Welcome to the Huberman Lab Podcast,

where we discuss science

and science-based tools for everyday life.

I’m Andrew Huberman,

and I’m a professor of neurobiology and ophthalmology

at Stanford School of Medicine.

Today, my guest is Dr. Chris Palmer.

Dr. Chris Palmer is a medical doctor

specializing in psychiatry at Harvard Medical School.

He is the world expert in the relationship

between metabolic disorders and psychiatric disorders.

He treats a variety of different conditions,

including psychosis, including schizophrenia,

as well as attention deficit hyperactivity disorder,

obsessive compulsive disorder,

anxiety disorders, and depression, among others.

He is best known for understanding the relationship

between how metabolism

and these various disorders of the mind interact.

And indeed, today, he describes

not only his own fascinating journey

into the field of psychiatry,

but also his clinical and research experience using diet

that is different forms of nutrition

in order to treat various psychiatric disorders.

He describes some remarkable case studies

of individuals and groups of people

who have achieved tremendous relief

from the types of psychiatric disorders

that I just mentioned a few moments ago,

as well as new and emerging themes

as to how metabolism and the mind interact

to control things like obesity.

Indeed, he raises the hypothesis

that perhaps obesity in many cases

is the consequence of a brain dysfunction

as opposed to the consequence of a metabolic dysfunction

that then impacts the brain.

During today’s episode,

he shares with us his overriding hypotheses

about the critical roles

that mitochondrial function and dysfunction

play in mental health and mental illness,

and how various particular types of diets,

ranging from the ketogenic diet to modified ketogenic diet,

and even just slight adjustments in carbohydrate intake

can be used in order to change mitochondrial function

and bring relief for various psychiatric illnesses.

He also highlights the essential and important theme

that various diet interventions,

including the ketogenic diet,

were not first developed for sake of weight loss,

but rather were developed as treatments

for neurologic conditions such as epilepsy.

Today, he shares with us

how the foods that we eat alone and in combination,

and how fasting, both intermittent fasting

and more lengthy fasts,

can interact with the way that our brain functions

to strongly control the way that we think, feel, and behave.

What’s wonderful is that Dr. Palmer

not only explains the science and his clinical expertise,

but also points to various actionable measures

that people can take

in order to improve their mental health.

I’d like to mention that Dr. Palmer

is also the author of a terrific new book.

The title is,

Brain Energy, A Revolutionary Breakthrough

in Understanding Mental Health

and Improving Treatment for Anxiety, Depression,

OCD, PTSD, and more.

I’ve read the book and it is a terrific read.

I came away from this book

with a much evolved understanding

of how the various psychiatric disorders

that I just described, as well as ADHD, emerge in people.

And it has completely revised my understanding

about the possible origins of various psychiatric disorders

and the best ways to treat them,

including both with medications,

but also with nutritional approaches.

If you’d like to learn more about Dr. Palmer’s work

and the book, please go to chrispalmermd.com.

We also provide links to the book

and to his website in our show note captions.

Before we begin, I’d like to emphasize

that this podcast is separate

from my teaching and research roles at Stanford.

It is, however, part of my desire and effort

to bring zero cost to consumer information

about science and science-related tools

for the general public.

In keeping with that theme,

I’d like to thank the sponsors of today’s podcast.

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And now for my discussion with Dr. Chris Palmer.

Chris, Dr. Palmer, thank you for being here.

Thank you, Andrew, for having me.

I have a lot of questions for you,

and I’m really excited about this topic

because I think most people know what mental illness is,

or they have some idea what that is.

Most people have some idea what nutrition is.

Fewer people certainly know

how closely those things can interact.

And I think everybody is familiar with the feeling of a food

or the ingestion of a food,

making them feel good in the short term.

You know, we eat a food that tastes delicious to us

or that we associate with something nice,

and we feel good mentally and physically.

Whereas when we eat something that gives us food poisoning

or maybe even something that just doesn’t taste that great

or that we associate with a bad experience,

we feel less good in the short term.

But I believe that very few people understand

or are familiar with the fact that nutrition

and our mental health interact in this very intimate,

maybe even causal way.

And that is something that occurs over long periods of time,

meaning what I ate yesterday, the day before,

maybe even 10 years ago,

could be impacting the way that my brain and body

are making me feel now.

So if you would, I’d love for you to just tell us

about a little bit of the history,

in particular your history,

with exploring the relationship

between nutrition and mental health.

And then we can dive into some of the more particulars

of ketogenic diets versus other diets,

and some of the truly miraculous findings

that you and others are coming up with

based on real patients and real experiences of people

who suffer and then find relief by altering their nutrition.

Sure.

This story really starts with my own personal story.

And I don’t need to go into great detail,

but to set the stage, when I was a kid,

I definitely had mental illness.

Started with OCD.

A series of events happened in my family.

My mother had a horrible, kind of psychotic break.

And all sorts of adverse childhood events for me.

She and I were actually homeless together for a while.

I went on to have subsequent depression,

suicidality, all sorts of things.

But somehow or another, I pulled myself together

and got through medical school,

actually did quite well in medical school,

got an award for being one of the top students,

and then was doing my internship and residency at Harvard.

And at that point in time,

I was diagnosed with metabolic syndrome.

So I had high blood pressure,

horrible lipids, and prediabetes.

And I was doing everything right, supposedly.

I was on a low-fat diet

and I was exercising regularly.

And year after year, my doctor kept telling me

diet and exercise.

I kept asking him what diet, what exercise.

I was doing everything he kept telling me to do.

Everything was getting worse.

My blood pressure kept going higher.

And at some point, he kind of said,

you’re gonna have to go on medication.

I need to put you on something for your prediabetes,

something for your cholesterol,

and something for your blood pressure.

So three pills out of the gate.

And I’m like, I’m only in my 20s.

Were you overweight?

No, technically no.

I had a gut, so that’s a sign of insulin resistance.

I know now.

I didn’t know it then.

And he actually kind of leaned in at one point

and said, do your parents have diabetes?

Yeah.

Do your parents have high blood pressure?

Yeah.

Are your parents overweight?

Yeah.

Oh, I’m really sorry, it’s genetic.

Basically, you’re screwed.

It’s your genes.

You’re just gonna have to bite the bullet and take meds.

And as a physician, I knew what that meant.

I knew that I’m in my 20s.

If I’m already on three meds for metabolic syndrome,

I’m gonna be screwed by the time I’m 40 or 50,

and I’m probably gonna be having heart attacks.

And I’d heard through the rumor mill

that the Atkins diet could somehow help people

improve their cholesterol and pre-diabetes.

I actually didn’t really believe it.

I was highly skeptical.

And I believed everything I was taught in medical school.

Why would my professors lie to me

that they knew what they were talking about?

Low-fat diet was the thing to do.

And the Atkins diet was clearly dangerous and reckless.

But I had been trying the medical dogma for years,

and it wasn’t working for me.

And so for whatever reason, I decided

this is gonna be my last attempt at something different.

And then I’ll just bite the bullet and go on meds.

So I tried the Atkins diet.

I did my own special version of it.

I still avoided red meat

because I was terrified of red meat.

I tried to do a healthy version,

which is probably more like the South Beach diet.

This was before the South Beach diet was invented.

But within three months,

my metabolic syndrome was completely gone.

So blood pressure normalized, lipids normalized.

Did your weight change?

Or you mentioned that you were of healthy weight,

but that you had a bit of abdominal fat.

So I lost the abdominal fat.

I probably lost about 10 pounds through this process.

But everything got normal.

And when I went back to my doctor, he was shocked.

He actually said, what the hell are you doing?

During the time before you switched to this new diet,

how was your mental health, if you don’t mind me asking?

Because it sounded like you’re very clear

that there was metabolic syndrome,

or you were headed towards more severe metabolic syndrome.

You mentioned OCD.

I actually am familiar with this as a kid.

I had a low-level kind of Tourette’s grunt

and probably maybe obsessive still to some extent,

although not full-blown clinically diagnosed OCD.

So I can relate somewhat.

If you’re willing, what was the context of all that

before and after this nutritional switch?

So before the nutritional switch,

I was still struggling with low-grade depression and OCD.

I, again, it wasn’t necessarily interfering

with my ability to function,

because I was functioning at a high level.

I mean, anybody looking from the outside,

you’re a top student,

you just got into one of the most competitive,

actually at that point, it was the most competitive

residency program in the country for psychiatry.

So they would have looked at me and said, you’re fine.

But I wasn’t, I was actually on medications.

I was trying different medications,

trying to figure out how to feel better,

how to stop obsessing so much, how to not be so depressed.

And I found that those medications,

they actually came with more side effects for me

than benefits.

I was on Prozac for a long time,

it totally messed up my sleep.

And then the psychiatrist was like,

you need pills to help you sleep now.

And I’m like, that’s not really resonating

very well with me.

And I’m now a psychiatrist, I’m in my psychiatry residency.

And I’m thinking, you know what?

That’s just not sitting well with me,

that you’re gonna prescribe more and more meds

for all the side effects that you’re causing.

And yet at the same time, I wanted to feel better.

And I was learning chemical imbalances.

This is what we do to get rid of depression and OCD.

You’re supposed to take your pills.

And so I was taking my pills.

I was in psychotherapy.

I had been in psychotherapy on and off for years.

I had received much more intensive treatment

when I was younger.

And that was essentially worthless for me.

It actually probably just caused harm

at the end of the day.

Psychoanalysis?

Various psychotherapies, not psychoanalysis per se,

but some of them were psychoanalytically oriented.

Psychotherapies, I was actually hospitalized at one point.

Had been put on lithium and imipramine,

which is a tricyclic antidepressant and other things.

And they were actually horrible.

They were horrible.

They did nothing beneficial for me.

I gave them a decent amount of time to work.

I really wanted to feel better.

So at the time that I tried this diet,

I certainly wasn’t impaired in the same way.

I wasn’t struggling that much,

but I still had these low-grade symptoms,

was trying to feel better.

And the thing that was the most striking to me

after doing the diet for three months

was not the fact that my metabolic syndrome was gone.

That was my goal.

And it was a seemingly miraculous achievement

because I got rid of everything with one dietary change.

But the thing that I noticed was dramatic improvement

in my mood, energy, concentration, and sleep.

For the first time in my life,

I started waking up before my alarm went off

and feeling rested.

That never happened to me before.

I was meticulous about planning when my alarm went off

and how many times I could push the snooze button

in order to be on time for wherever I needed to be,

whether it was school or the hospital or whatever.

I had a good system.

I was never late for anything.

But that was shocking to me that I felt so good.

And one of the things that I’ve often said to people,

prior to the diet,

I always felt like there are two types of people

in the world.

There are haves and have-nots.

There are these happy peppy people

who just are so positive and they’ve got energy

and they have this saying,

they like to work hard and play hard.

And I always understood working hard.

I totally got that because I was a hard worker

and I understood the value of hard work

and you gotta do something useful with yourself.

But I never understood who the hell wants to play hard.

Like who’s got energy for that?

Like, aren’t you tired from working so hard?

How on earth do these people have energy

to go and play hard?

And I assumed that they were just part of the haves

in the world.

And they were just lucky and privileged.

They either had good genetics

or maybe they had good childhoods or good parents

or something, something that I didn’t have.

The kids with genuine smiles in the yearbooks.

Yes, exactly.

The rest.

And by the way, I really appreciate you sharing

some of your personal story

because I think it is very important

for people to hear and understand

that people like yourself

who are extremely high functioning and accomplished,

that the road was, from everything I’m hearing

and understanding, very choppy internally at times

and that you’ve overcome a lot in order to get there.

And also have been going through

what sounds like a very long iterative process

of trying to figure out what works and what doesn’t work

to finally arrive at a solution

and then make that the basis of much of the work

that you’re doing today for other people.

I think it’s very important

because I think many people share with you this notion

that there are indeed two groups,

a happy group and then fated to be unhappy group.

And it speaks to the fact that your story,

or rather speaks to the fact

that what we see is not always

what’s going on internally with people.

And that this notion of there just being two groups,

the happy or the haves and the have nots,

can’t be the way that it works.

And there are probably many more people suffering

than we realize.

And that there is an important need for tools

to overcome that suffering.

So I really just here, even early in our discussion,

I just want to extend a genuine thanks

because so much of what I hear from people

is questions about health and mental health

and physical health,

but that clearly point to the fact

that many people are struggling to varying degrees.

And even the people who are in this category

of great childhood and happiness could do far better

for themselves and then also for other people.

So thank you for that.

I want to know at the point where you realized

that nutrition can play a profound role

in how you feel and operate in a large number of domains,

you were still a student or a resident at that point?

I was a resident.

At that point, did you decide

that you were going to explore this

in a professional context?

Not yet.

Okay, so what was the journey forward

into the work that you’re doing now?

So the next step was that I just had friends and family

who saw me, saw that I had improved my health,

saw that I lost some weight pretty easily.

In particular, I remember my sister and sister-in-law,

they got really pissed at me one Thanksgiving

because I could resist all the pumpkin pie

and apple pie and everything else.

They were like, how the hell are you doing that?

How are you resisting all of this food?

I said, I don’t crave it anymore.

I don’t want it.

I’m fine.

I’m having turkey and green beans

and that’s good enough for me.

So I got them to do the diet

and they too noticed dramatic improvement in their moods

and energy and sleep and everything else.

So within a few years,

the primary thing I noticed

is this powerful antidepressant effect.

And now I’m an attending physician.

I’ve got all these patients in my clinical practice

with treatment-resistant mental illness.

I’m in a tertiary care hospital.

So I almost never get somebody off the street

with their first episode of depression.

Out of the gate, as part of my career,

I get treatment-resistant mental disorders.

So I get people who’ve already been

to six plus psychiatrists, therapists.

They’ve usually tried dozens of different medications.

They’ve been in decades of psychotherapy.

They’ve often had ECT and other things

and nothing’s working.

And I’m thinking, well, we’re kind of out of options

for these other people and this diet

is having this really powerful antidepressant effect.

I think I’m gonna try it and just see

if any of my patients are game to try it,

to see if it might help them.

Sure enough, it did.

Didn’t help everyone and not everybody was interested

and or able to do it.

But some of the ones who were able to do it

ended up having a remarkable

and powerful antidepressant effect.

One woman actually became hypomanic within a month

and she had been depressed pretty much nonstop

for over five years, chronically depressed,

suicidal, in and out of hospitals.

And I saw her become hypomanic and I’m thinking,

wow, this really is a powerful antidepressant effect.

Like this is amazing.

This is like a medication but better

because it actually is working for her.

But I laid low at that point

because at that point we didn’t have many clinical trials

of the safety or efficacy of the Atkins diet

for even weight loss or diabetes,

let alone any mental disorders.

And so I really actually felt like I’m on the fringe here

and this is not going to be met with praise by anyone.

So I’m just gonna lay low.

I’m gonna offer it to patients.

And I went along that way up until

2016.

And may I just ask about the diet?

When you say Atkins diet,

so this is low to zero starch.

So low carbohydrate diet, certainly low sugar.

Yeah.

And was it traditional Atkins?

Were you tailoring it to the individual patient

depending on their psychiatric symptoms,

whether or not they were overweight or not overweight?

I’m assuming you’re not a nutritionist.

So how did you prescribe a nutrition plan for your patients

and what was involved in making sure

that they adhered to that?

Maybe even some of the things you observed

in terms of who was more willing to try this

or not try this, any observations or maybe even data.

So early on, I was winging it.

And I was, you know, the first few patients,

it was try this Atkins diet.

I wanna see ketosis.

So I was going for ketones.

So they were pricking their finger

and they were doing a blood ketone test?

I didn’t know about blood ketone monitors

if they existed back then.

So we were using urine strips.

Which are not quite as accurate,

but still useful as a general guide from what I understand.

Is that right?

Absolutely.

And so I was strongly recommending

that patients achieve urinary ketosis.

And the interesting thing is I noticed a pattern

that when they were trying the diet

and not getting ketones,

they often did not get a clinical benefit.

It was once they got into ketosis

that I began to notice the clinical benefit

and the powerful antidepressant effect.

So probably any nutrition plan, aka diet,

that elevated ketones in the urine

to the point where you would say this person is in ketosis

or they would say, I’m in ketosis.

That was a step in the right direction,

independent of exactly what they were eating

or not eating to get there, including fasting.

At that time, probably fasting wasn’t as popular.

Now, thanks to the incredible work,

I think it’s incredible.

And he is a former colleague

and I know there’s a lot of controversy about fasting,

but I think for many people,

fasting is a powerful tool.

For others, it’s a less useful tool,

but Sachin Panda and others.

But fasting certainly will limit your carbohydrate intake

and get you into ketosis, correct?

It will.

Did you have any patients fast or do intermittent fasting?

I did.

I had some patients who did what Atkins had called a fat fast

where they eat primarily fat.

So they either fast and or they eat primarily fats

to try to get into a state of ketosis.

So for some patients,

it was actually quite easy to get into ketosis,

especially overweight and obese patients.

They have a lot of fat stores on their body

and actually limiting carbohydrates

usually results in high levels of ketosis for them.

And they probably feel better too, I imagine,

because when we limit our starch intake,

we start to excrete a lot of water.

People can get some pretty quick weight loss

that even though it may not be fat loss,

makes them feel literally a little lighter

and maybe a little more energetic.

Is that right?

Absolutely.

And as the years went on,

the field was advancing, more research was coming out.

People were getting a little more sophisticated

with blood ketone monitoring,

with different versions of ketogenic diets.

And I was evolving my practice.

The thing that completely upended everything

that I knew as a psychiatrist though

was when I helped a patient in 2016 lose weight.

So this was a patient,

33 year old man with schizoaffective disorder.

He had been my patient for eight years now.

Could you clarify for people what schizoaffective disorder is?

I’m not a clinician, but as I recall,

it’s like a low level of schizophrenia.

So there might be some auditory hallucinations.

If I met this person,

I might think they’re kind of different,

quote unquote weird,

but they would not seem necessarily

scary to me and typically to other people.

And I mean that with respect, of course,

but oftentimes people with schizophrenia

can seem just like you don’t even know

how to interact with them

because their world seems so altered

because they have all these so-called positive symptoms,

hallucinations, and they’re talking to people

that no one else can see, et cetera.

Is that schizoaffective?

So no, actually.

So schizoaffective is the same as schizophrenia essentially.

The only difference is it’s schizophrenia

with superimposed mood episodes.

Oh, so it’s actually more severe than-

It can be.

Okay, so I have it backwards.

So schizoaffective disorder is essentially schizophrenia

plus some mood episodes.

Maybe I’m thinking of schizotypal.

Schizotypal is the low grade kind of mild paranoia

or kind of eccentric beliefs and other things.

Okay, so folks out there,

I have my nomenclature backwards.

Schizotypal is the quote unquote low level schizophrenia

or schizoaffective is as or more so.

Full-blown schizophrenia plus full-blown,

usually bipolar symptoms.

And now it’s absolutely clear

who the clinician in the room is.

Thank you for that reminder.

No worries.

So this man had schizoaffective disorder.

He had daily auditory hallucinations.

He had paranoid delusions.

He could not go out in public without being terrified.

He was convinced that there were these powerful families,

that they had technologies that could control his thoughts.

They could broadcast his thoughts to other people.

They were trying to hurt him.

They had targeted him for some reason.

He wasn’t quite sure why.

He had some suspicions and beliefs

about maybe when he did this bad thing

when he was 11 years old,

that’s why they decided to target him.

This man was tormented by his illness, tormented.

It ruined his life.

He had already tried 17 different medications

and none of them stopped his symptoms,

but they did cause him to gain a lot of weight.

These are the medications, as I recall,

for schizophrenia, the classical ones

are dopamine receptor blockers,

cause people to, huge increases in prolactin.

That’s why sometimes men will get breast development

and they’ll put on a lot of weight

and they’ll be catatonic or movement disorders.

They make you feel like, I have to imagine,

given how good most things that release dopamine

make us feel that blocking dopamine receptors

with antipsychotics makes people feel lousy.

Horrible.

And it’s a huge challenge in our field

because a lot of patients don’t want to take them.

And then you get these rebound effects

if patients are on them for several months

and then they stop them cold turkey,

they can get wildly psychotic and ill,

end up aggressive or hospitalized or sometimes dead.

So that’s him, he weighs 340 pounds

and for whatever reason he gets it in his head,

I’m never gonna get a girlfriend if I don’t lose some weight.

He also recognizes I’m never gonna get a girlfriend

cause I’m a loser, I’m schizophrenic,

I live with my father, I have nothing going for me,

but I could at least try to address

one of these awful, horrible things about myself

and maybe I could lose some weight.

So he asked for my help.

For a variety of reasons, we ended up deciding

to try the ketogenic diet.

Now at this point, I have no anticipation

that the ketogenic diet is gonna do anything

for his psychiatric symptoms

because this man has schizoaffective disorder,

that’s not depression.

Depression is very different,

they’re totally different disorders.

So he decides to give it a try.

Within two weeks, not only does he start losing weight,

but I begin to notice this dramatic antidepressant effect.

He’s making better eye contact, he’s smiling more,

he’s talking a lot more.

I’m thinking like, what’s gotten into you,

like you’re coming to life,

I’ve never heard you talk this much,

I’ve never seen you so excited or present or alive.

I haven’t changed his meds at all.

The thing that upended everything

that I knew as a psychiatrist was six to eight weeks in,

he spontaneously starts reporting,

you know those voices that I hear all the time?

They’re going away.

And he says, you know how I always thought

that there were all these families

who were controlling my thoughts and out to get me

and they had targeted me and I’m thinking,

oh yeah, we’ve been talking about that for eight years,

we could talk about that again.

He says, you know what?

Now that I think about it, I don’t think that’s true.

And now that I say it, it sounds kind of crazy.

It probably never was.

I’ve probably had schizophrenia all along

like everybody’s been trying to tell me

and I think it’s going away.

That man went on, he’s now lost 160 pounds

and kept it off to this day.

Wow.

He was able to do things he had not been able to do

since the time of his diagnosis.

He was able to complete a certificate program.

He was able to go out in public and not be paranoid.

He performed improv in front of a live audience.

At one point he was able to move out of his father’s home

and live independently.

And that completely blew my mind as a psychiatrist

and I went on a scientific journey

to understand what in the hell just happened.

That is indeed mind blowing.

I’d like to take a quick break

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I have a couple of questions.

First of all, did he stay on any kind of antipsychotic

or other medication?

If so, were the dosages adjusted, excuse me,

while undergoing this remarkable transition?

Because as we know, it’s not an either or medication

or nutrition changes, it can be both.

And then the other question is one of adherence.

You know, I think about someone

with schizoaffective disorder who’s suffering

from all the sorts of things that you described.

How does somebody like that organize themselves

in order to stay on a ketogenic diet?

And I say this with all the seriousness in the world.

I think there are a lot of people who do not have

schizotypal or schizoaffective disorder who have trouble,

they claim, adhering to a ketogenic diet.

It’s not the easiest diet, certainly in its extreme form.

At first, it’s not the easiest diet to stick to.

So how did he do it?

This sounds like a remarkable individual.

And I’d also like to just know your general thoughts

about adherence to things

when people are back on their heels mentally.

You know, how do they get motivated and stick to something?

So the questions were medication, yes or no?

If yes, dosage adjusted, yes or no?

And if people are suffering from depression

or full-blown psychotic episodes,

how does one ensure that they continue to adhere to a diet?

So in terms of medications, he has remained on medication.

So early on, I wasn’t adjusting anything.

I was just in disbelief and shocked that this was happening.

I didn’t know what was going on.

Over the years, we have slowly but surely

tried to taper him off his meds.

He has been on meds for decades.

He started medications when he was a young child.

His brain has developed in response

to all sorts of psychiatric medications.

And it has not been easy to try to get him off.

So we continue to try to get him off medication.

And it’s challenging and difficult.

And I just want to say for any listeners,

it is getting off your meds is very difficult and dangerous

and you need to do it with supervision,

with a mental health professional or a prescriber,

because it is dangerous.

When people reduce their meds too much,

they can get wildly symptomatic.

Is that true for depression as well?

It’s true for any psychiatric medication.

The brain makes adaptations

in response to psychiatric medications.

And when you stop them cold turkey,

some people are fine,

but I wouldn’t recommend finding out

because I’ve seen patients,

when they stop antidepressants,

I’ve seen patients get floridly depressed

and suicidal within three months.

I had one patient almost quit her job

because she became convinced that,

well, my life sucks and it’s all because of my boss.

And I know that she’s just a horrible human being

and she’s abusing me.

And I was like, whoa, whoa, whoa.

I think this is related to your medication change.

We got her back on her meds.

Within three days, she said,

oh my God, I can’t believe that happened.

Like I almost quit my job.

And that would have been the most illogical

and irrational decision I’ve ever made in my entire life.

But somehow it seemed so real just several days ago.

And now that I’m back on this medication,

and it doesn’t mean that she needs the meds,

but it doesn’t mean that he needs the meds.

It means that meds need to be adjusted very safely

and cautiously and gradually.

So that’s the medication piece.

The adherence piece was not easy

for him and for other patients.

It is very rare that I have a patient

who I can say, do the ketogenic diet,

come see me in three months and let me know how it’s going.

That almost never happens.

It has happened, I think on two occasions.

But that is, if I understand correctly,

what perhaps not you,

but many psychiatrists do with medication.

It’s here’s your prescription.

Let’s talk in a month or three months.

Yes.

So that’s a variable that is probably worth us

exploring a little bit here as the conversation continues.

Absolutely.

You know, that frequent contact

and making micro adjustments or macro adjustments

to medication or nutrition could be meaningful.

Absolutely.

So with this particular patient,

early on, he was actually pretty adherent.

I was seeing him once a week.

And so I could do a lot of education.

I was weighing him.

I was checking his ketones.

I was checking his glucose levels.

At that point, I had a blood ketone monitor in my office.

So I knew whether he was compliant or not,

which is so beneficial in doing clinical work

and research on this diet.

It’s the only diet where within seconds,

I can have an objective biomarker of compliance

or non-compliance.

Such a key point.

And again, it brings to mind for me

the parallel with medication.

I mean, a patient can say they’re taking their medication

and unless they’re in a hospital setting

where somebody is checking under their tongue

and you know, all of this,

they very well could not be taking it or taking more.

And you and I both know

that blood draws for neurotransmitter levels

are complicated because you wanna know what’s in the brain

and what’s functional in the brain.

So, and I have to imagine that most people

that are prescribed drugs

for any number of different psychiatric conditions

are not giving blood every time they talk

to their psychiatrist or psychologist.

No.

No, and when we’ve looked at, you know, on that front,

when we’ve looked at studies of compliance,

the majority of patients are at least somewhat non-compliant

with prescription medications.

It’s not on purpose.

It’s forget, they forgot.

They take it at night.

They were out late.

They were off their routine.

They forgot to brush their teeth

because that’s when they take their meds.

And so because they, you know, it was so late,

they just crashed when they got home.

They forgot to take their meds.

Happens all the time.

If it’s a medication that people take more than once a day,

the non-compliance rates are much higher

because it’s just easy to forget.

So it’s not that people are willfully, you know,

disobeying their doctors or anything else.

It’s just hard to remember

to take meds consistently every day.

When you say measuring ketones,

I want to drill into this a little bit

because it does seem that the presence of ketones

and somebody being quote unquote in ketosis

turns out to be the key variable.

Certainly in your book,

that’s one of the major takeaways,

although there were many important takeaways,

that people get into ketosis.

Do they have to stay in ketosis?

So for instance, I’ve followed the,

I don’t any longer,

but I’ve tried in the past

the so-called cyclic ketogenic diet

where every third or fourth day,

get some pasta or rice, et cetera.

And that was interesting as an experiment,

but to stay in ketosis,

what sort of blood levels of ketones

do you like to see in your patients?

What is the range

that you think most people could aspire to?

So it really depends on the patient

and what I’m treating, quite honestly.

So, and I don’t think every patient

needs the ketogenic diet.

For some patients, simply getting rid of junk food

can make a huge difference

in a mood disorder, for instance.

So a junk food, meaning highly processed food,

food that could last on the shelf a very long time.

Highly processed foods that are usually high

in both sugar, carbohydrate, carbs, and fats.

Those seem to be the worst foods.

That combination, high sugar, high fat,

seems to be the worst combination for metabolic health.

And lo and behold, we’ve got emerging data

that strongly suggests it’s also bad for mental health.

Depression and anxiety

are the most common mental disorders.

And so we have the best data for those disorders.

But we actually have a lot of data

with even bipolar disorder and schizophrenia

that insulin resistance in particular

and insulin signaling in the brain

is impaired in people with chronic mental disorders

kind of across the board.

All the way from chronic anxiety, depression,

to bipolar, to schizophrenia, and even Alzheimer’s disease.

We know that patients with all of those disorders

have impaired glucose metabolism

and that the insulin signaling system in the brain,

which is different than insulin signaling in the periphery,

seems to somehow possibly be playing a role.

So to step back from that.

So for some patients,

I might just wanna decrease glucose and insulin levels

and I can do that by getting rid of sweets.

For other patients,

like patients with schizoaffective disorder

or schizophrenia or bipolar disorder,

especially if it’s chronic,

if I’m using it as a brain treatment,

then I do want a ketogenic diet

and I usually want reasonably high levels of blood ketones.

Usually for depression,

I wanna see at least greater than probably 0.8 millimole.

For psychotic disorders and bipolar disorder,

I usually wanna see levels greater than 1.5.

That’s what I’m shooting for, if at all possible.

And so, yeah, I think that’s what I’d go for.

Yeah, so, and sorry, I didn’t mean to imply

that people need to be in ketosis

in order to see some mental health benefits

from changing their diet.

You make very clear in your book,

and we’ll go into this in more detail,

that avoiding insulin resistance,

reversing insulin resistance,

and essentially trying to reverse

what earlier you described as this metabolic syndrome,

which is a bunch of different things, is the target.

And for some people,

getting rid of highly processed foods

and focusing mainly on non-processed

or minimally processed foods will really help.

For others, going straight

to the full-blown ketogenic diet will be of most benefit.

I’d like to back up a little bit in history

and get to something which I find incredibly interesting,

which is epilepsy and the longstanding use

of ketogenic diet and fasting to treat epilepsy.

And the reason I want to kind of rewind

to that point in history is that I think that

for a lot of listeners and people out there

who are familiar with how changing your diet

or changing your exercise can positively impact sleep

and weight and all these things,

and it cascades into feeling better,

that makes perfect sense.

But for a lot of the world still,

the idea that changing or using nutrition

as a dissection tool or as a treatment tool

to understand and treat mental illness

is still a kind of heretical idea,

that to them it kind of falls in the,

that’s like a woo science or something like that.

Now, obviously, you’re a board-certified physician

and psychiatrist at arguably one of the finest

medical schools in the world, Harvard Medical School.

You know, even though I’m on the Stanford side,

we acknowledge our East Coast friends.

You’re the Harvard of the West Coast.

We’re not going to talk count.

We’re not going to talk count.

Or we’re the Stanford of the East Coast.

That argument could go back and forth a number of times,

but you’re a serious clinician

and a serious scientist, and you’re a serious thinker.

But for a lot of people out there,

the notion of using diet, they immediately think,

ah, well, that makes perfect sense.

Or I think there’s a category of people who think,

well, yeah, didn’t Atkins diet have a heart attack?

You know, I hear that a lot, you know?

So like, that was crazy.

You know, like people immediately discard

the Atkins diet for that reason,

which I do think is throwing the baby out

with the bath water,

but it’s an interesting thing nonetheless.

And then I think that the majority of people

sit in the middle and just want to see science and medicine

come up with treatments that work.

And I have to say, I’m very relieved

to hear what you said earlier, which was,

you never said that people should come off their medication

and just become, go on a ketogenic diet

and everything will be cured.

You’re certainly not saying that.

No.

And rather you’re saying, if I understand correctly,

that nutrition needs to be considered

one of the major tools in the landscape of effective tools,

and that it can be very effective,

evidenced by the story that you shared,

and there are many other stories in there as well,

of truly miraculous transformations.

So let’s talk about epilepsy and how the ketogenic diet

is not just used for epilepsy,

but is one of the oldest, if not the oldest examples

of the use of nutrition to treat a condition

of the nervous system that can be incredibly debilitating,

even deadly.

Yeah.

And the reality is that this literature

and this clinical history and all of the research we have

was the godsend that I needed to do the work that I’m doing.

Otherwise I would have been discredited on day one.

Chris Palmer’s claiming that a dietary change

can influence schizophrenia or schizoaffective disorder.

That’s impossible.

And he’s a quack.

But the thing that immediately got me credibility

was I didn’t focus on it as a diet.

I did a deep dive into the epilepsy literature.

So the ketogenic diet, unbeknownst to most people,

was actually developed 100 years ago, 1921,

by a physician for one and only one purpose,

to treat epilepsy.

It wasn’t developed as a weight loss diet.

It wasn’t developed as the diet

that all human beings should follow.

And the reason it was developed

is because of this longstanding observation

since the time of Hippocrates,

that fasting can stop seizures.

Now fasting is not a healthy diet.

Fasting is the process of no diet.

So we now understand a tremendous amount of science.

Most people think going without food is bad

and they equate it with starvation.

But in fact, when we go without food,

it causes tremendous shifts in metabolism,

both brain and body metabolism.

And it puts the body into a mode of autophagy

and conservation of resources and all sorts of things.

That are beneficial to human health.

And this is why fasting has been used

as a therapeutic intervention in almost every culture

and almost every religion for millennia.

But for the most part,

that was all thought to be religious folklore.

That was just crazy talk.

And those stupid people way back then,

thought God cured everything.

And so they fasted

and they just assumed that they were getting better.

Well, in 1921,

one physician used intermittent fasting

on a child with seizures and found that,

oh, lo and behold, this religious folklore stuff

has something to it.

It actually worked.

The problem with fasting is that you can only fast

for so long before you starve to death.

And that’s not a very effective treatment.

And this child was ingesting water, correct?

Yes.

Food elimination fasting.

Food elimination.

So no special diet.

But the problem with fasting for epilepsy

is that as soon as people start eating a normal diet again,

their seizures usually come right back.

Oftentimes with a vengeance.

And so it can be a good short-term intervention.

The fasting can take a few days

because it can take a few days to get ketosis.

And then you can get some relief from chronic seizures.

But it’s not a good long-term treatment

because, again, people will starve to death.

As soon as they start eating, seizures come back.

So it was actually Dr. Russell Wilder at the Mayo Clinic

who developed the ketogenic diet

with one and only one purpose.

He wanted to see, can we mimic the fasting state

using this special diet

to see if it might stop seizures long-term?

And lo and behold, it worked.

Early results were extraordinarily positive.

50% of patients who used the ketogenic diet

became seizure-free.

And another 35% had a 50% or greater reduction

in their seizure frequency.

So about 85% efficacy rate.

Sorry to interrupt.

I didn’t mean to do that there.

Was it just for pediatric epilepsy

or for adult epilepsy as well?

So back in the 1920s,

we didn’t have many anti-epilepsy treatments.

And a lot of adults were struggling as well.

So they were using it on anybody who would do the diet.

By the 1950s, pharmaceuticals were coming out

and we had many more anti-combulsant treatments.

And there’s no question, they work for a lot of people.

That’s great.

And taking a pill is so much easier than doing this diet.

So the diet pretty much fell out of favor

and nobody was using it from the 1950s to about the 70s.

But lo and behold, even to this day,

people with epilepsy, about 30% don’t respond

to the current treatments that we have available.

30% will have treatment-resistant epilepsy,

which means they continue to have seizures

no matter how many anti-combulsants they’re taking.

Even if they’ve had brain surgery,

it just doesn’t stop their seizures.

And so in the 1970s,

the ketogenic diet was resurrected at Johns Hopkins

for these treatment-resistant cases.

And lo and behold, it works.

Not for all of them, but it works.

And about one third become seizure-free.

And these are people who’ve tried everything

and nothing’s working.

So one third becomes seizure-free.

Another third get a clinical benefit,

meaning a 50% or greater reduction

in their seizure frequency.

And the other third, it doesn’t seem to work.

It’s not always clear if that’s because of non-compliance

or if that’s because the diet’s just not working.

But about a third, a third, a third.

Seizure freedom, reduction in seizures,

or it just doesn’t work.

And so the reality, the godsend for me

is that we have decades of neuroscience research

on the ketogenic diet and what it is doing to the brain.

We know that the ketogenic diet

is influencing neurotransmitter levels,

in particular glutamate, GABA, adenosine.

It changes calcium channel regulation and calcium levels,

which is really important in the function of cells.

It changes gene expression.

It reduces brain inflammation.

It changes the gut microbiome.

And gut microbiome is a huge topic right now.

And there are some researchers who argue

that is the primary benefit of the ketogenic diet.

It’s changing the gut microbiome in beneficial ways.

So it’s doing a lot of things.

It obviously improves insulin resistance,

lowers glucose levels, lowers insulin levels,

which improves insulin signaling.

The key for my research that I’ve outlined,

the real magic is that this diet

stimulates two processes that relate to mitochondria.

It stimulates a process called mitophagy,

which is getting rid of old and defective mitochondria

and replacing them with new ones.

And it also stimulates a process

called mitochondrial biogenesis,

which means that after people have done

the ketogenic diet for a while, months or years,

many of their cells in their bodies and brains

will have more mitochondria

and those mitochondria will be healthier.

And I believe that is the reason

the ketogenic diet is such a powerful treatment,

not only for epilepsy,

but also for people with chronic mental disorders.

Would you mind listing off a few of the mental disorders?

And I know this is not meant to be inside ball,

but we should distinguish between psychiatric disorders

and neurological symptoms and diseases.

The fields of psychiatry and neurology,

hopefully someday we’ll just merge.

But for instance, typically if somebody is presenting

with something that looks like Alzheimer’s, dementia,

they’ll talk to a neurologist.

Whereas if somebody is presenting with symptoms

like schizophrenia, bipolar, they’ll talk to a psychiatrist.

But if you wouldn’t mind wearing a dual hat,

could you just quickly list off

some of the neurologic and psychiatric disorders

for which ketogenic, or let’s just say nutrition changes

have been shown to improve symptoms significantly.

And then maybe we can dive into a couple of these

as well as get more deeply into

these two very interesting aspects

of mitochondrial function and repair and turnover.

Yeah, so the field, you know,

in terms of nutritional psychiatry, it’s a broad field

and it’s in its infancy is the real answer.

If you’re looking for randomized controlled trials,

documenting efficacy in large numbers of patients

with these disorders, we don’t have them.

They’re underway now, but we don’t have them yet.

What we do have are case studies.

We have a lot of mechanistic science papers

by some of the leading neuroscientists and psychiatrists

in the world and neurologists in the world

kind of outlining, this is everything we know

that the ketogenic diet’s doing.

These are the problems in the brains of people

with these chronic mental or neurological disorders.

So we know that they should work.

But the disorders range from chronic depression to,

we’ve got a trial underway for PTSD.

We’ve got one actually decent pilot trial

from the National Institutes of Health

for the ketogenic diet for alcohol use disorder

of all things, and we can go into that a little more.

We’ve got a couple of pilot trials

of the ketogenic diet for Alzheimer’s disease.

We’ve got, and those are randomized controlled trials.

We’ve got case studies of the ketogenic diet

for chronic depression, bipolar disorder, and schizophrenia.

The largest study that we’ve got

in that mental health sphere is a pilot study

of 31 patients admitted to a French hospital.

The 28 of those patients were able to do the diet

and stay on the diet.

So 10% off the bat, non-compliant, couldn’t do the diet.

So we need to include that.

But of the 28 patients who were able to do,

and these are 28 patients

with treatment-resistant mental disorders,

chronic depression, bipolar, and schizophrenia.

Of the patients who were able to do the ketogenic diet,

100% had at least some improvement in symptoms.

46% had remission of illness.

That does not happen with current treatments.

And 64%, I think, were discharged on less medicine

than they went into the hospital on.

So it wasn’t that the people

were prescribing more medicine,

and that’s why they were being discharged

on less medication.

We’ve got at least, again,

a lot of the hardcore scientists are gonna say,

show us the randomized controlled trials

with hundreds of patients.

And we’ve got five randomized controlled trials

underway now, funded primarily through philanthropy.

I can tell you that, you know,

we’ve talked about that one index patient,

but at this point, I have now treated dozens of patients,

and I’ve heard from hundreds of patients

who’ve been treated by other clinicians, researchers,

or I’ve just heard from patients from around the world

who have shared stories of complete remission

of long, chronic mental disorders,

like bipolar disorder and schizophrenia,

off of psychiatric meds, some of them, not all of them,

but some of them are able to get off all psychiatric meds

and remain in remission.

Again, I think, I didn’t say this before,

but it’s really important to mention.

For people who might be unfamiliar

with the mental health field

and its connection with epilepsy,

the reason that it’s such an important connection

is that we use epilepsy treatments

in psychiatric patients every day

in tens of millions of people.

So a lot of people don’t know this,

but I’ll list off some names

that a lot of your listeners may have heard of,

and they probably know them as psychiatric drugs,

but in fact, these are epilepsy drugs.

Depakote, Tegretol, Lamictal, Topamax,

Neurontin or Gabapentin, Valium, Klonopin, Xanax.

Those are all medications that stop seizures,

and many of them were developed initially for seizures,

but we in the mental health field quickly steal them

and start using them in tens of millions of people,

even if they’re off-label.

So that means we don’t have research studies

documenting that they’re effective,

but we go ahead and use them anyway

because the reality is far too many patients

aren’t getting better with the FDA-approved treatments

that we do have to offer.

So psychiatrists are just winging it in some cases,

and we’re just throwing whatever we can at them,

and we absolutely include epilepsy treatments.

So in many ways, using the ketogenic diet

as a treatment for serious mental disorders

is nothing new at all.

It’s an established evidence-based treatment for epilepsy.

We use evidence-based treatments for epilepsy

across the board for a wide range of mental disorders,

and so in many ways, that’s all I’m doing

with the ketogenic diet.

It just happens to be a diet.

I love it.

I love it, and I should say I love it

because we had a guest on here early days of the podcast.

He’s a colleague of mine at Stanford.

He’s a bioengineer and a psychiatrist,

a phenomenal scientist and psychiatrist,

Karl Deisseroth, who won the Lasker Prize

and so on and so forth,

and he made a really important point,

which should have been obvious to me,

but wasn’t until he said it,

which was the psychiatrist has tools

just like the surgeon has tools,

but the tools are language and observing behavior.

Those are the dissection tools

for what’s going on in someone’s brain,

and then as a neuroscientist,

I’m familiar with the neurotransmitters and neuromodulators,

and you mentioned that there are these tools

of altering brain chemistry,

which are of the sorts of drugs you just listed off

or antidepressants or antipsychotics

that fall into these major bins of adjusting dopamine

or adjusting serotonin or some combination

of dopamine, serotonin, epinephrine, adenosine,

and on and on and on,

and it seems to me it’s an incredible field,

that the field is still very much in its infancy,

that it wasn’t but 100 years ago

that people were measuring bumps on the head

as a way to diagnose phrenology,

and that there’s still so much to learn,

and so when I hear you say,

adjusting nutrition or putting people

into a ketogenic state

or even just eliminating highly processed foods,

sugars, et cetera,

taking care of metabolic syndrome

and then observing tremendous relief

in clinical syndromes or symptoms, rather,

of psychiatric disorders,

it makes perfect sense to me.

It’s yet another dissection tool

and a tool for altering brain chemistry.

I think that if I think about the landscape,

the sort of sociology out there of,

again, it seemed to be these bins,

like a third of people saying,

of course, diet and exercise and social connection

and limiting stress,

like that’s the good stuff,

that’s the stuff that we know really works,

and then about a third of people are sort of unclear,

and then a third of people think,

well, if it’s not a prescription drug,

then it just has no place in medicine,

and hopefully that’s changing,

and certainly the work that you’re doing

is gonna be important in that transition

that I think we will see.

I’d like to talk about mitophagy

and mitochondrial biogenesis.

I think most people learn that the mitochondria

are the energy factories of cells

and that indeed they are.

As a neuroscientist,

what I know about them

is that they are present everywhere in neurons,

not just in the so-called cell body,

but you can find mitochondria

in the furthest little bits of neurons,

and neurons can be quite big,

very large, in fact, meters long or more in some cases,

in some species, including us,

depending on how tall somebody is,

could be many meters or several meters rather,

and that mitochondria do a lot of stuff

besides just produce energy,

because I think people hear mitochondria energy

and they think, oh, so these patients felt better,

they lost weight, they have more energy,

and then they’re doing better,

but here we’re talking about

remission of auditory hallucinations,

people feeling suicidal

and then changing their diet

and feeling like life is something they can deal with

and maybe even function extremely well and et cetera.

So maybe we could just talk about mitochondria for a moment

and then talk about these two major effects.

What are some of the other things

that mitochondria are important for in neurons

and maybe other cells of the brain?

Because as an access point for all this,

I think it would be great if people could learn

a little mitochondrial biology.

Yeah, no, so I guess the first thing that I’ll say

is that, you know, this field

is one of the most cutting edge fields

in medicine right now.

20 years ago or so, I think the majority

of research scientists thought of mitochondria

as nothing more than little batteries.

They take food and oxygen and turn it into ATP

and that’s really important.

Yeah, we get that, but they’re just little batteries.

That’s all they are.

And so one of the reasons that this work is so important

is because it combines cutting edge research

in the metabolic field and the aging field

and we can start to pair it with the mental health

and neurological health field.

So mitochondria, you know, one scientist

gave me this analogy.

He said, if you think of the cell as a computer,

a lot of people think of mitochondria

as the power cord to that computer

because they’re providing the power

and they are in fact the power cord to that computer.

But actually their real function is the motherboard

of that computer.

So mitochondria are directing and allocating resources

throughout a cell.

That is their primary function

and then they happen to be powerhouses as well.

And so to give some clear examples,

mitochondria play a direct role in the production

and release and regulation

of some really key neurotransmitters

including serotonin, dopamine, glutamate, acetylcholine.

Those are pretty powerful neurotransmitters.

I would consider those the,

I know you listed more than three,

but the sort of primary colors of neurotransmission.

Any one of those in excess or deficiency

is going to have profound negative effects

on a nervous system

or it’s gonna alter the way that people and animals feel,

think, move, remember, et cetera.

And so mitochondria are providing

both some of the building blocks, if you will,

for some of those molecules.

They’re part of the Krebs citric acid cycle.

Some of the intermediate products

actually go into making those neurotransmitters.

Much more importantly, mitochondria provide the energy

for the production of those neurotransmitters

and fascinatingly, mitochondria are directly related

to the release of neurotransmitters.

ATP alone is not enough.

There’ve been some research studies

that have actually found that mitochondria

move along the membrane of the synapse

to release batches of vesicles of neurotransmitters

and that if the mitochondria are removed from the synapse

and researchers flood that cell with ATP,

neurotransmitters usually are not getting released.

Mitochondria are doing other things.

We don’t entirely even understand what all they’re doing

or how they’re doing it,

but they’re doing other things

than just providing the power.

Another really important example

is that mitochondria are actually

the primary regulators of epigenetics.

If you look at any one factor,

so one study actually found that they’re responsible

for the expression of about 60% of the genes in a cell.

Mitochondria do this through a lot of ways

that have been known for years and sometimes decades.

So mitochondria are directly related

to the levels of reactive oxygen species in a cell.

They are managing calcium regulation in cells.

And we know that those things play a role

in epigenetic expression.

We know the levels of ATP to ADP or AMP also play a role

and mitochondria are doing those things.

But it turns out mitochondria

are actually doing much more sophisticated things

than even those in terms of gene expression.

Mitochondria at least play a role

in all of the aspects of the human stress response.

So when humans are stressed,

either physically or psychologically,

there are several things that happen.

Increased cortisol, increased adrenaline, noradrenaline,

inflammation, and gene expression

in particular in the hippocampus occur

with the stress response.

And one group of researchers actually

genetically modified mitochondria in four different ways

and found that all of the stress response,

all those four buckets of stress response

were impacted in one way or another,

implying that mitochondria

are somehow playing a role in those.

In terms of their role in cortisol,

we know that mitochondria actually have the enzyme required

for the synthesis of steroid hormones.

So that includes cortisol, estrogen,

testosterone, and progesterone,

some names that maybe everybody’s heard of.

And so that means that if mitochondria

are in short supply or dysfunctional,

the production of those hormones may become dysregulated.

Mitochondria play a direct role in inflammation

and they turn the inflammatory system both on,

or they at least play a role

in turning the inflammatory system both on and off.

I think I’m not gonna be able to quote

the exact study and author,

but one paper in Cell actually identified mitochondria

as the key regulator

in turning certain inflammatory cells off.

And that when you inhibit mitochondrial function,

those cells don’t turn off.

That mitochondrial levels of reactive oxygen species

are a key signaling process

to turn the inflammatory process off.

Another study found that macrophages,

so macrophages are an important immune cell

that play a role in healing.

So if you cut yourself,

your body will send inflammation that way

and send immune cells that way to try to heal your skin.

And macrophages play an important role in that healing.

One group of researchers tried to figure out

how do macrophages know to switch

between the different phases of wound healing?

Because the macrophages do different things

in the different phases of wound healing.

And the conclusion of all of their research

was that it’s mitochondria.

Mitochondria are sending the essential signals

that change the state of the macrophages

to induce these different phases of wound healing.

So I’ve just talked about neurotransmitters,

hormones, epigenetic expression, inflammation.

For anybody familiar with the mental health field,

they know these are like some of the key variables

that researchers have been struggling with for decades,

trying to figure out how do these fit together?

We know that all of those buckets

can be disrupted in people with mental disorders.

And our field has struggled to understand

but how do they fit together?

How can we make sense of this disruption?

And I believe once you understand the science of mitochondria

you can actually connect all of the dots

of the mental illness puzzle.

Super interesting little sub-cellular goodies

these mitochondria are.

I come from a field where people are often divided

into lumpers and splitters and I’m somewhere in between.

For those of you who don’t know,

lumpers are people that like to make things really simple,

lists of no more than three functions

or dividing brain areas into no more than three.

Splitters are people that like to subdivide

into a ton of detail.

There’s a history of scientists being splitters

in order to be able to name things after themselves

because there’s more territory to go around

if you’re splitting than if you’re lumping.

But we are doing neither here.

What I’m hearing is that mitochondria,

in addition to being important sources

of energy production and output in cells,

which of course they are, probably have other roles

and that maybe someday what we call mitochondria

will actually be two or three different

little sub-cellular organelles.

Like there may be little bits in there

that are controlling gene expression

and little bits in there

that are controlling neurotransmitter production.

At least for now, the name is mitochondria.

And thank you, by the way,

for illustrating some of the other things that they do

because in the landscape of science education,

oftentimes people think, okay, energy production,

there’ll be a picture or a cartoon of mitochondria

like flexing its muscles.

People go, okay, energy, mitochondria, mighty mitochondria.

And then they’ll think,

oh, you know, they’re just sort of like

a dumb jock portion of the cell, right?

They’re not doing anything sophisticated.

And everything you listed off

is that they are doing many sophisticated,

intricate things within cells.

So I think how things are cartooned and discussed

actually has an impact

and not just on the general public,

but on the medical field and on the science fields.

Anyway, that’s more science sociology.

But now that everyone is well aware

that mitochondria are doing a large number

of very important things in a very regulated way,

let’s talk about mitophagy.

You know, a few years ago,

because a Nobel prize was given for autophagy,

sometimes called autophagy.

Look, people, you can say it either way.

People know hopefully what it means is more important,

which is the gobbling up of one’s own cells

that are dead or injured.

And this idea of autophagy,

of cells being eaten up or within a system,

nervous system or other system,

has come up again and again.

I actually wasn’t aware that mitophagy

could be such an important lever.

So tell us about mitophagy,

which I have to presume is the intentional

or not gobbling up of mitochondria,

presumably to replace them

with newer, healthier mitochondria.

Is that right?

It is.

So in many ways, mitophagy is a subset of autophagy,

but it’s got its own name

because it is specific to mitochondria.

There do appear to be some unique regulators of mitophagy

compared to autophagy more broadly.

Mitochondria actually are playing a role

in autophagy itself.

And this makes sense because one of,

so the global picture of autophagy

is stimulated by fasting states or fasting mimicking states.

So when your body senses that you don’t have enough food,

it actually hunkers down

and starts to recycle dead old parts

in this kind of carefully orchestrated way.

And it takes them to lysosomes, they get degraded,

and then those degradation products get used

for either energy or to build new things.

Autophagy is always occurring at a low level,

but you can really hyper-stimulate the process

through fasting, calorie restriction,

fasting mimicking diets, other things.

And this is why fasting and calorie restriction

is so kind of such hot topics in the medical field now

is because they’ve been shown to induce longevity

and we think it’s probably through that process

that you’re stimulating the body

to kind of become lean and conservative

in terms of its allocation of resources.

And the body doesn’t just destroy the healthiest tissue

along with the old dead stuff.

It has these processes that identify

the old and defective parts first and they go first

and that’s what’s beautiful about the whole thing

and that’s why fasting is so important.

So mitophagy we know plays a really important role

because so there’s this term called mitochondrial dysfunction

which some researchers are actually wanting to get rid of

and move away from because as you just said,

mitochondria do so many different things

and different mitochondria even within the same cell

may very well be specializing in different tasks

and mitochondria from one cell to another

are sometimes doing very different things.

Like not all mitochondria can produce cortisol.

That’s specific to specific cells

where those genes are getting turned on.

So it’s not like all mitochondria are producing cortisol

just the ones in your adrenal gland for instance

are producing cortisol.

But there is this term mitochondrial dysfunction

and it has long been known for decades

that mitochondrial dysfunction is associated

with everything that ails us essentially.

So in the 1950s we had a theory of aging

that was based on reactive oxygen species

and that essentially and that’s where all the inflammation

is bad for you comes from.

And where all the noise about antioxidants.

Yes.

Like in the 90s it was like it contains antioxidants.

Not to say antioxidants are bad

but they are certainly not the be all end all of health.

They are not but that’s exactly

where that research came from

is that researchers were narrowing in

on these reactive oxygen species

are highly, highly correlated with all of the diseases

of aging and poor health outcomes.

Turns out they’re also highly, highly correlated

with all chronic mental disorders interestingly.

And so researchers used antioxidants to see

if well maybe if we can stop somehow tame

these reactive oxygen species will improve health outcomes.

Doesn’t seem to work.

By the 1970s our understanding of mitochondria

and their role in the production

of reactive oxygen species expanded

and that led to the mitochondrial theory of aging.

So in the 1970s we had this mitochondrial theory of aging

based primarily and exclusively on reactive oxygen species.

Fast forward a couple of decades that was disproven

because we now know reactive oxygen species aren’t all bad.

They actually serve a signaling process.

They’re a normal part of human functioning

and cellular function.

So they’re not all bad but we still know high levels

of reactive oxygen species are bad for you.

Fast forward to just I think maybe last year

with this expanded role of all of the different things

mitochondria are doing.

So David Sinclair published a paper

in one of the cell journals I think

saying that oh mitochondria are actually the unifying link

of everything that we know about aging.

Mitochondria are the cause or defective mitochondria

or defective mitochondrial function,

mitochondrial dysfunction is possibly the unifying cause

of aging and all of the aging related disorders.

So mitophagy is trying to address all that.

It’s trying to say okay this is bad,

we don’t want defective mitochondria

and how can we get rid of old ones or defective ones

and replace them with new ones.

And I think the most powerful signal

and tool that we have right now is in fact related to diet.

It’s calorie restriction that is the oldest,

truest kind of best proven way to prevent aging

in a wide variety of animal species.

Fasting and intermittent fasting

and again you can only do those things for so long

and then fasting mimicking diets

can also stimulate this process of mitophagy.

Before we talk about mitochondrial biogenesis,

if and I certainly accept the idea

that mitochondria are extremely important

in physical health and mental health.

That’s for me is a straightforward conclusion at this point

based on what you’ve said, what I’ve read elsewhere,

et cetera and if various diets,

including ketogenic diet, including fasting,

reducing sugar intake, et cetera

can assist in mitochondrial function and mitophagy

and that’s at least one of the levers

by which diet can positively impact mental health

and physical health.

Can we conclude that there’s something special

about low blood glucose in the brain, right?

I mean that the sort of common pathway

of all of those things, fasting, ketogenesis

for some people maybe they,

maybe some people manage have great insulin management.

So just removing sweets, refined sugars,

brings down their blood glucose level substantially.

They don’t need to go on a ketogenic diet

in order to relieve a low level depression

or something like that.

It seems like the common theme here

is that glucose levels in the brain need to be reduced,

which for me is surprising because neurons love glucose.

I mean, there are some really nice studies,

one that I can think of recently

that was published in Neuron.

If you just look at the tuning of a neuron,

how well a neuron in the brain

represents some visual image in the environment

in terms of, here we can just generalize

and saying more action potentials,

more electrical signals from the neuron

generally correlates with better high fidelity representation

it’s like sort of, you have everyone’s time

someone says shout and then someone shouts

the neuron is like the one responding to the order

and these neurons just when there’s high glucose,

they are faithful representatives

of what’s out there in the world.

But then when you fast an animal,

they become less faithful representatives

of what’s out there.

And yet when I’ve done intermittent fasting

and I do a kind of modified version of it,

my mental clarity is far better

than when I’ve had a big bowl of pasta,

probably for other reasons,

related to serotonin and tryptophan.

And so I think for the typical listener out there,

I have to imagine it’s gotta be a little confusing, right?

We hear neurons love glucose, they live on glucose.

And here we’re saying, let’s deprive them of some glucose

or let’s just bring glucose levels down

or let’s switch the fuel source of the brain

from glucose to ketones.

And now the brain really works the way it’s supposed to.

So this raises a little bit of a just so story question,

like why would it be the case that neurons love glucose

and yet if there’s too much glucose around,

they become sick?

And of course with any, why would it be story?

As I always say, I wasn’t consulted at the design phase

and I’m going to presume

that you weren’t consulted the design phase either.

And that if any of us say that we are,

then we are probably the patients that need evaluation.

So I think there’s a name for that, right?

There’s delusion, right?

Okay, I threw up my first correct clinical assessment

of myself.

So how do I get my head around this, right?

You’ve got me sold on mitochondria,

not that I needed to be sold, but that’s an easy,

like, yes, yes, absolutely, yes.

The idea that diet can impact mental health

and physical health.

Yes, absolutely, by way of mitochondria, at least in part.

Great, but then neurons love glucose.

So what’s going on or what do you think is going on?

I am not convinced that glucose is the real story.

Glucose may in fact be a symptom.

So we know that parts of the brain,

there have been a couple of studies

that just came out in the last couple of weeks, I think,

documenting that actually astrocytes in the hypothalamus

play a key role in glucose regulation throughout the body.

And it appears to be a metabolic role,

which in my mind implies that the mitochondria

in those astrocytes are probably playing a key role

because we know mitochondria play a key role

in sensing glucose levels.

They play a key role in the release of insulin

from the pancreas.

But mitochondria in the brain is also playing a role

in kind of balancing how much glucose is around.

And so it’s a difficult question

because I think in some cases,

high glucose levels are actually a symptom

of metabolic dysfunction somewhere in the body or brain.

And when I think about, well, what does that mean?

In my mind, most of the evidence currently

is pointing to mitochondrial dysfunction

somewhere in the body or brain

that is the most likely cause of that dysregulation

of glucose levels.

But we know that if you consume massive amounts

of junk food, sugar, and other things,

that you can get dysregulation of glucose levels.

The conundrum though is that that’s not a universal response.

And what about the typical person?

Like I’ve never really liked junk food that much.

Maybe as a kid, I can recall liking candy,

but I was a sandwich for lunch person for a long time.

And as I’ve changed that out for salad

and maybe a small piece of meat with my salad

or something like that, I feel far better during the day,

far more alert, but I do eat carbohydrates.

I eat starches typically at night,

but I tend to do some very hard training

at some point during the day.

So I imagine I have some glycogen to repack.

Okay, that’s me.

I only mentioned that because I’m not in ketosis

as far as I know, unless you brought the strips.

I haven’t done the blood glucose test today.

So what about the typical person who’s an omnivore

eating some rice, some pasta, pasta salads,

people that are eating not junk food,

massive amounts of sugar,

but have blood glucose that’s in kind of moderate range.

Do you think, and here, feel free to speculate,

do you think that those people might feel far better

or even a little bit better

if they were in a lower glucose state?

And I ask this because I think there are a lot of people

out there who suffer from full-blown depression,

but there are also a lot of people who suffer

from like moodiness and feeling not so great,

subclinical depression.

Yes, burnout is what I would call it.

Yeah, and just feeling like some days are great

and then other days they feel lousy

for reasons they don’t understand.

Yeah.

And those make for less dramatic case studies,

and yet I have to assume that that description

will net a large fraction of the general public.

So the way that I kind of break this field,

and I’m probably getting too nerdy right now,

but I kind of break this field into cause,

what’s the actual root cause,

and what are effective treatments?

And I really see them as two separate things.

Just because the ketogenic diet is an effective treatment

does not imply that the cause of the problem

was eating carbohydrates.

And I think that’s a really important distinction.

There are many people who disagree with me on that.

There’s no doubt about it.

And everybody’s heard people say,

sugar is the cause of everything that ails you,

or carbs are the cause of everything that ails you.

If everybody does a low carb diet or a ketogenic diet,

and then they go to, so it must be sugar that was the cause.

I don’t see it as clearly black and white as that.

The calorie restriction, ketogenic diet,

carbohydrate restriction,

are inducing metabolic changes in the brain and body.

And regardless of what the person was eating,

they are inducing metabolic changes

that can be really beneficial to brain health.

So let me just give a clear black and white example of this,

and then I can speak to the broader topic

that you brought up about just the general population.

The easy example of the ketogenic diet

being an effective intervention

for somebody who was not following a bad diet

is an infant with epilepsy.

There are lots of infants who have uncontrollable seizures.

They are drinking breast milk.

To the best of our knowledge,

that is the primary most beneficial food source,

an infant could be consuming.

Now, some might say, well, maybe the mother’s,

whatever, I don’t buy that.

The mother’s breast milk is in fact

the optimal food source for that infant,

and yet that infant is still seizing.

If we put that infant on a ketogenic diet,

a lot of those infants seizures will stop.

It doesn’t mean that the cause of the infant seizures

was a bad diet,

but it means a dietary intervention

can change brain metabolism

and improve symptoms in that person.

So going to your broader question about adults modern day,

the real answer is, you know,

there was just this conference in London,

the Royal College of Obesity Medicine

or something like that, that’s not the name,

but it’s something along those lines.

The conclusion of that conference,

it invited the greatest minds in obesity medicine.

The overarching conclusion of that conference was,

we don’t know what causes obesity.

It’s really important that we sit with that.

We don’t know what causes obesity.

They don’t think excess caloric intake

beyond one’s daily metabolic needs is causing obesity.

Some will argue that,

and so some will say, yes, it’s all energy balance,

but why do we have an epidemic of obesity?

Well, that’s the gazillion dollar question.

And junk, some will say it’s all the junk food,

but we had junk food in the 1970s.

When I was growing up, I grew up on Kool-Aid

and Twinkies and King Dongs and Ho-Hos.

Oh, I’m re-watching the Mad Men series now.

I love that series and I’m re-watching it.

And I happen to know someone who worked on that series.

They research everything for the props

and the costumes and everything, but right down to diet.

And if you look at the diet, it was terrible.

It was mostly, yes, there was a lot of excessive amounts

of drinking and cigarette smoking,

but the diets were terrible.

It was prepackaged foods.

It was frozen dinners.

I mean, that really came to prominence

in the 70s and 80s, but even in the 50s.

And from what I’ve been reading, even in the 30s and 40s,

people were not eating grass-fed meat and Brazil nuts

with a little bit of broccoli rabe on the side.

That is not the typical intake.

So something out there, or maybe multiple things

are at play to increase obesity.

And at the end of the day, I believe,

some will call this speculative,

but I actually think we’ve got a tremendous amount

of evidence that continues to point in this direction.

I believe that mitochondria are the key

to the obesity epidemic,

that there is something in our environment.

So that is either our food, environmental toxins,

stress levels, poor sleep, not getting adequate sunlight,

whatever you wanna speculate on, all of the above.

All of those things are known

to impair mitochondrial function.

And if parts of your brain that regulate metabolism

and that regulate eating behaviors

are not metabolically healthy,

it means that they will not stop you from eating,

or it means that your metabolism will not rise

to the challenge of 10 doughnuts.

Because some people can eat 10 doughnuts

and go on staying thin and healthy.

I totally agree, although I would just like to say

that it seems to me that compared to when I was growing up,

and again, I haven’t run the statistics,

there are fewer and fewer of those individuals around now.

Just as when I was growing up,

it was one or two kids in class that were quite overweight.

And then there were some that were mildly overweight,

but most were of healthy weight.

Nowadays, that’s dramatically altered.

The landscape is dramatically altered

in the other direction.

It is rare when I encountered

one of those can-eat-anything type people.

I know one, he’s actually an employee at Stanford.

He’s on our media team at Stanford.

And this guy, when I take him to lunch,

it’s like, he’s in his early 70s and he can eat

and he’s incredibly lean.

He exercises a little bit,

but he’s one of these mutants

that just can eat and eat and eat.

And he’s lean and he’s vital and it’s wild.

And he’s an expensive lunch.

But those people seem rare.

And even those kids are now seem rare.

They’re getting increasingly rare.

And that leads me to think it may be epigenetic factors

in the womb environment,

so that kids are actually coming out

predisposed to obesity.

Well, let me ask you about that

because I had a note here to ask this later,

but I’m going to interrupt you now

in order to capture this moment.

My understanding is that, well, as everyone knows,

we inherit DNA.

We get genes from both of our parents and they mix.

Although there are incredible data

from Catherine Duloc’s lab at Harvard

and others showing that we actually have entire regions

of our brain that carry neurons

that are purely of mom’s or of dad’s DNA,

depending on the brain region.

This is a wild finding, but it’s accurate.

And this has actually been known about

in terms of heritability of disease, et cetera.

Maternal DNA, DNA from mom,

genes from our mother,

not to place blame on mothers at all.

My understanding is that the mitochondrial DNA

come exclusively through the maternal side.

Is that true?

So it’s a great question and I’ve been asked this before

and yeah, psychiatrists are known for blaming mothers

and some might say that I’m like trying to redo

that whole thing and blame mothers again.

The data are the data.

I’m not trying to blame mothers here.

Mothers play an essential role in everything.

But if it is true that mitochondria

are the linchpin of all this

and maternal DNA is what determines the mitochondrial DNA,

I think it’s an important place to look.

It’s an important question.

And the answer is unequivocally no,

that’s not the way it works.

Well then, vindication for anyone that was asserting that.

And so let me explain it.

So mitochondria have 36 genes unto themselves.

13 of those genes code for some of the mitochondrial

machinery of making ATP

and the other 36 play roles in epigenetic regulation,

play roles in whole body metabolism and other things.

But so that is what you’re inheriting from your mom

is the mitochondria and those 36 genes for the most part.

But the majority of proteins that make up mitochondria

over I think 1,300 genes that make up mitochondria

are actually encoded in the nuclear DNA.

And so you inherit a copy

from both your mother and your father.

So the majority of people who have mitochondrial defects

or rare mitochondrial diseases

actually could inherit them from either mom or dad

because it can be a defect in the nuclear genes

that code for proteins that make up mitochondria.

The much bigger issue,

so when I talk about mitochondrial dysfunction

being a primary driver of mental illness, metabolic illness,

it’s not that people inherit a defective mitochondrion

or mitochondria from mom

and then that just ruins their life forever.

That’s actually not the way it works.

The beautiful thing about this theory

is that it connects all of the risk factors

that we already know play a role in mental health

but also metabolic health.

Sleep disruption impairs mitochondria

and mitochondrial function.

Stress, high levels of stress and trauma

impair mitochondrial function.

Drug and alcohol use,

alcohol, tobacco definitely in terms of the smoke

and marijuana, THC in particular,

all impair mitochondrial function.

THC directly or the smoke?

THC directly.

Those studies have been done.

And so mitochondria actually have CB1 receptors

right on them.

And various researchers,

a couple of studies from Nature actually documented this,

that the mitochondrial CB1 receptors

are primary kind of primary points

of the influence of marijuana

on human behaviors and effects.

So because when they remove CB1 receptors in animal models,

these changes don’t happen.

So the CB1 receptors,

we’ve got some large studies of adolescents

who use a lot of marijuana.

And the areas where the mitochondria

have the greatest number of CB1 receptors

are areas of their brains that actually are atrophied

or shrunk compared to normal healthy controls.

So that means their brain tissue is aging prematurely.

It’s shrinking prematurely.

But the CB1 receptors on mitochondria

also seem to play a role in the memory impairment

that can be induced from THC.

And they also play a role in the kind of lack of motivation,

the behavioral amotivational state from THC.

Now again, for people who want to chillax,

that’s what they’re looking for.

They don’t wanna remember anything.

They don’t wanna think.

They wanna be spaced out.

They wanna relax.

That’s great.

But it’s important that they know

that they’re actually harming the mitochondria

in their brain cells.

And that although there’s always an opportunity

to repair mitochondria and always an opportunity

to stimulate mitochondrial biogenesis,

so you can get it back.

But if you keep doing it chronically,

you’re probably not helping your overall

mental or metabolic health.

Yeah, I’m glad you brought up THC.

We did an episode on cannabis.

We also did one on alcohol.

Probably lost some friends from that one.

I mean, when you look at the data, it’s very clear.

I mean, I’m not arguing that people dislike the effects

of these compounds when they take them.

But it is clear that, at least to me, based on the data,

that regardless of what people have read about red wine,

that not drinking any alcohol is going to be healthier

than drinking alcohol

and that the thresholds for alcohol ingestion

before people start to negatively impact their health

is about one or two per week.

And then THC, because of the very high concentrations of THC

that are present in a lot of products now,

vaping and smoking THC and even edibles,

that it can be problematic.

You mentioned adolescence,

predisposition to brain atrophy, psychosis, et cetera.

In any case, because you mentioned alcohol

and because it is a commonly used substance,

I heard you give a talk in which,

I think I have this right,

in which alcohol can disrupt the way

that the brain uses fuels of all kinds,

which may disrupt one’s response to alcohol,

make alcohol seem more rewarding

to those that drink alcohol.

So drinking alcohol makes alcohol more rewarding

to the brain’s alcohol drinkers,

but that it also might alter glucose metabolism,

that basically alcohol is not good for our brains.

Do I have that correct?

You do have that correct.

Okay.

What happens if you take an alcoholic

or somebody that just drinks two to four nights a week,

a couple of drinks,

which I think is pretty common out there,

and you put them on a ketogenic diet.

Has that experiment been done?

That experiment has been done.

And led by none other than a woman named Nora Volkow,

who is one of the leading neuroscientists

and addiction researchers in the world.

She is the director

of the National Institute of Drug Abuse.

She’s been hot on the trail of metabolic abnormalities

in the brains of people with alcohol use disorder,

which I will just refer to as alcoholics

because that’s what everybody knows it as.

So she’s been hot on this trail for many, many years.

And as you said,

it turns out that the reward pathways in particular

are metabolically compromised in alcoholics.

And the metabolic compromise essentially in a nutshell

means they aren’t getting enough fuel from glucose.

The interesting thing is that when people drink alcohol,

your liver converts alcohol into a molecule called acetate.

That acetate travels up to the brain

and fuels brain cells,

in particular some of these reward pathway cells

more than others.

And so chronic alcoholics have this chronic deprivation

of energy in these cells.

And so Nora Volkow and other researchers

at National Institutes of Health

did a study in which they set out to see

if we can change this brain metabolic problem in alcoholics,

will that affect clinical symptoms of alcoholism

and will it do anything that’s clinically useful?

And so they actually did a pilot randomized controlled trial,

admitted alcoholics to a detox unit.

Half of the patients got a ketogenic diet.

The other half got the standard American diet.

And everybody else, all of them got the same detox protocol.

The patients who got the ketogenic diet

required fewer benzodiazepines for their detox.

Despite that, they had fewer withdrawal symptoms

from the alcohol.

They reported fewer cravings for alcohol.

And the researchers did brain scans

which showed improved brain metabolism

in these key areas that they were looking at.

And their brains showed reduced levels of neuroinflammation

which was also something they were really interested in.

And so that one study says to us

that even though most people would think

alcoholism has nothing to do with diet,

alcohol is just drinking too much.

It’s a matter of willpower

or it’s somebody who’s addictive.

They’ve got an addictive personality and it’s that simple.

You come out of the womb with an addictive personality

and those people are novelty seekers and they’re impulsive

and they have no patience.

They have no discipline.

They can’t sustain any kind of rewarding experience.

Or childhood trauma.

There’s a story there, which there very well may be.

And there may be.

And but what that research study strongly suggests,

and again, yes, maybe we need larger controlled trials

but this is one of the leading neuroscientists in the world

who’s hot on this trail.

This is what she believes and this is what I believe,

is that if we can correct the brain metabolic defects

from chronic alcohol use,

we might be able to help people be sober

and give them a fighting chance or give them an edge up

or pull a lever that we can use in their favor

for their benefit.

There’s one caution to all of this research

that I really do want to highlight.

And so now I’m going to get hate mail

from all the keto community.

That’s okay.

I mean, anytime I admire you

for talking about nutrition at all

because anytime one talks about nutrition,

you’re going to get hate mail from somebody, but.

So the caveat to all of this is that as part of the research

that those researchers were doing,

they actually wanted to see what will happen

to alcohol levels if an animal consumes alcohol

while on a ketogenic diet.

So they didn’t do this in humans yet.

This is a fairly easy study to do.

So I’m hoping somebody will do this study soon.

But they instead put rats, half of them on a standard diet

and half of them on a ketogenic diet.

And then they exposed them

to the exact same amount of alcohol.

The rats who were on the ketogenic diet

had a five-fold increase in blood alcohol levels.

Five-fold increase.

Meaning they drank more or it was metabolized differently.

It was metabolized differently.

The rats all got the same amount of alcohol.

So for people out there who are ketogenic,

I’m chuckling, but who are not alcoholics,

please, alcoholics, please do something about it

because it’s so detrimental.

I guess, does this mean that they can drink less

in order to get the effect of alcohol

that most people are seeking?

Cheap dates.

Cheap date is what you call that.

You only need a half a drink instead of three drinks.

I would think the keto community would thank you for this

unless they somehow have a stake in the alcohol industry.

The reason that I put it as a caution

is that if anybody is struggling with alcoholism

and thinks, hey, I need an edge up,

I need a lever to pull

because I’m really struggling to give this stuff up,

I just find myself going back.

And if you’re telling me my brain metabolism is messed up

and this might help it, I’m all in favor of that.

And yes, that’s what the researchers are pursuing

and that’s what I’m saying with the following caveat

that if you relapse while on a ketogenic diet,

you better not drink the same amount of alcohol

that you think you can drink.

Could be deadly.

It could be deadly and or it could be really deadly

to you or someone else because unfortunately,

a lot of times when people drink,

they get behind the wheel

and they think that they can handle two drinks safely

and they think, well, I can go out for dinner

and have two glasses of wine and drive home safely.

I know myself.

If you go to a ketogenic diet,

please don’t drive with the same two drinks

because it means your blood alcohol level,

if it models anything that we found in the rat study,

your blood alcohol levels may be five times higher

than they would normally be.

And that means you are really wasted

and you’re probably not safe to be driving.

Probably the same is true

for drinking on an empty stomach, right?

Yeah.

Yeah, no, that’s a very important point

and thank you for raising that.

I mean, I hear this again about mitochondria,

about blood glucose.

You mentioned astrocytes

and for those of you who heard that earlier,

astrocytes are a non-neuron cell type in the brain,

a glial cell type that my postdoc advisor

was known for sort of popularizing

the modern science of glia, which include astrocytes.

And I’d be remiss if I didn’t say that they do,

they are considered the cells

that hold everything together in the brain

and are kind of passive observers,

but they do many things actively there.

I think now people appreciate the astrocytes

at least as important as the neurons.

And certainly for disease,

they are often implicated in warding off of disease, et cetera.

Everything that you’re telling me about,

the fact that the brain can regulate things

that are happening in the body, metabolism, et cetera,

organ health, obesity, et cetera.

To me as a neuroscientist, that’s not surprising.

All of it just screams hypothalamus, hypothalamus,

hypothalamus, because here you’re telling me

it’s regulating these basal functions like metabolism.

It’s regulating how much we crave things.

And of course, hypothalamus is involved

in motivation and craving.

There are other areas too,

other areas of the brain too, of course.

But I would imagine that someone ought to,

or has mapped out where the receptors

for all this business are in the brain.

And I guess that raises the question

of when one goes on a ketogenic

or low blood glucose diet or fast,

has anyone observed changes in the brain?

Has anyone had neuroimaging of humans and their brains

under conditions of ingesting one diet or another,

whether or not they’re suffering

from a psychiatric disorder or not?

I would think that’s where the gold is.

We do have some of those studies.

When you do a neuroimaging study,

you can measure a lot of different things.

So one thing with a PET scan,

you can measure glucose metabolism.

So a researcher, Stephen Cunane,

is doing that research in particular

in Alzheimer’s disease patients

and Alzheimer’s disease models, but in humans.

And that’s because we know that,

again, a common finding in patients

with Alzheimer’s disease is this glucose hypometabolism.

Some people are attributing it

to insulin signaling impairment.

And so some people are calling it type three diabetes.

The end of the day, I think the clearest signal that we have

is that cells aren’t getting enough energy

from glucose as a fuel source.

That is something that I think I can confidently say

that’s backed by numerous research studies.

There’s debate in the research field

about whether that’s a primary driver of the illness.

I happen to believe it is.

And if you ask the question,

why would cells not be getting enough fuel from glucose?

You have to focus on mitochondria

because they’re the ones producing the fuel

from that glucose.

So somehow you have to implicate mitochondria

in that process one way or another.

Others will say, no, that’s just a side effect

of whatever’s causing Alzheimer’s disease.

But so Stephen Cunane has done studies

where he even gives ketone supplements.

These are liquid ketone esters.

So yeah, ketone esters or ketone salts.

And it has actually found that these brain metabolism

deficits can be corrected at least short term

by giving a ketone supplement.

Is this in the context of people

also ingesting some carbohydrate?

Because I confess, I’ve tried the ketogenic diet.

I probably did it wrong.

This was years ago.

And then the cyclic ketogenic diet.

But in the last year or so,

I’ve started using liquid ketone esters.

And I do eat some carbohydrates each day,

usually in proportion to how much high intensity exercise

I’m doing.

Those liquid ketone esters for me, at least subjectively,

I feel like greatly increased my energy levels

and my ability to focus mentally.

And they improve my sleep.

This is my observation, tracking some data,

but just again, subjectively.

So in this example, are you talking about people

taking ketone esters or ketone salts

on a backdrop of a ketogenic diet

or on the backdrop of a more typical diet?

So he’s done both.

So he’s done studies where patients

aren’t doing anything special with the diet.

So they’re eating whatever they normally eat,

absolutely non-ketogenic,

giving them a ketone salt or ester,

and then noticing immediate and direct changes

in the metabolism of these

metabolically compromised brain cells

as measured by pet imaging.

These are not household pets, by the way.

I’m sorry, we have to just,

Petri, positron emission tomography, not pets.

Although I’m sure that there are people out there

who have their dogs or cats or whatever,

or their pet kangaroos, whatever you might own

on ketogenic diets.

Okay, not today.

Absolutely.

So he’s actually moved further.

He’s done a pilot trial in a nursing home, actually,

where he did not put the patients on a ketogenic diet.

He simply reduced carbohydrate consumption

at breakfast and lunch.

They still got the same dinner as everyone else.

And simply reducing carbohydrate consumption

at breakfast and lunch resulted in cognitive improvement

in a statistically significant way

in some of those subjects.

Oh, I love that result.

I’m sorry, I just have to highlight this.

I’m a huge believer in directing carbohydrates

to specific portions of the day

when one needs to be less focused and alert

and yet can replenish glycogen.

Limiting carbohydrates most of the time during the day

for me has been a game changer

in terms of maintaining alertness, et cetera.

I’m not aware that I have age-related cognitive decline,

but then again, people around me may argue otherwise.

Let me say, you are Andrew Huberman.

There is no way you have cognitive impairment.

Although you didn’t know me as a six-year-old.

If you have cognitive impairment, we’re all screwed.

Well, I have plenty of flaws and impairments.

I’m well over 3,000 documented by people very close to me.

But this is very interesting, I think,

in the context of everything we’ve been talking about,

because could it be that supplementing with liquid ketones

or prescribing liquid ketones

to people who are challenged with mood disorders

or things of that sort could be beneficial

even if they are not willing or able

to adhere to a ketogenic diet?

That is the million-dollar question right now,

and we don’t have good trial data to say yes or no.

My speculation, my hunch,

having tried that clinically with patients

is it doesn’t seem to work.

It’s not the same thing.

The bigger reason for my feeling confident in saying that

is that we’ve had ketone salts and esters

available for over a decade now.

We have tens of thousands of children and adolescents

who are following a strict,

ridiculously strict ketogenic diet to control their epilepsy.

Those kids would love to be off the ketogenic diet.

Their parents would love to have them off the ketogenic diet.

Yeah, no birthday cake, no ice cream.

There is not one case report

of any child controlling his or her seizures

using exogenous ketones

without also doing the ketogenic diet.

I just find it hard to believe

that at least some of those people

haven’t tried it out to see.

I do know some patients with bipolar disorder

and even schizophrenia

who are doing extraordinarily well on a ketogenic diet.

They have tried to switch off the ketogenic diet

using exogenous ketones.

Their symptoms came back,

and so they found that it just wasn’t effective.

Again, those are anecdotes.

My scientific speculation about why

is because the ketogenic diet is actually

not necessarily about ketones themselves.

Ketones are one of a multifaceted story there.

And so when people do a ketogenic diet,

they’re also improving, they’re lowering glucose levels,

they’re improving insulin signaling,

they’re ramping up mitochondrial biogenesis,

in particular in the liver,

because mitochondria actually make ketones.

That’s where they’re made,

and they’re primarily made in the liver mitochondria.

So when somebody’s in a fasting state

or on a ketogenic diet,

their liver mitochondria go through the roof

because they’re being called to action.

It’s like, hey, body’s in starvation mode, get to work.

And so the mitochondria, the cell senses,

we need more mitochondria to process fat,

to turn it into ketones,

so that those ketones can get up to the brain

and keep the brain fueled,

because fatty acids can’t fuel the brain.

Only ketones can.

Now, so my sense is that,

and the gut microbiome changes and everything,

the changes in hormones.

So if you’re eating a lot of donuts

and drinking a bottle of ketones,

the donuts are going to prevent your body

from lowering glucose levels.

You’re still gonna have the high glucose levels

from the donuts.

You’re still gonna probably have

the impaired insulin signaling.

You’re probably still going to possibly have

some inflammation from the inflammatory effects

of that food.

And so just drinking ketones alone won’t be enough.

I think for people who are metabolically healthy,

I’ll include you in that,

I think ketones can play a really beneficial role,

no doubt.

I think exogenous ketones may in fact

prove invaluable in clinical use

for patients who maybe can’t follow

a super strict ketogenic diet,

but maybe could do a low carb diet.

And then given the research that’s happening

with alcohol use disorder,

I could imagine a situation,

here’s the million dollar tip

to whoever wants to go out and get this

if it actually turns out to be true.

I could imagine a scenario where we use

exogenous ketones with alcoholics

and that every time they have a severe craving for alcohol,

they drink ketones instead.

Which sort of tastes like alcohol.

The ketone esters, when I take them,

I drink them straight.

Sometimes I’ll put them in seltzer

and I’m not a big drinker.

As I mentioned, I might have an alcoholic drink

every once in a while.

I just don’t ever crave it.

I just do it every maybe,

I think 2020 was the last time I had a drink of alcohol.

And so obviously I’m not a good representative example.

But the ketones taste good to me

and they obviously don’t get you drunk.

They do seem to flick on my alertness pretty quickly.

And my understanding is that they are

the brain’s preferred fuel source,

meaning they are going to be the first fuels

used by the brain when there’s a buffet of fuels available.

There’s glucose in my bloodstream,

there’s circulating liquid ketones,

that ketones would be used first or preferentially.

Is that true?

I think it’s a complex question.

I mean, some research that we have

suggests that there are brain areas or brain cells

that require glucose and cannot use ketones.

So 100% of the brain cannot be fueled with ketones

as far as we can tell.

So there are some areas that require glucose

and that’s probably the reason we have gluconeogenesis

is to keep the body going

and keep the brain going no matter what.

But when ketones are available,

especially if ketones are high,

the way I think about it is not that ketones

are like the preferred fuel source

and glucose goes to the wayside.

But the way I think about it is that

you have a range of cells

with varying degrees of metabolic health.

And some of those cells are gonna be extraordinarily healthy

with appropriate, healthy, abundant mitochondria.

And those cells are probably going to continue

to use glucose as a fuel source.

But if ketones happen to be there,

sure, they’ll use that too.

Like, why not?

But the real money is metabolically compromised tissues,

whether it’s brain cells or other tissues.

But we’re talking about the brain.

So if you’ve got metabolically compromised brain cells,

because it’s not across the board,

like with Alzheimer’s brain scans,

there are specific regions

that are more metabolically compromised than others.

And that’s why we see patterns of atrophy

in specific brain regions,

is because those regions are dysfunctional

metabolically for whatever reason.

And we can get into why that might be.

But my sense is that

if you’ve got a metabolically compromised cell,

that cell is sending out a distress signal.

That cell is calling resources from the body,

like, feed me, give me something.

And if it can’t use glucose effectively,

it is gonna suck up those ketones

and then start running on all cylinders or closer to it.

And that process is so critical

because what it means is that

if that cell was barely getting by on 60%,

of its real ATP requirement,

it means that it doesn’t have enough energy

for maintenance and repair functions.

As soon as you give that cell 100% energy or close to it,

even if you get it up to 90% of its preferred energy amount,

it can start to repair itself.

I mean, that’s the beauty of the human body

and living organisms,

is that they have a priority list of what they’re gonna do.

And if that cell senses that there are defective molecules,

defective proteins in this cell that need to be replaced,

once it gets enough fuel,

it will start repairing itself and doing that work.

That makes sense.

Thank you for that clarification.

I’d like to talk about Alzheimer’s

and age-related cognitive decline generally.

I know many people out there are just terrified

of losing their memory for the obvious reasons,

memory sets context, et cetera.

And many people have relatives that suffer from Alzheimer’s

or other forms of dementia.

I’ve heard that the ketogenic diet and diets like it

can be very effective for helping to offset

some of the symptoms of Alzheimer’s

and age-related cognitive decline.

In fact, I even have a friend,

I won’t out him by institution,

who’s the chair of cardiology,

who contacted me of all people,

asking whether or not I was aware of any studies

or whether or not I knew of anybody

who had benefited from ketogenic diet for Alzheimer’s.

And I thought,

well, why don’t you ask one of your colleagues in neurology?

But his response was really interesting.

He said, there are many books out there

for the general public.

There are a lot of online discussions about this.

There are a lot of assertions about this

in some animal studies.

But again, these are his words.

There are very few, if any, controlled clinical trials

exploring the role of the ketogenic diet

for the treatment or reversal of Alzheimer’s

and age-related cognitive decline.

I’m hoping that statement was incorrect

or soon will be incorrect

because those trials are ongoing.

But he said, yeah, the people who are most popular

for telling us about the important role

and positive role of being in ketosis for Alzheimer’s,

for some reason, they just won’t do a clinical trial.

And that’s been frustrating to the community.

So this is a very educated, very accomplished person

who’s a physician of heart medicine

as opposed to something else related to the brain.

But what is the story there?

And for goodness sake,

why aren’t there clinical trials

on ketogenic diet and Alzheimer’s?

I don’t expect you to be responsible for that fact,

but goodness, I would think this would be

the obvious thing for NIH.

I’m on the study section,

but not for these sorts of experiments.

Why isn’t money just avalanching into this area

based on all the anecdotal evidence

that people are talking about?

So we’ve got a couple of small pilot clinical trials.

The best one was a randomized controlled trial.

I think it only included 26 subjects, something like that.

Randomized to 12 weeks of a low fat diet,

10 week washout, 12 weeks of ketogenic diet.

Some of the participants got keto first and then low fat.

Other participants got low fat then keto.

And that trial actually found that

when patients were in ketosis,

they had statistically significant improvement

in activities of daily living and quality of life.

And they did have improvement in cognitive function,

but it didn’t reach statistical significance.

That improvement did not.

We’ve got other trials.

We’ve got several animal models

showing that the ketogenic diet can improve biomarkers

of Alzheimer’s disease in Alzheimer’s models.

So it can reduce plaques and tangles,

can even improve cognitive impairment in animal models.

We’ve got a couple of other small pilot trials

of ketogenic diet in humans

showing that it improves biomarkers

compared to say the low fat diet

or the American Heart Association diet.

So we’ve got those.

I think one of the biggest challenges

that I’ll just share openly,

and I’m somebody who’s pretty passionate about this research

and I believe it has a lot of potential,

but Johns Hopkins researchers attempted

to do exactly this kind of a study.

Alzheimer’s patients, ketogenic diet versus the,

I think American Academy of Aging

or something like that diet as the control diet.

Which presumably has starches in there.

I think that’s the key variable.

Probably lots of, yeah.

Lots of whole grains.

Lots of whole grains.

Yeah, some potatoes.

And they spent, I believe over three years,

they screened over 1,300 participants.

People who expressed interest.

The end of the day,

I think they only got 27 people to enroll

and only 14 of those people completed the study.

Wow.

Despite that, what they found was that

the subjects who achieved ketosis had cognitive improvement.

But people on study section

are gonna look at a study like that

and say, even if the science is there,

if you can’t get people to do this diet,

why would we spend money on researchers

trying to get people to do this diet?

I should mention study section

is this closed door panels of 40 or so people.

There are many of these panels.

Different divisions of the National Institutes of Health

use different panels and then grants are evaluated

in a very small,

because of the size of the federal budget for research,

a very small percentage,

usually about 10% of these studies are funded.

The rest don’t, generally don’t end up happening.

That is very informative.

What you just described is very informative

because now it makes sense to me

that there’s no conspiracy.

It’s not like big pharma, I don’t think,

is trying to suppress trials

of ketogenic diets on Alzheimer’s

because I would imagine the first thing

that pharma would want to do is to see that study done

so they didn’t have to.

And then the moment it was done,

if it showed a positive effect,

they’d probably wanna isolate the molecule

and wrap it up in something that people would take.

So I don’t think there’s any active suppression by pharma.

I think pharma would probably be cheering from the sidelines

because they could capitalize on it

because ultimately the studies are done by scientists,

but the treatments are generally doled out

by pharmaceutical companies and or physicians.

So I don’t believe there’s a conspiracy there.

That is very interesting.

And it’s kind of amazing given our discussion of earlier,

which is that you had a patient

that was having schizophrenic symptoms

who managed to stay on this diet.

So is there something special about Alzheimer’s patients

and people with age-related cognitive decline?

Presumably they’re very dependent on others

to cook for them and shop for them.

I think that this is a almost perfect controlled environment

for getting this study done.

I think that is the key issue.

So again, I get patients with bipolar disorder,

schizophrenia, extraordinarily impaired people

to do this diet and stay with it,

but it’s because I’m providing

like a weekly session for them.

And I imagine this study did not provide

that kind of intensive support.

So I think in the pilot trial that I described to you,

they actually got, I think, over 90% compliance

with the different dietary interventions.

So some of it is gonna be dependent on the research group

and does the research group understand

that this is not, it’s not like prescribing a pill.

Here, take this pill and take it every day

and come back in three weeks.

And even then we don’t know for sure

that the patient took the pill every day.

We just assume they took the pill every day

and studies say they probably didn’t.

But so I think when we think about a dietary intervention,

we need to think about more intensive support and education.

And that support could be a health and wellness coach.

It could be a dietician.

It could be education of the family.

It might even be providing them with dietary like meals

that maybe for six months,

we actually provide them with ketogenic meals once a week,

put them in your freezer, microwave them when needed

to make this diet as easy and doable as possible.

Because if we can get people to do the diet,

if we can get them through the first couple of months,

most people can learn how to do this diet

more importantly, I didn’t mention this before,

but the number one reason I am so successful

at getting patients to stay on this diet for years

is because of the consequences to them

when they go off of it.

That is the reason I can get schizophrenic patients

and bipolar patients to do this diet.

Whereas other people can’t get an everyday human being

to do it for weight loss

because the weight loss patient

doesn’t experience devastating, tormenting symptoms

when they break the diet.

Oftentimes they are rewarded.

They eat something they really enjoy

and they get a little bit of a dopamine rush from it

and they’re off to the races.

They’re like, I’m gonna, oh, I’ve already cheated.

I’ll cheat again.

I’ll get back on it someday.

And they never get around to it.

My patients, when they go off the diet,

they start hallucinating within 24, 48 hours.

And they quickly realize

that was a really stupid thing to do.

That piece of cake was not at all worth

the torment that I’m experiencing now.

So they get back on the diet.

I suspect with Alzheimer’s disease,

we might notice something similar.

These people, some of these people have very mild symptoms.

So maybe they won’t have that kind of a reinforcement

or negative reinforcing kind of experience.

But I think some of them will.

Some of them recognize that they are impaired cognitively.

And if this diet could help them remember better,

if this diet could help them function better.

And again, that’s what the pilot trial showed

is activities of daily living.

That means these people are able to go to the bathroom

on their own.

They’re able to get themselves dressed,

whereas they needed help with those things before.

Those are actually really important things

to both the patient and the caregiver.

And if they go off the diet

and then quickly revert into a more symptomatic state,

that might be reinforcing enough

for them to figure out a way to do the diet on their own.

And if we think about,

if this really is an effective intervention,

then yes, we need longer trials, larger trials, all of that.

Because there are plenty of stories in the medical field

where pilot trials looked really spectacular and promising,

and then larger trials just failed to show the benefits.

I believe based on all the science of metabolism,

mitochondria, glucose hypometabolism, all of that,

I believe the science makes this an obvious treatment

that has real potential.

So, you know, people will call me biased.

That’s fine, I’ve got my bias.

No, based on clinical observation

and extensive clinical observation at that.

I think biases that are simply

because we want to feel a certain way

or believe something are worth critiquing,

but bias based on observation.

Here, I should mention that, you know,

most of what we know about human memory

was sparked by one patient, a famous HM,

who I think was living in Harvard Medical,

in one of the hospitals around there,

many hospitals on Longwood Campus, but one patient.

I mean, the reason we associate the hippocampus with memory

is because we knew that HM’s hippocampus was damaged,

intentionally damaged for epilepsy treatment, right?

So this idea that everything has to be

a randomized clinical trial to me is crazy.

I mean, of course that’s a gold standard and it’s essential,

but there’s so much information in textbooks,

medical textbooks in particular,

that are gleaned from single patient case studies

or from three patient neurostimulation in the brain

or something of that sort.

So to me, I’m still perplexed as to, you know,

why there’s this insistence on only one form of evidence.

Clearly what you’re doing,

the important work that you’re doing clinically

and in the research side and in public communication

is assisting this.

I have a question about,

or more of a statement slash question

about the ketogenic diet.

Based on everything that we’ve talked about,

seems to me that the ketogenic diet for weight loss

is a very interesting aspect of the diet,

as is intermittent fasting for weight loss,

even though it might just be by way of caloric restriction.

Caloric restriction that occurs with fasting.

But then in some ways,

the effects of the ketogenic diet on weight loss

are a bit of a decoy for most people.

That’s where their mind goes.

This person lost X amount of weight.

Maybe that made them feel better.

Maybe that actually made them underweight.

I think you’ve talked about it for some people

that can actually bring them underweight.

But I’m glad that we got the chance to dive

into the description of ketogenic diet for epilepsy,

because it really is a medical intervention

that has a side effect of weight loss,

or could be used to treat obesity and induce weight loss.

But it’s really about far more than that.

And that raises a question for me,

which is, you know,

we’ve been talking about the ketogenic diet as one thing,

but I’ve heard you discuss this before,

where, you know, just as a physician

will prescribe different dosage ranges of a given drug,

you can prescribe different dosage ranges

of a nutritional plan, a diet.

It’s not one thing.

It’s not necessarily zero carbohydrates

or 100 grams or 50 grams.

It depends on the patient and a lot of other factors.

I’ve heard you list off various things, classic keto.

Maybe you could just briefly tell us what that typically is,

because I think most people think

it means eating a lot of meat and not carbohydrates,

but it might not be that.

Fasting, and then some of the other,

you mentioned Atkins earlier.

We don’t have to go into each of these in detail.

And I know in your book,

you talk about not just the science and clinical background,

but also some actionable steps that people could consider

so they can refer there for more detail.

But for somebody who, let’s say, is depressed,

they’ve had some rounds of depression,

maybe they’re on antidepressants, maybe not,

and they want to try something like this.

Obviously, this has to be done in concert

with a physician observing all this.

But what is the typical thing that you probe with first?

Just like with a drug,

you might probe with 20 milligrams of a drug.

What’s your typical initial dietary intervention probe?

Terrible languaging, I realize,

and I’m criticizing myself for that,

but I think people get the idea.

The real answer is that I don’t have

a one-size-fits-all recommendation for any person.

So the first thing that I’m going to assess with the patient

is what symptoms are they having?

What is their current diet like?

And what are they willing to do?

I try to meet them where they’re at.

So if somebody, and I want to point out,

like you mentioned the all-meat version of this diet,

which is often referred to as the carnivore diet.

A very controversial diet.

There is no doubt that exists,

and some people swear by it.

They swear that they’ve tried other versions

of ketogenic diets,

and only when they went to a carnivore diet

did they get benefits.

But there are vegetarian and vegan versions

of the ketogenic diet.

So in my mind, this is not at all about the diet wars

of animal-sourced versus plant-sourced foods.

It’s about inducing a state of ketosis,

which is mimicking the fasting state.

That is what it’s about.

And you can do that by not eating anything,

by fasting and or intermittent fasting,

and you get your results.

So no diet is a ketogenic diet.

So it’s not about the foods

or the types of foods that you’re eating.

It’s about inducing a state of ketosis.

The first variable I’m going to look at

when I recommend this or prescribe this

is the person’s current weight.

If somebody’s obese versus somebody who’s thin,

I’m going to use different dietary strategies

for those two situations.

In the obese patient,

they have tons of fat stores on their body already.

Usually it is a goal of theirs to tap into some of those,

and they’d like to lose some weight

if they’re going to try a ketogenic diet

for brain health anyway.

And so I’m going to use that.

So that person, really, the diet is carbohydrate restriction

and that usually is a sufficient intervention.

Both simple carbohydrates, meaning sugars,

and fructose also?

Fructose, definitely.

So no added sugars, essentially.

You can have added natural sweeteners

like stevia or monk fruit.

You might use artificial sweeteners.

I’d probably, years after doing this,

I’d probably recommend steer away from them if you can

because I think they tend to stimulate cravings

for high carb foods.

So if you can kind of get through a couple of weeks

without sweet things,

your cravings for those will go down

and it’ll make the diet easier

and a little more sustainable.

But let’s say you can have your artificial sweeteners

if that’s what you really want.

So I’m going to say less than 20 grams of carbs a day

for those people.

They can have all the protein they want.

They can have vegetables

and they can have all the fat they want,

but I’m not going to push fat on those people.

I’m not going to tell them eat a lot of fat at the same time

because I want to use the fat on their body

as the fat source, at least early on.

Are you encouraging healthy fats like monounsaturated fats

like olive oil or are you encouraging people

to eat a little less butter, et cetera?

I tend to encourage,

again, a wide range of fats

and it’s going to depend on the person.

A lot of times people come to me with very specific ideas,

but I’m going to tend to encourage olive oil,

avocados, nuts,

which are usually considered

even by the American Heart Association,

healthy sources of fat.

The more controversial thing

are things like coconut oil or coconut cream,

which the American Heart Association might say

is not a healthy fat.

I kind of disagree with that

and don’t think it’s unhealthy at all actually.

And when you look at the epidemiological studies

of saturated fat causing heart disease

or causing adverse outcomes at best,

maybe increases your risk 10 to 15% at best.

How much coconut oil can people ingest anyway

before they either develop diarrhea, no joke,

or just sort of get tired of coconut oil?

But anyway, your point is taken.

But they can eat meat if they like meat

or they could eat eggs

or if they don’t like meat and eggs,

they could eat sardines or things of that sort.

I mean, I personally can’t,

yeah, I can’t even stomach the,

I don’t even like the word sardine.

I have nothing against the actual fish,

but that’s just me.

But obviously people have,

I say this because people have different preferences, right?

Yes.

I’ll eat a steak, but I’m not gonna eat a sardine.

And I’m gonna go with that.

And again, there are vegan sources of protein

that people can eat tempeh and other things.

So that’s the obese person.

It’s carb restriction is the primary initial phase.

The thin person is gonna need to eat a lot of fat

because they don’t have a lot of fat stores on their body.

And if I want them in ketosis, clinical ketosis,

I’m gonna have to feed them fat.

So that’s the person that I’m gonna say,

make sure you get in avocados, olive oil, butter,

maybe a cream, heavy cream.

So heavy cream is delicious.

It’s a delicious way to get your fats in.

And I have one patient who just drinks it straight

to just try to get it in.

I get it.

I’ve never had an appetite for sweets.

I absolutely love savory fatty food.

When I was in high school, I was thin,

so I was able to do this,

but I used to drink half and half.

Sometimes I wake up in the middle of the night

and drink it just because it tastes so, so good.

It does taste good.

So if they’re on a ketogenic diet,

I’m gonna push them away from half and half

and toward heavy whipping cream.

And so you can whip that up.

You can freeze it.

It turns into ice cream.

You can add vanilla.

You can add cocoa powder.

You can add all sorts of things

and you’re off to the races with shakes

and ice cream and mousse

and all sorts of things that you can have.

With any of these patients,

the beauty of this diet is I have objective biomarkers.

I’m gonna have them measuring ketones

and I’m going to adjust the diet

based on their state of ketosis

and or the clinical benefits that I’m looking for.

If it’s an average person

who is not currently under psychiatric care,

not taking prescription medicines,

but is saying, I’m burned out, I’m exhausted,

I want some of that brain energy

that Andrew Huberman’s talking about.

He talks about feeling good.

I want some of that.

I’m probably actually gonna recommend

the protocol you described,

which is let’s see if we can just carb restrict for a while

and see if that produces clinical benefit.

I have one, he’s not even a patient,

just somebody who read my book.

I didn’t tell him anything.

He came away from it saying

he was ready to start an antidepressant for his anxiety.

He had chronic anxiety.

He was trying meditation, was trying all sorts of things.

Nothing, those things weren’t enough.

He was ready to go on prescription medicine.

He read an early copy of the book.

He took it upon himself without consulting with me

to restrict carbohydrates alone.

He did not go ketogenic.

He is a vegetarian.

He restricted carbs.

Within three weeks said,

I don’t need prescription medicine.

I can’t believe how much better I feel.

And all I did was cut out

some of the high carb foods in my diet.

So I think for some people it can be that simple.

For people with serious mental disorders,

if they are chronically depressed,

if they’re on lots of prescription meds,

if they’re disabled by their symptoms,

and certainly if you’re bipolar

or have schizophrenia or something,

those are the people I really do want them

to work with a medical professional

because meds may need to be adjusted.

They really need a real shot at this diet.

It’s not like weight loss.

Weight loss, everybody wings it.

And either you’re successful or you aren’t.

You look on the internet or you read a book

or you do, even the colleague that you mentioned,

he’s probably just reading,

who knows whether it’s credible information or not.

And just winging it and seeing whether it works or not.

For people with serious mental disorders,

I want you to treat it like you have epilepsy.

Because you do have a serious brain disorder.

Like it’s impairing your ability to function in the world.

It’s impairing your health and happiness.

You deserve a competent medical treatment.

And we have that.

We have a hundred year evidence base.

We’ve got dieticians who know this

like the back of their hand.

They can monitor your level of ketosis.

They can help look for vitamin and nutrient deficiencies

that can be a consequence of the diet

and make sure that you’re not developing those.

They can help tweak the diet if needed.

They can give you ideas

if you’re getting bored with eggs every morning.

They can give you ideas for what else you might have.

And if you’re using it to treat a serious disorder,

I think you need serious help.

A couple of questions, a little more detailed,

but I think a lot of people will have this on their mind.

Is it ever the case that you’ll prescribe somebody

the ketogenic diet in conjunction with intermittent fasting?

So eat keto, but eat between the hours of whatever,

11 a.m. and 8 p.m. or something like that.

That’s the first question.

Absolutely.

So, and I have one patient with type two diabetes

and chronic depression,

and he will try to follow a diet

and he will try to follow the ketogenic diet

and sometimes his blood sugars are still very high.

And sometimes I will ask him to do either intermittent fasting

or even a three or four day water fast.

And it is shocking.

When he does a three or four day water fast,

you know, the first day or two feels like crap.

I’ll just say up front,

don’t do it if you’ve got an important meeting

or business trip or any like, don’t be.

So this is just consuming water.

This is just consuming water.

No black coffee.

I usually tell him he can have plain black coffee or tea,

but…

You have mercy after.

I have a tiny ounce of mercy,

but when he does it,

his blood sugars plummet in a good way.

Like his blood sugars are normalizing.

But the last time he did it,

he actually got to seven days at one point.

And he said, I feel great.

I want to keep going.

I can’t believe that I’m not hungry,

but I am not hungry at all.

I don’t miss food at all.

And at seven days, I kind of cut the cord.

I was like, no, no, we’re done.

You got to eat.

Well, I find it really interesting

that the intermittent fasting, of course,

controversial at some level,

but as to whether or not it’s just beneficial

by way of caloric restriction,

because it is one way to achieve caloric restriction,

whether or not it has additional benefits.

But I’m very interested in the neural side of it.

And it does seem that the fasted state

can start to take on its own rewarding properties

where people get dopamine release,

not from eating as most everyone does,

but from abstaining from food.

Now this can be pathologic

in the sort of example of anorexia nervosa,

which is, we both know,

is the most deadly psychiatric illness.

But for non-anorexics,

I think it’s interesting to note

that eventually not eating

can have its own rewarding properties to it

that aren’t just related to weight loss,

but in the short term, feeling,

in other words, feeling really good

by way of abstaining from eating.

Yes.

Well, and that’s actually,

it raises an important risk that I haven’t mentioned yet,

but at least in psychiatric patients,

but even in some patients

who just use the keto diet for weight loss,

I have seen definite hypomania.

So these are people that aren’t sleeping very much.

Are they also getting kind of delusional thinking?

They’re going to run for president?

No.

So the distinction between hypomania and mania,

so mania, you might become psychotic and delusional.

Mania, by definition, is problematic.

It’s causing a problem in some way or another.

And if you have psychotic symptoms,

it’s definitely called mania, full-blown mania.

Hypomania, for better or worse,

is something every human being probably craves.

So it is feeling extraordinarily good.

It’s getting by on less sleep,

but you don’t need the sleep.

Who needs sleep?

I’ve got things to do.

My brain is running on all cylinders.

I feel so creative.

There’ve been lots of famous people through the ages

who have been bipolar, probably bipolar,

and some of their most productive periods of time,

whether it’s art or creating scientific models

or what have you, were probably during hypomanic episodes.

So what do you do in that case?

I mean, I’m obsessed with getting sufficient quality sleep.

It’s a kind of a repeating theme in our podcasts

and on many of my social media posts.

And I always recommend behavioral tools first,

then exercise, viewing sunlight, et cetera,

the appropriate times,

avoiding late night artificial light exposure, et cetera.

And occasionally, for people who are doing all that

and still struggle with sleep supplementation,

one of the things that I’ve seen some data on

is that for people who are following

a low-carbohydrate diet,

that inositol in particular can be helpful

for getting into sleep,

probably because it has a bit of an anti-anxiety effect.

But presumably there are other things out there too.

The magnesiums will generally do that.

A hot bath will do that too, for that matter.

But what you’re talking about is people who are going,

what, a day and a half without sleep,

or they’re just two hours of sleep a night?

I have, so the worst case I saw

was actually a mental health professional

who didn’t recognize it initially.

He went six months with two to four hours

of sleep every night.

Because they were on a ketogenic diet.

He was on a ketogenic diet,

was getting by on two to four hours of sleep every night,

did not initially recognize that this was a problem.

He was feeling great.

He was feeling that keto high.

And he was actually waking up

and like at 4 a.m. going for 10 to 20 mile runs most days.

He finally stopped the ketogenic diet

after about six months

because he said, I can’t maintain my weight.

I’m losing too much weight.

Sorry, I didn’t mean to interrupt.

So what do you, I was just thinking

there’s some social media personalities

that are associated with nutrition that might be hypomanic.

I’ll let you do the clinical evaluation.

So what does somebody do in that case?

So I don’t know that I’ve ever been hypomanic,

but as I mentioned earlier,

unless I’ve done a very high intensity workout

early in the day and I need to replenish carbohydrates,

I typically eat meat, fruit, and vegetables

throughout the day.

Minimum amounts of fruit, but some.

And then at night I switch over to mainly carbohydrate.

It really helps me sleep.

It replenishes glycogen stores.

I sleep really well.

Wake up the next morning, repeat.

And of course, this goes against a lot of the dogma that,

oh, you’re not supposed to eat carbohydrates late in the day.

And this is what works for me.

And so I do it.

For somebody like this mental health professional

who was hypomanic,

would going off the ketogenic diet

entirely be the best idea?

Or could it be that adjusting when they eat

their carbohydrates would be advantageous

in order to make sure that they felt alert

and great during the day,

maybe not hypomanic,

but then could have a four to eight hours a night sleep

as opposed to a two to four hours a night,

which is really very little sleep.

It can’t be healthy.

It’s not healthy.

Even if you can do it and feel great,

I imagine that the brain is suffering.

It is.

And the body is suffering.

And your friends and family are suffering.

The body is repairing itself with sleep.

And so, yeah, it’s the,

if it’s somebody who’s is not a patient,

they’re not a mental health patient,

they’re not using the ketogenic diet

as a mental health treatment,

they’re simply doing it for whatever.

I actually start with everything you’ve just outlined.

Let’s start with behavioral measures first.

And the first intervention is education.

You need at least six hours of sleep a night, period.

End of story.

That’s non-negotiable.

If you’re not getting at least six hours of sleep a night,

we need to consider this a problem.

So figure out a way to get six hours of sleep.

For some people, that’s enough.

Just the education.

They don’t get out of bed at 3 a.m.

It might take them an hour to fall back to sleep.

They fall back to sleep.

For most people, if you can get three nights

of decent sleep in a row, the hypomania goes away.

That is the way to extinguish it.

And then they still go on feeling a high from it.

They feel great.

Their brain feels good in terms of memory,

concentration, motivation, all of those things.

But they’re not hypomanic anymore.

And then I might use supplements, melatonin,

others that you mentioned.

Magnesium is a big one.

And for some, I will recommend exactly what you’re doing.

Eat some carbohydrates in the evening

before you’re going to bed.

Either have them at dinner and then wait a few hours

before you’re gonna go to bed

or have them right before you’re gonna go to bed

just to try to calm your body down and get it going.

For when I’m using this as a clinical intervention,

especially with patients with serious mental illness,

I actually want them in a state of ketosis long-term.

So I’m not gonna do the carbohydrate intervention.

I’m gonna try all the other ones.

But if they still can’t sleep even with supplements,

over-the-counter supplements,

then I’m probably gonna go with prescription

sleeping medicines as a temporary stopgap

to try to get them three to seven days of decent sleep

that usually breaks the hypomanic cycle.

And then they stay on the ketogenic diet

because it ends up resulting

in all of these other improvements that I’ve described.

Their illness can sometimes go into full remission.

Is it low-dose trazodone as a first-line prescription?

I would not use trazodone.

I would actually specifically avoid trazodone

because it’s an antidepressant

and they’re already hypomanic,

and I certainly don’t wanna push that further.

So as long as it’s somebody without a history of addiction,

I’m gonna use a benzodiazepine

or either commonly called the Z medicines for sleep,

Zolpidem or Ambien or something like that.

Those tap into the opioid pathway, GABA-opioid.

GABA, GABA.

So I’m probably, I usually start with something

like Ativan or Klonopin or something like that,

probably Ativan because it’s shorter acting.

And again, I’m only looking to use it short-term.

I let them know that upfront.

We’re looking for three to seven days of decent sleep

and then we’re gonna try to get them off that medicine.

And usually people are off to the races

and can sustain it well.

A question about hormones.

Many of the Hubern Lab podcast listeners will ask,

anytime we’re talking about something like exercise

or drug treatment or behavioral treatment,

people will say, what about the menstrual cycle?

How is that impacted by this?

And how does this impact,

how does the menstrual cycle impact its efficacy, et cetera?

Carbohydrates and caloric restriction

have been implicated in different interaction,

are known to interact with the endocrine system.

So what do you do if you have a patient

who is depressed or could have psychotic symptoms,

but let’s go with depression

because that’s probably a bit more familiar to most people.

And then they’re on a low carbohydrate

or full ketogenic diet, but their menstrual cycles cease.

How do you deal with those adjustments?

And I guess we could expand this conversation

and say, what about male fertility also?

Because sub-caloric diets seem to,

my understanding is that sub-maintenance caloric diets,

so weight loss diets,

will improve testosterone, estrogen ratios

in males that are obese,

but for someone that’s not obese

to go on a sub-caloric diet

that it can start to impair testosterone levels

and probably not render them infertile,

but certainly adjust that whole axis.

So what about interactions between ketosis diets, et cetera,

and the endocrine system?

The real answer is I don’t think anybody knows

and there’s not a one size fits all answer

because I’ve seen examples

and I’m aware of science

to back up polar opposite conclusions.

So the first general observation that I’ll make,

I know so many couples,

husbands and wives, boyfriends and girlfriends,

heterosexual couples

who have tried the ketogenic diet to lose weight together.

And end up with a baby.

Almost universally, the men have a much easier time

with it than the women.

It’s not across the board,

but I know so many examples where the women say,

I couldn’t tolerate that diet.

It did not make me feel better.

It actually made me feel worse.

And I think in those cases,

it probably does relate to hormones.

I’m aware of animal models of mice in particular,

ketogenic diet and mouse models.

One researcher shared with me,

the thing that was striking

is that the female mice never got pregnant

on the ketogenic diet.

Whereas the mice on the standard diet

were just having babies right and left.

And it was just shocking, the difference.

On the surface, it makes sense.

The ketogenic diet is mimicking the fasting state.

Women who are trying to reproduce should not be fasting.

If your body is in a fasting state,

it probably does not wanna expend resources,

metabolic resources, calories, nutrients,

and other things to creating a baby

because your very life is being threatened

by quote unquote fasting or starvation.

That even though the ketogenic diet

is a sustainable non-starvation diet,

we’re really using that diet to trick the body

into thinking that it is in a fasting or starvation state.

And so just from a kind of evolutionary stance,

it makes sense that women’s bodies

may actually have significant changes in hormonal status

to prevent pregnancy

because a woman should not be having a baby

when she’s starving to death.

I know of examples of women who are the opposite though,

who have benefited dramatically

and tremendously from the ketogenic diet,

have put schizophrenia, bipolar disorder

into full remission.

And I do actually know of one case, at least one case,

a woman infertile, she and her husband

had been trying for three years, no pregnancy,

she went keto, within four months she was pregnant.

How do I make sense of that?

I don’t know.

And unfortunately, I don’t think we really have

good controlled data on what does the ketogenic diet do

to male hormonal systems?

What does the ketogenic diet do to female hormonal systems?

But, you know, clearly I think changes are happening

and I don’t have a way to predict it at least.

If somebody else has great insights, I welcome them,

but I haven’t seen them published.

So it’s a terrific answer because when things are

all over the place and bi-directional,

depending on one circumstance or the other,

I think it screams for controlled studies

and more descriptions of case studies

and anecdotal data too.

So I think it’s an excellent answer.

It also calls to mind the important

public service announcement that

because of these bi-directional effects that you describe,

please don’t use fasting or the ketogenic diet

as a reliable form of contraception.

Yes, please don’t.

I have a final question, which relates to something

that is very much starting to get buzzed now

and maybe more so for people that hang out

in the Twitter space or the nutrition space.

But there’s a new class of drugs that I think initially

were developed to treat diabetes,

but are now being evaluated for their efficacy

to treat obesity.

And these are the semi-glutide drugs

that are involved in,

they tap into these glucagon-related GLP-1 pathways.

And as is a story that we’ve talked about

a little bit on the podcast before,

but many people I imagine probably

haven’t heard that conversation.

I would just simply like to know

what you think about these drugs.

They obviously adjust the way that glucose and insulin

are managing energy, both in the body and the brain,

and can produce weight loss.

So that to me, when I look at the data,

you know, it’s impressive, but a good,

you know, a good logical shift in diet and exercise

could achieve similar weight loss,

but a lot of people just won’t do that.

So the question I have is,

what are your thoughts on semi-glutide and other GLP,

I think I might’ve said GLT before, excuse me,

GLP-1-related compounds?

And do you ever prescribe these

in conjunction with these dietary shifts?

Because it seems to me they would fall right in

with the catalog of other approaches

that you have available.

The real answer is I am not at all an expert

on these medications.

But what are your thoughts about them?

I mean, they seem to be weight loss drugs,

not unlike the fen-fen drugs of the 90s

that then were banned because a few people

didn’t handle them well.

They are.

And, you know, we had fen-fen,

and even before that in the 1950s and 60s and 70s,

dexedrine.

Amphetamine.

Amphetamine.

Mother’s little helper.

Was, yes, was the treatment of choice

for women across the United States

to keep their slim figures.

And we created addicts and all sorts of problems,

but they were widely used in probably millions of women

because they work.

Because they kill appetite.

They kill appetite.

My overall thoughts are this.

There is zero doubt in my mind

that the obesity epidemic is a threat to human health

and potentially the human species.

If it keeps going at the rate it’s going,

it is a threat to our species.

We have to figure out what on earth is happening

and what can we do about it.

These medications in early studies

are highly effective over a year or two.

That’s promising.

I am worried, though,

that we’re not attacking the root cause of obesity.

And if we’re not,

if the root cause of obesity ends up being

some kind of poisoning of the metabolic machinery

in the brain or body,

and I would argue that probably relates

to mitochondrial health and mitochondrial function,

I have every reason to believe that taking a medication

that helps you lose weight

may not be addressing that problem

and therefore may not be addressing

all of the negative health consequences

of what we call obesity.

So obesity in and of itself,

we know that excess fat can become inflammatory

and can cause problems in and of itself,

but I actually see obesity as a symptom.

I see obesity as a symptom of metabolic derangement

in the body or brain.

And that is why people become obese.

And that if we’re really going to get anywhere,

we need to identify what is causing

that metabolic derangement.

Using a symptomatic treatment like a GLP-1,

you know, medication,

to the best of my knowledge,

is not addressing that core problem.

And we’re just ignoring it.

Maybe I’ll be wrong,

and maybe these will be the wonder drug

that saved the human species

and everybody will be thin and healthy forever and ever.

I’m not hopeful,

because we’ve had so many promising drugs come along,

Fen-Phen, Dexagen, other things.

We’ve had so many promising drugs.

And at the end of the day,

when you try to muck with human metabolism

using a single processed molecule, man-made,

I can’t think of even one example

where it’s been great for large numbers of people.

I mean, certainly manufacturing insulin

is life-saving for people with type 1 diabetes,

so that would be an example.

But giving massive doses of insulin

to people with type 2 diabetes

actually is a downward spiral.

I would much rather see people with type 2 diabetes

control their diabetes through diet and lifestyle,

and that might be a ketogenic diet or a low-carb diet

or exercise or good sleep or all of the other thing,

all of it.

I’d much rather see that,

because when people try to control their type 2 diabetes

with a molecule,

even though it’s a natural molecule, insulin,

we know that that results in really poor health consequences,

results in higher rates of cardiovascular disease,

higher rates of mental disorders,

higher rates of premature mortality.

Do I think GLP-1 molecules are going to be different?

No, I don’t have any reason to think they are going to be.

So that would be buying two cents,

but we’ll see, time will tell.

Time will tell.

Meanwhile, I want to thank you for doing

what is, without question, pioneering work.

I mean, again, I’m not a clinician,

but I’ve been around this space long enough

to know that, indeed, there are no wonder drugs, right?

There are drugs that certainly can help alleviate symptoms

in some individuals,

but that lifestyle, and in the case of your work in particular

and the discussion today,

diet and the ketogenic diet in particular,

it’s clear can have incredible effects,

miraculous effects in some individuals

and positive effects in others

that might not be of the same magnitude,

but nonetheless are extremely important.

So I, on behalf of myself and the listeners,

and certainly just on behalf of everybody out there,

because everyone does need to be concerned

about mental health issues,

whether or not they have them in their family themselves

or otherwise, because they impact everybody.

Just really want to thank you

for doing the work that you’re doing,

because it really is pioneering and it’s brave.

And I can see now, based on our discussion,

why it would work.

You’ve given us a lot of hints into the underlying mechanisms

that suggest as to why it would work.

And you’ve given us examples as to how it has worked

in patients that you’ve worked with.

And this field is expanding fast.

I think this is an area of psychiatry

and medicine in general,

meaning behavioral and nutritional interventions

that is expanding very fast.

So thank you for being brave and for taking this on

and doing it in such a structured way

and for communicating it here today

and with the general public through your book

and your online presence.

We will certainly point people in the direction

of those valuable resources.

Thanks so much, really appreciate it.

Thank you, Andrew, for being brave

and having me on your show and for a great conversation.

Thank you for joining me

for my discussion with Dr. Chris Palmer.

I hope you found it to be as an informative,

actionable and exciting in terms of the various treatments

that we can now think about

when considering treatments for psychiatric disorders.

Once again, if you’re interested in his work

or his new book, Brain Energy,

I encourage you to go to his website.

That’s chrispalmermd.com.

You can also find the book Brain Energy by Chris Palmer

on Amazon and other sites where books are sold.

And we provide links to the book

and to Dr. Palmer’s website in the show note captions.

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