New Study: Microdoses Of Psilocybin Can Reverse Obesity, Fatty Liver, And Diabetes At The Cellular Level

While everyone’s been focused on heroic doses for consciousness expansion and mental health, researchers just discovered that tiny, imperceptible amounts of psilocybin (aka microdoses) might be the metabolic intervention we’ve been searching for.

And the evidence is stacking up fast.

Published in Pharmacological Research this month, researchers led by Sara De Martin from the University of Padova investigated whether psilocybin has cellular metabolic effects, if it can improve ageing markers throughout the body, and what happens when you give incredibly low doses to animals with metabolic disease.

The researchers gave mice with diet-induced metabolic syndrome just 0.05 mg/kg of psilocybin for 12 weeks straight. These aren’t psychedelic doses so the mice weren’t tripping.

The mice in this study were fed a high-fat/high-fructose diet – basically the rodent equivalent of processed junk food every day. As you’d expect, these mice developed a full metabolic breakdown: obesity, fatty liver disease, type 2 diabetes, insulin resistance, and muscle weakness. The Western lifestyle in a mouse, if you will.

Then they gave them psilocybin.

The treated mice experienced near-complete metabolic reversal.

Body weight gain was significantly reduced, despite eating the same bad diet as the control group. Their livers, which had become fatty and inflamed, normalised. Under the microscope, you could actually see the fat droplets disappearing from liver cells.

Blood sugar levels that had been dangerously high dropped back to normal ranges. Insulin resistance (a hallmark of metabolic disfunction) was slashed by nearly 70%. And perhaps most fascinating, their muscles got stronger and maintained their function, even while remaining on this terrible diet.

Everyone knows psilocybin works primarily through the 5-HT2A serotonin receptor in your brain. That’s what causes the psychedelic effects, the visual distortions, and the profound insights.

But these researchers discovered that psilocybin’s metabolic benefits don’t come from 5-HT2A at all. Instead, they come from a different receptor called 5-HT2B. And surprisingly, psilocybin acts as an antagonist at this receptor. It blocks it.

To prove this, the team used CRISPR gene editing to knock out the 5-HT2A receptor in liver cells. Psilocybin still worked. Then they tested a selective 5-HT2B blocker, and it produced identical anti-steatotic effects. The conclusion was that this is a completely different mechanism from psilocybin’s psychedelic action.

This is huge because it means you can potentially get profound metabolic benefits without any central nervous system effects. No hallucinations or supervision needed.

Let’s zoom into what’s actually happening in the liver. The researchers used cutting-edge techniques called transcriptomics and lipidomics – essentially reading out every gene being expressed and every fat molecule present in liver tissue.

The high-fat diet had completely scrambled the liver’s metabolic programming. Genes involved in fat storage were cranked up. Genes responsible for glucose metabolism were disregulated. The liver had essentially shifted into a pathological state where it was hoarding fat and losing its ability to manage energy properly.

Remarkably, psilocybin reversed nearly all of this. Gene expression patterns normalised. The researchers identified 185 different lipid species that were significantly altered by treatment, with most returning to healthy levels.

Particularly interesting were the ceramides and diacylglycerols, which are lipid molecules known to directly interfere with insulin signalling. These dropped dramatically with psilocybin treatment. One gene that stood out was Cidea, which promotes the formation and growth of fat droplets in liver cells. Psilocybin strongly downregulated this gene, consistent with the dramatic reduction in liver fat they observed.

Here’s where we start to see how psilocybin works as truly holistic intervention. The researchers noticed something peculiar: genes related to leptin signalling were being restored by psilocybin treatment, both in the liver and in skeletal muscle.

Leptin is one of those hormones that doesn’t get enough attention in mainstream health discussions, but it’s absolutely critical. Produced by your fat cells, leptin is supposed to tell your brain when you have enough energy stored and should stop eating. It also plays crucial roles in muscle function and metabolic regulation.

The problem is that in obesity and metabolic disease, you develop leptin resistance. Your body is screaming that it has plenty of energy stored, but the signal isn’t getting through. It’s like your metabolic thermostat is broken.

What this study suggests is that psilocybin might be restoring leptin sensitivity. This could explain not just the improvements in liver fat and insulin resistance, but also the remarkable preservation of muscle function they observed. In the muscle tissue, genes involved in energy metabolism, mitochondrial function, and muscle growth were all normalised by psilocybin treatment.

The muscle findings deserve special attention because metabolic diseases don’t just make you fat or diabetic. They make you weak. The medical term is dysmetabolic sarcopenia, and it describes the loss of muscle mass and function that accompanies metabolic dysfunction.

In this study, mice on the junk food diet showed significant deterioration in muscle strength and function. But the psilocybin-treated mice maintained their performance. In physical tests, they could hang on a grid longer and showed greater muscle strength.

At the molecular level, psilocybin restored what the researchers call the AMPK-SIRT1-PGC-1α axis. This is a crucial regulatory system controlling mitochondrial function and preventing muscle breakdown. Genes promoting muscle atrophy were suppressed, while genes supporting muscle growth and regeneration were activated.

This is important because most treatments for obesity and diabetes either ignore muscle health or actively make it worse. Some diabetes drugs and even certain weight-loss interventions can accelerate muscle loss. The fact that psilocybin preserves and potentially enhances muscle function while improving metabolic health is a game-changer.

Another striking finding came from looking at the pancreas under an electron microscope. The high-fat diet had caused severe damage to the beta cells (the specialised cells that produce insulin). Their internal structures were dilated and damaged, and the insulin-containing granules inside them were abnormal.

In the psilocybin-treated mice, the beta cells looked healthy. The insulin granules were normal. Psilocybin was actually protecting the cells that make insulin in the first place.

The researchers also measured a whole panel of metabolic hormones and found widespread normalisation. Insulin levels, C-peptide, pancreatic polypeptide, GIP (glucose-dependent insulinotropic polypeptide), leptin, and resistin were all restored to healthy ranges by psilocybin treatment.

Let’s step back and look at the bigger picture.

Metabolic-associated steatotic liver disease (MASLD) affects roughly 30% of the global population. Type 2 diabetes is approaching epidemic status. These conditions are interconnected, each one making the others worse, creating a vicious cycle of metabolic dysfunction that includes inflammation, insulin resistance, fat accumulation, and progressive organ damage.

Current treatments are woefully inadequate. For MASLD, there are essentially no approved medications Doctors can only recommend weight loss and exercise. For diabetes, we have drugs, but many come with significant side effects, and most don’t address the root metabolic dysfunction. They’re managing symptoms, not restoring health.

What this psilocybin research suggests is the possibility of a fundamentally different approach. A therapy that addresses multiple aspects of metabolic dysfunction simultaneously, working through a novel mechanism, with apparent minimal side effects at low doses that produce no psychedelic effects.

This latest study adds to a thread I’ve been following for a while. It builds on groundbreaking research that’s been revealing psilocybin as something far more than just a psychedelic compound.

In July 2025, researchers at Emory University and Baylor College of Medicine published something extraordinary in npj Aging. Louise Hecker and her team provided the first experimental evidence that psilocybin fundamentally impacts cellular ageing at multiple levels throughout your entire body, not just your brain.

They found that in isolated cells, psilocin (the active form of psilocybin) extended cellular lifespan by 29-57% depending on dose. It preserved telomere length, reduced oxidative stress, improved DNA stability, and increased SIRT1, which is the master regulator of cellular ageing and metabolism that gets elevated during caloric restriction.

But when researchers tested psilocin on isolated fibroblasts in a petri dish (so cells with absolutely no connection to a brain whatsoever) they still got the lifespan extension and metabolic improvements.

This suggests that there need be no brain, no consciousness, and no mystical experience for these cellular metabolic effects.

The Emory researchers found that psilocybin activates 5-HT2A serotonin receptors that aren’t just in your brain. They’re expressed throughout metabolic organs like the liver and pancreas. And this activation induces SIRT1-dependent expression of antioxidant enzymes and improvements in mitochondrial function (aka the fundamental energy-production machinery of your cells).

This explains what we saw in the Italian study. That AMPK-SIRT1-PGC-1α axis being restored in muscle tissue is the exact same longevity pathway the Emory team identified. SIRT1 is what gets elevated during caloric restriction and is associated with lifespan extension. PGC-1α is the master regulator of mitochondrial biogenesis.

So psilocybin is working through two simultaneous mechanisms:

Via 5-HT2B antagonism (the Italian discovery): Direct effects in the liver blocking fat accumulation and improving insulin signaling. This is a local, organ-specific effect that requires no brain involvement whatsoever.

Via 5-HT2A activation (the Emory discovery): Systemic activation of cellular aging pathways – SIRT1, improved mitochondrial function, reduced oxidative stress, better DNA stability – throughout the entire body.

It’s hitting metabolic dysfunction from two completely different angles simultaneously. And at low doses, you could get both mechanisms without any psychedelic effects.

What’s fascinating to me is how psilocybin seems to work with the body’s existing regulatory networks rather than forcing a particular outcome. Unlike drugs that narrowly target one pathway (think statins for cholesterol or metformin for blood sugar), psilocybin appears to restore balance across multiple interconnected systems.

It’s not centrally controlling your metabolism from the top down. Instead, by modulating the 5-HT2B receptor and restoring leptin sensitivity, it’s allowing your body’s own distributed intelligence to reassert itself. Your liver can properly manage fat again. Your muscles can respond appropriately to metabolic signals. Your pancreas can produce insulin without burning itself out.

This is regenerative medicine in the truest sense.

There has been some concern that if psilocybin works through the 5-HT2B receptor, it could cause heart valve problems. This is actually an important and valid concern. Some drugs that activate 5-HT2B receptors, like the weight-loss drug fenfluramine and the Parkinson’s drugs pergolide and cabergoline, were found to cause heart valve disease and were pulled from the market.

But those drugs were agonists of 5-HT2B, meaning they activated the receptor. Psilocybin, as this study demonstrates, is an antagonist. It blocks the receptor. This is the opposite mechanism.

The researchers specifically tested this and found that psilocybin has no agonist activity at 5-HT2B. If anything, blocking this receptor might be protective against certain types of fibrosis, including in heart valves and the liver. This is speculative, but it’s a possibility worth exploring.

The researchers also note that they’ve completed a Phase I human trial (data not yet published) showing that low doses of psilocybin (0.5-2 mg) are well-tolerated in both normal-weight and obese individuals with no CNS effects. This is reassuring, though obviously we need much more human data.

Imagine you’re someone struggling with fatty liver disease, pre-diabetes, and gradual muscle loss. Your doctor tells you to lose weight and exercise more – advice that’s technically correct but incredibly difficult to follow when your metabolism is already broken and you’re fighting against dysfunctional leptin signalling.

Now imagine a therapy that could help restore your liver’s ability to properly process fats, improve your insulin sensitivity, protect your insulin-producing cells, and maintain your muscle strength, all while you work on lifestyle changes. That’s the potential we’re looking at here.

This isn’t a magic pill that lets you eat junk food with impunity. The treated mice in this study were still on a terrible diet. But it gave their bodies the metabolic flexibility to not be completely destroyed by it. Presumably, it would work even better in conjunction with dietary improvements.

Before anyone rushes out to start microdosing for metabolic health, several important caveats:

First, this is a mouse study. Mice are not humans. Many promising findings in mice don’t translate to people. We need human trials.

Second, the dose matters enormously. The researchers used 0.05 mg/kg, which in a 70 kg human would be about 3.5 mg, which is well below typical microdosing ranges and far below psychedelic doses. Getting the dose right is crucial.

Third, this was a controlled study with pure psilocybin. Mushrooms contain variable amounts of psilocybin plus other compounds. Self-experimentation with mushrooms is not the same as a pharmaceutical intervention.

Fourth, the legal status of psilocybin varies by jurisdiction. In most places, it remains a controlled substance.

That said, this research – combined with the Emory findings on cellular ageing and the preliminary human observations – opens fascinating possibilities for a completely new approach to metabolic health.

What we’re witnessing is a fundamental reframing of what psychedelics are and how they work.

The old model is psychedelics are consciousness-altering drugs that work on the brain to produce psychological effects.

The new model emerging from this research is psychedelics are systemic metabolic compounds that work throughout the body at the cellular and mitochondrial level, with profound effects on fundamental ageing processes – effects that happen to also produce consciousness-altering experiences at higher doses.

There’s a growing appreciation in both scientific and holistic health communities that mushrooms represent a largely untapped pharmacopeia. From the immune-modulating beta-glucans in functional mushrooms to the potential metabolic benefits we’re now discovering, fungi are revealing themselves as powerful tools for human health.

In an age of metabolic disease epidemics, this research offers hope.

Keep watching this space, because i’ve got a feeling there’s more to come.

References:

Colognesi, M., Gabbia, D., Signor, A., et al. (2026). Low, non-psychedelic doses of psilocybin as a novel treatment for MASLD, obesity and type 2 diabetes via 5-HT2B receptor-dependent mechanisms. Pharmacological Research, 224, 108080.

Hecker, L., et al. (2025). Psilocybin extends cellular lifespan and improves healthspan across multiple aging hallmarks. npj Aging, July 2025.