Dr. Rhonda Patrick here. I love indoor cycling, and it's not strictly an obsession with heart health or maintaining a svelte figure. No, for me, it's about mood and brain benefits. While virtually all exercise at any dose is probably beneficial, when it comes to full mental recalibration, for me, a 60-minute cycling session uniquely stands out. And it's not just my personal experience either. The scientific evidence continues to stack up that exercise may help prevent and treat depression. Attributing causality to the role exercise plays in preventing depression was difficult early on, largely due to the fact that many of the studies that linked exercise and depression were observational studies, which are always limited by confounding factors.

If all we have to go on are observational studies, it's difficult to rule out reverse causality. Who's to say people that are physically active just aren't depressed to begin with? The good news is the case for exercise can be bolstered when we begin to look at some of the recent evidence ranging from molecular to genetic to randomized controlled trials. When the observational data begins to converge with some of the molecular and mechanistic data, and then ultimately with data from the randomized controlled trials, the case for exercise as a possible treatment for depression becomes very promising. So let's talk about some of that data, starting with genetics.

When we talk about genes, it's important to realize that even complex behaviors such as whether or not someone will engage in physical activity can partially be influenced by genetics. That's where things start to get really interesting. One recent study examined over 400,000 individuals and found that those individuals with certain genetic variants that increase the likelihood that they'll be physically active were— big surprise— protected from getting depression. Moreover, these findings have a stronger case for causality thanks to a technique called Mendelian randomization. Mendelian randomization treats natural genetic variation like a randomized experiment. It assigns individuals to higher or lower mean levels of an environmental exposure, which in this case is physical activity.

This type of genetic study is able to establish causality in a way that observational studies cannot, but only to the extent that these genetic variants influence depression directly through physical activity and not some other unknown mechanism. The good news is there are even more direct paths to establishing causality. The gold standard, randomized controlled trials. There have been numerous randomized controlled trials that have shown exercise plays an important role in mitigating depressive symptoms, facilitating recovery from depressive disorders, and preventing relapse. For example, a meta-analysis of 25 randomized controlled trials found that exercise improved depression, and this effect was particularly strong for aerobic exercise, of moderate to vigorous intensities.

At the molecular level, there may be a few reasons why intense aerobic exercise gives such a strong benefit. The first has to do with a precursor for a neurotoxic substance called kynurenine, which is formed from the amino acid tryptophan. Some of you may be familiar with tryptophan because of its important role as a precursor for other bioactive compounds, including serotonin. Mm-hmm. A neurotransmitter that's important for mood and cognition. Exercise actually increases the availability of tryptophan to be transported into the brain, which is a good thing because in the brain it forms serotonin. However, tryptophan is also a precursor for another compound called kynurenine, which can cross the blood-brain barrier and in the brain form a neurotoxin called quinolinic acid.

Quinolinic acid can cause cells to die in the brain. It's also associated with depression and other mental health and neurological disorders. So what determines whether tryptophan will be transported into the brain to form serotonin or whether it will form kynurenine? Well, it turns out the bioavailability of tryptophan for these different biochemical pathways is influenced by a variety of factors ranging from stress to inflammation to exercise. Stress hormones like cortisol can shunt tryptophan away from forming serotonin because it activates enzymes that are involved in converting tryptophan into kynurenine.

Similarly, chronic low-grade inflammation can also shunt tryptophan away from forming serotonin because it activates other enzymes that are involved in converting tryptophan into kynurenine. This unique relationship between kynurenine metabolism, depression, and exercise is addressed a bit more in depth in a clip from a conversation I had with Dr. Charles Raison. You know, a very interesting— there's a few interesting studies that have been cropping up over the last couple of years in terms of another mechanism by which exercise, and specifically activating muscle cells, helps treat depression through this kynurenine pathway. Mm-hmm.

And I guess, you know, for people that aren't familiar with kynurenine, it's basically a byproduct of tryptophan metabolism when your immune system's activated. In the case of chronic inflammation, for example, you're not converting tryptophan into serotonin. That's right. You're actually converting into something else called kynurenine, which activates immune cells. And, you know, so— but the problem is that kynurenine can form— is it quinolinic acid? You can form kynurenic acid and quinolinic acid. Quinolinic acid is definitely a neurotoxic agent. Okay. It's involved in depression somehow. Yeah, it is. So we actually did this study, again, this is Andy Miller and I, years ago in the interferon alpha work. We had the good sense to do spinal taps on people, right?

So we drew out the fluid around the brain, spinal fluid, and looked to see, does chronic inflammation delivered by interferon alpha change serotonin metabolism? Wow. So Michael Moss and Lucille Capiron and a number of people in the early 2000s began to show that chronic inflammation activated an enzyme called indoleamine 2,3-dioxygenase, right? Indoleamine. And this is an enzyme that basically, as you said, takes tryptophan and shunts it away from serotonin into kynurenine. Now, there's an evolutionary advantage to this too. You don't want your bugs to have the serotonin, and you don't want them to have the tryptophan. So you block that enzyme and death rates spiral in certain environments.

infections, and I can't remember, I used to know all this stuff, but there's certain infections where it's just lethal. I think leishmaniasis is one of them, I think, but I'm not sure about that. So anyway, yes, you get everything shunted to kynurenine. So what we showed was that— so everybody thought, so we knew that the more that enzyme got kicked up, the more depressed people got under chronic inflammation. That was shown by several different groups. It seems to be a reliable thing. But of course, this was just in people's You can look at the ratio of kynurenine to tryptophan, and that tells you how active that enzyme is. We got spinal fluid and showed that indeed, and this is really interesting, that the interferon definitely jacks up kynurenine.

Kynurenine levels in the blood and the spinal fluid are very, very similar. So we think it's getting across. Mm-hmm. But you see a massive increase in quinolinic acid and kynurenic acid. And setting aside the kynurenic acid, which is interesting, it's an NMDA antagonist. Quinolinic acid is an NMDA agonist. It causes neurotoxic effects. Quinolinic acid skyrocketed under interferon treatment. That's what's associated with depression powerfully. The good news is, is that positive lifestyle factors such as exercise can have a beneficial effect on kynurenine metabolism.

For example, exercise, and specifically endurance exercise, causes muscle tissue to increase the activity of a gene called kynurenine aminotransferase, which stops kynurenine from forming the neurotoxin quinolytic acid and instead makes it form another compound called kynuric acid, which is actually neuroprotective. Another contributing factor for how exercise may decrease depression may be through a beneficial change in trophic support for the brain. A short boost of immune molecules that are produced from muscle tissue— they're called myokines— can stimulate the brain's resident immune cells called microglia to produce neurotrophic factors, which are growth factors that are involved in the production of new brain cells called neurogenesis.

This puts another spin on some of these immune molecules like IL-6, which are widely thought to be a negative component of inflammation, and when chronic, it's definitely definitely negative, but a short transient burst of these pro-inflammatory cytokines might be just what we need when it comes to maintaining brain health. Dr. Charles Raison explains. So now I think what's going on is that, you know, so, you know, you talk about the immune system and the brain being one unified organ. Really, of course, so are the muscles. And IL-6, which is, we think of as mostly an inflammatory cytokine in the context of Sickness is a myokine in the context of exercise. And we know in the context of exercise that IL-6 plays a key role in exercise's ability to induce insulin sensitivity.

So if you block IL-6 in a rodent that exercises, you block all the beneficial metabolic effects. Now, what's interesting about that is that there's a relevant animal study from Rajamia in Israel. where they took mice, and I'm pretty sure it's mice, not rats, and subjected them to this 20-day horrible stressor. And they showed that the stressor crazy activates inflammation, leads to apoptosis, death of microglial cells in the brain, and, you know, huge anxious depressive behavior afterwards, right? So what's interesting was they showed that if you blocked inflammation right before the start of the stressors, you sort of— it starts, you block it, you can prevent the apoptosis, you can prevent the downstream behavioral effects. It's protective, right?

If you do nothing here and you let the little rodents go through the horrible stressor and you block inflammation afterwards, they do worse. Hmm. If you stimulate inflammation, they get an antidepressant response. So there's a little bit of a backcurrent that I am just one of the few people, but there are some of us that are interested in this idea That inflammation is a funny thing, right? So these cytokines, these classic inflammatory molecules like TNF, tumor necrosis factor alpha, IL-1 beta, IL-6, at lower levels in the brain, they actually have neurotrophic effects. Kind of like a hormetic stressor where they're— We don't know. Is it a stressor or is it just that they evolved?

Nature is so cheap, you know, it always wants to reuse things and that's what makes things Evolutionary processes do this constantly. And it's why things are— one of the reasons why biologic systems are hard to understand. You know, if they've generated TNF knockout mice, they can't find their way out of a bag. They're dumb as dirt, right? You know, so there's something about lower levels of these mediators that may actually be beneficial in the CNS at least. One of the arguably most important and beneficial trophic factors that is produced upon exercise and may also be implicated in what Dr. Charles Raison explained a minute ago is called brain-derived neurotrophic factor, or BDNF. Brain-derived neurotrophic factor is produced throughout the body and also in the brain.

In the brain, it plays a very important role in promoting the growth of new neurons and also promoting the survival of already existing neurons. But it does so much more than that. BDNF plays a very important role in neuroplasticity, which is the ability of the brain to remodel and reorganize itself based on experiences, behavior, and genes. by forming new neural connections throughout life. Neuroplasticity is disrupted in depression and other mental health disorders, and the changes in neuroplasticity induced by stress and other negative stimuli have been shown to play a significant role in the development and onset of depression.

Reductions in serum and plasma levels of BDNF have been found in people with depression, and also decreases in BDNF in certain brain regions have been found in people with major depressive disorder. Stress and other factors can reduce BDNF, whereas exercise consistently increases BDNF in serum, which can cross the blood-brain barrier and have beneficial effects in the brain. Physical activity resulted in an average 32% increase in serum BDNF levels compared to baseline, and that resulted in about a 45% increase compared to controlled conditions. Both exercise duration and intensity play an important role in determining how much BDNF is produced. For example, moderate and intense physical exercise for 40 minutes produces more BDNF than moderate or intense exercise for 20 minutes.

And animal studies have consistently shown that exercise increases BDNF and neurogenesis in the brain. There are many other possible mechanisms that may explain why exercise is good for mental health, including endocannabinoids, which may be responsible for some of the positive feelings of well-being and reductions in anxiety. Cannabinoids are a family of compounds that bind to receptors on cells like immune cells and brain cells. Some of the most well-known cannabinoids are THC and CBD, which are found in cannabis. But humans naturally produce cannabinoids called endocannabinoids, and some endocannabinoids such as anandamide are produced upon exercise.

Endocannabinoids are able to cross the blood-brain barrier, and they may be responsible for part of the euphoric feeling that we associate with exercise. People that engage in moderate-intensity running or cycling increase their endocannabinoid levels, and this especially holds true when people reach around 70 to 80% of their maximum heart rate. And of course, there are beta endorphins, those feel-good opioids. Beta endorphin activity has been shown to be increased in the brain after long endurance runs. From genetic to molecular to intervention studies, the evidence supporting a role for exercise in easing the symptoms of depression is strong.

On the molecular level, whether we're talking about increased tryptophan transport into the brain to form serotonin, or preventing the formation of the neurotoxin quinolitic acid that's associated with depression, or a transient increase in immune molecules, or increasing neurotrophic factors in the brain, or boosting those positive endocannabinoids or endorphins, exercise has you covered. But this is especially true if the exercise happens to be vigorous and aerobic. And it's important to mention that while aerobic exercise has been shown to help in the prevention and treatment of depression, strength training also has a place. Resistance exercise has been associated with a 45% reduction in depressive symptoms, according to a meta-analysis of 33 randomized controlled trials.

My personal favorite flavor of exercise is indoor cycling or going for a long run, but there's probably some flexibility in there to find whatever fires you up and go for it. One final important note. While I think this video does a pretty good job laying out the scientific evidence for why exercise may help ameliorate depressive symptoms, this video in no way should be a substitute for a proper diagnosis and treatment for any depressive disorder. Instead, this video should be understood as a review of the scientific literature. If you think you have a bona fide clinical disorder, please seek out the help of a qualified mental health practitioner. I'm Dr. Rhonda Patrick, and I'll catch you next time.