Episode Transcript hideshow
**Voice-over:** *I try to imagine a fellow smarter than myself, then I try to think - What would he do?*
**Announcer:** *Charge up your axons, ready your receptors and shift your lobes in to upper beta phase. You're listening to Smart Drug Smarts - the podcast dedicated to helping you optimize your brain with the latest breakthroughs in neuroscience, nootropics and psychopharmocology.*
**Jesse:** Hello and welcome to Smart Drug Smarts, I'm your host Jesse Lawler excited to bring you episode #54 in this podcast, dedicated to the betterment of your own brain by any and all means at your disposal. This is going to be, I believe, our second ever holiday-themed episode. We're going to be celebrating the American holiday, Thanksgiving, in just a couple of days. Thanksgiving, of course, is associated with turkeys and turkey meat is associated with L-tryptophan, which is an amino acid, one of, I believe, 20 amino acids that are strung together within our cellular machinery to make up proteins and tryptophan actually has some fairly direct effects on our neurotransmitter levels, particularly, serotonin. So, we're going to be speaking with a tryptophan expert whose name, I'm unfortunately almost sure I am going to butcher. He is a Frenchman living in Australia, Dr. Gilles Guillemin, and he has been studying tryptophan and its effects within the body for the last 17 years, so he is a heavyweight expert in this particular chemical. If you hang around till the end of this episode, I am going to tell you something that you can pull out from your bag of tricks to impress your friends and family at Thanksgiving, which is, how one should refer to a group of turkeys. It is probably not what you think. I didn't know this. This is actually something that was tossed at me by my editor prior to us editing this episode. It was so cool that I figured let's get that in the episode. But, before we get into any of that, let's do This Week in Neuroscience.
**Voice-over:** *Smart Drug Smarts - This week in Neuroscience!*
**Jesse:** So, I am going to do my best to do this without being overly preachy or moralistic because, if there is one thing nobody likes, it is preachy or moralistic people. But, it is the holidays, it is a time of year that is well-known for excessive consumption of alcohol and that has some nasty effects, like, more car accidents and things like that every single year. But, alcohol is also doing a lot of damage which can go unseen within people's brains even if nothing as dramatic as a car accident results from it. A new study that is going to be published in the December 2014 issue of Alcoholism: Clinical & Experimental Research, goes into detail on a study that was just completed at Harvard University and the Boston University School of Medicine. They were looking at gray matter and white matter within the brain. One of the lead researchers, Catherine Brawn Fortier, describes gray matter and white matter thus, "Gray matter or cortex consisting of neurons, the critical cells that support brain function and white matter, the connection among large groups of those cells. We, now, know that alcohol impacts both gray matter and white matter with the greatest impact affecting the parts of the brain called the frontal lobes. These brain areas are critical for learning new information and even more importantly, in self-regulation, impulse control and the modification of all complicated behaviors. In other words, the very parts of the brain that may be most important for controlling problem drinking are damaged by alcohol, and the more alcohol consumed, the greater the damage."
One interesting, and somewhat bleak, finding with this study is that it really does seem to be a dose-dependent negative response to alcohol. It's not something where you either have brain damage or you don't; it seems to be very much a sliding scale, just based on the amount of alcohol that's abused. Says Fortier, "Alcohol, however, is more like sunburn. Our study shows that the damage occurs as a function of quantity and exposure; the more you drink, the greater the damage to key structures of the brain, such as the inferior frontal gyrus, in particular. This part of the brain mediates inhibitory control and decision-making, so tragically, it appears that some of the areas of the brain that are most effected by alcohol are important for self-control and judgment, the very things needed to recover from misuse of alcohol." This study was based on brain scans of men and women, some of whom were alcoholics, some of whom were light, regular drinkers, essentially, people who consumed alcohol but not at what's considered a problem level. The mean age of the alcoholic group was 51, and the control group was matched to the alcoholic group with regard to gender, age, education, and estimated intelligence.
One interesting finding was that people who are alcoholics, who had stopped drinking and had ceased alcohol use before a threshold age, which seems to be about 50, based on this study, then their brains were able to partially recover. Beyond the age of 50, it seemed like the physiological infrastructure wasn't even there to repair the damage even if somebody stopped drinking beyond that point.
So, not great news for the alcohol industry. Not that this is probably going to make people stop drinking in droves, but, definitely does not paint a pretty picture of what alcohol is doing inside the human brain. So, drink responsibly, as they say during the holidays and really recognize that responsible doesn't just mean not running over somebody in a car, it can really mean thinking about what is going to be best for your own long-term health and cognition.
**Voice-over:** *Smart Drugs Smarts.*
**Jesse:** A couple of pieces of Smart Drug Smarts news, the Most Enthusiastic Email of the Week Award goes to JT Olsen, who said of our app, Axon, "I have almost 200 apps on my phone, and, by far, this is my favorite. It's packed with useful information." We loved getting that email, of course, but I am a little bit afraid that we are going to give JT a complete heart attack when he sees where the app is going to go in the course of the next 6 months. We're just getting started, buddy. We really appreciate the email and for those of you who are iOS users, who have not yet downloaded Axon, I will politely nudge you in that direction. Also, on the Smart Drug Smarts website, I just wrote an article. I don't really do much article writing on the site, which is something I'd like to get more in the habit of doing, because I do enjoy writing articles from time to time. But, I have been goofing around with my sleep habits for the last couple of months, I have been trying to up my number of naps`pretty significantly throughout the day and I want to get another sleep episode in here sometime soon. The more I think about it, more I think that sleep hacking is one of the biggest potential wins. If you can do something to improve your quality of sleep. Anyways, I am not going to get into it right now. But, new little article that I wrote dealing with a sleep hack that I have been fiddling with- that's up on the Smart Drug Smarts website. It's called Hypnagogic Harvests of a Sputtering Brain.
**Voice-over:** *Smart Drugs Smarts.*
**Jesse:** Our guest today is Gilles Guillemin from the Macquarie University in Sydney, Australia. He's got one of these amazing French accents that just kind of make you wish that you were French and among other things, we're going to be speaking about the French Paradox. He talks about that a couple of times in the interview and I just want to make sure that everyone knows what the French Paradox is. It's a term that was popularized in the late 1980s which deals with the counter-intuitive fact that while French people have a diet that's rich in saturated fats with lots of heavy sauces and butters and things like that, they have a relatively low incidence of coronary disease and heart attacks`and circulatory problems that we typically associate with high-fat diets. What science has come to accept is that atleast one of the clues in that mystery is a substance called Resveratrol which the French`consume a lot of in their red wines. It's also present in some other foods, like blueberries. It is probably deserving of an episode unto itself in the future on Smart Drug Smarts. Anyways, just wanted to give you a cheat sheet for some of the words that are going to be bandied about here. So, the mythology of L-tryptophan and Thanksgiving goes something like this: turkey meat is particularly high in L-tryptophan so when people get together and eat Thanksgiving meals, they have turkey meat and everyone gets tired after the meal because something about L-tryptophan makes you sleepy. Turns out that's not particularly accurate and the first hole in that is that turkey meat is not all that high in L-tryptophan compared to plenty of other things. That's kind of where we kick off the interview.
**Voice-over:** *Smart Drugs Smarts.*
** Gilles Guillemin:** So you're right. Basically it's a misconception because among the different type of food the turkey is pretty low, say in the middle of in terms of concentration of tryptophan. The highest meats, the highest things you can find tryptophan is sea lion meat. We don't eat sea lions everyday but that's the highest one. I don't know why it's like that. Probably because it needs a lot of energy to protect from the cold or whatever. After that you have the elk meat. Among the food that we eat everyday one of the richest food in tryptophan is egg white. So it's about 1 gm per 100 gm of food. Spirulina is pretty rich as well. But when you look at the turkey itself, when you look between the different poultry, turkey comes in fourth. Number 1 is quail, number 2 is duck, number 3 is pheasant, number 4 is turkey. So it's rich in tryptophan but not that rich.
**Jesse:** So where do you think that this sort of mythology around turkeys and tryptophan, how did that come into being?
** Gilles Guillemin:** You should be able to answer that, that's an American legend so I'm not too sure. We don't eat that much turkey in Europe or in Australia so I don't know where it's coming from, the original story. It's funny because a couple of years ago I had already interviewed for a newspaper in US. They contacted me and asked, "Is it dangerous to eat too much turkey? Falling asleep while driving? I said, "Oh I don't think so. I think you have to eat a lot of turkey before falling asleep. It's more what's coming with the turkey, I think what you're drinking with the turkey maybe."
**Jesse:** Let's roll back to our basic biochemistry 101 and sort of tell us what tryptophan is in the broader context.
** Gilles Guillemin:** Tryptophan is one of the 20 amino acid. It's an essential amino acid. That means our body cannot make it. The only way to have it in our protein, in our body is to get it from the diet. So it's an amino acid. It's like a piece of Lego you will use to make your protein. Protein is a combination of different amino acids like you're building with different color Lego blocks. Tryptophan is just one of these blocks and it is very important for all the small molecule in your brain, we'll probably discuss this a bit later but neuro active compounds like seratonin and melatonin, tryptophan is a precursor of this kind of molecule, it's really important in your body.
**Jesse:** Tell us about what the effects on our neurochemistry are that result from the consumption of tryptophan? I know that tryptophan is often talked about as being a metabolite of 5HTP which is a supplement that a lot of people are probably familiar with and 5HTP in turn affects the seratonin levels within the brain.
** Gilles Guillemin:** Yes, so tryptophan has 2 pathways. It can be used by 2 different pathways or 2 branches. One branch called the seratonin pathway where the tryptophan will be broken to make 5-Hydroxytryptophan (5HTP) to make seratonin or make melatonin. The other branch is called Kynurenine Pathway which I've been working on for 17 years. This pathway is mostly used to make an essential enzyme called Nicotinamide adenine dinucleotide (NAD+) which is very very essential enzyme in your body. It's an anti-aging, we just recently demonstrated that it is very very important for anti-aging because e.g the genes in your body regulating your aging called the Sirtuin cannot work without NAD. That's a branch of the Kynurenine Pathway branch. The other branch is making seratonin in normal condition that triggers your mood. When seratonin is catabolized it's making melatonin. Melatonin is regulating your sleep.
**Jesse:** And does the creation of melatonin would that have something to do with the drowsiness effects that people associate with the big turkeys at the Thanksgiving dinners or is that a wild goose chase, to keep on the poultry analogy?
** Gilles Guillemin:** No, I feel it's not the case. If you take supplement of tryptophan you will not sleep. The conversion from seratonin to melatonin is regulated by light as well. So there's a different system regulating your small molecules. When you have light your brain sees the light and it only makes seratonin. When you're in the dark you will increase your melatonin.
**Jesse:** Is this one of these things where if you wanted to take it at night but still get the effects of seratonin, then buying one of these blue lights that's giving daytime wavelength of light would be useful to somebody? Is there a hack there?
** Gilles Guillemin:** That's a very good question. I don't know the answer to this one. I know that people have working on the regulatory mechanism. There's a tryptophan metabolite which is light sensitive called ... and in the body there is a receptor called aryl hydrocarbon receptor whose property is to make any --- of the day or night, regulating as well your ---. But, people are still working on this small molecule.
**Jesse:** Tell us a little bit about the NAD+.
** Gilles Guillemin:** Yes, the NAD is really important actually. I have heard about the work from David Sinclair. He is one of the guys from Harvard; he is working on resveratrol, a natural compound. He has been named one of the top scientists in Time Magazine or something like that, last year. His work shows that resveratrol, the ____ of the French Paradox ___. It increases the NAD+ in your body. NAD+ is very important for __ activity, the anti-ageing genes. So, NAD+ is truly essential; it is so important for so many things in your body, like your DNA repair, to limit cancer development, increasing energy- the more you increase your energy level, the more every single cell in your body will make energy ___. So, it's a very essential enzyme. That's why, basically, tryptophan metabolism is so important as a source of NAD+.
**Jesse:** I've read that there are some differences between tryptophan when it's consumed in the diet versus when it is taken as a supplement; that, supplements do more to increase brain levels of serotonin versus eating Tryptophan.
** Gilles Guillemin:** Yes, that's a very good point. Actually, to penetrate the blood-brain barrier, to get inside the brain, tryptophan, there is a transporter called LAT1, low amino acid transporter 1. To reach the brain, there is a competition between several amino acids. So, if you take only one, like, if you take only tryptophan, you will be the only one going to the door. If you have a big meal with a lot of different amino acids, they will compete and there will be a limitation for getting through this transporter. But, if you only get a pure high dose of only one amino acid, it will go straight to your brain, whereas, the full meal, it's a competition between different amino acids to penetrate the brain.
**Jesse:** Can you talk about neurotransmitter levels and L-tryptophan in the diet?
** Gilles Guillemin:** You mentioned earlier about the 5-Hydroxytryptophan. Which is a good thing to take- tryptophan or 5-Hydroxytryptophan, when you have a mood problem. I will say that it is probably better to go straight away with 5-HTP because you cannot go back to the Kynurenine Pathway and you cannot make the toxin Quinolinic Acid, so, if you take 5-HTP, your brain will only be able to make serotonin or melatonin. So, if you have the choice between tryptophan or 5-HTP, if it is to target your mood problem or depression, I will probably take 5-HTP. There are some natural products which you can buy. I think there is a plant from Brazil or from Amazonia called Griffonia simplicifolia, which is really rich in 5-HTP. If you don't want to take any drug, just take the natural compound.
**Jesse:** Is there any appreciable difference between the chemically synthesized version of 5-HTP and what one would get from the plant?
** Gilles Guillemin:** Not really, no. It is the same molecule but a lot of people prefer natural compound. I'm a bit like that. And, it has the same effect. I have been testing a lot of different molecules as enzyme inhibitor of this trytophan metabolism. When, sometimes, I compare natural compounds with chemical, I found that the natural compound, actually, has at least the same activity on the neurotoxicity array. So, I didn't believe before but, now, I am really a believer in this kind of molecules. It is impressive. When you see the result under the microscope, you say, "Wow! It's working." And, if it's a drug, it will take years to reach the patient but if it is a natural compound, it`can come under nutraceutical and reach the patient much faster.
**Jesse:** We generally think of serotonin in the brain as being a good thing, of having anti-depressant properties and things like that, but is that an overly simplistic analogy?
** Gilles Guillemin:** There is a story about serotonin at the moment. This is another very good question. For many years, people have been treated with serotonin. Only a small percentage of these people respond to this kind of drug. More recently, in the last 2 or 3 years, people like some groups in the US have been doing some amazing work showing that another molecule deriving from tryptophan called Quinolinic Acid is actually activating some specific receptor on neurons. This toxin, actually, is deriving from tryptophan with responsible for depression and suicidal behavior. Serotonin has become the second base, it's not the main guy, it's number 2 now. A lot of people have being trying to identify what is the process. Over the last 2 or 3 years, some very exciting results from different countries- Sweden and US- have shown that Quinolinic Acid activating NAD receptor on neurons is probably the main cause of depression or suicidal behavior.
**Jesse:** That's one of those things that makes you think back evolutionarily if it's as simple as that, if there is one compound within the brain that can make an organism want to take its own life, it's like, "How the heck did that survive in the gene pool?" It seems like that would be the kind of thing that evolution would have weeded out of the system a long long time ago unless there is some second order benefit for having a very minute amount or something.
** Gilles Guillemin:** You must be wondering why the human brain cell making this toxin. It's one of the weapon actually; they use it to kill parasite or bacteria. In your normal condition, this molecule is not a toxin. If you reach at lower levels, it's a good thing because it is a substrate to make NAD+. As soon as you have inflammation, that's another story. In depression, you have a basic and chronic inflammation in your`brain. With time, what happens is you have this toxic building and building and stimulating your neurons. It's a long term effect and it is chronic. You know recently that people discovered that ketamine, this recreational drug, actually is a very potent anti-depressant. What ketamine does is it blocks the receptor where quinolinic acid binds.
**Jesse:** What are the physiological downsides of ketamine? I presume there, probably, are some.
** Gilles Guillemin**: Yes, it's like any drug because any drug that over-activates your neurons, basically, binding with a receptor on your neuron, always stimulating your neuron, that's why you get this effect. So, if you take too much, you will over-stimulate your neurons and sometimes, you damage them irreversibly and they die. So, long-time exposure to some drugs, basically, you start to have memory problems and things like that. So, ketamine can be dangerous as well. One thing important is how a lot of people are working on using this tryptophan metabolism as therapeutic as well as a biomarker. Because e.g any cancer they use tryptophan metabolites to switch off the human response to protect themselves. It's basically any type of cancer, I work on glioblastoma, prostrate cancer, lot of different cancer use the tryptophan metabolites to stop the human response to attack them. So lot of people are trying to switch off the system from inside to unmask the tumor to the immune system. That's a very interesting topic. The tryptophan metabolites from the Kynurenine Pathway, they are very very potent immuno-modulator.
This has been discovered by a couple of American scientists. During pregnancy what is protecting the fetus from the immune system of the mother - there are tryptophan metabolites. So it's truly important during the pregnancy to have the right amount of tryptophan because your placenta, the woman placenta will metabolize tryptophan to make small molecules to protect the fetus from the immune system of the mother. If you block the enzyme making this small molecule, you will see within hours the immune system of the mother penetrating the placenta and going to destroy the fetus.
**Jesse:** There is an interesting question for women that are vegetarian or are on other sort of low protein diets while they're pregnant. Is that a cause for concern?
** Gilles Guillemin:** Actually the recommended daily allowance for people is about 10 mg per day of tryptophan. Women they always need a little bit more specially when they are pregnant. They need about 20 mg per day but they can get that from milk. If they're vegetarian they can get from spirulina, they can get from spinach. Spinach has tryptophan as well. I think tryptophan is really important during the pregnancy. There was a Japanese study where they gave a very high dose of tryptophan to pregnant women and they couldn't see any bad effects on the women or the fetus. So even if you increase your daily intake of tryptophan during pregnancy, they don't find any problem with the other or the baby or nothing like that.
**Voice-over:** *Smart Drugs Smarts.*
**Jesse:** So, thank you very much to Dr. Guillemin for shedding some light on L-tryptophan and it's many related compounds. Also, something that was on the cutting room floor of the interview but I want to make sure that it snuck in here somewhere- what's the deal with the 'L' in L-tryptophan. Turns out that 'L' in front of an amino acid is the free form of the amino acid, it means it is not attached to other amino acids with peptide bonds forming the chain`that we know as a protein. So, you connect some tryptophans to any other amino acid, you make a protein out of them and it ceases to be L-tryptophan. At that point, it is just a tryptophan. When it's eaten and digested by your body, broken down by your digestive enzymes, you wind up with L-tryptophan, which can make it through your gut into your blood stream etc. etc. And, now to keep on the theme of turkeys, our Ruthless Listener Retention Gimmick.
**Voice-over:** *Smart Drug Smarts - Ruthless Listener Retention Gimmick!!!*
**Jesse:** So, you know how different animals come in groups- you have flocks of birds and packs of wolves and things like that. Apparently, turkeys, there's 3 choices that you can use when you are referring to a group of turkeys. They are all weird. Turkeys`come in posses, like a group of guys going out to hunt somebody down in the Wild West. Turkeys also come in gangs and finally, turkeys come in rafters, which I guess is like a group of turkeys sitting on the rafter of a barn, where that term originated from but I really like the idea of posses and gangs of turkeys. So, that's a bit of Thanksgiving trivia for you. I'll put up a link to the website where we found this which is a listing site for a bunch of different weird animal groupings. My favorite was a congress of salamanders. Salamanders, apparently, come in congresses, who knew?
**Voice-over:** *Smart Drug Smarts - The podcast so smart, we have smart in our title, twice!!*
**Jesse:** So, thank you very much for hanging out until the end of the episode. This is the end but I think that you are now in a great position to be the raining champion within your family on the biochemistry of L-tryptophan and your Thanksgiving meal. When somebody pulls out the 'I know why you are all getting sleepy' card, I'm sure that the first thing you're going to say is, "Well, if we were eating sea lion meat instead of turkey meat, maybe, you'd be right, Uncle Ned." But, and then when everybody backs off in shock and awe and wonders where you got that awesome scientific knowledge, I hope that you take the time to tell them about the Smart Drug Smarts podcast and our associated website, http://www.smartdrugsmarts.com, where you will find links to everything that we talked about here. I will be back at you next week with a non-holiday themed episode and apologies to everyone listening who is not American and couldn't give 2 craps about Thanksgiving. But, we'll be a little more cosmopolitan and universally applicable again next week with Episode 55 about a subject which I will not yet reveal. Until then, have a great week and stay smart.
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