Herxheimer Die-Off Reaction: Inflammation Run Amok.

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Herxheimer reaction in a Lyme disease treatment Image from Marty Ross MD

"If you feel worse after herbal anti-microbials or prescriptive antibiotics to treat Lyme are started it is likely you are having a Herxheimer die-off reaction." 

A die-off reaction, also called a Herxheimer reaction, can occur when treating the Lyme germ, some co-infections, and yeast. It occurs as bacteria or yeast die during antibiotic treatment. It is common to have Herxheimer die-off reactions when starting herbal anti-microbials or antibiotics when treating Lyme. These reactions can also occur when new antibiotics are introduced into a treatment.

Is It a Lyme Disease Herx?

See my free article Is It a Lyme Disease Herx Reaction? for steps you can take to figure out if your decline in health is due to a herx. 

What This Lyme Disease Herxheimer Article is About

Fortunately there are a number of good natural medicines that you can take to stop or limit Herxheimer reactions. In this article I review

  • how these reactions occur,
  • the various supplements I use with my patients to successfully limit the reactions, and
  • my recommended dosing of each supplement.

In a die-off reaction, there is a release of endotoxins, proteins, and oxidizing agents that results in an increase in inflammatory cytokines such as tumor necrosis factor alpha, interleukin-6, and interleukin-8.

The symptoms of a die-off reaction are generally a worsening of the underlying symptoms of Lyme disease and its associated infections. A majority of Lyme disease symptoms are actually excess inflammatory cytokine symptoms. So in a die-off reaction there is a worsening of many Lyme disease symptoms including: fatigue, brain-fog, muscle and nerve pain, chills and sweats, and/or memory and thinking.

Cytokines: The Good and The Bad

Good: Cytokines are proteins made by various types of white blood cells to fight infections. They perform a number of functions that include:

  • making antibodies work more effectively,
  • increasing active white blood cells to fight infections,
  • recruiting white blood cells to the location of an infection,
  • turning on white blood cells to fight infections, and
  • decreasing viral and bacterial replication.

Bad: Too many cytokines:

  • suppress the immune system,
  • cause pain,
  • decrease hormone production from organs like the thyroid and the adrenal glands,
  • disturb sleep,
  • decrease brain function,
  • increase fatigue and tiredness,
  • waste muscles,
  • cause depression, and
  • decrease the function of various organs throughout the body resulting in many other symptoms and medical problems.

Cytokines: How They are Made and Regulated

Cytokines are made when immune cells are stimulated by germs, toxins, oxidizing agents, other cytokines, other agents, and insomnia.

NF-kB Signals for Cytokine Production

Once the immune cells are stimulated, an intracellular messenger called NF-kB (nuclear factor kappa beta) causes genetic programming for the production of cytokines and the turning on of white blood cells.  Antioxidants like glutathione, quercetin, and curcumin lower oxidation triggers for NF-kB. Supplements, like curcumin also block the function NF-kB.

Kinase Enzymes

Within the white blood cells, the production of cytokines require enzymes called kinases. Herbs that block kinase enzymes, like quercetin, can help lower ctyokines.

Nrf2 Signals Production of Antioxidants.

Cells also have a genetic messenger that increases cell production of antioxidants like glutathione. This messenger is called Nrf2 (nuclear factor 2). There are some supplements like resveratrol and curcumin that turn on Nrf2. Antioxidants decrease oxidizing agents that trigger cytokine production. So turning on Nrf2 creates antioxidants which decrease cytokine production.

Sleep Lowers Cytokine Inflammation in Lyme Disease

Sleep also has a big impact on cytokines. Lack of sleep triggers more cytokines. And high cytokines can cause insomnia. 

How to Lower Cytokines

Get Sleep.

First it is important to get 7-9 hours of sleep a night. Sleep lowers cytokines.

Use Supplements.

To lower cytokines there are a number of interventions to:

  • increase antioxidants,
  • decrease NF-kB genetic programming of cells,
  • increase Nrf2,
  • block kinase enzymes and,
  • detox.

Antioxidants. Based on the work of Martin Pall, PhD, it is critical to lower oxidizing agents that trigger cytokine production. Glutathione which is made in every cell and its building blocks alpha lipoic acid (ALA) and n-acetyl cysteine (NAC) are helpful. Curcumin which is a component of turmeric and quercetin are also good antioxidants. Ecklonia Cava (brown seaweed extract) is another good antioxidant.

Detox. Glutathione and its precursor building blocks, ALA and NAC also help remove toxins.

NF-kB. Curcumin, quercetin, and resveratrol decrease NF-kB induced genetic signals to produce cytokines.

Nrf2. Curcumin, resveratrol, and black tea extracts containing the polyphenol EGCG increase Nrf2 which increases cell level production of glutathione and other antioxidants.

Kinase Enzymes. Quercetin also blocks kinase enzymes required in the production of cytokines. Blocking kinases with quercetin interferes with the cytokine production line.

My Recommendations

Step 1: The Beginning of Treatment to Prevent Herxheimer Die-off Reactions.

Use a good multivitamin that includes alpha lipoic acid n-acetyl cysteine, antioxidants, and other micronutrients that decreases oxidizing agents and supports liver detoxification. I prefer multivitamin products in powder form made by Thorne or Integrative Therapeutics.

  • Curcumin 500 mg 1 pill 3 times a day OR 
  • AntiCytokine Combination (find a combination product that contains curcumin, resveratrol, black tea extract, and NAC such as Cytoquel by Researched Nutritionals) 1-2 pills 3 times a day.
  • Multivitamin. Use multivitamin powders by Thorne or Integrative Therapeutics. Use as directed on the product label.

Step 2: Moderate Herxheimer Die-off Reactions.

For more severe cases add oral glutathione and double the Curcumin to 1000 mg 3 times a day (or increase the AntiCytokine Combination to 2 pills 3 times a day.

Glutathione is also a great choice if there is nerve pain or numbness. If the addition of glutathione is not effective then add ecklonia cava and consider adding quercetin. You can use all four. This combination works to block the cytokine production line and decreases oxidizing agents that trigger production. These treatments can take 1-2 weeks for maximum effect.

  • Glutathione (as oral liposomal glutathione) 400-500 mg 1 or 2 times a day.
  • Quercetin 250 mg 2 pills 3 times a day.
  • Ecklonia Cava 400 mg 2 pills 2 to 3 times a day

If glutathione is not tolerated then work with one or a combination of the following anti-oxidants that are used to make glutathione.

  • Alpha Lipoic Acid 350 mg 1 pill 2 times a day.
  • N-Acetyl Cysteine 500 mg 1 pill 3 times a day.

Step 3: Severe Herxheimer Die-off Reactions.

For severe die-off reactions use IV glutathione as a potent antioxidant and to support liver detoxification. This is administered in an integrative medicine physician's office. Another option is to use glutathione in a nebulizer. Glutathione IV is stronger than glutathione by nebulizer in my experience. Using a nebulizer you breath in a fine mist of the glutathione which is absorbed into the blood through the blood vessels in the lungs. Sometimes I will start a person with four IV glutathione treatments and then change to glutathione by nebulizer to continue the treatment.

  • Glutathione IV 1200 mg to 2500 mg 2 times a week for a minimum of four treatments. If it helps but there are still improvements with the last treatment, consider weakly treatments until improvements plateau. You will likely feel more tired after the first treatment.
  • Glutathione by nebulizer 200 mg/ml 2ml 2 times a day for adults. Children can take 100mg/ml 1ml to 2ml 2 times a day.


  1. Ballatori N, Krance SM, Notenboom S, Shi S, Tieu K, Hammond CL. Glutathione dysregulation and the etiology and progression of human diseases. Biol. Chem. 2009;390:191–214. doi:10.1515/BC.2009.033.
  2. Bocci V, Valacchi G. Nrf2 activation as target to implement therapeutic treatments. Frontiers in Chemistry. 2015;3:4. doi:10.3389/fchem.2015.00004.
  3. Butler T. (2017). The jarisch-herxheimer reaction after antibiotic treatment of spirochetal infections: a review of recent cases and our understanding of pathogenesis. Am. J. Trop. Med. Hyg. 96:46–52. 10.4269/ajtmh.16-0434
  4. D’Andrea G. Quercetin: a flavonol with multifaceted therapeutic applications? Fitoterapia. 2015;106:256–71.
  5. Gulcubuk A, et al. Effects of curcumin on proinflammatory cytokines and tissue injury in the early and late phases of experimental acute pancreatitis.. Pancreatology. 13(4):347-354.
  6. Krysta K, Krzystanek M, Bratek A, Krupka-Matuszczyk I. Sleep and inflammatory markers in different psychiatric disorders. Journal of Neural Transmission. 2017;124(Suppl 1):179-186. doi:10.1007/s00702-015-1492-3.
  7. Lee DW, Gardner R, Porter DL, et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood. 2014;124(2):188-195. doi:10.1182/blood-2014-05-552729. 
  8. Linus Pauling Institute, Oregon State University. Curcumin. Micronutrient Information Center; Phytochemicals website. lpi.oregonstate.edu/mic/dietary-factors/phytochemicals/curcumin Accessed August 18, 2018.
  9. Lu SC. Glutathione synthesis. Biochimica et biophysica acta. 2013;1830:3143-3153
  10. Pall M. Approaches to curing chronic fatigue syndrome/myalgic encephalomyelitis, fibromyalgia, multiple chemical sensitivity, gulf war syndrom, and possibley many others. Townsend Letter. 2010 (Feb/March) www.townsendletter.com/FebMarch2010/cureNO0210.html Accessed August 19, 2018
  11. Peacock BN, Gherezghiher TB, Hilario JD. et al. New insights into Lyme disease. Redox Biol. 2015;5:66–70. doi.org/10.1016/j.redox.2015.03.002.
  12. Pizzorno J. Glutathione! Integrative Medicine: A Clinician’s Journal. 2014;13(1):8-12.
  13. Pound MW, May DB. Proposed mechanisms and preventative options of Jarisch-Herxheimer reactions. J. Clin. Pharm. Ther. 2005;30:291–295. 10.1111/j.1365-2710.2005.00631.x
  14. Shachar I, Karin N. The dual roles of inflammatory cytokines and chemokines in the regulation of autoimmune diseases and their clinical implications. J Leukoc Biol. 2013;93(1):51–61. doi: 10.1189/jlb.0612293.
  15. Sinha R, Sinha L, Calcagnotto A, Trushin N, Haley JS, Schell TD, Richie Jr JP. Oral supplementation with liposomal glutathione elevates body stores of glutathione and markers of immune function. European Journal of Clinical Nutrition. 2018;72:105–111.
  16. Strle K , Drouin EE, Shen S, El Khoury J, McHugh G, Ruzic-Sabljic E, Strle F, Steere AC. Borrelia burgdorferi stimulates macrophages to secrete higher levels of vytokines and vhemokines than Borrelia afzelii or Borrelia garinii. The Journal of Infectious Diseases. 2009;200(12):1936–1943, doi.org/10.1086/648091
  17. Strle K, Sulka KB, Pianta A, Crowley JT, Arvikar SL, Anselmo A, Sadreyev R, Steere, AC. T-Helper 17 cell cytokine responses in Lyme disease correlate with Borrelia burgdorferi antibodies during early Infection and with autoantibodies late in the illness in patients with antibiotic-refractory Lyme srthritis, Clinical Infectious Diseases. 2017;64(7):930–938. doi.org/10.1093/cid/cix002
  18. Zhao F, Gong Y, Hu Y, Lu, M, Wang J, Dong J, Qiu F. Curcumin and its major metabolites inhibit the inflammatory response induced by lipopolysaccharide: Translocation of nuclear factor-κB as potential target. Molecular Medicine Reports. 2015;11:3087-3093. doi.org/10.3892/mmr.2014.3079

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