A newly studied synthetic psychedelic compound promotes rapid structural growth of brain cells and reverses depressive behavior in rodents. The drug, known as 25C-NBF, appears to lack the addictive properties and sensory disturbances 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 worldwide. Symptoms range from persistent low mood to severe loss of interest in daily life. Many conventional treatments provide insufficient symptom relief and can take weeks or months to become effective. This delay in onset has led researchers to explore alternative options, such as psychedelics, which may change the brain more quickly.
Psychedelics have received attention because of their potential to act as psychoplastogens. These are substances that can rapidly change the physical structure of brain cells. In people with depression, parts of the brain involved in regulating mood often lose synaptic connections, the communication points between neurons.
Psychedelic compounds are broadly classified into different chemical classes. Tryptamines, such as psilocybin and dimethyltryptamine, occur naturally in some plants and fungi. Phenethylamines include synthetic compounds such as mescaline analogs and the 2C series of drugs. Some synthetic phenethylamines induce strong antidepressant effects but are associated with recreational abuse and a high risk of heart disease.
Pharmacologist Nuria Nadal Gratakos of the University of Barcelona and her colleagues began a study to determine whether small changes to these chemical structures would change 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 the therapeutic benefits could be maintained without causing addictive behavior.
First, the researchers conducted experiments on cells grown in the lab to observe how three variations of the NBF compound interacted with serotonin receptors. Serotonin is a chemical messenger in the brain involved in regulating mood. Its 2A receptors are the main targets that produce the hallucinogenic effects of hallucinogens.
The research team observed that these compounds tightly bound to serotonin 2A receptors. At the same time, these chemicals showed very low interaction with serotonin 2B receptors. This detail is noteworthy because previous studies have linked long-term activation of 2B receptors by drugs to heart valve damage.
When analyzing the serotonin 2A receptor, researchers looked at how the drug activates various internal cellular pathways. Receptors can direct signals down multiple pathways, a concept known as biased agonism. The research team found that the NBF compound activated the receptor in a balanced manner and behaved very similarly to natural serotonin.
The scientists then conducted tests on male mice and rats to observe the drug’s physical and behavioral effects. Administration of NBF compounds to mice elicited a moderate head twitch response. This rapid side-to-side head movement is a standard marker used in animal models to measure how strong a drug causes hallucinations in humans. Head twitches were less frequent than those induced by more potent hallucinogens, suggesting a relatively mild hallucinogenic effect.
The researchers also subjected the mice to a sensory processing test using a startle reflex measurement tool called prepulse inhibition. In this test, a quiet tone is immediately followed by a loud tone. Usually, quiet sounds stimulate the brain, causing a small startle response to loud sounds.
Hallucinogens often interfere with this sensory gating function. This means that the brain becomes overwhelmed with environmental stimuli and is unable to block out surrounding noise. Mice treated with NBF compounds exhibited normal startle reflexes and no signs of sensory overload. Animals also exhibited normal locomotor patterns and exploratory behavior within the test enclosure.
The main element of the study was to assess whether the drug was addictive. The researchers used a standard behavioral test in which mice were allowed to choose between two chambers. One chamber was pre-combined with drugs and the other chamber was combined with neutral saline. The mice did not spend any extra time in the drug-combined room, indicating that the substance was not a reward for the mice.
In another experiment, rats were placed in special cages and trained to press a retractable lever to self-administer methamphetamine, a highly addictive stimulant. Once the rats learned the behavior, the researchers replaced the stimulant with an NBF compound. The animals immediately stopped pressing the lever. This behavioral extinction mirrors what happens when the drug is replaced with harmless saline.
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 facilitate drug abuse and reinforce addictive habits. Because those spikes were absent, researchers characterized these drugs as having low addictive potential.
After these safety assessments, the researchers focused specifically on one variation of the drug, called 25C-NBF, and tested its ability to change brain cells. They applied various concentrations of chemicals to primary mouse neurons grown in laboratory dishes. After 24 hours, cells were observed under a microscope using fluorescent markers.
Treated neurons quickly sprout new dendritic branches, acting like tiny antennas that receive signals from other cells. The highest dose of drug generated the highest number of new branches and increased the total length of cell outgrowth. The drug also caused increased production of brain-derived neurotrophic factor, an important protein that supports neuron survival and growth.
The researchers then administered the drug to live mice and examined their brain tissue one day later. They found an increased number of dendritic spines in the prefrontal cortex and hippocampus. Both of these brain regions play key roles in emotional regulation and memory, and both are typically impaired by prolonged stress.
Finally, the researchers sought to find out whether these cellular changes resulted in measurable improvements in mood. They used two different methods to stress the mice. One group was placed in a physical restraint tube for 5 hours. The other group was injected with corticosterone, a stress hormone known to cause depression in animals, for 21 days.
After the stress period, mice received a single dose of 25C-NBF. Within 24 h, restrained mice were evaluated using the tail suspension test. For this step, suspend the mouse temporarily by its tail. Typically, stressed and depressed mice quickly give up, become immobile, and exhibit desperate behavior.
Mice that received the experimental treatment showed increased effort and mobility, and struggled against restraint without giving up. This positive response lasted up to a week after taking exactly one dose of the drug. The treated group outperformed untreated stressed mice on these behavioral assessments over multiple test days.
Mice receiving chronic hormone injections were given a sugar water preference test to measure their ability to experience pleasure. Initially, the stressed mice preferred plain water to sweets and were generally uninterested in pleasant foods. One day after receiving the experimental drug, the mice regained their preference for sugar water.
Although this finding points to the possibility of a fast-acting treatment option, the researchers noted several limitations to the current study. This study included only male rodents, so the findings cannot be fully generalized to female subjects. Future studies should include both sexes to determine whether biological responses differ.
The scientific team plans to continue testing to find the optimal dosing schedule. They want to investigate exactly how drugs cause structural changes in the brain and map out the precise cellular pathways. They also want to find out whether antidepressant effects can be achieved at doses low enough to avoid psychedelic experiences altogether.
“The psychedelic phenethylamine 25C-NBF, a selective 5-HT2A agonist, exhibits psychodysgenic properties and rapid antidepressant effects in male rodents,” the study was conducted by Núria Nadal-Gratacós, Pol Puigseslloses, Laura Guzmán, Nicola Weiss, Eline Rittie, Claire-Colo, Poera, Virgen Written by. Lardou, Nathalie Tillier, Fuhua Wang, Liselotte Kersten, Irene Pérez Esteban, Gabriel Quetzela, Joel Margal, Xavier Versosa, David Pubil, Marta Rodríguez Arias, Mirén Echet, Jan Kehr, Christophe Staub, Marcello Solinas, Elvedo, Halvedo, Raulescu. López-Arnau.
