowing the system to exert behavior flexibility which will ultimately reduce the detrimental effects of chronic stress.”

The findings collected by Leão and his colleagues also suggest that the timing of psychedelic treatments matters greatly. Specifically, DMT appeared to prevent mood-related symptoms if administered during exposure to stressors, but only improved cognitive function if the mice received it after the stress-inducing protocol had concluded.

“Perhaps most provocatively, our findings suggest that the behavioral and cellular benefits of DMT persist under anesthesia, albeit in an attenuated form,” said Lima.

“While these results warrant cautious interpretation, they provide preclinical evidence that therapeutic ‘repair’ may be driven by underlying molecular changes rather than being exclusively dependent on the conscious psychedelic experience. However, the observed attenuation of these effects—as evidenced by the reduced effect size—suggests that while subjective effects may not be strictly necessary for DMT’s benefits, they likely potentiate them.”

The initial results gathered by this research team suggest that DMT could be a promising fast-acting therapeutic intervention for depression that prompts the repair of neural circuits. However, more animal studies and human clinical trials will need to be performed to ascertain its safety and therapeutic value.

“This could be a game changer for patients with treatment-resistant depression who cannot wait weeks for traditional medications to take effect,” said Leão.

“Moreover, cognitive fog often persists in human patients even after their mood improves. Our research highlights DMT’s potential to specifically address these cognitive deficits, which are crucial for a patient’s full functional recovery and return to daily life.”

Future research avenues

This recent study offers new valuable insight that could inform further psychedelic-related research. While it shows that one dose of DMT improves depression-like symptoms in mice, it also highlights the role of timing in the effectiveness of interventions.

“Our findings provide crucial evidence that the neuroplasticity window reopened by psychedelics does not inherently promote symptom remission,” explained Lima.

“If the subject remains under the influence of chronic stress, newborn neurons may integrate into stress-related circuits. Rather than ameliorating cognitive deficits, this may reinforce detrimental behaviors. Consequently, while ‘next-generation’ medicines offer significant brain-repairing potential, clinicians must carefully consider the environmental milieu and the timing of the intervention.”

Leão and his colleagues are now planning further studies aimed at assessing the therapeutic potential of psychedelics. Among other things, they are developing new technology that would allow them to detect “hallucinatory-like” behavior in mice or other animals, without using invasive sensors or neural markers.

“Currently, identifying a ‘trip’ in a rodent relies on proxy behaviors like the head-twitch response, which can be inconsistent,” said Leão.

“We are now working on advanced, noninvasive behavioral tracking systems to identify these states more accurately, which will help us definitively determine if the subjective experience is necessary for therapeutic brain repair.”

The researchers are also trying to devise clinically relevant strategies to administer psychedelics without relying on injections. As part of this line of research, they will try to determine whether administering the drugs in specific ways could maximize the repair of brain circuits while minimizing potential side effects.

“We are also working on the development of more relevant psychiatric models that go beyond the emulation of single DSM symptoms applying endophenotypes,” said Leão.

“Rather than looking at ‘depression’ as a single block, we are focusing on specific biological markers (endophenotypes) that bridge the gap between genes and behavior. Finally, we are developing protocols to study rodents in enriched, seminaturalistic environments.”

So far, most psychedelic research has been conducted on mice that are locked in cages within a laboratory setting. Yet these environments can be stressful for the animals and they also pose limits on the natural behaviors they can exhibit.

“By observing how DMT affects social interaction, exploration, and complex problem-solving in a more natural setting, we could get a much clearer picture of its true potential for human functional recovery,” added Leão.

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