A recent study published in the journal Neuropharmacology provides evidence that a single dose of the psychedelic compound N,N-dimethyltryptamine can produce rapid and long-lasting antidepressant effects in mice. The research suggests that this naturally occurring hallucinogen might also reduce anxiety, offering a potential advantage over existing fast-acting treatments like S-ketamine. These findings highlight the promise of psychedelic compounds as future therapies for severe, treatment-resistant mental health conditions.
Major depressive disorder is a widespread psychiatric condition that affects millions of people globally. Standard treatments typically take several weeks to begin working, leaving patients vulnerable during the waiting period. Approximately a third of these individuals do not respond to traditional medications, leading to a diagnosis of treatment-resistant depression.
In recent years, medical professionals have sought out faster-acting alternatives to help these patients. Ketamine, a medication originally used for anesthesia, has become a prominent rapid-acting antidepressant. A specific version of this drug, known as S-ketamine, is now an approved nasal spray for treatment-resistant depression.
At the same time, scientists have renewed their interest in serotonergic psychedelics, which are compounds that alter perception and mood by interacting with the brain’s serotonin system. N,N-dimethyltryptamine, commonly known as DMT, is a fast-acting hallucinogen found in various plants and animals. Clinical trials with human patients suggest that inhaling or injecting DMT can safely alleviate depressive symptoms.
Despite these promising clinical results, researchers lacked comprehensive laboratory data directly comparing DMT to existing fast-acting drugs like S-ketamine. The scientists conducted this study to evaluate the behavioral effects of DMT against S-ketamine in a controlled animal model. They aimed to establish exactly how long the benefits of DMT last and whether it provides any additional relief for anxiety.
“Current antidepressants often take weeks to produce clinical improvement, which represents a major limitation, especially for patients with severe symptoms. Rapid-acting antidepressants such as S-ketamine have shown promising results, but their clinical use is limited by adverse effects and potential for abuse,” said study author Elaine Gavioli, a professor of pharmacology at the Federal University of Rio Grande do Norte.
“As N,N-dimethyltryptamine (DMT) has recently gained attention as a potential rapid-acting antidepressant, preclinical evidence comparing its effects with established rapid-acting treatments remains limited. So, we investigated and compared the antidepressant- and anxiolytic-like effects of DMT and S-ketamine in a preclinical model, aiming to better understand how emerging compounds might perform relative to an already established rapid-acting treatment.”
The scientists utilized male Swiss mice, a widely used breed of white laboratory mouse known for having diverse genetics, which helps researchers better mimic the natural biological variations found in human populations. They started with a sample of 136 mice and exposed them to unpredictable, inescapable foot shocks over two days. This procedure is designed to induce a state called learned helplessness, a condition where animals stop trying to avoid stressful situations.
Learned helplessness is a standard scientific model used to mimic the core symptoms of human depression, such as a lack of motivation and behavioral despair. Out of the original group, 75 mice developed this helpless behavior. The researchers then divided these 75 mice into different housing situations and treatment groups.
Some mice were housed in groups, while others were housed individually to see how social isolation might affect the treatments. The animals received a single injection of either a saline placebo, S-ketamine, or DMT. The researchers used exact dosages, giving S-ketamine at either 10 or 30 milligrams per kilogram of body weight, and DMT at either 10 or 25 milligrams per kilogram.
Following the injections, the scientists put the mice through a series of behavioral assessments. To measure behavioral despair, they used a tail suspension test, which records how quickly a mouse stops struggling when held upside down by its tail. To evaluate a symptom called anhedonia, which is an inability to feel pleasure, they provided the mice with a choice between regular water and sweetened sucrose water.
Healthy mice naturally prefer the sweet water, but depressed mice tend to lose interest in it. The scientists also used an elevated plus-maze and an open field arena to test for anxiety-like behaviors. They recorded exactly how the animals moved, explored, and reacted to new environments over the course of eight days.
The analysis revealed that both S-ketamine and DMT successfully reversed the learned helplessness behavior in the group-housed mice. Exactly 24 hours after receiving either drug, these animals regained the motivation to escape the mild foot shocks. In the single-housed mice, neither drug restored the immediate escape reflex, suggesting that the presence of other mice is necessary for that specific recovery.
The isolated mice still experienced other significant benefits from the medications. Both S-ketamine and DMT completely prevented the loss of interest in the sweetened water five days after the injection. This outcome provides evidence that both substances effectively treat anhedonia, restoring the animals’ normal reward-seeking behaviors.
The tail suspension test highlighted some differences between the two drugs over time. S-ketamine at the 30 milligram dosage reduced behavioral despair 28 hours after the injection, but this effect did not persist. DMT at the 10 milligram dosage produced a much longer-lasting benefit. The mice treated with DMT continued to struggle and try to escape during the tail suspension test up to eight days after receiving their single injection.
DMT also displayed unique benefits in the anxiety tests. Five days after the treatment, mice given DMT spent significantly more time exploring the exposed, open arms of the elevated maze. Mice typically avoid open, elevated spaces unless their anxiety levels are quite low.
“An interesting finding was the prolonged duration of behavioral effects following a single administration of DMT, which persisted for at least eight days,” Gavioli told PsyPost. “This suggests that DMT may trigger longer-lasting neurobiological changes.”
S-ketamine failed to increase the exploration of these open areas in the experimental animals. This observation suggests that DMT acts as an anxiolytic, meaning it actively reduces anxiety. S-ketamine did not display these anti-anxiety properties in this specific model of stress.
The researchers noted that both drugs caused a brief period of reduced movement immediately following the injection. This temporary sedative effect wore off within an hour of the animals receiving the treatment.
“Our findings suggest that DMT may produce rapid antidepressant- and anxiolytic-like effects in an animal model of depression,” Gavioli said. “This supports the search for new, faster-acting antidepressant treatments beyond traditional options. However, these findings are based on animal studies, and further research is needed before considering clinical applications in humans.”
“The effects we observed were robust in a well-established animal model of depression and appeared after a single dose, which is particularly relevant for fast-acting treatments. However, these findings are still preliminary. They help guide future research but do not yet translate directly into clinical use.”
While these animal tests provide strong evidence for the therapeutic potential of DMT, the scientists noted a few limitations in their work. The study exclusively used male mice, primarily because the specific learned helplessness model is historically difficult to replicate in female Swiss mice. Exploring how female animals respond to DMT remains a necessary step for future investigations.
Technical issues with video equipment prevented the researchers from counting the frequency of head twitches in the mice. In rodent studies, head twitches are typically used as a physical marker for a hallucinogenic experience. Because of this missing data, the team could not determine if the intensity of the psychedelic experience correlates with the degree of depression relief.
Understanding exactly how DMT interacts with serotonin receptors could eventually help medical professionals design new treatments for stress-related disorders. A deeper understanding of these processes might even allow scientists to create drugs that offer the emotional benefits of psychedelics without the intense hallucinations.
“It is important to emphasize that these findings do not support the recreational or unsupervised use of DMT,” Gavioli noted. “The results come from a controlled preclinical study in animals using carefully defined doses, and effects observed in animal models do not always translate directly to humans. Further research is needed to evaluate safety, effectiveness, and appropriate use in humans. Currently, our laboratory is investigating the biological mechanisms underlying these effects. Additionally, we are exploring the antidepressant effects of DMT in different animal models of depression and in both sexes.”
The study, “N,N-dimethyltryptamine elicits antidepressant and anxiolytic effects in helpless mice: a comparative study with S-ketamine,” was authored by Anne Nathalia de Sousa-Silva, Clarissa de Almeida Moura, Carina Ioná de Oliveira Torres, Vitória Barros Marques, Jayane M. do Nascimento Silva, Bruno Lobão-Soares, Sérgio Ruschi Silva, Nicole L. Galvão-Coelho, Fernanda Palhano-Fontes, Draulio Barros de Araújo, Edilson Dantas da Silva Jr., and Elaine C. Gavioli.
