Transcript
[0:00] Welcome to Huberman Lab Essentials,
[0:02] [music] where we revisit past episodes
[0:04] for the most potent and actionable
[0:06] science-based [music] tools for mental
[0:08] health, physical health, and
[0:09] performance.
[0:12] I'm Andrew Huberman, and I'm a professor
[0:14] of neurobiology and ophthalmology at
[0:16] Stanford School of Medicine. And now for
[0:18] my discussion with Dr. Chris Palmer.
[0:21] Chris, Dr. Palmer, thank you for being
[0:23] here.
[0:23] >> Thank you, Andrew, for having me.
[0:25] >> I have a lot of questions for you, and
[0:27] I'm really excited about this topic
[0:29] because I think most people know what
[0:32] mental illness is, or they have some
[0:33] idea what that is. Most people have some
[0:35] idea what nutrition is.
[0:37] Fewer people, certainly, know
[0:40] how
[0:41] closely those things can interact. I
[0:44] think everybody is familiar with the
[0:46] feeling of a food or the ingestion of a
[0:49] food making them feel good in the short
[0:51] term. But, I believe that very few
[0:54] people understand or are familiar with
[0:58] the fact that nutrition and our mental
[1:00] health
[1:02] interact in this very intimate, maybe
[1:04] even causal, way. And that is something
[1:06] that occurs over long periods of time,
[1:08] meaning what I ate yesterday, the day
[1:10] before, maybe even 10 years ago, could
[1:13] be impacting the way that my brain and
[1:15] body are making me feel now. So, if you
[1:17] would, I'd love for you to just tell us
[1:19] about a little bit of the the history,
[1:21] in particular your history with
[1:23] exploring the relationship between
[1:25] nutrition and mental health, and then we
[1:27] can dive into some of the um more
[1:30] particulars of ketogenic diets versus
[1:32] other diets, and
[1:34] some of the truly miraculous findings
[1:36] that you and others are coming up with
[1:39] based on real patients and real
[1:41] experiences of people who suffer and
[1:43] then find relief by altering their
[1:45] nutrition.
[1:46] >> Sure. This story really starts with my
[1:48] own personal story. I don't need to go
[1:50] into great detail, but to set the stage,
[1:53] when I was a kid, I definitely had
[1:56] mental illness. Started with OCD. I went
[1:59] on to have subsequent depression,
[2:02] suicidality, all sorts of things. But
[2:04] somehow or another, I pulled myself
[2:06] together and got through medical school,
[2:08] actually did quite well in medical
[2:10] school, and then was doing my internship
[2:13] and residency at Harvard. And at that
[2:15] point in time, I was diagnosed with
[2:18] metabolic syndrome.
[2:20] So, I had high blood pressure, horrible
[2:22] lipids, and pre-diabetes. And I was
[2:26] doing everything right, supposedly. I
[2:28] was on a low-fat diet, and I was
[2:31] exercising regularly.
[2:33] And year after year, my doctor kept
[2:34] telling me, "Diet and exercise." I was
[2:37] doing everything he kept telling me to
[2:38] do. Everything was getting worse. My
[2:40] blood pressure kept going higher. And at
[2:42] some point, he said, "You're going to
[2:44] have to go on medication for your
[2:46] pre-diabetes, something for your
[2:47] cholesterol, and something for your
[2:49] blood pressure."
[2:50] So, three pills. Basically, you're
[2:52] screwed. It's your genes. You're just
[2:54] going to have to bite the bullet and
[2:56] take meds. As a physician, I knew what
[2:58] that meant.
[2:59] I knew that I'm in my 20s, if I'm
[3:01] already on three meds for metabolic
[3:04] syndrome, I'm going to be screwed by the
[3:06] time I'm 40 or 50, and I'm probably
[3:08] going to be having heart attacks. I'd
[3:10] heard through the rumor mill that the
[3:13] Atkins diet could somehow
[3:16] help people improve their cholesterol
[3:19] and pre-diabetes. I was highly
[3:21] skeptical, and I I you know, I believed
[3:23] everything I was taught in medical
[3:24] school. Why would Why would my
[3:26] professors lie to me? They They knew
[3:28] what they were talking about. Low-fat
[3:30] diet was the thing to do.
[3:32] And the Atkins diet was clearly
[3:34] dangerous and reckless. And I had been
[3:36] trying the medical dogma for years, and
[3:39] it wasn't working for me.
[3:41] And so, for whatever reason, I decided
[3:43] this is going to be my last attempt at
[3:46] at something different. And then I'll
[3:48] just bite the bullet and go on meds. So,
[3:51] I tried the Atkins diet. Within 3
[3:54] months, my metabolic syndrome was
[3:55] completely gone. I probably lost about,
[3:58] you know, 10 lb through this process,
[4:01] but everything got normal. And when I
[4:03] went back to my doctor, he was shocked.
[4:05] The thing that was the most striking to
[4:08] me after doing the diet for 3 months was
[4:11] not the fact that my metabolic syndrome
[4:13] was gone. That was my goal, and it was
[4:16] a, you know, seemingly miraculous
[4:19] uh achievement because I got rid of
[4:22] everything
[4:23] with one dietary change. But, the thing
[4:26] that I noticed was dramatic improvement
[4:28] in my mood, energy, concentration, and
[4:31] sleep. For the first time in my life, I
[4:34] started waking up before my alarm went
[4:36] off and feeling rested. That never
[4:39] happened to me before. I was meticulous
[4:42] about planning when my alarm went off
[4:45] and how many times I could push the
[4:47] snooze button in order to be on time for
[4:50] wherever I needed to be, whether it was
[4:52] school or the hospital or whatever.
[4:55] Prior to the diet, I always felt like
[4:58] there are two types of people in the
[4:59] world. There are these happy, peppy
[5:01] people who just are so positive, and
[5:04] they've got energy, and they have these
[5:06] the saying, they like to work hard and
[5:08] play hard. But, I never understood who
[5:12] the hell wants to play hard. Like, who's
[5:14] got energy for that? Like, aren't you
[5:16] tired from working so hard? I assumed
[5:19] that they were just lucky and
[5:20] privileged. They either had good
[5:22] genetics or maybe they had good
[5:25] childhoods or good parents or something,
[5:27] something that I didn't have.
[5:29] >> What was the journey forward into the
[5:31] the work that you're doing now?
[5:33] >> So, within a few years, I'm, you know,
[5:36] an attending physician. I've got all
[5:38] these patients in my clinical practice
[5:40] with treatment-resistant mental illness.
[5:41] I'm in a tertiary care hospital. So, I
[5:44] almost never get somebody off the street
[5:48] with their first episode of depression.
[5:50] Out of the gate as part of my career, I
[5:53] get treatment-resistant mental
[5:54] disorders. So, I get people who've
[5:56] already been to six plus psychiatrists,
[5:59] therapists. They've usually tried dozens
[6:01] of different medications. They've been
[6:03] in decades of psychotherapy. They've
[6:06] often had ECT and other things, and
[6:09] nothing's working.
[6:10] And I'm thinking, you know, well, we're
[6:12] kind of out of options for these other
[6:13] people, and this diet is having this
[6:16] really powerful antidepressant effect. I
[6:18] think I'm going to try it and just see
[6:20] if any of my patients are game to try it
[6:22] to see if it might help them. Sure
[6:25] enough, it did.
[6:27] Didn't help everyone, and not everybody
[6:28] was interested and or able to do it, but
[6:31] some of the ones who were able to do it
[6:34] ended up having a remarkable and
[6:36] powerful antidepressant effect. One
[6:38] woman actually became hypomanic within a
[6:40] month.
[6:41] And she had been depressed pretty much
[6:44] non-stop for over 5 years, chronically
[6:47] depressed, suicidal, in and out of
[6:49] hospitals.
[6:50] And I saw her become hypomanic, and I'm
[6:52] thinking, wow, this really is a powerful
[6:54] antidepressant effect. Like, this is
[6:56] amazing. This is like a medication, but
[6:59] better because it actually is working
[7:01] for her. At that point, we didn't have
[7:04] many clinical trials of the safety or
[7:07] efficacy of the Atkins diet for even
[7:09] weight loss or diabetes, let alone any
[7:12] mental disorders. And so, I really
[7:14] actually felt like I'm on the fringe
[7:15] here, and this is not going to be met
[7:19] with with praise by anyone. So, I'm just
[7:22] going to lay low. I'm going to offer it
[7:24] to patients.
[7:26] And uh and I I went along that way up
[7:30] until
[7:31] 2016.
[7:32] >> So, low-carbohydrate diet, certainly low
[7:35] sugar.
[7:35] >> Yeah.
[7:36] >> I'm assuming you're not a nutritionist,
[7:37] so how did you prescribe a nutrition
[7:40] plan for your patients?
[7:42] >> The first patients, it was try this
[7:44] Atkins diet. I want to see ketosis, so I
[7:48] was strongly recommending the patients
[7:51] achieve urinary ketosis. And the
[7:54] interesting thing is I noticed a pattern
[7:56] that when they were trying the diet and
[7:58] not getting ketones, they often did not
[8:00] get a clinical benefit. It was once they
[8:02] got into ketosis that I began to notice
[8:05] the clinical benefit. The thing that
[8:07] completely upended everything that I
[8:10] knew as a psychiatrist, though, was when
[8:11] I helped the patient in 2016.
[8:14] 33-year-old man with schizoaffective
[8:16] disorder. He'd been my patient for 8
[8:18] years now. He had daily auditory
[8:21] hallucinations. He had paranoid
[8:23] delusions.
[8:24] He could not go out in public without
[8:26] being terrified. This man was tormented
[8:29] by his illness. It ruined his life. He
[8:32] had already tried 17 different
[8:34] medications, and none of them stopped
[8:36] his symptoms. He weighed 340 lb. And for
[8:40] whatever reason, he gets it in his head,
[8:42] I'm never going to get a girlfriend if I
[8:43] don't lose some weight. He also
[8:45] recognizes, I'm never going to get a
[8:47] girlfriend cuz I'm a loser. I'm
[8:48] schizophrenic. I live with my father. I
[8:51] you know, I have nothing going for me.
[8:53] For a variety of reasons, we ended up
[8:55] deciding to try the ketogenic diet. He
[8:57] decides to give it a try. Within 2
[9:00] weeks, not only does he start losing
[9:02] weight, but I begin to notice this
[9:04] dramatic antidepressant effect. He's
[9:06] making better eye contact. He's smiling
[9:09] more. He's talking a lot more. I'm
[9:11] thinking like, what's gotten into you?
[9:12] Like, you're coming to life. Like,
[9:14] you're I've never heard you talk this
[9:15] much. I've never seen you so excited or
[9:19] present or alive. I haven't changed his
[9:22] meds at all. The thing that upended
[9:25] everything that I knew as a psychiatrist
[9:27] was 6 to 8 weeks in, he spontaneously
[9:30] starts reporting, "You know those voices
[9:32] that I hear all the time?
[9:34] They're going away." And he says, "You
[9:36] know, you know how I always thought that
[9:38] there were all these families who were
[9:40] controlling my thoughts and out to get
[9:42] me and they had targeted me and I'm
[9:44] thinking, oh, yeah,
[9:45] we've been talking about that for eight
[9:46] years. We could talk about that again.
[9:48] He says, now that I think about it, I
[9:50] don't think that's true.
[9:52] And now that I say it, it sounds kind of
[9:54] crazy. It probably never was. I've
[9:56] probably had schizophrenia all along
[9:58] like everybody's been trying to tell me.
[10:01] And I think it's going away. He's now
[10:03] lost 160 pounds and kept it off to this
[10:05] day.
[10:06] >> Wow.
[10:07] >> He was able to do things he had not been
[10:09] able to do since the time of his
[10:11] diagnosis. He was able to complete a
[10:12] certificate program. He's able to go out
[10:15] in public and not be paranoid. He
[10:17] performed improv in front of a live
[10:19] audience.
[10:20] At one point, he was able to move out of
[10:22] his father's home and live
[10:24] independently.
[10:25] >> Did he stay on any kind of antipsychotic
[10:28] or other medication?
[10:30] >> We have slowly but surely tried to taper
[10:32] him off his meds. He has been on meds
[10:35] for a decades. He started medications
[10:37] when he was a young child.
[10:40] His brain is developed in response to
[10:44] all sorts of psychiatric medications.
[10:47] And it has not been easy to try to get
[10:48] him off. And I just want to say for any
[10:50] listeners, getting off your meds is very
[10:53] difficult and dangerous and you need to
[10:55] do it with supervision with a
[10:58] a mental health
[10:59] professional or a prescriber.
[11:01] >> To stay in ketosis,
[11:03] uh what sort of blood levels of ketones
[11:06] do you like to see in your patients?
[11:08] What is the range that you think most
[11:11] people could aspire to?
[11:13] >> So, it really depends on the patient and
[11:15] what I'm treating, quite honestly. And I
[11:17] don't think every patient needs the
[11:19] ketogenic diet. For some patients,
[11:21] simply getting rid of junk food can make
[11:23] a huge difference in a mood disorder,
[11:25] for instance.
[11:25] >> So, a junk food meaning highly processed
[11:28] food, food that could last on the shelf
[11:29] a very long time.
[11:30] >> Highly processed foods that are usually
[11:33] high in both sugar, carbohydrate, and
[11:36] carbs and fats. Those seem to be the
[11:40] worst foods. That combination, high
[11:44] sugar, high fat, um seems to be the
[11:47] worst combination for metabolic health.
[11:50] And lo and behold, we've got emerging
[11:53] data that suggests that strongly
[11:54] suggests it's also bad for mental
[11:57] health. So, to step back from that. So,
[11:59] for some patients, I might just want to
[12:01] decrease glucose and insulin levels, and
[12:04] I can do that by getting rid of sweets.
[12:06] For other patients, like patients with
[12:08] schizoaffective disorder or
[12:09] schizophrenia or bipolar disorder, or
[12:11] especially if it's chronic, if I'm using
[12:13] it as a brain treatment, then I do want
[12:17] a ketogenic diet, and I usually want
[12:19] reasonably high levels of blood ketones.
[12:22] For depression, I want to see at least
[12:24] greater than probably 0.8 mmol. For
[12:27] psychotic disorders and bipolar
[12:29] disorder,
[12:31] I usually want to see levels greater
[12:33] than 1.5. That's what I'm shooting for
[12:36] if at all possible.
[12:37] >> I think that for a lot of listeners
[12:41] and people out there who
[12:43] are familiar with how changing your diet
[12:45] or changing your exercise can positively
[12:47] impact sleep and weight and all these
[12:49] things, and it cascades into feeling
[12:51] better. That makes perfect sense.
[12:54] But for a lot of the world still,
[12:57] the idea that changing or using
[12:59] nutrition
[13:00] as a dissection tool or as a treatment
[13:04] tool to understand and treat mental
[13:06] illness
[13:07] is still a kind of heretical idea. That
[13:10] to them, it kind of falls in the okay,
[13:11] well, that's like a woo science or
[13:14] something like that. They immediately
[13:16] think, "Didn't Atkins die have a heart
[13:18] attack?" You know, I hear that a lot,
[13:19] you know, which I do think is throwing
[13:21] the baby out with the bathwater, but
[13:22] it's an interesting thing nonetheless.
[13:24] And then I think that the majority of
[13:25] people sit in the middle and just want
[13:28] to see science and medicine come up with
[13:30] treatments that work. And I have to say
[13:32] I'm very relieved to hear what you said
[13:35] earlier, which was you never said that
[13:36] people should come off their medication
[13:38] and just become go on a ketogenic diet
[13:40] and everything will be cured. You're
[13:41] certainly not saying that.
[13:43] >> No.
[13:43] >> And rather you're saying
[13:46] if I understand correctly that nutrition
[13:49] needs to be considered one of the major
[13:50] tools in the landscape of effective
[13:53] tools and that it can be very effective.
[13:55] Talk about epilepsy and how the
[13:57] ketogenic diet is not just used for
[14:00] epilepsy, but is one of the oldest, if
[14:02] not the oldest examples of the use of
[14:05] nutrition to treat a condition of the
[14:08] nervous system that can be incredibly
[14:10] debilitating, even deadly.
[14:11] >> Yeah. The reality is that this
[14:13] literature and this clinical history and
[14:16] all of the research we have was the
[14:18] godsend that I needed to do the work
[14:21] that I'm doing.
[14:23] Otherwise, I would have been discredited
[14:24] on day one. The ketogenic diet,
[14:27] unbeknownst to most people, was actually
[14:29] developed 100 years ago, 1921,
[14:33] by a physician for one and only one
[14:36] purpose, to treat epilepsy. It wasn't
[14:39] developed as a weight loss diet. It
[14:41] wasn't developed as the the diet that
[14:43] all human beings should follow. And the
[14:45] reason it was developed is because of
[14:47] this
[14:49] long-standing observation since the time
[14:51] of Hippocrates
[14:53] that fasting
[14:55] can stop seizures. Most people think
[14:57] going without food is bad and they
[15:00] equate it with starvation. But in fact,
[15:04] when we go without food, it causes
[15:06] tremendous shifts in metabolism, both
[15:10] brain and body metabolism.
[15:12] And it puts the body into a mode of
[15:16] autophagy and conservation of resources
[15:19] and all sorts of things that are
[15:21] beneficial to human health. And this is
[15:23] why fasting has been used as a
[15:25] therapeutic intervention in almost every
[15:27] culture and almost every religion for
[15:30] millennia. But for the most part, that
[15:32] was all thought to be religious
[15:33] folklore. In 1921,
[15:36] one physician used intermittent fasting
[15:40] on a child with seizures and found that
[15:42] oh, lo and behold, this religious
[15:43] folklore stuff has something to it.
[15:45] Actually worked. The problem with
[15:47] fasting is that you can only fast for so
[15:49] long before you starve to death and
[15:51] that's not a very effective treatment.
[15:53] As soon as people start eating a normal
[15:54] diet again, their seizures usually come
[15:56] right back, often times with a
[15:58] vengeance. And so it can be a good
[15:59] short-term intervention. The fasting can
[16:02] take a few days cuz it can take a few
[16:03] days to get ketosis and then you can get
[16:06] some relief from chronic seizures, but
[16:09] it's not a good long-term treatment
[16:11] because again, people will starve to
[16:14] death. As soon as they start eating,
[16:16] seizures come back. So it was actually
[16:18] Dr. Russell Wilder at the Mayo Clinic
[16:21] who developed the ketogenic diet with
[16:23] one and only one purpose. He wanted to
[16:25] see, can we mimic the fasting state
[16:29] using this special diet
[16:32] to see if it might stop seizures
[16:35] long-term.
[16:36] And lo and behold, it worked. Early
[16:39] results were extraordinarily positive.
[16:41] 50% of patients who used the ketogenic
[16:43] diet became seizure-free and another 35%
[16:48] had a 50% or greater reduction in their
[16:50] seizure frequency. So about 85% efficacy
[16:54] rate. By the 1950s,
[16:56] pharmaceuticals were coming out and we
[16:58] had many more anticonvulsant treatments
[17:01] and there's no question they work for a
[17:03] lot of people. That's great. And taking
[17:06] a pill is so much easier than doing this
[17:08] diet. But lo and behold, even to this
[17:11] day, people with epilepsy, about 30%
[17:14] don't respond to the current treatments
[17:17] that we have available.
[17:18] 30% will have treatment-resistant
[17:20] epilepsy, which means they continue to
[17:22] have seizures, no matter how many
[17:24] anticonvulsants they're taking,
[17:26] even if they've had brain surgery, it
[17:28] just doesn't stop their seizures. And
[17:30] so, in the 1970s, the ketogenic diet was
[17:32] resurrected at Johns Hopkins for these
[17:35] treatment-resistant cases, and lo and
[17:37] behold, it works. Not for all of them,
[17:40] but it works, and about 1/3 become
[17:43] seizure-free. And these are people
[17:45] who've tried everything, and nothing's
[17:46] working. So, 1/3 become seizure-free.
[17:49] Another third get a clinical benefit,
[17:51] meaning a 50% or greater reduction in
[17:53] their seizure frequency. And the other
[17:55] third, it doesn't seem to work. And so,
[17:57] the reality, the godsend for me, is that
[18:00] we have decades of neuroscience research
[18:03] on the ketogenic diet and what it is
[18:04] doing to the brain. We know that the
[18:07] ketogenic diet is influencing
[18:09] neurotransmitter levels, in particular,
[18:11] glutamate, GABA, adenosine. It changes
[18:14] calcium channel regulation, uh and
[18:17] calcium levels, which is really
[18:18] important in the function of cells. It
[18:20] changes gene expression. It reduces
[18:23] brain inflammation. It changes the gut
[18:26] microbiome, and there are, you know, gut
[18:27] microbiome's a huge topic right now, and
[18:29] there are some researchers who argue
[18:31] that is the primary benefit of the
[18:32] ketogenic diet. It's changing the gut
[18:34] microbiome in beneficial ways.
[18:37] Um so, it's doing a lot of things. It
[18:39] obviously improves insulin resistance,
[18:42] uh lowers glucose levels, lowers insulin
[18:45] levels, which improves insulin
[18:47] signaling. The key for
[18:50] my research that I've outlined,
[18:54] the real magic, is that this diet
[18:58] stimulates two processes that relate to
[19:00] mitochondria.
[19:02] It stimulates a process called
[19:03] mitophagy,
[19:05] which is getting rid of old and
[19:07] defective mitochondria and replacing
[19:09] them with new ones. And it also
[19:11] stimulates a process called
[19:12] mitochondrial biogenesis,
[19:14] which means that after people have done
[19:17] the ketogenic diet for a while, months
[19:20] or years, many of their cells in their
[19:23] bodies and brains will have more
[19:26] mitochondria, and those mitochondria
[19:29] will be healthier.
[19:31] And I believe that is the reason the
[19:34] ketogenic diet is such a powerful
[19:36] treatment not only for epilepsy, but
[19:39] also for people with chronic mental
[19:41] disorders. If you're looking for
[19:43] randomized controlled trials documenting
[19:45] efficacy in large numbers of patients
[19:48] with these disorders, we don't have
[19:51] them.
[19:52] >> They're underway now, but we don't have
[19:54] them yet. Maybe we could just talk about
[19:56] mitochondria for a moment and then talk
[19:57] about these two major effects. What are
[19:59] some of the other things that
[20:00] mitochondria are important for
[20:03] in neurons and
[20:05] maybe other cells of the brain?
[20:07] >> If you think of the cell as a computer,
[20:09] a lot of people think of mitochondria as
[20:11] the power cord to that computer, cuz
[20:13] they're providing the power. And they
[20:15] are in fact the power cord to that
[20:16] computer. But actually, their real
[20:18] function is the motherboard of that
[20:20] computer. So, mitochondria are directing
[20:23] and allocating resources throughout a
[20:26] cell. That is their primary function,
[20:28] and then they happen to be powerhouses
[20:30] as well. To give some clear examples,
[20:33] mitochondria play a direct role in the
[20:35] production and release and regulation of
[20:39] some really key neurotransmitters,
[20:41] including serotonin, dopamine,
[20:44] glutamate, acetylcholine.
[20:47] Those are pretty powerful
[20:48] neurotransmitters.
[20:49] >> Yeah, I would call those I would
[20:50] consider those the I know you listed
[20:52] more than three, but
[20:54] the sort of primary colors of
[20:56] neurotransmission. You know, any one of
[20:58] those
[20:59] in excess or deficiency is going to have
[21:02] profound negative effects on a nervous
[21:04] system.
[21:05] >> Mitochondria are providing both some of
[21:08] the
[21:09] building blocks, if you will, for some
[21:10] of those molecules. They're part of the
[21:13] Krebs citric acid cycle. Some of the
[21:15] some of the intermediate products
[21:17] actually go into making those
[21:19] neurotransmitters. Much more
[21:21] importantly, mitochondria provide the
[21:23] energy for the production of those
[21:25] neurotransmitters. And fascinatingly,
[21:28] mitochondria are directly related to the
[21:31] release of neurotransmitters. ATP alone
[21:34] is not enough. There have been some
[21:36] research studies that have actually
[21:38] found that mitochondria move along the
[21:42] membrane of the synapse to release
[21:46] batches of vesicles of
[21:48] neurotransmitters.
[21:50] And that if the mitochondria are removed
[21:52] from the synapse, and researchers flood
[21:55] that
[21:56] cell with ATP,
[21:59] neurotransmitters usually are not
[22:01] getting released. Mitochondria are doing
[22:04] other things. We don't entirely even
[22:07] understand what all they're doing or how
[22:09] they're doing it. But they're doing
[22:11] other things than just providing the
[22:13] power. Mitochondria at least play a role
[22:17] in all of the aspects of the human
[22:20] stress response.
[22:22] So, um when humans are stressed either
[22:24] physically or psychologically,
[22:26] there are several things that happen.
[22:28] Increased cortisol, increased
[22:30] adrenaline, noradrenaline,
[22:33] uh inflammation, and gene expression in
[22:36] particular in the hippocampus occur with
[22:38] the stress response. And one group of
[22:41] researchers actually genetically
[22:43] modified mitochondria in four different
[22:45] ways and found that all those four
[22:47] buckets of stress response were impacted
[22:50] in one way or another.
[22:52] Implying that mitochondria are somehow
[22:54] playing a role
[22:56] in those.
[22:58] In terms of it their role in cortisol,
[23:00] we know that mitochondria actually have
[23:03] the enzyme required for the synthesis of
[23:06] steroid hormones. So, that includes
[23:09] cortisol, estrogen, testosterone, and
[23:12] progesterone, some names that maybe
[23:14] everybody's heard of. So, that means
[23:16] that if mitochondria
[23:18] are in short supply or dysfunctional,
[23:22] the production of those hormones may
[23:24] become
[23:26] dysregulated.
[23:27] Mitochondria play a direct role in
[23:30] inflammation, and they turn
[23:33] the inflammatory
[23:35] system both on or they they at least
[23:38] play a role in turning the inflammatory
[23:40] system both on and off. One paper in
[23:43] Cell actually
[23:45] identified mitochondria as the key
[23:46] regulator in turning certain
[23:48] inflammatory cells off. And that when
[23:51] you inhibit mitochondrial function,
[23:53] those cells don't turn off that
[23:55] mitochondrial levels of reactive oxygen
[23:57] species are a key signaling process to
[24:02] turn the inflammatory cell process off.
[24:06] Another study found that macrophages, so
[24:09] macrophages are an important immune cell
[24:12] that play a role in healing. So, if you
[24:13] cut yourself,
[24:15] your your body will get you know, send
[24:17] inflammation that way and
[24:20] and send immune cells that way to try to
[24:22] heal your skin. And macrophages play an
[24:25] important role in that healing. One
[24:28] group of researchers tried to figure out
[24:30] how do macrophages know
[24:33] to switch between the different phases
[24:35] of wound healing? Cuz the macrophages do
[24:37] different things in the different phases
[24:40] of wound healing. And the conclusion of
[24:43] all of their research was that it's
[24:45] mitochondria. Mitochondria are sending
[24:47] the essential signals that change the
[24:51] state of the macrophages to induce these
[24:54] different phases of wound healing. So,
[24:57] I've just talked about
[24:58] neurotransmitters, hormones, epigenetic
[25:01] expression, inflammation.
[25:04] For anybody familiar with the mental
[25:05] health field,
[25:08] they know these are like
[25:11] some of the key variables that
[25:13] researchers have been struggling with
[25:15] for decades trying to figure out how do
[25:18] these fit together. We know that all of
[25:20] the those buckets
[25:23] can be disrupted
[25:25] in people with mental disorders, and our
[25:27] field has struggled to understand but
[25:30] how do they fit together? How can we
[25:32] make sense of this disruption? I believe
[25:36] once you understand the science of
[25:39] mitochondria,
[25:41] you can actually connect all of the dots
[25:43] of the mental illness puzzle. What I'm
[25:45] hearing
[25:47] is that mitochondria, in addition to
[25:49] being important sources of energy
[25:51] production and output in cells, which of
[25:54] course they are,
[25:55] um probably have
[25:58] other roles, and that maybe maybe
[26:01] someday what we call mitochondria will
[26:03] actually be two or three different
[26:04] little subcellular organelle. In the
[26:06] landscape of science education, uh often
[26:09] times people will think, "Okay, energy
[26:10] production." There'll be a picture or a
[26:12] cartoon of mitochondria like flexing its
[26:13] muscles. People go, "Okay, energy,
[26:15] mitochondria, mighty mitochondria." And
[26:17] then they'll think, "Oh, you know,
[26:18] they're just sort of like a dumb jock
[26:19] portion of the cell." Right? They're not
[26:21] doing anything sophisticated. And
[26:23] everything you listed off is that they
[26:25] are doing many sophisticated, intricate
[26:28] things within cells. So, now that um
[26:31] everyone is well aware that mitochondria
[26:33] are doing a large number of very
[26:35] important things
[26:37] in a very regulated way,
[26:39] let's talk about mitophagy, which I have
[26:40] to presume is the
[26:42] um
[26:43] intentional
[26:44] or not gobbling up of mitochondria,
[26:47] presumably to replace them with newer,
[26:49] healthier mitochondria. Is that right?
[26:51] >> It is. So, in in in many ways mitophagy
[26:54] is a subset of autophagy, but it's got
[26:57] its own name because it is specific to
[26:59] mitochondria.
[27:00] There do appear to be
[27:03] some unique regulators of mitophagy
[27:06] compared to autophagy more broadly.
[27:09] Mitochondria actually are playing a a
[27:12] role in autophagy itself.
[27:14] Um and this makes sense because one of
[27:17] the So, the global picture of autophagy
[27:20] is stimulated by fasting states or
[27:24] fasting mimicking states. So, when your
[27:26] body senses that you don't have enough
[27:30] food,
[27:32] it actually hunkers down and starts to
[27:36] recycle
[27:38] dead old parts in this kind of carefully
[27:42] orchestrated way, and it takes them to
[27:45] lysosomes, they get degraded, and then
[27:47] those
[27:48] degradation products get used for either
[27:51] energy or to build new things.
[27:54] Autophagy's always occurring
[27:56] um at a low level, but you can really
[27:59] hyper-stimulate the process through
[28:01] fasting, calorie restriction, fasting
[28:04] mimicking diets, other things.
[28:06] And this is why fasting and fast you
[28:08] know, calorie restriction is so
[28:10] kind of such hot topics in the medical
[28:12] field now is because we it they've been
[28:15] shown to induce longevity, and we think
[28:17] it's probably through that process.
[28:20] That you're you're stimulating the body
[28:21] to become lean and
[28:25] conservative in terms of its allocation
[28:28] of resources.
[28:30] And the body doesn't just destroy the
[28:32] healthiest tissue along with the old
[28:34] dead stuff. It has these processes that
[28:37] identify the old and defective parts
[28:39] first, and they go first. And that's
[28:41] what's beautiful about the whole thing,
[28:43] and that's why fasting is so important.
[28:46] So, mitophagy
[28:48] we know plays a really important role
[28:51] because there's this term called
[28:53] mitochondrial dysfunction, which some
[28:55] researchers are actually wanting to get
[28:56] rid of and move away from because, as
[28:59] you just said, mitochondria do so many
[29:00] different things, and different
[29:02] mitochondria, even within the same cell,
[29:04] may very well be specializing in
[29:06] different tasks, and mitochondria from
[29:08] one cell to another are sometimes doing
[29:10] very different things. Like not all
[29:12] mitochondria can produce cortisol.
[29:14] That's specific to specific cells where
[29:16] those genes are getting turned on. So,
[29:19] it's not like all mitochondria are
[29:20] producing cortisol, just the ones in
[29:23] your adrenal gland, for instance, are
[29:24] producing cortisol. And it has long been
[29:28] known for decades
[29:30] that mitochondrial dysfunction is
[29:33] associated with everything that ails us,
[29:36] essentially. So, David Sinclair uh
[29:40] published a page paper in one of the
[29:42] cell journals, I think, saying that,
[29:44] "Oh, mitochondria are actually the
[29:46] unifying link of everything that we know
[29:48] about aging. Defective mitochondria or
[29:51] defective mitochondrial function,
[29:53] mitochondrial dysfunction, is possibly
[29:57] the unifying cause of aging and all of
[30:00] the aging-related disorders." So,
[30:02] mitophagy
[30:05] is trying to address all that. It's
[30:06] trying to say, "Okay, this is bad. We
[30:08] don't want defective mitochondria, and
[30:10] how can we get rid of old ones or
[30:13] defective ones and and replace them with
[30:15] new ones?" And I think the most powerful
[30:19] signal
[30:20] and tool that we have right now
[30:23] is, in fact, related to diet. It's
[30:26] calorie restriction. That is the oldest,
[30:29] truest, best-proven way to prevent aging
[30:34] in a wide variety of animal species.
[30:37] Fasting and intermittent fasting.
[30:40] And again, you can only do those things
[30:42] for so long, and then fasting mimicking
[30:44] diets um can also stimulate this process
[30:48] of
[30:50] mitophagy.
[30:51] >> So, what about the the typical person
[30:53] who's an omnivore eating
[30:56] um you know, some rice, some pasta. Do
[30:58] you think that those people might feel
[31:01] far better
[31:03] or even a little bit better if they were
[31:05] in a
[31:06] lower glucose state? I ask this because
[31:09] I think there are a lot of people out
[31:10] there who suffer from full-blown
[31:11] depression, but there are also a lot of
[31:13] people who suffer from like moodiness
[31:15] and feeling not so great, subclinical
[31:18] depression.
[31:18] >> Yes, burnout is what I would call it.
[31:20] >> Yeah, and and just feeling like some
[31:22] days are great, and then other days they
[31:24] feel lousy for reasons they don't
[31:25] understand.
[31:26] >> I kind of break this field, and I'm
[31:29] probably getting too nerdy right now,
[31:30] but I kind of break this field into
[31:32] cause, what's the actual root cause, and
[31:36] what are effective treatments. And I
[31:39] really see them as two separate things.
[31:41] >> Calorie restriction, ketogenic diet,
[31:44] carbohydrate restriction
[31:47] are inducing metabolic changes in the
[31:50] brain and body.
[31:53] And [snorts]
[31:54] regardless of what the person was eating
[31:57] they are inducing metabolic changes that
[32:00] can be really beneficial to brain
[32:01] health. So, going to your broader
[32:04] question about adults modern day, if
[32:07] it's an average person who is not
[32:09] currently under psychiatric care
[32:12] not taking prescription medicines but is
[32:15] saying, "I'm burned out. I'm exhausted.
[32:18] I want some of that brain energy that
[32:20] Andrew Huberman's talking about." I
[32:22] He He talks about feeling good. I want
[32:23] some of that. I'm probably actually
[32:25] going to recommend, "Let's see if we can
[32:27] just carb restrict for a while."
[32:30] Um and see if that produces clinical
[32:32] benefit. I have one he's not even a
[32:34] patient, just a somebody who read my
[32:37] book. He chronic anxiety, was trying
[32:40] meditation, was trying all sorts of
[32:41] things. He was ready to go on
[32:42] prescription medicine. He read an early
[32:44] copy of the book.
[32:45] He took it upon himself without
[32:47] consulting with me to restrict
[32:48] carbohydrates alone. He did not go
[32:50] ketogenic. He is a vegetarian. He
[32:54] restricted carbs. Within 3 weeks said,
[32:57] "I don't need prescription medicine. I
[32:59] can't believe how much better I feel."
[33:02] And all I did was cut out some of the
[33:04] high-carb foods in my diet. So, I think
[33:06] for some people it can be that simple.
[33:09] For people with serious mental
[33:11] disorders, if they are chronically
[33:13] depressed, if they're on lots of
[33:15] prescription meds, if they're disabled
[33:17] by their symptoms, and certainly if
[33:19] you're bipolar or have schizophrenia or
[33:22] something, those are the people I really
[33:24] do want them to work with a medical
[33:25] professional because meds may need to be
[33:28] adjusted, they really need a
[33:31] They need a real shot at this diet. It's
[33:34] not like weight loss. Weight loss,
[33:36] everybody wings it.
[33:38] And either you're successful or you
[33:39] aren't. You You look on the internet or
[33:41] you read a book and seeing whether it
[33:43] works or not. But, if you're using it to
[33:45] treat a serious disorder, I think you
[33:48] need serious help.
[33:50] On behalf of myself and the listeners
[33:51] and
[33:52] certainly just on behalf of everybody
[33:54] out there because everyone
[33:56] does need to be concerned about mental
[33:58] health issues whether or not they have
[34:00] them in in their family, themselves, or
[34:02] otherwise because they impact everybody.
[34:04] So, I really want to thank you for doing
[34:05] the work that you're doing. You've given
[34:06] us a lot of hints into the underlying
[34:08] mechanisms that suggest as to why it
[34:10] would work, and you've been us giving us
[34:12] examples as to how it has worked in
[34:14] patients that you've worked with. So,
[34:16] thank you for being brave and for taking
[34:19] this on and doing it in such a
[34:21] structured way, and for communicating it
[34:23] here today and with the general public
[34:25] through your book and your online
[34:26] presence. We will certainly point people
[34:28] in the direction of those valuable
[34:29] resources.
[34:31] Thanks so much. We really appreciate it.
[34:33] >> Thank you, Andrew, for being brave and
[34:35] having me on your
[34:36] >> [laughter]
[34:36] >> show and uh
[34:37] >> It's been a pleasure.
[34:38] >> and for
[34:39] uh for a great conversation.
[34:42] >> [music]