A newly studied synthetic psychedelic compound promotes rapid structural growth in brain cells and reverses depressive behaviors in rodents. The drug, known as 25C-NBF, appears to lack the addictive qualities and sensory disruptions associated with similar recreational substances. These results were recently published in the journal Molecular Psychiatry.
Depression is a widespread mental health condition that affects millions of people globally. Symptoms range from persistent low mood to a profound loss of interest in daily activities. Many conventional treatments provide inadequate relief and require weeks or months to begin working. This delayed onset has driven researchers to explore alternative options, including psychedelic drugs that might change the brain much faster.
Psychedelics are gaining attention because they can act as psychoplastogens. These are substances capable of rapidly altering the physical structure of brain cells. In people with depression, parts of the brain associated with mood regulation often lose synaptic connections, which are the communication points between neurons.
Psychedelic compounds are broadly categorized into different chemical classes. Tryptamines, such as psilocybin and dimethyltryptamine, naturally occur in some plants and fungi. Phenethylamines include synthetic compounds like mescaline analogs and the 2C series of drugs. While some synthetic phenethylamines induce strong antidepressant effects, they carry a high risk of recreational abuse and heart problems.
Núria Nadal-Gratacós, a pharmacologist at the University of Barcelona, and her colleagues initiated a study to determine if a slight modification to these chemical structures might alter their safety profile. They focused on specific chemical analogs known as NBF compounds. The research team sought to evaluate the biological effects to see if they retain therapeutic benefits without triggering addictive behaviors.
To begin with, the researchers conducted experiments on laboratory-grown cells to observe how three variations of the NBF compound interact with serotonin receptors. Serotonin is a chemical messenger in the brain involved in mood regulation. Its 2A receptor is the primary target that produces a psychedelic drug’s hallucinogenic effects.
The team observed that the compounds bound tightly to the serotonin 2A receptor. At the same time, the chemicals showed very low interaction with the serotonin 2B receptor. This detail is notable because long-term activation of the 2B receptor by medications has been linked to heart valve damage in previous studies.
When analyzing the serotonin 2A receptor, the researchers looked at how the drug activated different internal cellular pathways. Receptors can direct signals down multiple routes, a concept known as biased agonism. The team found that the NBF compounds activated the receptor in a balanced way, behaving very similarly to natural serotonin.
The scientists next conducted tests on male mice and rats to observe the physical and behavioral effects of the drugs. When administered to mice, the NBF compounds caused a moderate head-twitch response. This rapid, side-to-side head movement is a standard marker used in animal models to gauge how strongly a drug might cause hallucinations in humans. The head twitches were less frequent than those induced by more potent psychedelics, suggesting a relatively mild hallucinogenic effect.
The researchers also subjected the mice to sensory processing tests using a startle reflex measurement tool called prepulse inhibition. In this test, a quiet sound is quickly followed by a loud noise. Usually, the quiet sound primes the brain, causing a smaller startle reaction to the loud noise.
Often, hallucinogenic drugs disrupt this sensory gating ability, meaning the brain becomes overwhelmed by environmental stimuli and cannot block out the ambient noise. The mice treated with the NBF compounds exhibited normal startle reflexes and no signs of sensory overload. The animals also showed normal walking patterns and exploratory behavior inside their test enclosures.
A major component of the study was evaluating whether the drugs are addictive. The researchers used a standard behavioral test where mice were allowed to choose between two chambers. One chamber was previously paired with the drug, and the other with a neutral saline solution. The mice did not spend extra time in the drug-paired chamber, indicating the substance was not rewarding to them.
In another experiment, rats were placed in specialized cages and trained to self-administer methamphetamine, a highly addictive stimulant, by pressing a retractable lever. Once the rats learned the behavior, the researchers replaced the stimulant with an NBF compound. The animals quickly stopped pressing the lever. This behavioral extinction mirrors what happens when a drug is replaced with a harmless saline solution.
Additionally, brain scans using a microscopic probe revealed that the drug did not increase dopamine levels in the animals’ nucleus accumbens. Dopamine spikes in this brain region drive substance abuse and reinforce addictive habits. Because those spikes were absent, the researchers characterized the drugs as having a low potential for addiction.
Following these safety evaluations, the investigators focused specifically on one variation of the drug, called 25C-NBF, to test its ability to alter brain cells. They applied the chemical in varying concentrations to primary mouse neurons grown in laboratory dishes. After twenty-four hours, they observed the cells under a microscope using fluorescent markers.
The treated neurons quickly sprouted new dendritic branches, which act like tiny antennas receiving signals from other cells. The highest doses of the drug produced the highest number of new branches and increased the overall length of the cellular extensions. The drug also triggered an increase in the production of brain-derived neurotrophic factor, a vital protein that supports the survival and growth of neurons.
The researchers then administered the drug to live mice and examined their brain tissue a day later. They found an increased number of dendritic spines in the prefrontal cortex and the hippocampus. Both of these brain regions play major roles in emotional regulation and memory, and both are typically impaired by prolonged stress.
Finally, the researchers sought to find out if these cellular changes produced a tangible improvement in mood. They stressed the mice using two different methods. One group was placed in physical restraint tubes for five hours. The other group received twenty-one days of injections with corticosterone, a stress hormone known to induce depressive symptoms in animals.
Following the stress periods, the mice were given a single dose of 25C-NBF. Within twenty-four hours, the restrained mice were evaluated using a tail suspension test. In this procedure, mice are temporarily suspended by their tails. Typically, stressed and depressed mice give up quickly and hang motionless, indicating despair-like behavior.
The mice that received the experimental treatment exhibited increased effort and mobility, struggling against the restraint rather than giving up. This active response continued for up to a week after taking exactly one dose of the drug. The treated group outperformed the untreated stressed mice in these behavioral assessments across multiple testing days.
The mice subjected to chronic hormone injections were given a sugar water preference test to measure their capacity to experience pleasure. Initially, the stressed mice favored regular water over the sugary option, displaying a lack of interest in normally enjoyable things. One day after receiving the experimental drug, the mice regained their preference for the sugar water.
While the findings present a potential fast-acting treatment option, the researchers noted several limitations to their current work. The study only included male rodents, which prevents the findings from being completely generalized to female subjects. Future studies will need to include both sexes to determine if the biological responses differ.
The science team plans to continue testing to find the optimal dosing schedules. They want to explore exactly how the drug initiates structural changes in the brain and map out the exact cellular pathways. They also hope to find out if the antidepressant effect can be achieved at a dose low enough to avoid any hallucinogenic experiences entirely.
The study, “The psychedelic phenethylamine 25C-NBF, a selective 5-HT2A agonist, shows psychoplastogenic properties and rapid antidepressant effects in male rodents,” was authored by Núria Nadal-Gratacós, Pol Puigseslloses, Laura Guzmán, Nicola Weiss, Eline Pottie, Clara Riera-Colomer, Virginie Lardeux, Nathalie Thiriet, Fu-Hua Wang, Liselott Källsten, Irene Pérez-Esteban, Gabriel Ketsela, Joel Margall, Xavier Berzosa, David Pubill, Marta Rodríguez-Arias, Miren Ettcheto, Jan Kehr, Christophe Stove, Marcello Solinas, Harald H. Sitte, Elena Escubedo, and Raul López-Arnau.