Recent research published in journals neuropharmacology provide evidence that a single dose of the psychedelic compound N,N-dimethyltryptamine can produce rapid and long-lasting antidepressant effects in mice. This study suggests that this naturally occurring psychedelic drug may reduce anxiety and may offer potential benefits compared to existing fast-acting treatments such as S-ketamine. These findings highlight the potential of psychedelic compounds as future treatments for severe and treatment-resistant mental health conditions.
Major depressive disorder is a widespread mental illness that affects millions of people worldwide. Standard treatments usually take several weeks to become effective, leaving patients vulnerable during the waiting period. Approximately one-third of these people do not respond to conventional drug therapy and are diagnosed with treatment-resistant depression.
In recent years, medical professionals have sought immediate alternatives to help these patients. Ketamine was originally used as an anesthetic, but is now attracting attention as a highly effective antidepressant. A specific version of this drug, known as S-ketamine, is currently approved as a nasal spray for treatment-resistant depression.
At the same time, scientists are renewing their interest in serotonergic psychedelics, 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 a variety of plants and animals. Clinical trials in human patients suggest that inhaling or injecting DMT can safely reduce symptoms of depression.
Despite these promising clinical results, researchers lacked comprehensive laboratory data directly comparing DMT to existing fast-acting drugs such as S-ketamine. Scientists conducted this study to evaluate the behavioral effects of DMT on S-ketamine in a control animal model. They aimed to establish exactly how long DMT’s effects last and whether it further reduces anxiety.
“Current antidepressants often take several weeks to achieve clinical improvement, which is 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 side effects and potential for abuse,” said study author Elaine Gavioli, professor of pharmacology at the Federal University of Rio Grande Norte.
“Although N,N-dimethyltryptamine (DMT) has recently received attention as a potential fast-acting antidepressant, preclinical evidence comparing its efficacy to established fast-acting treatments remains limited. We investigated and compared the antidepressant- and anxiolytic-like effects of DMT and S-ketamine in a preclinical model, with the aim of better understanding how the proposed compounds perform compared to already established fast-acting treatments.”
The researchers used male Swiss mice. The Swiss mouse is a widely used breed of laboratory white mouse known for its diverse genetics, helping researchers better mimic the natural biological variation found in human populations. They started with a sample of 136 mice and subjected them to unpredictable and unavoidable foot shocks over two days. The procedure is designed to induce a state called learned helplessness, where the animal stops trying to avoid stressful situations.
Learned helplessness is a standard scientific model used to mimic the core symptoms of human depression, such as lack of motivation and behavioral hopelessness. Of the original group, 75 mice exhibited this helpless behavior. The researchers then divided these 75 mice into different housing and treatment groups.
Some mice were housed in groups, while others were housed individually to see how social isolation affected treatment. Animals received a single injection of either saline placebo, S-ketamine, or DMT. The researchers used precise doses, administering S-ketamine at 10 or 30 milligrams per kilogram of body weight and DMT at 10 or 25 milligrams per kilogram of body weight.
After the injection, the scientists conducted a series of behavioral assessments on the mice. To measure despair behavior, they used the tail-hanging test. This records how quickly mice stop struggling when held upside down by their tails. To assess a condition called anhedonia, the inability to feel pleasure, researchers gave mice a choice between regular water and sweetened sucrose water.
Healthy mice naturally prefer sweet water, but depressed mice tend to prefer sweet water. The scientists also tested anxiety-like behaviors using an elevated plus maze and open field arena. The researchers recorded exactly how the animals moved, explored, and reacted to new environments over eight days.
Analysis revealed that both S-ketamine and DMT were successful in reversing learned helplessness behavior in group-housed mice. Just 24 hours after receiving either drug, these animals regained their willingness to escape mild foot shock. In mice housed alone, neither drug restored the immediate withdrawal reflex, suggesting that its specific restoration required the presence of the other mouse.
The isolated mice still received other important benefits from drug therapy. Both S-ketamine and DMT completely prevented loss of interest in sweetened water 5 days after injection. This result provides evidence that both substances effectively treat anhedonia and restore normal reward-seeking behavior in animals.
Tail suspension testing highlighted several differences between the two drugs over time. A 30-milligram dose of S-ketamine reduced behavioral hopelessness 28 hours after injection, but this effect was not sustained. DMT at a dose of 10 milligrams produced much longer lasting effects. DMT-treated mice continued to struggle and attempt to escape during the tail suspension test for 8 days after a single injection.
DMT also showed unique benefits in anxiety tests. Five days after treatment, mice receiving DMT spent significantly more time exploring the exposed open arms of the elevated maze. Mice typically avoid open, high places unless their anxiety levels are fairly low.
“An interesting finding was that the behavioral effects after a single dose of DMT were long-lasting, lasting at least eight days,” Gavioli told PsyPost. “This suggests that DMT may cause more long-lasting neurobiological changes.”
S-ketamine failed to increase exploration of these open areas in experimental animals. This observation suggests that DMT acts as an anxiolytic, meaning that it actively reduces anxiety. S-ketamine did not exhibit these anxiolytic properties in this particular stress model.
The researchers noted that both drugs caused a short-term decrease in movement immediately after injection. This temporary sedative effect disappeared within 1 hour after the animals received the treatment.
“Our findings suggest that DMT may produce rapid antidepressant- and anxiolytic-like effects in animal models of depression,” Gavioli said. “This supports the search for new, fast-acting antidepressant treatments beyond traditional options. However, these findings are based on animal studies and require further research before considering clinical application in humans.”
“The effects we observed were strong in a well-established animal model of depression and appeared after a single dose, which is particularly relevant for a fast-acting treatment. However, these findings are still preliminary. Although they can help guide future research, they do not yet translate directly into clinical use.”
Although these animal studies provide strong evidence for DMT’s therapeutic potential, scientists found some limitations to the study. Only male mice were used in this study, primarily because certain models of learned helplessness have historically been difficult to reproduce in female Swiss mice. Investigating how female animals respond to DMT remains a necessary step for future research.
Due to technical problems with the video equipment, the researchers were unable to count the frequency of the mice’s head twitches. In rodent studies, head twitches are commonly used as a physical marker of hallucinatory experiences. Because this data was missing, the research team could not determine whether the intensity of the psychedelic experience correlated with the degree of depression relief.
Understanding exactly how DMT interacts with serotonin receptors could ultimately help medical professionals design new treatments for stress-related disorders. A deeper understanding of these processes may even allow scientists to develop drugs that provide the psychological benefits of psychedelics without the intense hallucinations.
“It is important to emphasize that these findings do not support recreational use of DMT or unsupervised use of DMT,” Gavioli noted. “These results come from controlled preclinical studies in animals using carefully defined doses, and effects observed in animal models do not necessarily translate directly to humans. Further studies are needed to assess safety, efficacy, and appropriate use in humans. Our laboratory is currently studying the biological mechanisms underlying these effects. Additionally, we are investigating the antidepressant effects of DMT in various animal models of depression and in men and women.”
The study, “N,N-dimethyltryptamine elicits antidepressant and anxiolytic effects in asthenic 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, and Bruno Lobão-Soares. Sergio Luschi Silva, Nicole L. Galván-Coelho, Fernanda Parajano-Fontes, Draulio Barros de Araujo, Edilson Dantas da Silva Jr., Elaine C. Gavioli.
