Depression has to be one of the most misunderstood and poorly treated health conditions in our modern age. Yet depression isn’t the monster it appears to be. Depression like all health problems has a root cause; and once the root cause is addressed amazing things happen. I know this subject well because for 20 years of my life I was one of those people fighting and flailing with chronic depression (this is a big reason why I become a functional medicine chiropractor and dedicated my life to educating people about methylation and root causes of problems). While my previous blog post discussed how BH4 and methylation imbalances make us more susceptible to depression, our genes alone cannot explain why so many people are now living with chronic depression. There is more to depression than bad genes. There is a problem called the Tryptophan Steal which is the real, underlying biochemical reason we become depressed.
I like to remind my patients your genes are not your destiny, but they are your tendency especially when you are under stress. Genes react to the environment in either healthy or unhealthy ways depending on the signals you give them via your thoughts, your choices, your diet and your lifestyle. When we understand the environment and how it impacts our genetic response, then we begin to take control of our destiny. I have helped hundreds of patients overcome depression using these concepts of methylation and epigenetics; and I have worked to fill the pages of BeyondMTHFR with the science that makes it all possible. With that in mind we now turn our focus to the topic of tryptophan. There is more to depression than just a lack of methyl donors – there is also a lack of tryptophan in the brain! For reasons you will soon discover, people with depression simply don’t have enough tryptophan to go around.
As we begin this article about depression and tryptophan I would like to ask you a simple, but serious question. The answer to this question will help to explain why we, our loved ones and our friends all tend to act the way they do. It helps to shed light on why many people suffer with mental health issues that never seem to be adequately addressed. It’s the reason why millions of Americans are prescribed anti-depressants each year in a seemingly endless battle with feeling down, blue and unhappy. And so the question is this: are we programmed to be depressed? And I must say that yes in fact we are.
It may be hard to believe that our genius body is programmed for depression, but that is what the best science and research clearly show. I don’t mean that we are supposed to be depressed, that we are destined to be depressed. Quite the contrary in fact. We are supposed to be happy and balanced; level-headed and relaxed most of the time. Only our modern, stressful and toxic world makes it very difficult for that to happen without working diligently towards a healthy lifestyle, optimum genetic expression and spiritual wellness. Not only does our modern environment present new and frightening challenges for our bodies to cope with, we also must deal with the myriad of genetic variations each of us carry that can influence our growth, repair, detoxification and more. Understanding how genetic variations and environmental influences make us sick is key for us to heal and move forward. And this is especially true for anyone seeking to heal their root causes of depression.
Destined to Be Depressed
We as people are not destined to be depressed, but our body has developed a sort of biochemical reflex, an automatic response, to toxins, stress and inflammation that creates depression. In other words, we are programmed to be depressed because our body sacrifices our supply of tryptophan when we come under stress of any form. I say stress in any form because literally the research shows it doesn’t matter if you are worried about your mortgage, planning a wedding, mourning the loss of a loved one, recovering from food poisoning, sleeping poorly, or dealing with a chronic leaky gut issue just to name a few. Each one of these problems represents a condition where the body will be forced to lower levels of tryptophan so that our cells have a better chance of survival. Under these common, everyday conditions of stress, our body is programmed to steal tryptophan away from the production of serotonin. I have termed this phenomenon the Tryptophan Steal.
The 3 Common Causes of the Tryptophan Steal:
- Adrenal stress – We live in a very stressful society full of toxins, busy schedules, economic challenges, divorce, and terrorism just to name a few. Each of these factors triggers a powerful, ancient reflex in our brain that causes our adrenal glands to activate. If our adrenal glands are always being activated, then they enter what is called the adrenal stress reaction. This adrenal stress reaction creates wild swings in cortisol levels which impact all areas of our body – especially our brain, energy and mood. As you will soon learn, high cortisol from adrenal stress is a major cause of low serotonin and a big player in the Tryptophan Steal.
- Blood sugar swings – Most people know that blood sugar problems like diabetes involve high levels of insulin and glucose. But what is less known is that people with blood sugar issues often experience hypoglycemia or low blood sugar. This actually lowers insulin and glucose, but raises another powerful hormone from the pancreas called glucagon. High levels of glucagon can devastate our tryptophan supplies and lead to low serotonin, depression and poor sleep. It too is another major player in the phenomenon of the Tryptophan Steal.
- Inflammation – It is no secret that inflammation makes us feel bad. The pain, stiffness, achiness that accompanies inflammation can really put a damper on our mood. Inflammation doesn’t just make our body hurt, it also has a huge impact on our brain by changing the chemistry of our nervous system. An activated, irritated and inflamed immune system releases hundreds of chemicals, called cytokines, which can trigger the Tryptophan Steal in our brain. The result of all this inflammation isn’t just pain, swelling, achiness and fatigue; it literally changes our brain chemistry and makes us depressed.
It is worth pointing out how these three causes of the Tryptophan Steal are increasingly common in our modern, stressed-out society. Adrenal stress is being called the black plague of the 21st century and is now directly responsible for illnesses like stroke, heart disease, cancer and even back pain.1 Diabetes rates continue to climb with nearly 30 million people, about 10% of the population of the United States, diagnosed with full blown diabetes.2 This number might seem really high, but sadly the real numbers are even higher. The Journal of the American Medical Association published a report in 2015 showing that approximately 50% of all adults in the US have diabetes or pre-diabetes.3 Since the actual number of people with a blood sugar issue is somewhere around 150 million people, this health crisis is only going to get worse! With half the population well on their way to diabetes, and just about everyone fighting off the negative effects of stress, it’s no wonder that Big Pharma is making a killing selling us drugs for depression. While those statistics are a bit disturbing and deserve our attention, we also need to look at the impact of inflammation.
Most of us have felt a sore throat from a cold virus or the swelling and itching from a bug bite. These symptoms of inflammation are not caused by the bug or virus per se, they are in fact caused by the body’s response to the toxic insult – our “auto” immune system. Just like stress and blood sugar problems, we now know that autoimmunity rates are also skyrocketing. Recent estimates now suggest that somewhere 24-50 million Americans currently live with some form of an autoimmune condition.4,5 That means one of out every six Americans is walking around with some kind of inflammatory immune system disorder!
With millions and millions of people living with chronic problems of stress, blood sugar, and inflammation that can destroy tryptophan levels, it is no wonder depression is so common. Luckily for us it’s not all doom and gloom. There are simple, natural solutions that can reverse depression naturally by treating the cause – by treating the Tryptophan Steal. As with all the other methylation and gut related issues I’ve shared with you, my advice for treating the Tryptophan Steal can be found in Protocols section of BeyondMTHFR.
The Tryptophan Steal
Since we have just outlined the three most common causes of the Tryptophan Steal, it is a good time to introduce you to exactly what I mean by that term. Stealing something involves theft, and the body is certainly stealing from one pathway in order to give to another. But it isn’t a theft of malice; it’s actually an expression of the body’s wisdom, of its genius, in managing the limited resource of tryptophan. In other words, the body is doing an excellent job at putting its limited supply of tryptophan to use where it is needed most. The following chart helps us to see this idea more clearly.
Overview of the Tryptophan Steal
Figure 1.1 – Trytophan Steal showing how the IDO and TDO enzymes are both able to steal tryptophan and 5-HTP and push it down the pathway to make vitamin B3.
As you can see in the figure above, tryptophan follows two main pathways inside our body. On one hand tryptophan can get turned into 5-HTP, which creates serotonin, and then turns into melatonin. This is the pathway that helps us make the neurotransmitters which improve our sleep, our energy and our libido – what I call the feel good pathway. On the other hand, tryptophan gets pushed into the pathway that is used to produce vitamin B3, CO2 and ATP. We call this second pathway the kynurenine (ky-nur-e-neen) pathway and it is the crime scene where the Tryptophan Steal takes place. This second kynurenine pathway normally consumes about 95% of all the tryptophan in our bodies, with only 1-2% of tryptophan being used to produce serotonin and melatonin.6 It is this second pathway that holds our tryptophan hostage and creates so many problems for those of us with depression. When tryptophan is stolen away from the feel good pathway then you will feel just the opposite – irritated, depressed, anxious, and generally not your best.
Fortunately, you don’t have to be a biochemical scientist to understand how this works. The way in which the body steals tryptophan from our brain is straight forward. The TDO and IDO are the two enzymes shown in the figure above which are responsible for the Tryptophan Steal. Normally these two enzymes help to make sure our cells get enough tryptophan so they can grow, repair and reach optimum function. However if stress, inflammation or blood sugar problems enter the picture then the volume on these two enzymes gets turned way up and our serotonin and melatonin levels get pushed way down. In other words, the body uses these two enzymes to steal tryptophan. They pull tryptophan into the kynurenine pathway to make more NAD and ATP at the expense of our calming neurotransmitters.
These two enzymes are very sensitive to changes in their environment so the greater the biochemical stress the faster these enzymes will go. And once again we will turn our attention to published biochemical research that helps us all see this issue more clearly. In a study published in 2014 researchers highlighted for us how the TDO enzyme is activated by cortisol (stress) and low blood sugar swings (glucagon) while the IDO enzyme is turned on by inflammation.7 Here we have dedicated scientists proving to us how it is that cortisol, glucagon and inflammation can each flush tryptophan levels down the drain. Again with so much mental and emotional stress, poor eating habits and a modern, toxic world is it any wonder that depression is so common in our society?
NAD and Vitamin B3
I can see everyone reading this shaking their head saying “okay, I understand that stress, hypoglycemia and inflammation cause the Tryptophan Steal and that causes depression.” And I could probably stop here and call it good, but there is a key part of this story we have yet to discuss. We must talk about the vitamin called nicotinamide adenine dinucleotide (NAD) since it truly explains why the body steals your supply of tryptophan in the first place. NAD is a fascinating chemical that you will recall is made from vitamin B3. Since tryptophan is the only method we have for making B3, we can say that tryptophan is very, very important for NAD production. And you will soon see why NAD levels are big deal for our health, our brain and our cells.
Think of NAD like a catalyst in the mini-nuclear reactors we call our mitochondria. It plays a role in the movement of electrons inside our mitochondria that is essential for the cell to produce energy. Normally our cells produce plenty of energy when oxygen and vitamins are abundant. During times of low stress, low inflammation and optimum blood sugar balance our cells receive all the oxygen and nutrients they need to create an abundance of energy. High levels of NAD are not needed during the easy times because the cells mitochondria can harvest an enormous amount of energy from burning oxygen for fuel. However, as soon as glucagon, cortisol or inflammation goes up the cells begin to lose oxygen and nutrients. Under conditions of stress with low oxygen and low nutrition, cells must use NAD to continue to produce energy or else they will perish.8 NAD has the unique capacity to allow our cells’ mitochondria to continue to produce energy in the absence of oxygen. This is a handy trait given that energy is life; and the more energy our cells make the better we all feel. Whenever the body becomes low in NAD it will absolutely turn on the Tryptophan Steal as a means to survive. So the body has a good reason for stealing your tryptophan, it just doesn’t feel very good while it’s happening!
Why the Body Steals Tryptophan – A Summary
- The tryptophan supply is essential. The body cannot make tryptophan which leads to situations where there isn’t enough to share, forcing the body to steal tryptophan from neurotransmitter pathways to make more NAD.
- Stress, blood sugar swings, and inflammation lower oxygen inside cells increasing the need for NAD which only comes from tryptophan.
- Ultimately body would rather its cells increase NAD levels and survive, instead of making serotonin, sleeping well and enjoying a good libido whilst its cells were being destroyed. (hint: the body never makes mistakes!)
Remember that the body doesn’t make mistakes – it is too genius for that. It has a very good reason for stealing tryptophan away from serotonin and using it to make niacinamide and NAD. When the body is stressed with inflammation, low blood sugar, and high levels of adrenal hormones oxygen levels drop inside of our cells. Without oxygen cells cannot produce energy very efficiently. Without oxygen our cells will die. In order to prevent the destruction of our cells when oxygen is low, our body uses a type of vitamin B3 called NAD. NAD allows our cells to produce energy even during times of stress and low oxygen. Again, stress causes low oxygen which threatens our cells, and NAD prevents cells from dying. So obviously NAD becomes a very important biochemical in our bodies. Since NAD and serotonin both come from tryptophan, the body has to choose where its bank account of tryptophan will be spent.
As I just said above energy is life. And NAD levels will ultimately determine if our cells survive or if they perish. In fact, NAD isn’t just a vitamin, it helps our cells acting as an antioxidant, improving cell survival, and even preventing autoimmunity.9,10,11 NAD is so powerful that new research is looking at NAD as the proverbial fountain of youth and anti-aging molecule. Researchers have recently discovered that injecting NAD into 22-month old mice changes their muscle tissue back to that of a mouse just 6 months old.12,13 Its pretty amazing that NAD, which comes from tryptophan, can reverse the aging process in mice. I also find it interesting that depression makes you feel old and tired. Yet the very vitamin the body is trying make by stealing tryptophan can reverse the aging process and energize our cells. Maybe we should look at giving people with depression support for their NAD levels instead of drugs to mask the symptom. What do you think?
Epigenetics, MAO-A and MAO-B
The question often comes up when I am working with patients and doctors: How can someone have low serotonin if they are homozygous (+ for men or +/+) for women on their MAO gene? In other words, how can people with a slowed version of MAO rs6323 (the most influential SNP) end up with low serotonin? Doesn’t having an MAO SNP mean you are going to have more serotonin not less? These are all great questions and I have asked them myself years ago as I began to study this subject in earnest. What is missing from these questions is an understanding of something I have repeated throughout BeyondMTHFR™ and mentioned at the beginning of this article. Our genes are not static and the environment is always changing how our genes express. You may be born with a certain SNP that predicts something should happen more often, such as low serotonin, but the environment ultimately rules the roost.
I have seen this concept in action in my own life and in the lives of thousands of patients whom I have been fortunate enough to meet. To clarify this idea further we will look at a couple powerful research studies. One critical study on this topic came out in 2004 and blew my mind when I read it. Researchers used a model of inflammation from our immune system and measured how it impacted the genetic expression of the MAO enzyme. These researchers exposed human cells to the Th2 cytokines called IL4 and IL6 and noticed that MAO-A expression was increased more than 2000 fold or 200,000%, while MAO-B showed no noticeable increase.14 What is this proves in an elegantly simple fashion is how the environment is in control of the genes, esp. for people with depression. MAO-A the cytokines they studied, IL4 and IL6, are associated closely with histamine problems. So not only do we have a study giving us clear evidence of the process of epigenetics, we also have a better understanding of why people with histamine issues are also depressed with low tryptophan (perhaps a topic for a future post). But that isn’t all this study shows us.
Another takeaway from this study is to recognize that MAO-A was massively upregulated by these inflammatory signals while MAO-B wasn’t effected at all. Now I realize many of you aren’t epigenetic science nerds such as myself nor do you speak the scientific language as part of your everyday life. So let’s be clear on what I mean by MAO-A and MAO-B. These two genes are very similar but have a slightly different shape which is why scientists gave them a different name. In addition to their different names, they also have a different preference for neurotransmitters. For example, MAO-A is really, really hungry for serotonin while MAO-B isn’t especially interested in breaking down serotonin. MAO-B prefers dopamine and other less known neurotransmitters which are outside of our discussion. In fact, MAO-A is so hungry for serotonin that studies have shown MAO-A has a 120X greater affinity for serotonin than does MAO-B.15 So if MAO-A already has a 12,000% greater hunger for serotonin, we can only imagine what happens when inflammation increases the expression of MAO-A by an additional several orders of magnitude. You don’t have to be a PhD scientist to see what will follow. When MAO-A is upregulated by inflammation, it will literally devour any and all serotonin in the vicinity. It will trigger the mother of all Tryptophan Steals. This is why those who are dealing with excess inflammation are simultaneously dealing with low serotonin and chronic depression. Realize that you cannot fix depression without treating the underlying inflammation!
Finding the Tryptophan Steal on the Organic Acid Test
Many of you are aware that I am a big fan of the organic acid test from Great Plains Laboratory, and this is especially true in cases of depression. What the organic acid test reveals to the trained eye is the evidence of the Tryptophan Steal. It wasn’t until I had looked at hundreds of these tests that I began to see what the body was trying to do with our neurotransmitters. Pieces of information separated from the whole are difficult to understand – without context or place most information is practically useless. So it was with all the data on tryptophan, MAO enzymes, and depression. I knew it was important, but until I started seeing the same pattern repeat on hundreds of organic acid tests I didn’t know I was looking at a powerful, preprogrammed reflex – Tryptophan Steal.
With so much of our body’s tryptophan devoted to the kynurenine pathway (95%) and so little devoted to the production of serotonin and melatonin (1-2%), it doesn’t take much to disrupt our brain’s level of feel good neurotransmitters. Imagine if the body needed more NAD and had to shift – to steal – more tryptophan than normal? That might lower available tryptophan from 1% to .1% or even lower. With only .1% of tryptophan available for serotonin it would be like living on only 10% of your income – that wouldn’t be good for your budget or your brain! This undoubtedly is one of the causes of chronic insomnia, chronic fatigue and even chronic pain that we often in our patients. Each year I see hundreds of organic acid tests from my patients, and I find that over 75% of them have evidence of the Tryptophan Steal. It is not exactly a “rare’ problem. Many patients have serotonin levels in the urine that are practically zero or very, very close. Not only that, they also often have high levels of quinolinic acid which is the neurotoxin that can build up if the body’s NAD levels are too low and the Tryptophan Steal is activated in earnest. As you can see in the Figure 2.1 below, the Tryptophan Steal can be easily found once you know what to look for.
Figure 1.2 – Great Plains Laboratory Organic Acid Test showing the biochemical evidence of the Tryptophan Steal. This is a mild case but is still enough of a problem to impact brain function, etc.
At first blush we might question why the body would create depression automatically in response to stress, but looking deeper we see the genius of our body’s design. Given that NAD is needed to keep our cells alive, we can see that the body is acting intelligently. The body basically decides that sleeping well, having a healthy sex drive, and mental relaxation is not as important as keeping its cells alive. When forced to choose between survival or destruction, the body always makes the right choice. Thus we can see that the Tryptophan Steal is a genius adaptation to stress – low blood sugar, cortisol, and inflammation. While those of us who have battled depression know the pain and anguish it causes, those problems are still mild compared to living in our body without adequate levels of NAD. The body is still making the intelligent choice even though it sours our mood and life. That is still less of a health problem than developing a mitochondrial disorder or suffering from the diarrhea, dermatitis, dementia and even death that comes from vitamin B3 deficiency!
In this in-depth look at the root cause of depression, the Tryptophan Steal, we have talked about many things. We have looked at how modern life creates a perfect storm of stress, blood sugar problems and inflammation that drastically impact our brain and neurotransmitter pathways. If we can agree that every single person on earth has experienced at least one of these health challenges before, then we are also agreeing that everyone is potentially at risk for suffering depression. The only difference between us as individuals is how long we experience stress (hours, days, months or years?). If the Tryptophan Steal only happens for a short time and you have a balanced methylation cycle with a healthy gut, then there is only a small chance that depression will creep into your life. However, if you are like me and had years of chronic stress, poor diet and gut inflammation then it’s almost a guarantee that tryptophan is being stolen and serotonin levels are low. Everything happens in our body for a reason, and depression has a cause which we know now is the Tryptophan Steal!
By understanding how depression is caused by the Tryptophan Steal we have better defined the root cause of this mental health problem. With this more accurate picture of the problem we gain the ability to truly heal depression by treating its root cause. From here the way forward for millions of people battling depression is both simple and challenging. It is simple because it doesn’t involve expensive drugs, thousands of dollars in psychiatric counseling and other traditional approaches. It simply involves treating the individual person, their genes and environment. The challenging part comes into play because everyone is an individual and no two people live the exact same life.
With the science of methylation and functional medicine at our disposal it is now possible to be laser specific in how we treat the individual. Just like with many other health problems we start treating depression by treating the gut as this is the source of stress, inflammation and blood sugar issue for many. Once that process is working smoothly we dig in deeper making sure oxalates, sulfates, mitochondria and more are working properly. After those layers are addressed we can treat the underlying genetic imbalances and enhance lifestyle factors to make depression a thing of the past. The science and solutions to treat depression naturally are already here and available to you now. When you are ready to get started on making your depression a thing of the past, then I welcome you to contact my office about how we can help you optimize your genes and change your life!
Yours in Health,
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- Penberthy WT, Tsunoda I. The importance of NAD in multiple sclerosis. Curr Pharm Des. 2009;15(1):64-99.
- Ayla S, Seckin I, Tanriverdi G, et al. Doxorubicin induced nephrotoxicity: protective effect of nicotinamide. Int J Cell Biol. 2011;2011:390238.
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- Suarez-Pinzon WL, Mabley JG, Power R, et al. Poly (ADP-ribose) polymerase inhibition prevents spontaneous and recurrent autoimmune diabetes in NOD mice by inducing apoptosis of islet-infiltrating leukocytes. Diabetes. 2003 Jul;52(7):1683-8.
- Prolla TA, Denu JM. NAD+ deficiency in age-related mitochondrial dysfunction. Cell Metab. 2014 Feb 4;19(2):178-80.
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- Chaitidis P, Billett EE, O’Donnell VB, et al. Th2 response of human peripheral monocytes involves isoform-specific induction of monoamine oxidase-A. J Immunol. 2004 Oct 15;173(8):4821-7.
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