New research published in the Journal of Psychopharmacology has found that a single dose of psilocybin leads to widespread changes in gene expression for several neuropeptides in the rat hypothalamus, while ketamine has a more limited effect. The findings suggest that these psychedelics may influence systems involved in mood, appetite, and stress regulation through different molecular pathways in the brain.
Psilocybin and ketamine are both psychoactive substances being studied for their potential as fast-acting antidepressants. Psilocybin is found naturally in psychedelic mushrooms and is known for its effects on perception and consciousness, while ketamine is a synthetic drug originally developed as an anesthetic.
Psilocybin works by stimulating serotonin receptors in the brain, particularly a subtype known as 5-HT2A, which is involved in mood, cognition, and perception. Ketamine acts on a different system—it blocks a type of glutamate receptor called NMDA, which plays a role in learning, memory, and synaptic plasticity.
The new study was conducted by researchers at the Medical University of Silesia in Poland, Lancaster University in the UK, and the Polish Academy of Sciences. Their goal was to better understand how these psychedelics affect the hypothalamus, a region deep in the brain that controls many basic functions like hunger, temperature regulation, sleep, and emotional responses. The researchers focused on the expression of genes related to various neuropeptides—small protein-like molecules that help neurons communicate and regulate physiological states.
To explore this, the researchers used adult male Wistar–Han rats. The animals were housed in standard laboratory conditions and given either psilocybin or ketamine. Psilocybin was administered in two doses (2 mg/kg and 10 mg/kg), while ketamine was given at a dose of 10 mg/kg. Control animals received an injection of saline.
The drugs were administered just once. Seven days later, the animals were euthanized and their brains were dissected to extract the hypothalamus. The researchers then measured the levels of messenger RNA (mRNA)—the molecules that carry genetic instructions for protein production—for a range of neuropeptides and their receptors using a technique called real-time PCR.
The neuropeptides examined included both well-known and recently discovered molecules, such as nesfatin-1, phoenixin, spexin, neuromedin U, neuropeptide S, and 26RFa. These molecules are involved in processes such as hunger and satiety, stress responses, and emotional regulation. The team also measured expression of several serotonin receptors, which are thought to play a key role in the action of psilocybin.
The results showed that psilocybin, particularly at the higher 10 mg/kg dose, led to widespread changes in gene expression in the hypothalamus. Several neuropeptides and their receptors showed increased mRNA levels, including phoenixin, nesfatin-1 (through its precursor NUCB2), neuropeptide S, and the receptors GPR173, NPSR, and MC4R. These increases suggest enhanced activity in multiple neuropeptide signaling pathways.
Interestingly, psilocybin also significantly raised the expression of the serotonin receptors 5-HT1A, 5-HT2A, and 5-HT2B, but not 5-HT2C. This pattern points to selective engagement of serotonin receptor subtypes in the hypothalamus.
One notable exception was neuromedin U (NMU), which showed decreased expression following psilocybin treatment. NMU is known to suppress appetite, so its reduction may indicate a potential mechanism for appetite-promoting effects observed in some settings. The dual increase in both appetite-suppressing and appetite-stimulating neuropeptides highlights the complex and sometimes contradictory nature of psychedelic effects at the molecular level.
Ketamine, in contrast, produced a much smaller set of changes. It increased the expression of NUCB2, GPR173, and POMC, but did not affect most of the other neuropeptides or serotonin receptors. These limited changes may reflect ketamine’s different pharmacological profile and its main action on NMDA receptors rather than serotonin systems.
The researchers suggest that the effects of psilocybin on the hypothalamus may be linked to its potential therapeutic benefits for disorders like depression and anorexia. For instance, a recent clinical study found that a single dose of psilocybin helped reduce symptoms in women with anorexia nervosa, a condition often associated with abnormalities in appetite regulation and body image. Although this animal study does not directly model anorexia or depression, it raises the possibility that psilocybin could be altering brain circuits involved in food intake and emotional processing.
Still, the study also raises new questions. While changes in mRNA levels suggest shifts in gene activity, it is unclear how these changes affect protein production and actual neuropeptide function in the brain. The authors did not measure protein levels or behavioral outcomes in the rats, so the functional significance of the gene expression changes remains speculative. Follow-up studies using techniques like immunohistochemistry or behavioral assays would be needed to connect these molecular changes to actual effects on feeding behavior, mood, or stress responses.
The researchers also acknowledge limitations related to the use of rodent models. Although rats offer a controlled and well-studied system for examining brain mechanisms, they do not experience consciousness or self-awareness in the same way humans do. Disorders like anorexia involve complex cognitive and emotional disturbances, including distorted body image and compulsive behaviors, that are difficult or impossible to replicate in animals. As such, results from rodent studies must be interpreted with caution when trying to draw conclusions about human psychiatric conditions.
Another caveat is the relatively small number of animals used and the limited focus on gene expression rather than downstream protein or behavioral outcomes. Despite these constraints, the study provides a new starting point for exploring how psychedelic drugs may interact with deep brain regions like the hypothalamus, which have been less studied compared to cortical areas involved in perception and cognition.
Future research will need to examine whether the gene expression changes observed in this study lead to long-term shifts in behavior, hormone levels, or energy regulation. It will also be important to investigate how stress, social factors, or chronic exposure to psychedelics might interact with these molecular pathways. If supported by further evidence, this line of research could help explain how psychedelics influence appetite, mood, and physiological balance—and potentially inform new treatments for disorders involving disrupted homeostasis and emotional regulation.
The study, “Psilocybin and ketamine affect novel neuropeptides gene expression in the rat hypothalamus,” was authored by Artur Pałasz, Marta Pukowiec, Katarzyna Bogus, Aleksandra Suszka-Świtek, Łukasz Filipczyk, Kinga Mordecka-Chamera, John J Worthington, Maria Sygidus, Adam Wojtas, Agnieszka Bysiek, and Krystyna Gołembiowska.
