As interest in psychedelics grows for treating mental health conditions, researchers are now exploring whether these compounds may also help manage obesity. A recent animal study from Monash University offers compelling preliminary evidence that psilocybin, the active compound in “magic mushrooms,” might help support weight loss when combined with dietary interventions.[1]*
Unlike traditional weight loss drugs that suppress appetite or increase metabolism, psilocybin may work by changing how the brain processes food-related cues. The new research on mice suggests the compound doesn’t directly reduce food intake or boost energy expenditure. Instead, it increases the brain’s susceptibility to change, making it potentially easier to lose weight through diet*.
What is psilocybin?
Psilocybin is a naturally occurring psychedelic found in ‘magic mushrooms.’ Once ingested, it’s converted into psilocin, which activates serotonin receptors in the brain, particularly the 5-HT2A subtype.
These receptors affect mood, perception, and cognition. But more recently, researchers uncovered that psychedelics like psilocybin also promote neuroplasticity—the growth of new neural connections and dendritic spines. This kind of brain remodeling could be critical for reversing some entrenched behaviors and biological processes that sustain obesity.
Obesity and the brain's "set point"
Obesity isn’t only about willpower or diet. Long-term obesity can cause persistent changes in brain circuits, particularly in areas involved in hunger, reward, and self-control. These structural shifts may lock the body into a higher weight “set point,” making it harder to lose and keep it off, even with intense lifestyle changes.
Diets often fail not because people aren’t trying, but because the brain actively resists change. Signals in the hypothalamus ramp up hunger and reduce energy use, nudging the body back toward its previous weight. This study explores whether psilocybin can help break that cycle by reopening a period of neural flexibility.
The study: Psilocybin in obese mice
The researchers tested the effects of a single psilocybin dose (1 mg/kg) on diet-induced obese (DIO) mice. After 16 to 20 weeks on a high-fat diet, the mice were either kept on the same diet or switched to a lower-fat chow—an approach meant to simulate human dieting efforts.
Some mice received psilocybin, while others received saline as a control. Over 28 days, researchers tracked body weight, food intake, energy use, and even synaptic changes in the brain using advanced imaging tools.
What they found: Not a magic weight loss drug
Psilocybin did not directly lead to weight loss in obese mice who remained on the high-fat diet. These mice continued to gain weight at the same rate as those that received saline. That’s an important finding: psilocybin alone isn’t an appetite suppressant, nor does it increase calorie burn.
However, the results changed dramatically in mice switched to the lower-fat diet. Among these animals, those treated with psilocybin were significantly more likely to experience pronounced weight loss. Psilocybin-treated mice were about 2.5 times more likely to lose more than 13% of their body weight compared to those who received saline.
This effect wasn't due to increased metabolism. Calorimetry measurements showed no difference in oxygen use, carbon dioxide output, or energy expenditure. The key difference appeared to be behavioral—psilocybin-treated mice who lost more weight also consumed fewer calories and had reduced feeding efficiency during the diet phase.
Psilocybin seems to make dieting "work better"
The authors suggest that psilocybin’s ability to enhance neuroplasticity may make the brain more adaptable or suggestible during lifestyle changes. Psilocybin could help reset the neural circuits involved in hunger and reward, making it easier for dieting efforts to take effect.
Interestingly, these effects only emerged after two weeks on the new diet. That delay aligns with what researchers know about psilocybin’s action on synaptic plasticity: the peak in new dendritic spine growth occurs around 7 days post-injection. It may persist for up to a month.
This suggests that combining psilocybin with a sustained diet could capitalize on a “window of plasticity” where the brain is more responsive to behavior change.
No changes in brain synaptic markers
Despite the promising behavioral data, researchers found no significant changes in synaptic markers (synapsin-1 or PSD-95) in key brain areas like the prefrontal cortex or hypothalamus 30 days after treatment. That doesn’t necessarily rule out structural changes, but it suggests they may be transient or require more sensitive imaging techniques to detect.
Worth noting is that the mice in this study were not observed in real time during the critical window of neural remodeling—future studies may need to examine changes closer to the 7-day peak.
Why this research matters
Obesity is notoriously difficult to treat, especially in people who have been overweight for many years. Most commercial diets fail over time; even bariatric surgery isn’t always a permanent fix. That’s because the brain, not just the body, adapts to maintain a higher weight.
Psilocybin may offer a way to disrupt this homeostatic defense by temporarily increasing the brain’s flexibility. By making the brain more responsive to new routines, the compound could act as a cognitive amplifier, not replacing diet but enhancing its effectiveness.
These findings echo other early research into psilocybin for smoking cessation and alcohol use disorder, where the drug seems to enable behavioral change rather than directly causing it.
What psilocybin won't do
The study makes clear what psilocybin won’t do:
- Suppress appetite (like GLP-1 drugs such as Ozempic)
- Prevent weight regain when high-calorie foods are reintroduced regularly
- Affect metabolism or calorie burning
- Work without dietary change
In other words, it’s not a psychedelic version of Ozempic or phentermine. It helps some people get more out of the lifestyle changes they’re already attempting, especially people who struggle with emotional eating or food addiction-like patterns.
The bottom line
This new study doesn’t position psilocybin as a standalone treatment for obesity. But it does offer a promising new direction: using psychedelics to enhance brain flexibility and help people respond more effectively to behavioral interventions like diet and exercise.
By supporting deeper neural change, psilocybin may help the brain “let go” of the patterns that make weight loss so hard to sustain. While more research is needed, especially in humans, the findings suggest that psychedelics could one day play a role as an adjunct therapy for chronic obesity.
As always, these results should be interpreted cautiously. The study was conducted in mice, not people, and no peer-reviewed human trials have yet confirmed similar effects. But the idea is worth exploring, especially given the overlap between obesity, mental health, and entrenched behavioral habits.
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