Does ketogenic diet improve mitochondrial function? And if so, how does that work? The quick summary story for people who don't know ketogenic... So ketogenic diet is a 100-year-old evidence-based treatment for epilepsy. It can stop seizures even when medications fail to. We have over a dozen controlled trials of ketogenic diets in children, in particular, with treatment-resistant epilepsy.

We have two Cochrane reviews that came out positive. So Cochrane reviews are the gold standard in the medical field for meta-analyses. Very rigorous. And they analyzed the data that exists and came to the conclusion that ketogenic diet... If somebody has treatment-resistant epilepsy, compared to treatment as usual, which is try another anti-epileptic medication, the ketogenic diet is six times more likely to result in seizure freedom.

...than just trying yet another epilepsy pill. So the ketogenic diet is a powerful anti-convulsant treatment. We use anti-convulsant treatments in psychiatry every day in tens of millions of people. Lots of these medications are used. So at this point, we now have over 50 published pilot trials, case series, case reports, other lines of evidence of the ketogenic diet for psychiatric disorders.

Schizophrenia, bipolar disorder, depression, anxiety, anorexia, nervosa, surprisingly. These 50 reports represent over 1,900 people. And on balance, the ketogenic diet appears to be an effective treatment, sometimes an extraordinarily effective treatment, like in able to induce remission of schizophrenia or bipolar in people who otherwise had treatment-resistant disorders. And they're going off medication simultaneously?

Some of them are. So there are, you know, I have heard probably from thousands of people around the world since my work has become more public. And actually, our first podcast together, hands down, the most cited reason people know who I am. As they should. Well, I know about you, but it's Huberman, that Huberman Lab podcast.

Well, I'm just a runway for people to, incredible messages to take off. Thank you again for the opportunity to disseminate this word. And because at the end of the day, I'm hearing from thousands of people who simply listened to that podcast, made changes, started a ketogenic diet for their schizophrenia or other treatment-resistant mental disorder, reach out to me.

You saved my life. I can't tell you how many times I've gotten handwritten notes, emails, messages from people who use those words. You saved my life. I never met this person. All I did was share this knowledge. And then they saved their own lives with knowledge. Coming back to your question now, in a roundabout way, does the ketogenic diet impact mitochondrial health?

We have strong evidence that it does. And so it appears, so the ketogenic diet is mimicking the fasting state. And I just want to say that again. The ketogenic diet mimics the fasting state. What does that mean? It means the ketogenic diet is mimicking no food consumption. So is the ketogenic diet the healthiest diet that everybody should follow?

No, that's not the way I think about it. The ketogenic diet is an intervention. It is shifting metabolism. It is shifting countless kind of systems, signaling pathways, other things, gene expression in the human body and brain. And that results in effects. And the good news is these effects appear to be life-changing and life-saving sometimes.

So they're highly beneficial effects. Again, dose and the way you do it matter because fasting, the extreme version of fasting is starvation and that results in death. So that is not at all a good thing. Not feasible. So let's make sure that if you're going to do a ketogenic diet or a fasting regimen that you're not depriving yourself of essential nutrition, that you're getting enough calories, you're getting enough nutrients, that you're doing it in a medically sound way so that you're optimizing your health and not hurting your health.

We have, you know, it's hard to measure this in humans in vitro because we can't like do an intervention to a human and then dissect their brain and like biopsy it and look at the mitochondria under the microscope. So we mostly have animal data that supports this, but animal data strongly supports that ketogenic interventions improve mitophagy, so getting rid of these old and defective mitochondria.

So you're kind of cleaning house, you're getting rid of the bad, and then you're replacing them with new fresh ones, mitochondrial biogenesis, so that at the end of the day, the cell will have more healthy mitochondria. Now, some researchers have really hyper-focused on the ketogenic diet might be working through the gut microbiome, this gut-brain connection, and we have some evidence that that is true.

So researchers actually took feces from human children with epilepsy before starting a ketogenic ketogenic diet, and then afterward while they were stable on a ketogenic diet, and then they transferred these fecal samples to mice who were predisposed to epilepsy or predisposed to seizures. When they took the feces from the children while the children still had or seizing, the mice were more likely to seize when they took the feces from the children doing the ketogenic diet and transferred it to the mice, the mice were less likely to have seizures.

Interesting. Even though the mice were not on ketogenic diets. So there's something in the feces of children with epilepsy doing ketogenic diets that has an anti-seizure effect. What could that something be? It could be the gut microbiome, but it could be molecules, neurotransmitters, neuropeptides, other things that those microbes are producing, or it could be neuropeptides and other factors that the gut cells are producing.

So we really don't know for sure what exactly is it. So on the surface, there's something in the feces. There's a gut microbiome, a gut-brain connection thing. What does that have to do with mitochondria? So another research group did that same model, got mice to have an anti-seizure effect from a ketogenic diet, and then dissected their brains looking for what changed in the brain.

How exactly is a ketogenic diet having an anti-seizure effect in the brain? Because that's the pathology, the pathological finding seizure is occurring in the brain. And when they analyzed genetic changes, up-regulation, down-regulation, it all centered on mitochondria. That the changes in the gut were resulting in mitochondrial changes in the brain, which means brain energy metabolism in the brain.

And so again, it's an umbrella theory doesn't replace what we know. It's not gut microbiome or serotonin. It's not gut microbiome or mitochondria. It's both. Both of them are true, and it's all interconnected. So I do think we've got more than enough data that ketogenic therapies impact brain metabolism, which then impacts neurotransmitters.

That's really what I hope will become one of many really important studies published by Ian Campbell and colleagues in the UK, that they just did a pilot trial, 20 patients with bipolar disorder, put on ketogenic diets, and they found wide-ranging improvements in metabolic health biomarkers, like weight, blood pressure, other things.

But they also found a reduction in brain glutamate activity, which is often associated with bipolar disorder and hyperexcitability and seizures. And so that helps us understand, again, it's not metabolic or glutamate, a neurotransmitter. It's both. It's putting it together. Yeah, the Campbell study is really interesting. We will link to that in the show note captions.

And incidentally, we will also link to this American Heart Association appalling quote-unquote testimony. Sorry, AHA. I'm not sorry. I'm not sorry. But then again, I'm not a physician, so I don't have to worry about that. Well, maybe I do. Anyway. I'm not a cardiologist. Is there any rationale for people who don't have epilepsy or don't suffer from bipolar or schizophrenia, but like myself, would like to keep our mitochondrial function as strong as possible for doing a brief ketogenic intervention?

Yes. The answer is yes. Can intermittent – so I'm going to lump ketogenic with other fasting-mimicking diets and fasting itself. So can intermittent fasting or can cycles of fasting have health-improving qualities or health-improving effects? Absolutely. So interestingly, before I talk about even some of the science on this, and it's not super robust.

Why? Because again, we don't fund diet studies. There's no money to be made from dietary interventions. Really? There's no patent on it. Nobody cares about dietary interventions. But there are a lot of studies on exercise interventions. But even those are – they're not huge randomized controlled trials with 10,000 participants.

They're not – you know, like even the federal government will fund large-scale medication trials, statin studies, and others. But they often don't. I mean, there have been a few – the Women's Health Initiative funded a massive dietary intervention study, and unfortunately, that was a huge disappointment to the field because it was negative.

They randomized women to just keep doing the diet you're eating or go on a low-fat diet, and the low-fat diet didn't do anything for their heart health or other objective kind of outcome measures. And put another way, just to really close this for people, it means a low-fat diet is no better than the standard American diet.

A low-fat diet is equivalent. You get equivalent health effects from a low-fat diet to a standard American diet. That's really bad. So low-fat diets need to go away, and people who promote low-fat diets need to stop promoting. They need to come up to speed with the science and just, like, move on.

Like, at least acknowledge there are healthy fats. Even though fat has more calories, don't worry about those calories. Worry about the health effects, the long-term health effects. Yeah. You got to get those monounsaturated fats, and you got to get your omega-3s, and you have to – you know, and I'm a believer in eating some butter here and there.

You were asking me about intermittent ketogenic diets or intermittent fasting. Intermittent fasting. So I'll just say that we have a long history in multiple cultures on Earth for thousands of years. Fasting has been part of healing rituals. India, India, China, Christian – fasting has been a part of rituals.

And, you know, most people just assume it's religious folklore or just silliness or whatever. But I actually think millennia of humans were not all stupid idiots. And that some people along the way actually noticed this seems to do something useful. And that's probably why it found its way in every culture and persisted for thousands of years, because there was actually something meaningful happening.

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