Why Chronic Lyme Treatment Fails - A Review with Strategies

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Updated: 1/31/23

Some People Remain Ill after Antibiotics

This article is about the reasons people remain ill with chronic Lyme disease even after taking one, two, or even more years of herbal or prescription antibiotics. In my experience, about 15 percent of people with chronic Lyme disease remain ill after a multi-year course of antibiotics. The other 85 percent of people do have various degrees of recovery—most getting very well.

Lyme-literate medical doctors (LLMDs) have very limited science to guide them about why treatment works or fails—and what the best treatment options are. The last U.S. National Institutes of Health-funded human trials looking at treating Lyme occurred nearly 20 years ago. We do know from a study conducted by the MyLymeData project by LymeDisease.org that the best chance of recovery is provided by a year or more of antibiotics and working with an LLMD. You can read more about the MyLymeData studies, including those on alternative medicine outcomes versus antibiotic outcomes in What Works? Navigating Prescription & Alternative Medicine Lyme Treatments.

With the lack of human studies, most of the science I use to guide my treatment decisions comes from non-human laboratory experiments. Fortunately, these experiments provide insights about herbal and prescription treatment options that can work in many patients. These experiments also provide several theories about what can work for treatment and why people do not recover even with long-term antibiotics.

How to Avoid Chronic Lyme Treatment Failure

Before I review the treatment failure theories, let’s discuss what steps you should take to have a successful Lyme recovery.

Kill Germs AND Correct All Body-Wide Imbalances

Treating Lyme is complicated. The infection triggers an immune system cytokine reaction that affects most organs and systems of the body. In my experience, the great majority of people can recover if they address each of the steps in The Ross Lyme Support Protocol. This protocol is designed to kill Lyme and coinfection germs and to correct all the sleep, immune system, detoxification, inflammation, and hormonal imbalances created by Lyme. If your treatment did not work, but you only took herbal or prescription antibiotics alone, review The Ross Lyme Support Protocol to see all the areas to address to provide the best chance of recovery.

Find and Treat Mold Toxicity

Chronic mold toxicity looks just like chronic Lyme disease, therefore, make sure you do not have this problem. If you do, correct it by reviewing Mold and Lyme Toxin Illness.

Theories & Strategies About Lyme Treatment Failure

Several theories exist why people remain ill even after getting rid of mold toxins and treating with a comprehensive regimen that kills germs and addresses all imbalances identified in The Ross Lyme Support Protocol. These reasons include:

  • Borrelia (Lyme) persisters;
  • autoimmune disease triggered by the Lyme infection;
  • disruption of a healthy gut microbiome;
  • germ debris;
  • limbic system brain holding of the illness;
  • tissue damage from the infection;
  • chronic inflammation and immune dysfunction; and
  • learned illness behavior and/or somatic disorder.


The Borrelia persisters theory is an in-vogue and relatively new idea about why treatments do not work. The theory suggests that under assault from antibiotics (RX or herbal), some of the Lyme germs go into a persister hibernation state. As a result, these persisters do not respond to regular antibiotics. We will have to see in time if addressing persisters does help to prevent or correct treatment failures. In my practice, all my current treatments include antimicrobial approaches to address persisters.

For more information about persisters and how to address them, see How to Treat Persister Lyme & Bartonella.

Autoimmune Disease

Through a process known as molecular mimicry, the immune system may attack tissues with protein and molecular parts that look just like parts of Lyme or related infections. Currently, no Lyme-specific way to address molecular mimicry exists. For some individuals, however, using Low Dose Naltrexone (LDN) can regulate or reverse the autoimmune attack.

For more information about LDN, see Low Dose Naltrexone (LDN) & Lyme.

Disruption of Healthy Gut Microbiome

Treating Lyme with herbal or prescription antibiotics disturbs the healthy balance of good germs and microbes in the gut. The germs that live in the intestines are called the gut microbiome. These include healthy bacteria, viruses, parasites, yeasts and fungi. To put the number of microbes in perspective, more than 90 percent of the genetic material in human bodies come from the microbes in the gut!

We allow these germs to live in us because they serve a purpose. Studies show these microbes regulate the immune system, signal healthy brain function, digest food, remove toxins and things we are allergic to, and provide many other healthy body regulating functions.

The theory is antibiotics disturb the healthy gut microbiome leading to ongoing body-wide illness. It is not clear yet how best to address this issue, or even if the gut disruption really does cause ongoing illness.

One treatment option is to create a healthy gut microbiome using probiotics. Another one is to replace the dysfunctional microbiome through a stool transplant, also called fecal microbiota transplant (FMT). However, since FMT is regulated by the U.S. Food and Drug Administration (FDA), only treatment of C. difficile bacteria overgrowth in the intestines is currently allowed. Furthermore, no research has been conducted if FMT could change the outcome of those with chronic Lyme disease.

Treating Lyme is about balancing risks and benefits. The benefit of using herbal and prescription antibiotics is decreasing or eliminating the Lyme or coinfection (like Bartonella or Babesia) germs leading to improved health. Yet, the risk of doing so is disturbing the gut microbiome.

See Probiotic Strategies in Lyme Disease Treatment for information about probiotics and C. Difficile Diarrhea: Prevention & Treatment for more information about FMT.

Germ Debris

A functioning immune system is supposed to break down and dispose of dead germs and their parts, including DNA, RNA, proteins, and fats. One theory why people remain ill is that the immune system does not get rid of all the borrelia germ debris, thereby triggering an ongoing immune inflammatory response. Currently, there is not a treatment I am aware of for this possible problem.

Limbic System Brain Holding of The Illness

The limbic system is a part of the brain that regulates our emotional responses and behaviors. This includes fight-or-flight responses, fear, and survival behaviors, such as feeding the young and reproduction.

For some with Lyme disease, the limbic system becomes overly reactive and chronically turned on. A turned-on limbic system causes some of the ongoing symptoms like pain or even fatigue.

Several programs can help reprogram the limbic system to turn off, except for when it should be on. Two of the more popular programs are the Gupta Program and Annie Hopper Dynamic Neural Retraining System. Many of my patients have found benefit from these practices. Short of doing these programs, developing a meditative mindfulness practice can help, too. Counseling may also help to decrease emotional reactivity.

Tissue Damage

Another theory why Lyme treatment fails is the immune reaction to Lyme causes ongoing tissue damage and injury—even when the infection is gone or under control—leading to pain, neurologic and brain dysfunction, mitochondria cell energy factory dysfunction, and even immune dysfunction.

My current approach to repairing musculoskeletal tissue injury and peripheral nerve injury is to use the peptide BPC-157. For brain injury, I also add the peptide Cerebrolysin. See Key Oral Peptide Strategies to Repair & Restore in Lyme Disease & Mold Toxicity for more information about peptides and BPC-157. For people with low energy, I work to repair the mitochondria. See How to Fix Mitochondria & Get Energy in Lyme Disease.

Chronic Inflammation and Immune Dysfunction

Another reason people may not recover is explained by the chronic inflammation and immune dysfunction theory. In this theory Lyme infection sets off an ongoing immune inflammation reaction that takes on a life of its own, causing more inflammation and immune dysfunction. One reason this could happen is due to an imbalance between what is known as Th1 and Th2/Th17 parts of the immune system. Th1 is made up of immune cells that attack germs like T white blood cells and macrophages. Th1 is the immune system offense squad. Th2/Th17 is made up of B white blood cells that make antibodies, mast cells involved in allergies and histamine production, and immune barrier cells that line the mucous and skin membranes designed to keep germs out. Think of Th2/Th17 as the immune system defensive squad. If Th2 and Th17 get too active, they release inflammatory cytokines that lead to many ongoing Lyme type symptoms, in addition to suppressing Th1 and its germ-fighting abilities.

In my practice, I work with LDN to increase regulatory T white blood cells (TRegs). TRegs create balance between Th1 and Th2/Th17. Another option is to use the peptides TB4 Frag or Thymosin Alpha 1. For more information about these treatment options, see Repair & Restore with Peptides in Lyme Disease or Mold Toxin Illness and Low Dose Naltrexone (LDN) & Lyme.

Learned Illness Behavior and/or Somatic Illness

Learned illness behavior and somatic illness are two psychological conditions. I list them here to be thorough, but I am concerned that many non-LLMDs use these diagnoses to say Lyme disease is in a person’s head instead of acknowledging and treating them for a physical illness. In my experience, it is a rare person with chronic Lyme that has one of these conditions contributing to their illness. Counseling is helpful if one of these occurs.


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View Citations

  1. Bobe JR, Jutras BL, Horn EJ, et al. Recent progress in Lyme disease and remaining challenges. Front Med. 2021;8:666554. doi:10.3389/fmed.2021.666554 (View)
  2. Cabello FC, Embers ME, Newman SA, Godfrey HP. Borreliella burgdorferi antimicrobial-tolerant persistence in Lyme disease and posttreatment Lyme disease syndromes. mBio. 2022;13(3):e0344021. doi:10.1128/mbio.03440-21 (View)
  3. Fallon BA, Sotsky J. Conquering Lyme Disease: Science Bridges the Great Divide. Columbia University Press; 2018.
  4. Sanabria-Mazo JP, Montero-Marin J, Feliu-Soler A, et al. Mindfulness-based program plus amygdala and insula retraining (MAIR) for the treatment of women with fibromyalgia: A pilot randomized controlled trial. J Clin Med. 2020;9(10):3246. doi:10.3390/jcm9103246 (View)
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About The Author

Marty Ross, MD is a passionate Lyme disease educator and clinical expert. He helps Lyme sufferers and their physicians see what really works based on his review of the science and extensive real-world experience. Dr. Ross is licensed to practice medicine in Washington State (License: MD00033296) where he has treated thousands of Lyme disease patients in his Seattle practice.

Marty Ross, MD is a graduate of Indiana University School of Medicine and Georgetown University Family Medicine Residency. He is a member of the International Lyme and Associated Disease Society (ILADS), The Institute for Functional Medicine, and The American Academy of Anti-Aging Medicine (A4M).

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