How Does Dapsone Work?
Author: Dr. Richard Horowitz
The International Lyme and Associated Diseases Society (ILADS) is a nonprofit, international, multidisciplinary medical society dedicated to the diagnosis and treatment of Lyme and other complex inflammatory diseases. With these educational blog posts from experts and members of our board, ILADS aims to promote awareness and understanding of health and wellness, especially as it relates to complex inflammatory diseases, so that we can all learn and grow together. If you have any questions or want more information, you can email us at contact@ilads.org.
Disclaimer: Every patient is an individual with unique characteristics. This blog article is not medical advice. It does not constitute a physician-patient relationship. It is for educational purposes only. Do not try out what is in this article without medical advice, working with your licensed physician and licensed healthcare providers
- How does Dapsone work, and why was it chosen for this trial in the context of Lyme disease treatment?
There have been many controversies in the field of Lyme disease, specifically in the diagnosis and treatment of Chronic Lyme Disease/PTLDS. One of the greatest debates has revolved around why people remain ill after having had the infection for more than several months. In the past, we believed that the bacteria primarily persisted in what are called cell-wall-deficient forms, otherwise known as cystic forms, L-forms, S-forms, or round body forms.
[L-form (cell wall deficient) bacteria] from CDC’s Prevention Public Health Image Library
Approximately 25 years ago, I presented a study with Dr. Martin Atkinson Barr at the Lyme Disease Foundation’s (LDF) International Scientific Conference, which showed that Flagyl (metronidazole) was effective in helping certain individuals suffering from Chronic Lyme Disease (CLD). We established the efficacy of metronidazole after finding that individuals with CLD who also had Helicobacter pylori got better after using Flagyl, even without bismuth and a tetracycline, which is one of the standard therapies used for this infection. Roughly 6 months later, Dr. Brorson published a study showing that metronidazole hit the cystic forms of Borrelia Burgdorferi. We therefore believed that it was these cell-wall-deficient forms that were responsible for the relapsing and remitting symptoms seen in those with chronic Borreliosis. This led to us using medications like Plaquenil (hydroxychloroquine), grapefruit seed extract, and/or Flagyl in antibiotic regimens, along with antibiotics that hit the cell wall forms/actively growing bacteria (penicillins/cephalosporins) and intracellular forms of the bacteria (using macrolides, tetracyclines, rifampin, and or quinolones). This formed the basis of our treatment regimens for approximately 2 decades.
[“Corkscrew-shaped” bacteria known as Borrelia burgdorferi.
Image courtesy the Centers for Disease Control and Prevention’s Public Health Image Library.]
At the time we were using Flagyl, we did not know that there was a fourth form of the bacteria–biofilm/persister forms. This was established by researchers from different universities about a decade ago, including John’s Hopkins University, where Dr. Ying Zhang and colleagues showed that most of the inflammation we see in CLD is from these biofilm/persister forms. We also didn’t know 10 years ago that Lyme was a biofilm bacterium, similar to other chronic persistent biofilm Infections like subacute endocarditis (SBE), osteomyelitis, chronic sinusitis and otitis, candidiasis. and salmonellosis. These “persister” forms of the bacteria either are completely dormant, hiding under biofilms, or barely metabolically active, and it has been shown that these persister bacteria are responsible for relapsing and remitting symptoms in many different chronic infections. With the use of dapsone, we have demonstrated that this is also the case in CLD.
[“Persister” forms of the bacteria]
Zhang Y. Persisters, persistent infections and the Yin-Yang model. Emerg Microbes Infect. 2014 Jan;3(1):e3. doi: 10.1038/emi.2014.3.
Why did I decide to use dapsone, and mix it with other intracellular antibiotics including rifampin, tetracyclines like doxycycline or minocycline, and azithromycin once Borrelia was discovered to have persister forms? One of the treatments used to cure leprosy, another biofilm/persister infection, is the use of rifampin and dapsone for one year. When I looked up the qualities of dapsone, I noticed that it met all the basic criteria we needed for an oral, generic antibiotic for the treatment of CLD. Dapsone has excellent central nervous system penetration, making it an ideal candidate for neuroborreliosis; it is used for autoimmune illnesses, like Behcet’s syndrome, and we do frequently see autoimmune phenomenon in those suffering from chronic Lyme disease. It is anti-inflammatory, and we know that chronic inflammation is one of the primary reasons that people remain ill with CLD/PTLDS; it has antimalarial effects, which made it a potential candidate for also helping to treat overlapping Babesiosis, a frequent resistant parasitic infection we find in our patients; and finally, it is a potent persister drug, with decades of safety/efficacy in treating a biofilm/persister bacterial infection like leprosy. I therefore decided to have my patients try it, and was immediately impressed with the results, even at very low doses like 25 mg per day.
What I didn’t know when I started using dapsone in 2015 was the optimal dosing, necessary length of treatment, means to control the side effects (the side effects can be described as “Do no H. A. R. M.”: Herxheimer reactions, folic acid induced Anemia, potential Rashes in those who are sulfa sensitive, and Methemoglobinemia, where the oxygen-carrying capacity of the blood is impacted from the oxidative stress of the drug). Over the years, we have been continuously tweaking the protocol to make it the most effective and safe short-term oral generic drug regimen available for the treatment of CLD/PTLDS.
- What are the key findings from the latest update on the Dapsone trial, and how do they compare to previous research on Lyme disease treatments?
When we first started to use dapsone therapy, we started with low doses (25 mg every other day or every day) and tried using dapsone up to 100 mg a day for several months’ time. You can see the results in the first article we published on dapsone back in 2016:
Horowitz RI, Freeman PR (2016) The Use of Dapsone as a Novel “Persister” Drug in the Treatment of Chronic Lyme Disease/Post Treatment Lyme Disease Syndrome. J Clin Exp Dermatol Res 7: 345. doi:10.4172/2155-9554.1000345
It showed that we statistically improved 7/8 symptoms of those suffering from CLD/PTLDS, e.g., sweats and chills, fatigue, muscle pain, joint pain, neuropathy, memory/concentration problems, and sleep, just not headaches. However, people relapsed when the drugs were stopped, and as we kept increasing the doses, we found greater efficacy with higher dosing, with 100 mg or higher. This dose statistically improved all major Lyme symptoms, including headaches:
Horowitz, R.I.; Freeman, P.R. Precision Medicine: retrospective chart review and data analysis of 200 patients on dapsone combination therapy for chronic Lyme disease/post-treatment Lyme disease syndrome: part 1. International Journal of General Medicine 2019:12 101–119
Horowitz, R.I.; Freeman, P.R. Precision Medicine: The Role of the MSIDS Model in Defining, Diagnosing, and Treating Chronic Lyme Disease/Post Treatment Lyme Disease Syndrome and Other Chronic Illness: Part 2. Healthcare 2018, 6, 129.
Horowitz RI, Freeman PR (2016) Are Mycobacterium Drugs Effective for Treatment Resistant Lyme Disease, Tick-Borne Co-Infections, and Autoimmune Disease?. JSM Arthritis 1(2): 1008.
Then by accident, a patient took double the dose of dapsone for one month–100 mg twice a day–and after I stopped the protocol he went into long-term remission for one year. At that point, I knew we had come upon an important finding. So I turned to my wife and asked her to be a guinea pig, since she had been suffering with CLD for over 20 years, and although she felt great on dapsone 50 mg or 100 mg for a year, she would constantly relapse off the medication (and had a positive PCR in her blood for Borrelia, indicating an ongoing active infection). She did one month of double-dose dapsone about 6 years ago, and has been in long-term remission since then. We published our findings on a larger patient group in the journal Antibiotics:
Horowitz, R.I.; Freeman, P.R. Efficacy of Double-Dose Dapsone Combination Therapy in the Treatment of Chronic Lyme Disease/Post-Treatment Lyme Disease Syndrome (PTLDS) and Associated Co-infections: A Report of Three Cases and Retrospective Chart Review. Antibiotics 2020, 9, 725. https://doi.org/10.3390/antibiotics9110725
[ Bulls-eye rash seen with Lyme Disease.]
This study demonstrated that among 40 patients, tick-borne symptom improvements in 98% of patients, with 45% remaining in remission for one year or longer. In those with PTLDS, the remission rate was even higher. So, we took our findings to Eva Sapi and her group at the University of New Haven, and asked her to look in culture to see if dapsone was effective against the biofilm/persister forms of Borrelia. It was:
Horowitz, R.I., Murali, K., Gaur, G. et al. Effect of dapsone alone and in combination with intracellular antibiotics against the biofilm form of B. burgdorferi. BMC Res Notes 13, 455 (2020). https://doi.org/10.1186/s13104-020-05298-6
This study showed that dapsone, alone or in various combinations with doxycycline, rifampin, and azithromycin, produced a significant reduction in the mass and protective glycosaminoglycan layer and overall viability of B. burgdorferi biofilm forms. In fact, 4 drugs worked better than 3, which worked better than 2, which was superior to single drug therapy. This in vitro study strongly suggested that dapsone combination therapy could represent a novel and effective treatment option against the biofilm form of B. burgdorferi and explained in part, why we were having the superior results we were having.
From: Horowitz et al. BMC Research Notes 2020. Effect of dapsone alone and in combination with intracellular antibiotics against the biofilm form of B. burgdorferi
However, we still were seeing relapses. The higher the doses of dapsone we were using, although more effective in stopping relapses, also led to higher side effect rates of anemia, Herxheimer reactions, and methemoglobinemia. We needed to figure out how to minimize the side effects and maximize the effectiveness of the combination therapy. Part of the relapses were occurring in those who were co-infected with active Babesia and or Bartonella, so we went back to the drawing board, and looked into pulsing dapsone therapy based on earlier work by Dr Kim Lewis. At Northeastern University, Dr Lewis demonstrated that pulse therapy could be effective against persister forms of the bacteria, even using a non-persister drug like Rocephin. That led us to publish a study where we tried a 4-day high dose dapsone pulse (HDDCT, at 200 mg twice a day) after doing double-dose dapsone therapy to see if we could improve our outcomes, since it was clear at this point that it was not simply the length of the drug itself that made a difference, but the dosage. The results can be found here:
Horowitz RI, Freeman PR. Efficacy of Short-Term High Dose Pulsed Dapsone Combination Therapy in the Treatment of Chronic Lyme Disease/Post-Treatment Lyme Disease Syndrome (PTLDS) and Associated Co-Infections: A Report of Three Cases and Literature Review. Antibiotics. 2022; 11(7):912. https://doi.org/10.3390/antibiotics11070912
“A total of 25 patients with a history of Lyme and associated co-infections, most of whom had ongoing symptoms despite several courses of DDDCT, took one or more courses of high-dose pulsed dapsone combination therapy (200 mg dapsone × 3–4 days and/or 200 mg BID × 4 days), depending on persistent symptoms. The majority of patients noticed sustained improvement in eight major Lyme symptoms, including fatigue, pain, headaches, neuropathy, insomnia, cognition, and sweating, where dapsone dosage, not just the treatment length, positively affected outcomes.”
Although it was clear that a higher dose of dapsone, pulsed for 4 days, did improve clinical symptomatology, we kept seeing resistant Bartonella show up as a major factor interfering with our clinical results (as did Babesia). I then went back to the scientific literature and reviewed the work by Johns Hopkins University researchers on the efficacy of drug combinations in culture against Bartonella. They showed that a 6-day course of rifampin and methylene blue or Zithromax and methylene blue was needed to clear Bartonella. We therefore extended the length of our pulse from 4 to 6 days, and did see superior results. The full study is listed below:
Horowitz, R.I.; Fallon, J.; Freeman, P.R. Comparison of the Efficacy of Longer versus Shorter Pulsed High Dose Dapsone Combination Therapy in the Treatment of Chronic Lyme Disease/Post Treatment Lyme Disease Syndrome with Bartonellosis and Associated Coinfections. Microorganisms 2023, 11,2301. https://doi.org/10.3390/microorganisms11092301
Abstract
Twenty-five patients with relapsing and remitting Borreliosis, Babesiosis, and bartonellosis despite extended anti-infective therapy were prescribed double-dose dapsone combination therapy (DDDCT), followed by one or several courses of High-Dose Dapsone Combination Therapy (HDDCT). A retrospective chart review of these 25 patients undergoing DDDCT therapy and HDDCT demonstrated that 100% improved their tick-borne symptoms, and patients completing 6–7-day pulses of HDDCT had superior levels of improvement versus 4-day pulses if Bartonella was present. At the completion of treatment, 7/23 (30.5%) who completed 8 weeks of DDDCT followed by a 5–7-day pulse of HDDCT remained in remission for 3–9 months, and 3/23 patients (13%) who recently finished treatment were 1 ½ months in full remission. In conclusion, DDDCT followed by 6–7day pulses of HDDCT could represent a novel, effective anti-infective strategy in CLD/Post Treatment Lyme Disease Syndrome (PTLDS) and associated co-infections, including Bartonella, especially in individuals who have failed standard antibiotic protocols.
Figure 1. MSIDS Variables Present Among 25 Patients with CLD/PTLDS on DDDCT/HDDCT.
Horowitz, Freeman. Microorganisms 2023, 11, 2301
So it was clear that several pulses of high-dose dapsone combination therapy was needed in those suffering from chronic Bartonella, and we are now finding that the majority of our chronically ill patients have a chronic infection with Bartonella, Babesia, as well as mold toxicity and overlapping variables on the 16-point MSIDS map as illustrated above. We followed 3 of those patients from our prior study, and they are all in long-term remission (one who was in remission for several months is now more than a year in remission, and the other two are more than 2 years in remission). You can read their case studies here:
Horowitz, R.I.; Fallon, J.; Freeman, P.R. Combining Double-Dose and High-Dose Pulsed Dapsone Combination Therapy for Chronic Lyme Disease/Post-Treatment Lyme Disease Syndrome and Co-Infections, Including Bartonella: A Report of 3 Cases and a Literature Review. Microorganisms 2024, 12, 909. https://doi.org/10.3390/microorganisms12050909
The last tweaks of this protocol, using higher dose methylene blue, up to 300 mg twice a day, not only helped treat Bartonella more effectively, but lowered methemoglobin levels, making dapsone more tolerable. We also found that increasing our doses of folic acid (Leucovorin and L-methyl folate) with B12 and iron helped to minimize dapsone-induced anemia, although the average person will still drop approximately 4 grams of hemoglobin during the protocol. It takes about 1-2 months for lab work to return to normal, but we have never seen long-term adverse effects from the protocol, and we have seen higher efficacy rates as we have instituted 2-week pulses of antibiotics with HDDCT every few months.
- How does the efficacy of dapsone in treating Lyme disease compare to other existing treatments, and what makes it unique?
There is no other treatment that is as effective or safe as dapsone combination therapy for the treatment of CLD/PTLDS, but the efficacy requires screening and properly treating abnormalities on the 16-point MSIDS map. The only other persister drug treatment that is available is disulfiram, and it can take 6 months or longer for the medicine to get some patients into remission, with the long half-life of the drug making side effects of fatigue, pain, neuropathy, neuropsychiatric issues, and liver function abnormalities difficult for some to tolerate. Not that dapsone is a walk in the park! The Herxheimer reactions and methemoglobinemia can be difficult for some to tolerate. I compare this therapy to cancer chemotherapy, which can be effective and put patients into long-term remission, but is difficult to tolerate. But worth it IMO! I have many patients in my practice who are now in long-term remission, for years, after doing DDDCT and HDDCT pulses. This should give hope to the Lyme community.
- How might the results of the Dapsone trial impact current clinical practices in treating Lyme disease, particularly for patients with persistent symptoms?
For me, it is the standard of care in our practice. I have tried many different methods and antibiotic trials over the years, including natural therapies and functional medicine therapies. Although these can also be effective and help patients to feel better, it is only knocking down the biofilm/persister load of the bacteria, while effectively treating Babesia and Bartonella and MSIDS abnormalities, that has a good chance of getting patients into long-term remission. But patients have to have an enzyme called G6PD to take dapsone to avoid worsening anemia, and have to be on 70+ pills a day for several months to help minimize side effects. We also find it essential to treat mold toxicity for the protocol to be most effective, and lately have been finding some individuals have a long Covid overlap, complicating their clinical presentation. Health care practitioners need to go through the 16-point MSIDS map carefully to identify overlapping causes of inflammation (active Borrelia, Babesia, Bartonella, Mycoplasma species, leaky gut, food sensitivities, and mast cell activation; environmental toxins, mineral and vitamin deficiencies, and sleep disorders) and downstream effects of the inflammation (POTS, adrenal and sex hormone dysfunction, neuropsychiatric symptoms, autoimmunity, liver function abnormalities, deconditioning, etc.) in order to discover all of the overlapping causes why a patient remains ill. You can read about these in my bestselling book, How Can I Get Better? An Action Plan for Treating Resistant Lyme and Chronic Disease (St. Martin’s Press, 2017) and the above articles published in the peer-reviewed literature.
- What are the implications of the dapsone trial findings for patients with chronic Lyme disease, and how might it influence future research in this area?
I am presently working with Eva Garland Consultants to identify grant opportunities to do a multicenter, randomized, placebo-controlled study on dapsone combination therapy. That is the gold standard that will convince the world that I have in fact discovered answers for this devastating illness. I hope to get a randomized study started by late 2025 after the manuscript for my third science book is finished, which will be published by Simon and Schuster in 2026. Stay tuned!
For more information on dapsone, and hearing patient success stories, please see the link for the documentary that we recently filmed for the Doctors Talks, Healing from Lyme Summit.
Dapsone documentary: https://players.brightcove.net/6314452011001/PAMDt93Yi_default/index.html?videoId=6353288590112
Once you read the scientific articles we have published, understand how we arrived at our present protocol, and have listened to patient stories of those individuals who were sick for many years, the Lyme community will have hope. Anyone wishing to help fundraise for a future dapsone trial, please contact research@hvhac.com
You can follow my Substack, The Medical Detective, for ongoing writings to fuel your wellness journey, and you can evaluate your tick-borne illness disease likelihood by downloading the Multiple Systemic Infectious Disease Syndrome Questionnaire.
Yours in health, Dr Richard Horowitz
Listen to Dr Richard Horowitz speak about his dapsone trial at the upcoming 2024 ILADS Annual Conference in San Antonio.