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An Introduction to Tumor Necrosis Factor (TNF)

The three most common inflammatory cytokines that are responsible for chronic inflammatory diseases are Tumor Necrosis Factor (TNF), Interleukin-1beta (IL-1b) and Interleukin-6 (IL-6). These are the most commonly talked about cytokines in the literature.

The transcription factor nuclear factor NF-kappaB is also heavily spoken about and these four proteins are what people most likely refer to when they talk about chronic inflammation (whether they are aware of this or not).

TNF can be increased in either Th1 dominance or Th2 dominance.

TNF increases CRP, which is a common blood measurement to gauge inflammation.  However, CRP is not sensitive enough to detect lower, but chronic levels of TNF.  See my discussion of this in my IL-6 post.

It’s important to realize that you can have TNF elevated locally in areas such as your hypothalamus or gut and it wouldn’t show on blood tests.

Many kinds of cells release TNF and then TNF goes on to stimulate other immune cells.

TNF is released by Macrophages, Dendritic cells, T cells, Fat cells, and Fibroblasts.

TNF then affects various cells. In particular, it will affect cells that line our blood vessels (endothelial cells), which causes vascular problems and this strongly causes cancer, as it causes angiogenesis and increased blood vessel formation (hypervascularization). It can also cause heart disease, kidney disease, and cognitive problems.

TNF negatively affects intestinal cells, causing cell death, leaky gutIBS, and IBD.

TNF stimulates macrophages and effector T cells, which leads to more inflammatory cytokine production and apoptosis resistance (which contributes to cancer).

The Good

TNF induces sleep and it increases non-rem sleep (R).

Therefore, it’s good to have this elevated somewhat at night when we want to fall asleep. TNF is elevated naturally in healthy people at night time.

The duration of daytime sleep in Alzheimer’s disease correlated with the degree of functional impairment in the patient (R), which is a result of elevated inflammation.

Other examples of daytime sleepiness in chronic inflammatory states are Parkinson’s disease (R), traumatic brain injury (TBI) (R), stroke (R), heart failure (R), and type-2 diabetes (R).

TNF is a direct fat buster, which leads to insulin resistance in fat cells (R), but also insulin resistance in muscle cells (R). This means that glucose can’t make its way into these cells.

TNF suppresses appetite by suppressing orexin (RR2R3).

So high levels of TNF makes you thinner by causing you to eat less and by inhibiting glucose into fat cells.

If you decrease TNF, you will become more hungry and store more fat.

Hence, it’s not surprising that anti-TNF therapy results in weight gain -an average of 5.5kg or 11 pounds in only 12 weeks (R).  It’s incredible that only one variable changed (TNF) and the study participants gained on average 11 pounds.

Low doses of TNF given to mice caused insulin and leptin resistance in the hypothalamus, which should contribute to obesity (R).

Even a relatively low level of TNF decreases aldosterone synthesis in response to ACTH (precursor of cortisol), which increases in response to stress and intense exercise (R). This can lower blood pressure.

Exercise increases ACTH, which normally tells our body to conserve salt by increasing aldosterone. However, if we have inflammation, then aldosterone production will be limited and if we sweat a lot it can cause low levels of salt in the body.

The Bad

I have already spoken about how I think trying to increase your motivation or mood by hacks, tricks, or by changing your mindset will only increase your neuroticism.

If you have elevated TNF and you bring it down, this will positively affect your mood and motivation.

TNF plays a major role in many diseases and is a cytokine that is a performance killer.

TNF can cause lasting harm by damaging your mitochondria (R).

TNF makes you tired, lowers your mood and decreases cognitive and physical performance by suppressing orexin (RR2R3).

Orexin is an extremely important neurotransmitter for many bodily functions.

Orexin performs a number of key roles in memory acquisition and consolidation, as well as in long-term memory reinforcement (R). Hence, if you have elevated inflammation, it will harm your cognitive performance (also by decreasing BDNF, etc).

TNF can also lower thyroid hormones, causing ‘low T3 syndrome’ (R). It can also lower testosterone (trended, but not significant) (R).

TNF slows wound healing, which means you’ll need more time to recover from exercise/injuries. (RR2).

TNF can induce a leaky gut (R).

Chronically elevated TNF-alpha can also disturb the circadian rhythm and cause fatigue in the day (R).

TNF can keep you from getting into ketosis (R).

When your natural skin fungus gets out of control, the body attacks it with cytokines that include TNF (also IL-6, IL-1b, IL-8), which recruits other aspects of the immune system (R).

Diseases Associated With TNF-alpha

The Most Significant Factors That Influence TNF

The two main factors that cause elevated TNF, if I had to guess, are lectins (R) and obesity (R), since fat cells produce TNF. If we ate less, a lot of people’s inflammation problems would disappear.

Other likely causes are sleep deprivation (R) and high blood glucose levels (R) from eating too much, especially high glycemic index foods.

Other common factors are a lack of exercise (R), excess alcohol (R), smoking (R), and not enough fruits and veggies (R, R2).

UV acutely increases TNF (RR2R3) (but eventually downregulates it). This is the likely reason why some people experience fatigue from sunbathing.

Recent research indicates that TNF is potently inhibited by exercise (specifically, myokines or proteins produced by the muscles such as IL-6) (R). However, excessive exercise or Marathons will elevate TNF (R).

An infection can also elevate TNF. Bacterial (rather than viral) infections are more likely if you have elevated TNF (R).

TNF-alpha Increasers

TNF-alpha Inhibitors

Joe’s Top ways to Inhibit TNF alpha


Since TNF is one factor that makes us tired at night,  I recommend taking most supplements in the day time.

All of the products that are not drugs are in my toolkit unless there’s a star next to it.

The vast majority of herbs and natural products inhibit TNF, IL-1b, IL-6, and NF-kB to one degree or another.

There are drugs that target TNF (monoclonal antibodies). They are effective and should be taken if all else fails and if they are indicated for your condition (with the approval of your doctor). You’d also want to measure your blood levels of TNF before you take these drugs.

The biggest problem with inhibiting TNF too much is that you become more susceptible to infections – and when you do get sick it’s more dangerous.

When researchers tried to give drugs to inhibit TNF and IL-1b together, they had to stop the trials because people started to get sick very easily. The supplements are not as strong, so there’s not much concern here. Also, when herbs inhibit TNF, they are simultaneously acting as antimicrobials, which prevents you from getting infections to begin with (or activating latent infections).

If you take multiple supplements and combine them with diet and lifestyle, the effect should be significant, but I haven’t noticed an increase in infections on myself.

Diet And Lifestyle To Inhibit TNF

One study found no difference in IL-6 or TNF in people who ate whole grains vs refined grains for 12 weeks (R). However, I’ve come across many studies that do show a reduction in inflammation with legume consumption (RR2) — but obviously not for lectin sensitive people.

Interestingly, in men, red meat was associated with lower TNF (but was correlated with CRP in women) (R).

Foods To Inhibit TNF



Top Supplements To Inhibit TNF

 Other Supplements To Inhibit TNF

Drugs That Inhibit TNF

  • Cannabis/THC/Marijuana/Pot (R, R2)
  • Low Dose NaltrexoneLDN (R)
  • Metformin (R)
  • Red Yeast Rice/Statins (R)
  • MDMA (R)
  • Psychedelics/Hallucinogens, via 5-HT2A agonism (extremely potent) (R). These include: Magic mushrooms (psilocybin, the psychedelic) (R), LSD(R), DOI (R), DMT (R), Ayahuasca (R) and Mescaline (R)
  • Cocaine (R)
  • Allegra/Fexofenadine (R)
  • Mizolastine (antihistamine) (R)
  • Bupropion (drug, Wellbutrin) (R)
  • Rapamycin (R) longevity drug.
  • Thalidomide and analogs (R) (Drug)
  • Monoclonal antibodies are obviously the strongest: infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia), and golimumab (Simponi), etanercept (Enbrel).

Pathways To Inhibit TNF

Elevated TNF and Chronic Infection

It’s possible that TNF is activated by a chronic infection. An infection can also cause lectin sensitivity. Many of the herbs should help here, but in some cases, antibiotics are more useful.

Antibiotics like doxycycline should be explored as a last resort.  While Doxycycline might not work and may have some side effects, at least it has some potential benefits.  Doxycycline is a nootropic, where it increases neurogenesis and reduces microglia in the hippocampus (memory center) (R) and has been found to extend worm lifespans (R). Minocycline also increases neurogenesis in adults (R) and lifespan in flies (R).

Why Some People Produce More TNF Than Others

The reason why some people produce TNF more than others is at least partially as a result of genetic predisposition.

Here are genes in the TNF gene that influence this cytokine’s production on SelfDecode, a program that analyzes and decodes your genetics from 23andme.

  1. RS1041981 (TNF)
  2. RS1799724 (TNF)
  3. RS1799724 (TNF)
  4. RS1799964 (TNF)
  5. RS1800629 (TNF)
  6. RS1800630 (TNF)
  7. RS1800750 (TNF)
  8. RS2229094 (TNF)
  9. RS2844484 (TNF)
  10. RS3093662 (TNF)
  11. RS3093665 (TNF)
  12. RS3093726 (TNF)
  13. RS361525 (TNF)
  14. RS673 (TNF)
  15. RS909253 (TNF)

Evolutionary Reason For Different TNF-alpha Levels

In different environments, different genes are better for survival. For example, higher levels of TNF help prevent a tuberculosis (TB) infection (R) and other infections. The microbe that caused the plague was able to decrease TNF (R), contributing to its deadliness. We might not think of this as significant, but in our history it mattered quite a bit.

With better hygiene and antibiotics and the desire for longer life, people with genes that cause elevated TNF are at a disadvantage in the modern era, even though it would’ve been useful in the past.

Skeletal remains show prehistoric humans from 4000 BC had TB, and researchers have found tuberculosis in the spines of Egyptian mummies dating from 3000–2400 BC. In Europe, rates of tuberculosis began to rise in the early 1600s to a peak level in the 1800s, when it caused nearly 25% of all deaths. By 1918, one in six deaths in France was still caused by TB (R).

In the year 588 AD, the Plague of Justinian (caused by the bacteria, Yersinia) killed as many as 100 million people across the world.  It caused Europe’s population to drop by around 50% between 541 and 700 (R).

From 1347 to 1351, the Black Death (also caused by Yersinia) swept through Asia, Europe and Africa. It may have reduced the world’s population from 450 million to between 350 and 375 million.  China lost around half of its population, from around 123 million to around 65 million; Europe around 1/3 of its population, from about 75 million to about 50 million; and Africa approximately 1/8 of its population, from around 80 million to 70 million.   The plague kept killing huge swaths of Europe’s population until the late 1700’s and also affected China and the Islamic world, but seemingly less so (R).

Health Tools I Wish I Had When I Was Sick

At SelfHacked, it’s our goal to offer our readers all the tools possible to get optimally healthy. When I was struggling with chronic health issues I felt stuck because I didn’t have any tools to help me get better. I had to spend literally thousands of hours trying to read through studies on pubmed to figure out how the body worked and how to fix it.

That’s why I decided to create tools that will help others cut down the guesswork:

  • Lab Test Analyzer – a software tool that will analyze your labs and tell you what the optimal values are for each marker — as well as provide you with actionable tips and personalized health and lifestyle recommendations to help you get there.
  • SelfDecode – a software tool that will help you analyze your genetic data from companies such as 23andme and ancestry. You will learn how your health is being impacted by your genes, and how to use this knowledge to your advantage.
  • SelfHacked Secrets – an ebook where we examine and explain the biggest overlooked environmental factors that cause disease. This ebook is a great place to start your journey if you want to learn the essential steps to optimizing your health.
  • SelfHacked Elimination Diet course – a video course that will help you figure out which diet works best for you
  • Selfhacked Inflammation course – a video course on inflammation and how to bring it down
  • Biohacking insomnia – an ebook on how to get great sleep
  • Lectin Avoidance Cookbook – an e-cookbook for people with food sensitivities
  • BrainGauge – a device that detects subtle brain changes and allows you to test what’s working for you
  • SelfHacked VIP – an area where you can ask me (Joe) questions about health topics

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The information on this website has not been evaluated by the Food & Drug Administration or any other medical body. We do not aim to diagnose, treat, cure or prevent any illness or disease. Information is shared for educational purposes only. You must consult your doctor before acting on any content on this website, especially if you are pregnant, nursing, taking medication, or have a medical condition.


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  • Mark

    You might want to add mirtazapine to the list of substances that increase TNF. I’ve had personal experience with it, and it’s also been documented.

  • luis

    hi im trying with psychedelic mushrooms and they are amazing, thanks for posting this, i was in need of some good info about the reduction of tnf levels, i am taking prednisone and trying to get it off and psilocibin is help me to do this instead of use biologics.

  • Kacy

    What is the quickest way to boost the alpha levels?

  • Jen

    Hi there , this question may sound ignorant but here goes. I quit smoking 4 years ago, within 4 days of quitting I encountered muscle problems and have lived in a pretty good amount of pain since. I just started researching the good things nicotine can do for you because up until then I was in perfect health and no amount of testing has given me an answer.. Just thought you may have some insight, I am really willing to try anything at this point . Thanks,

    1. WhisperSunny

      Jennifer within a Month after quitting smoking cold! I started showing all signs of severe immune issues. I have Crohns Disease and Bechets, and take a PPI for my Bile Reflux, Gastritis and Hernia in my stomach after losing my Gallbladder in 2012. Every time I take my 1 Pill a day of PPI’s, (I lowered it myself was having strange issues with 2 a day recommened). It makes my Immune issues even worse. Well if you read carefully, PPI inhibit good bacteria, so I added a Excellent Probiotic. It helps but not as well as it did before 1 year ago. I added in Lactoferrin when I had bad stomach issues, it finally made me realize I had severe Gut issues. Nothing was helping my Bechets symptoms or Crohn’s issues more then Lactoferrin, dislike taking any meds but Lactoferrin is all natural and gelps the Immune system by stopping some of my Bacteria growth or slowing it down. I have many other Immune Issues, Proriasis, Psoriatic Arthritis, ect! I am and will try to never take a TNF blocker Meds only Natural meds if at all possible. Curcumin is a TNF blocker, many Natural products are TNF blockers. We must Educate ourselves, and Self Hacked seems to help many. Also read the Book on how Cortisol small doses could be a lifesaver. Never use Cortisol without extreme excellent knowledge and a Doctors wise assessments. Steroids can kill your immune system also, if taken Unwisely or Inappropriately. Although Small doses 1 mg. of Prednisone once a day have saved my life years ago. They thought I had Addisons disease, it was the Crohns disease and Bechets disease lurking for years! Read read read! I never stop Educating myself. Smoking hides Immune Issues!

  • Bridget

    Hi, why do you suppose TNFalpha antagonists have been linked to an increased susceptibility to demyelinating disease? Trying to figure that one out.

  • Scloud

    I have low TNF and can’t find any info on this subject. My dr. Believes it could be a cause for my infertility and we are trying to get it up. Have you heard anything like this or have any information on really low TNF? Your article was very interesting.

  • Just Another Russian

    Hey, Joe! You know anything about whether finasteride inhibits TNF-alpha? Thanks.

  • Kanchan Changder

    Amazing n full of knowledge … Many Thanks I have acute AS n I have been suggested Anti TNF Biologics but I want to go with the natural way as its more safe from side effects. What should I include in my diet to block TNF naturally.

  • Luca

    Pentoxifylline! (Trental)

  • にょろ♂

    Amazingly awesome contents !
    BTW, why some are barred on its word in “Top 16 Ways To Inhibit TNF” section ?

  • Jean

    Just got an idea. L-Carnitine Tartrate could possibly yield the same benefits as tamarind (tartaric acid). It’s way cheaper than plain L-carnitine too.

  • Daniel

    Thanks again Joe. I have done some Dna Tests. I have problems with tnf and il 6 and ended up with leaky gut, psoriasis, and ms. Thanks to you I understand more and more about my test results and how to fight my inflamed body.

    1. Joseph M. Cohen

      My pleasure 🙂

  • Jack

    As usual. Top five most effective, based on existing evidence, yet completely safe?

  • Jay

    Have you tried kratom?

    1. Joe


      1. Jay

        And what were the effects? Good/bad?

        1. Joe


          1. Jay

            Lol ok don’t give too much away 😉

            reply icon
          2. WhisperSunny

            Be careful.

            reply icon
  • YimYam

    What dosage?

  • Joanna

    Interesting on the MDMA. Might explain why you feel alert and great after 5-6 hours of sleep despite rolling the whole night. The subsequent days seem like less sleep is required as well.

    MDMA is also a selective TH2 and TH1 immunosuppressant. Not sure exactly where I read that but I pulled out a related source anyways.

    I would tend to agree with this as my rhinitis and cough completely goes away for a couple days after rolling.

    However, I think you’d run into more problems using MDMA regularly… but interesting none the less.

    Smoking weed semi regularly you can probably get away with without suffering as much adverse effects though.

    Have not tried psychedelics, but the benefits of micro-dosing LSD probably comes from what you mentioned above

    1. Joe

      Lol, you may have seen it here:

      I don’t suggest regular MDMA usage.

      Ya microdosing LSD is interesting I plan on trying that too

  • kobilica

    Hello! I am extremely glad you have posted this!

    I can report, that magic mushrooms do indeed have really good potent effect. I feel clearheaded days after the experience (5 days or so, do not remember)

    1. Joe


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