A new study in rats suggests that three classic psychedelics, psilocybin, LSD, and 2C-B, produce distinct patterns of brain energy use, both immediately and a week after a single dose. The findings, published in Nature Communications, challenge the common practice of treating these drugs as interchangeable, though the authors stress that any implications for treating specific mental health conditions remain speculative.
Scientists classify psilocybin, LSD, and 2C-B as serotonergic psychedelics because they all bind to the serotonin 2A receptor, a specific protein on the surface of brain cells whose activation is linked to the altered states psychedelics produce. Because they share this primary target, these drugs are often grouped together as potential treatments for mental health conditions like depression and anxiety.
But their chemical structures differ, and they interact with other brain receptors in distinct ways. A 2023 review argued that while these drugs all stimulate the serotonin 2A receptor, their varying interactions with other biological targets could allow them to affect the brain quite differently.
To map these effects, researchers often track how the brain consumes energy. Brain cells use glucose, a simple sugar, for fuel, so measuring where glucose goes can reveal which brain areas are highly active and which are quiet. A 1997 study in humans used this technique, called positron emission tomography or PET, to show that psilocybin increased activity in the frontal cortex.
The research team was led by Mikael Palner, an associate professor at the University of Southern Denmark and head of the Palner Lab, alongside first author Frederik Gudmundsen, now a postdoctoral researcher at Aarhus University Hospital. “This was the idea of Frederik Gudmundsen, who was a PhD student in my lab at the time,” Palner told PsyPost. “After discussing it back and forth a lot and seeing that many papers and researchers were combining these psychedelic drugs into one bucket we knew we had to test the hypothesis, that serotonergic psychedelics are not just one drug class, but quite distinct drugs.”
The researchers wanted to see if psilocybin, LSD, and 2C-B produce similar or different metabolic patterns over time. They focused specifically on two interconnected webs of brain regions. The first is a network linking the outer layer of the brain to deep structures that regulate movement, habits, and compulsive behaviors. The second is a system spanning memory and emotion centers that is involved in fear and anxiety.
Understanding how different drugs alter these networks could provide a biological map for matching specific psychedelics to specific psychiatric disorders. In related work, a study covered by PsyPost in 2026 found that a single dose of psilocybin reduced depression-like behavior in rats for up to 12 weeks, alongside lasting increases in the excitability of prefrontal brain cells.
To test the effects of the three drugs, the researchers divided 48 rats into four groups of 12. Three groups received a single injection of either psilocybin, LSD, or 2C-B, while the fourth group received a saline injection as a control. The researchers gave the rats doses of psilocybin (1 milligram per kilogram), LSD (0.3), and 2C-B (3). In a separate group of nine rats, they confirmed that these doses occupied 51 to 70 percent of serotonin 2A receptors, a level associated with intense psychedelic effects in humans.
Finding the right dose to mimic the human experience yielded an unexpected result. “We compared three different drugs that are often used in humans: LSD, 2C-B and psilocybin,” Palner explained. “One thing was a big surprise and that is how much LSD we need to give a rat per body weight compared to a human.”
Scaled up by body weight, the rat dose would equal about 200 times a typical human dose. “The dose of LSD is 0.3 mg/kg in the rat; in a 70 kg human that’s 21 mg LSD (a regular dose is 0.1 mg),” he continued. “We don’t know why, but the rat has several protective mechanisms towards neurotoxins that may play a role.”
“The dose issue above is a common flaw in animal research with psychedelics and other neuropharmacological drugs for that matter,” Palner added. “One can’t just extrapolate the dose per kg and give the same to a rodent. We need to measure target effects and estimate the correct dose to translate between rodents and humans.”
Each rat underwent three PET scans: a baseline scan before receiving any drugs, an acute scan shortly after the injection, and a long-term scan one week later. During each scan, the rats were injected with the radioactive glucose tracer and allowed to remain awake in their cages for 45 minutes while their brains absorbed the fuel.
Afterward, they were temporarily anesthetized and placed in a PET scanner for 35 minutes to image the tracer’s distribution. The researchers also examined how strongly activity levels in pairs of brain regions tended to rise and fall together across the rats in each group, a rough indicator of how those regions work together.
Because all three psychedelics reduced overall glucose tracer uptake across the brain, which the authors suspect may partly reflect reduced blood flow, the researchers mathematically adjusted the data to look at relative changes. They calculated how much glucose each specific brain region absorbed compared to the rest of the brain. This adjustment allowed them to spot localized spikes or drops in activity relative to the animal’s global brain metabolism.
The acute scans showed that each drug produced a distinct metabolic signature. Psilocybin led to a relative increase in energy use in the dorsal striatum, a deep brain structure involved in habit formation, as well as in the insula, an area linked to emotional processing and bodily awareness. Unlike the 1997 human study, the researchers found no psilocybin-related changes in frontal regions in rats, and a possible strengthening of the link between two frontal areas did not hold up after statistical correction.
In contrast, LSD was associated with widespread decreases in metabolism across the outer layer of the brain, alongside increased activity in the midbrain and emotional centers like the amygdala and hypothalamus. 2C-B shared some features with LSD, including decreased frontal cortex activity and increased activity in midbrain areas that produce dopamine, a chemical messenger linked to reward and motivation, but its midbrain increase was larger and formed a distinct hotspot in a whole-brain analysis. 2C-B and psilocybin both increased activity in the insula.
A week after the single injection, the immediate spikes and drops had mostly faded, but some distinct network changes remained. Psilocybin left a lasting trace of increased metabolism in the insula and strengthened the link between activity in the insula and the prefrontal cortex, the only such network change in the study that held up after statistical correction. Psilocybin and LSD, but not 2C-B, also showed modest lasting decreases across several cortical, limbic, and midbrain areas.
For LSD, most acute metabolic changes had faded by one week, and a possible change in coordination between the cortex and the striatum did not hold up after statistical correction. The drug 2C-B left lasting effects primarily in dopamine-producing midbrain regions, without the sustained cortical effects seen with the other two drugs.
The authors offer what they describe as purely speculative ideas about therapeutic matching. Given their effects on the insula, psilocybin and 2C-B might suit disorders involving anxiety or disturbed bodily awareness; psilocybin’s tentative effects on links involving the orbitofrontal cortex, a frontal region, might make it suited to impulse-control conditions such as obsessive-compulsive disorder; and LSD’s effects on circuits linking the midbrain and striatum might suit substance use disorders. Overall, the results point to drug-specific brain responses rather than a single, universal psychedelic effect.
“Understand that just because one psychedelic drug is reported to do something to your mental health, it’s not necessary that others do the same,” Palner emphasized. “I think with the increased focus and ease of legislation this will be really important to understand.”
“I hope this is taken further and we will see that the right drug is given to the right patients,” he continued. “Whether it’s LSD or psilocybin for depression or anxiety. We need to do the comparison at some point.”
In earlier work, Palner’s lab found that repeated low doses of psilocybin made rats more resilient to stress and reduced compulsive behavior. “We are especially interested in dose reduction and finding the right drug, as our prior experiments with psilocybin microdosing were also interesting,” Palner noted.
As with all research, there are a few things to keep in mind. Because the measurements were relative to each brain’s overall average, an apparent increase in one region could partly reflect decreases elsewhere. Each drug’s effects were also measured against the same rats’ own baseline scans; the paper does not report statistical tests comparing the drugs directly with one another. And the drugs occupied somewhat different shares of serotonin 2A receptors (51 to 70 percent), so some differences could reflect intensity rather than drug identity.
The study was also small, with 11 or 12 rats per group, and most of the network changes did not survive correction for multiple comparisons. “This is a small study, yet still significant, meaning that the distinct effects are quite robust, otherwise they would drown in noise,” Palner noted. “With rodent work we must balance ethics and significance and justify how many subjects we included.”
Finally, the study was conducted in healthy rats, and no behavior was measured, meaning the links to specific mental health conditions cannot be directly tested here. The emotional and psychological experiences of a psychedelic trip cannot be measured in animals, so the behavioral impact of these metabolic changes remains a topic for future study.
“This was a huge team effort and so many talented young researchers were involved,” Palner said. “I really want to thank them for their time in my lab and wish them all the best in their next adventure.”
Palner disclosed owning shares in Compass Pathways and ATAI, companies developing psychedelic treatments.
The study, “Serotonergic psychedelics induce distinct patterns of metabolic activity and covariance within biologically informed rat brain networks,” was authored by Frederik Gudmundsen, Julia Czurylo, Daniel R. Rijsketic, Camilla Trang Vo, Janika Fortunato, Naja S. Jessen, Sophie Woodruff, Christina Baun, Matthias M. Herth, Vladimir Shalgunov, Boris D. Heifets, Patrick M. Fisher, and Mikael Palner.
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