10 Ways to Improve Resilience & Prevent Depression & Anxiety by Hacking the Kynurenine Pathway

I wrote this in response to someone who works with survivors of domestic violence and wants to incorporate more exercise into their life. None of this should be taken as medical advice. Consult your primary care provider before changing anything about your healthcare. 

How Stress Causes Neuropsychiatric Disorders:

First, I must say I admire the work you’re doing. All work is hard, but helping the people who need it the most comes with an extra layer of stress. I agree with you that vicarious trauma is real. A prominent grief psychologist I care about got PTSD with short term memory impairment from it. He had to retire to recover. Also, my grandfather suffered from Parkinson’s, and depression runs in my family.

Learning how to reverse these sorts of problems is one of my favorite things. I have a lot left to learn, but there are a couple of strategies I’m aware of that may be able to help prevent the damage.

The chronic stress of trauma causes chronic inflammation in the brain, which activates an enzyme in the brain called 2,3-dioxygenase, which throws out of balance a biochemical pathway called the kynurenine pathway. This shunts the amino acid tryptophan away from making serotonin (what antidepressants like SSRIs increase levels of) and melatonin (a sleep & healing hormone) and towards kynurenine. Kynurenine is then converted into various metabolites, some of which are neurotoxic and can eventually cause symptoms like depression, anxiety, and memory loss (Velasquez 2016, Oxenkrug 2013).

Tryptophan is also converted into kynurenine outside the brain. If it builds up in the bloodstream, it can cross the blood brain barrier, where it is turned into various neurotoxic metabolites like quinolinic acid and 3-hydroxykynurenine, which destroy your brain. It increases oxidative stress and makes your neurons more vulnerable to glutamate excitotoxicity, which can also kill your brain’s neurons (Okuda 2002).

Over time, this destruction of neurons can lead to symptoms like memory loss, depressed mood, loss of pleasure, fatigue, brain fog. If left unchecked, this can eventually result in diagnosable neuropsychiatric disorders (Harkin 2014, Oxenrug 2013).

With all those pro-apoptotic signals flying around, it may be harder for neurogenesis to occur in the hippocampus. That could be part of the mechanism by which memory is impaired by stress & inflammation, as neurogenesis in the hippocampus may be an essential for the formation of new memories.

How to Hack the Kynurenine Pathway

The good news is that there are a couple of things that may be able to prevent the damage. Even if the process has already caused a diagnosable disorder like major depressive disorder, generalized anxiety disorder, bipolar disorderPTSD, Parkinson’s, or Alzheimer’s, preventing any further damage from occurring is the key to preventing the disease from getting any worse (Anderson 2016, Tan 2012, Maddison 2015, Harkin 2014). It’s also the first step before a reversal of the disease process is even possible.

Imbalance of the kynurenine pathway is implicated in not just psychiatric disorders and neurodegenerative disorders, but also autoimmune diseases and cancers (Tan 2012, Maddison 2015).

You’ve already discovered one proven way to rebalance the kynurenine pathway through the wisdom of your own body and experience: endurance exercise. Stress always activates the kynurenine pathway outside the brain whether you exercise or not. The difference is that exercise causes certain genes to be expressed as active proteins called peroxisome proliferator-activated receptor alpha and delta (PPAR-δ), PPAR-alpha, and PGC-1alpha (Harkin 2014, Agudelo 2014). These proteins activate kynurenine aminotransferase enzymes in active skeletal muscle tissues, which kynurenine into the harmless kynurenic acid, which cannot cross the blood brain barrier (Harkin 2014). Neurons saved!

Effect of exercise on kynurenine pathway, depression, anxiety, neurodegenerative conditions
Source:  Phimister EG, Harkin A. Muscling In on Depression. N Engl J Med. 2014;371(24):2333-2334. doi:10.1056/NEJMcibr1411568.

Since PPAR-δ is also activated by states of nutrient deprivation, ketogenic diets, intermittent fasting, the fasting mimicking diet should also protect against vicarious trauma as well (speculation).

ketogenic diet
A Ketogenic Diet

A relatively easy intervention to start based on this principle is trying to make sure you always finish eating and drinking for the night pretty early. A study found that not eating anything at all after 7pm significantly decreased relapse in women with breast cancer. If that’s not realistic for you, just know that the earlier you stop eating for the night, the better. I’ve noticed that finishing by 8 or even 9 seems fine & even preferable for me. Finishing by 10 is suboptimal though, and by 11 or 12 you’re running an exponentially increasing risk for poor sleep and inflammation and loss of resilience the next morning.

In addition to exercise and fasting strategies, there’s also good evidence that vitamin B6 helps rebalance the kynurenine pathway prevents chronic inflammation and all those other nasty symptoms caused by death of neurons (Zhang 2016). The phosphorylated version of vitamin B6, pyridoxal-5-phosphate (P5P) may have additional benefits over normal the common pyridoxal found in most vitamin B6 supplements. It’s been shown to make immune cells called macrophages produce less reactive oxygen species, which is probably a good thing in most contexts (Zhang 2016).

This Solgar P5P is the cheapest on Amazon and presumably good. Personally, I take this P5P, which is a little more expensive, because I know from experience it’s free from things I’m allergic to (gluten, all nightshade vegetables, e.g. white potatoes, other lectins). This P5P is a safer bet if you’re sensitive to nightshades and/or lectins.

Only levels of P5P (not pyridoxal vitamin B6) levels have been found to correlate significantly with lower levels of 3-hydroxykynurenine, a metabolite that kills neurons, literally. Deac et al. found that 3-hydroxykynurenine “was inversely associated with P5P (r = −0.14, P < 0.01).” In addition, “users of vitamin B-6 supplements (n = 671) had 6% lower concentrations of 3-hydroxykynurenine than nonusers (n = 1765; P = 0.0006; Deac 2015).”  In other words, there’s only a 6 in a millionth chance that this 6% increase was a coincidence. Although this correlational study cannot be used to establish causality, taking P5P seems like a reasonable recommendation since it’s also so low risk.

However, plain-jane pyridoxal B6 supplements are cheaper and do at least part of the anti-inflammatory work that P5P does if they contain pyridoxal (by inhibiting the NLRP3 inflammasome and the master regulator of inflammation the NFKB pathway, for those of you keeping score at home; Zhang 2016). So if budget is the rate-limiting reactant, consider a common B6 supplement that’s just pyridoxal.

However, be careful and check the ingredients. Do NOT buy a B6 supplement that lists pyridoxine as the active ingredient, as many cheaper ones do, as that has not been shown to have any of these activities (Zhang 2016).

Another supplement that may help rebalance the kynurenine pathway is curcumin (Singh 2016, Cox 2015). In a randomized, clinical control trial of a specific formulation of curcumin called LongVida that crosses the blood brain barrier, Cox et al. found that it significantly improved working memory and mood in a sample of older adults (2015). Sadly, this one of the most expensive kinds. I’m also allergic to it, probably due to the potato starch in it, so you’re sensitive to nightshades it probably isn’t for you. It’s sold under names like CurcuBrain, etc.

Sing et al. found similar improvements in rats fed curcumin with piperine, which is one of the cheapest forms of curcmin (2016), so that’s a good option too. I personally have good results with this curcumin with piperine.

Warning: Curcumin with piperine should only be taken with a physician’s supervision, however, as piperine slows down your body’s ability to clear lots of substances from your system, including pharmaceutical drugs.

Another category of useful hacks is mind-body practices like yogas, meditations, and Qigong (Jain 2007, Telles 2013,. The grief psycologist has had good results with Qigong. I’ve experienced benefits from Qigong breathing and movement techniques, yoga poses, kundalini yoga, mindfulness meditation, mantra-focused meditation, prayer, and practicing gratitude.

How do mind-body practices work? They decrease stress and decrease the activation of the default mode network, which is the network in the brain we (over)use when we things like analyze, empathize, think, plan, etc (Killingsworth 2010). Decreasing chronic stress by any means decreases inflammation by activating the cholinergic anti-inflammatory pathway via the vagus nerve (Won 2016, Haroon 2012, O’Farrell 2017). This may help the brain prevent glutamate excitotoxicity. I personally believe there are probably some other mechanisms too.

In my n=1 experience, napping also prevents and reverses acute kynurenine imbalance associated symptoms. Even just lying down for 20 minutes in the afternoon without falling asleep can make a dramatic difference for my mood and performance. The way I get through my 8-hour volunteer shifts at the hospital is that after eating, I use the remainder of my lunch break to lie down quasi-vertical in my car with the seat back all the way. It doesn’t seem like much, but it makes all the difference for me.

My speculation is that napping and lying down may work by allowing toxic kynurenine metabolites and glutamine to be cleared out the brain via the glymphatic system.

Interestingly, another metabolite of the kynurenine pathway, called xanthurenic acid (XA), is reduced in schizophrenic patients, and it has an antipsychotic on a mouse model of schizophrenia. It actually prevents excitotoxicity. People who drink alcohol were found to have higher XA levels, as were women who took oral contraceptives (Deac 2015). There’s some evidence that vitamin B3 (niacin, nicotinamide, or nicotinamide riboside) may be implicated in schizophrenia via the kynurenine pathway (Miller 2011).

Speaking of women & trauma, women have more of the neurotoxic 3-hydroxykynurenine than men on average (Deac 2015). That may be part of the reason that some women are even more sensitive to certain neuropsychiatric disorders like depression and anxiety than men are (although all genders are quite vulnerable). It may also be a reason to suggest to the survivors you work to ask their healthcare providers about exercise, P5P or plain vitamin B6, curcumin, eating dinner early and then not snacking, and mindfulness practices. Maintaining a consistent sleep schedule is also likely to help.

Optimizing the Exercise Mini-Habit:

That’s a long-winded way of saying, I applaud you on this mini-habit! The improvement in mood and mental functioning is such a strong incentive to exercise, but ironically, it can be hard to feel motivated by those benefits unless you’re regularly experiencing them already.

I think you’re right that finding a place to walk in doors would be a good solution. Pushing through it, while possible, is difficult to sustain every time. I believe in going downhill to reach your goals whenever possible in life. The Taoists call that Wu-Wei, or doing without doing / effortless doing.

Your body runs thousands of energy-intensive biochemical reactions every minute. How? One way is that it couples uphill reactions that requires lots of energy with downhill reactions that release a lot of energy. You’re already doing the equivalent of that by coupling the energy-requiring reaction of walking to the energy-releasing reaction of feeling good mentally, emotionally, and physically.

I suggest you add another biochemical strategy, like an enzyme. An enzyme catalyzes a chemical reaction, making it happen faster and more often. It does this by lowering the activation energy, which is the energy of the transition state, the unstable intermediate between the initial reactant and the final product.

The initial reactant is you sitting at the computer doing your homework. Most people think the final product is you having already finished the mile-long walk, but it isn’t. It’s actually just you getting dressed and fully ready to walk, and taking literally the first step at the place where you walk (outdoors on a sunny day or indoors if it’s raining). That’s the mini-habit. If you can do that, you’ll find that most days you walk about a mile anyway. But some days you won’t walk the full mile because you’re too tired or you don’t have time, and that’s fine. What matters is consistently executing the mini-habit (dressed, ready, in place, & first step) long enough that it becomes a fully-fledged habit (about 30 days in a row). After that, you’ve built a strong enough neural circuit in your brain that runs that habit that it goes partially on autopilot. Then it’s easy, and you get the full benefits all the time.

Speaking of which, to avoid being a hypocrite, I’m going to go do my mini-habit of one pushup, one sit up, one jumping jack, and one squat now. I’ll probably wind up doing more of each, but I don’t have to, which makes it feel easy to start.

Copyright 2017 Owen Sanders.


  1. Velasquez S, Rappaport J. Inflammasome Activation in Major Depressive Disorder: A Pivotal Linkage Between Psychological Stress, Purinergic Signaling, and the Kynurenine Pathway. Biol Psychiatry. 2016. http://www.biologicalpsychiatryjournal.com/article/S0006-3223(16)32341-1/abstract. Accessed January 11, 2017.
  2. Oxenkrug G. Serotonin-kynurenine hypothesis of depression: historical overview and recent developments. Curr Drug Targets. 2013;14(5):514-521. http://www.ncbi.nlm.nih.gov/pubmed/23514379. Accessed May 5, 2017.
  3. Zhang P, Tsuchiya K, Kinoshita T, et al. Vitamin B6 prevents IL-1β production by inhibiting NLRP3 inflammasome activation. J Biol Chem. 2016:jbc.M116.743815. doi:10.1074/jbc.M116.743815.
  4. Deac OM, Mills JL, Shane B, et al. Tryptophan Catabolism and Vitamin B-6 Status Are Affected by Gender and Lifestyle Factors in Healthy Young Adults. J Nutr. 2015;145(4):701-707. doi:10.3945/jn.114.203091.
  5. Agudelo LZ, Femenía T, Orhan F, et al. Skeletal Muscle PGC-1α1 Modulates Kynurenine Metabolism and Mediates Resilience to Stress-Induced Depression. Cell. 2014;159(1):33-45. doi:10.1016/j.cell.2014.07.051.
  6. Fazio F, Lionetto L, Curto M, et al. Xanthurenic Acid Activates mGlu2/3 Metabotropic Glutamate Receptors and is a Potential Trait Marker for Schizophrenia. Sci Rep. 2015;5:17799. doi:10.1038/srep17799.
  7. Phimister EG, Harkin A. Muscling In on Depression. N Engl J Med. 2014;371(24):2333-2334. doi:10.1056/NEJMcibr1411568.
  8. Wang X, Zhang D, Lu X-Y. Dentate gyrus-CA3 glutamate release/NMDA transmission mediates behavioral despair and antidepressant-like responses to leptin. Mol Psychiatry. 2015;20(4):509-519. doi:10.1038/mp.2014.75.
  9. Averill LA, Purohit P, Averill CL, Boesl MA, Krystal JH, Abdallah CG. Glutamate dysregulation and glutamatergic therapeutics for PTSD: Evidence from human studies. Neurosci Lett. 2016. doi:10.1016/j.neulet.2016.11.064.
  10. Köhler O, Benros ME, Nordentoft M, et al. Effect of Anti-inflammatory Treatment on Depression, Depressive Symptoms, and Adverse Effects. JAMA Psychiatry. 2014;71(12):1381. doi:10.1001/jamapsychiatry.2014.1611.
  11. Miller CL. The Kynurenine Pathway: Modeling the Interaction between Genes and Nutrition in Schizophrenia. J Orthomol Med. 2011;26(2). http://web.a.ebscohost.com/abstract?direct=true&profile=ehost&scope=site&authtype=crawler&jrnl=08344825&AN=62608063&h=V4IhnU8otQLMIJg92vQgZ5DtY7lNW8B20xUQgkz7y4CT%2F2ZqPRwICyhuhQVozxmGJRJzuZbwpdgVKVvsQKgAPw%3D%3D&crl=c&resultNs=AdminWebAuth&resultLocal=Er. Accessed January 27, 2017.
  12. Hazari N, Bhad R. Kynurenine pathway (KP) inhibitors: Novel agents for the management of depression. J Psychopharmacol. 2015;29(10):1133-1134. doi:10.1177/0269881115599386.
  13. Maddison D, Giorgini F. The kynurenine pathway and neurodegenerative disease. Semin Cell Dev Biol. 2015. http://www.sciencedirect.com/science/article/pii/S1084952115000452. Accessed January 27, 2017.
  14. Tan L, Yu J, Tan L. The kynurenine pathway in neurodegenerative diseases: mechanistic and therapeutic considerations. J Neurol Sci. 2012. http://www.sciencedirect.com/science/article/pii/S0022510X12004340. Accessed January 27, 2017.
  15. O’Farrell K, Harkin A. Stress-related regulation of the kynurenine pathway: Relevance to neuropsychiatric and degenerative disorders. Neuropharmacology. 2017;112:307-323. doi:10.1016/j.neuropharm.2015.12.004.
  16. Killingsworth MA, Gilbert DT. A wandering mind is an unhappy mind. Science. 2010;330(6006):932. doi:10.1126/science.1192439.
  17. Mason H, Vandoni M, Debarbieri G, Codrons E, Ugargol V, Bernardi L. Cardiovascular and respiratory effect of yogic slow breathing in the yoga beginner: what is the best approach? Evid Based Complement Alternat Med. 2013;2013:743504.
  18. Telles S, Raghavendra BR, Naveen KV, Manjunath NK, Kumar S, Subramanya P. Changes in autonomic variables following two meditative states described in yoga texts. J Altern Complement Med. 2013;19(1):35-42. doi:10.1089/acm.2011.0282.
  19. Jain S, Shapiro SL, Swanick S, et al. A randomized controlled trial of mindfulness meditation versus relaxation training: effects on distress, positive states of mind, rumination, and distraction. Ann Behav Med. 2007;33(1):11-21. doi:10.1207/s15324796abm3301_2.

3 thoughts on “10 Ways to Improve Resilience & Prevent Depression & Anxiety by Hacking the Kynurenine Pathway

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Google+ photo

You are commenting using your Google+ account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )


Connecting to %s