Trial Report A pilot study of disulfiram for individuals with persistent symptoms despite prior antibiotic treatment for Lyme disease, 2025, Kuvaldina et al

[forestglip]

A pilot study of disulfiram for individuals with persistent symptoms despite prior antibiotic treatment for Lyme disease

Mara Kuvaldina, Jessica Preston, Denise McClellan, Martina Pavlicova, Thomas H. Brannagan, Brian A. Fallon

[Line breaks added]

Introduction
In vitro studies report that disulfiram is effective in killing Borrelia burgdorferi. Case series suggest disulfiram may help to reduce the symptoms of patients with persistent symptoms despite prior antibiotic treatment for Lyme disease. This pilot study assessed safety, tolerability, and signs of clinical response.

Materials and methods
Participants with a history of previously treated Lyme disease and persistent fatigue were randomly assigned in a double-blinded fashion to either Group A (disulfiram for 4 weeks and placebo for 4 weeks) or Group B (disulfiram for 8 weeks). Primary outcome endpoint was at 10 weeks with a follow-up at 14 weeks. The primary aim was to assess safety and tolerability. A clinical aim assessed signs of clinical improvement using well-validated measures, focusing on improvement in fatigue and quality of life. Target enrollment was 24 participants.

Results
940 individuals were screened, 11 were enrolled and nine participated in the trial. Dosing started low and increased based on response and tolerance to a maximum of 500 mg daily.

Safety. Two participants discontinued medication due to clinical worsening, one of whom was briefly hospitalized. Three additional participants were withdrawn from treatment due to lab test abnormalities.

Tolerability. Only three of nine participants completed the full course of treatment (two in Group A and one in Group B). Lower doses were better tolerated than the highest dose.

Clinical response. Of nine participants, clinically meaningful improvement was noted in fatigue for six and in quality of life for four. Among the six fatigue responders, improvement was also noted on a multiple domain symptom index (six of six), overall symptom burden (five of six), and functional impairment (four of six).

The study was terminated early due to end of project funding, higher than expected adverse events, and recognition that sufficient information was gathered to inform future studies.

Conclusions and relevance
This study reveals the risks associated with disulfiram, especially at higher doses, while suggesting potential clinical benefits among some participants. Efficacy could not be assessed given the small sample size and the lack of a placebo-control group.

Clinical trial registration: NCT03891667

Link | PDF (Frontiers in Medicine) [Open Access]

 

[Utsikt]

The study was terminated early due to end of project funding, higher than expected adverse events, and recognition that sufficient information was gathered to inform future studies.

While our goal was to enroll 24 participants, we stopped enrollment after nine participants completed the study. The study was stopped due to delays in enrollment related to the COVID pandemic, end of project funding, higher than expected adverse events, and recognition that sufficient information was gathered to inform future studies.

It’s good that they state this outright.

There also seems to be a contradiction in the paper. They say both that this was a placebo-controlled trial, and that it was not a placebo-controlled trial.

Discussion
This double-blind placebo-controlled randomized study was designed to assess safety, tolerability, and initial signs of effectiveness of disulfiram in reducing symptoms among patients with persistent symptoms despite prior antibiotic treatment for Lyme disease.

However, these results must be interpreted cautiously. There has been considerable enthusiasm on social media about disulfiram as a treatment for persistent Lyme disease associated symptoms, leading to a bias toward a strong expectation of benefit.

Without a placebo-control group, we cannot say whether the improvement among these individuals was due to disulfiram or not. We can say that the improvement among these responders was seen in multiple domains, both on self-report and clinician ratings. We can also say that in general the improvement had short-term durability (lasting at least 6 weeks after finishing study treatment).

 

[EndME]

It’s good that they state this outright.

There also seems to be a contradiction in the paper. They say both that this was a placebo-controlled trial, and that it was not a placebo-controlled trial.

I don't think there's necessarily a contradiction. They can't say whether improvement from baseline to end was due to disulfiram or not because everyone got disulfiram but it's possible they can still get some form of control via a placebo after week 4 by having two groups and taking measurements at week 4 and 10. I'm not sure whether any of that was actually done but it would seem theoretically possible, for instance if if Group A showed more benefit than Group B during weeks 5–8, that benefit can be attributed more confidently to continued disulfiram. Since, the authors didn't seem to look at response to blinding and overall the sample size is negligible, it's just as equally possible that the study provides no meaningful data besides the treatment having side effects. Presumably at that amount of treatment adverse effects and side effects it might be rather easy to tell who is receiving placebo and who isn't after week 4.

 

[Utsikt]

I don't think there's necessarily a contradiction. They can't say whether improvement from baseline to end was due to disulfiram or not because everyone got disulfiram but it's possible they can still get some form of control via a placebo after week 4 by having two groups and taking measurements at week 4 and 10. I'm not sure whether any of that was actually done but it would seem theoretically possible, for instance if if Group A showed more benefit than Group B during weeks 5–8, that benefit can be attributed more confidently to continued disulfiram. Since, the authors didn't seem to look at response to blinding and overall the sample size is negligible, it's just as equally possible that the study provides no meaningful data besides the treatment having side effects. Presumably at that amount of treatment adverse effects and side effects it might be rather easy to tell who is receiving placebo and who isn't after week 4.

But they say that it was a placebo-controlled trial and that they didn’t have a placebo control. Per definition, you can’t have the former without the latter.

 

[EndME]

But they say that it was a placebo-controlled trial and that they didn’t have a placebo control. Per definition, you can’t have the former without the latter.

I think you may be able to call it a placebo-controlled trial because they had a group where a placebo offered control even though it's not the classic “placebo vs. drug” simply because the placebo offers some control during the second half of the trial, so it's more than a dose-duration study with 2 groups.

In that sense they aren't doing what you're saying they are doing, but it isn't clear to me what they are doing either. Perhaps they also don't know?

 

[Utsikt]

I think you may be able to call it a placebo-controlled trial because they had a group where a placebo offered control even though it's not the classic “placebo vs. drug” simply because the placebo offers some control during the second half of the trial, so it's more than a dose-duration study with 2 groups.

In that sense they aren't doing what you're saying they are doing, but it isn't clear to me what they are doing either. Perhaps they also don't know?

I tried to look up what their design is called, and this document describes something I believe is similar as a randomised withdrawal trial (section 2.1.5.2.4).
https://www.ema.europa.eu/en/docume...e-control-group-clinical-trials-step-5_en.pdf

If that’s the case, their assertion that they do not have a placebo-control group is wrong.

Without a placebo-control group, we cannot say whether the improvement among these individuals was due to disulfiram or not.

The issue isn’t that they did not have a placebo-control group (because they technically did), but that the placebo arm was designed so that they got the treatment first. Therefore, you can’t properly isolate the effect of the treatment because it might have a long-lasting or permanent effect.

So it seems to me like their two statements are contradictory, and that the last statement is wrong.

 

[EndME]

I tried to look up what their design is called, and this document describes something I believe is similar as a randomised withdrawal trial (section 2.1.5.2.4).
https://www.ema.europa.eu/en/docume...e-control-group-clinical-trials-step-5_en.pdf

I don't know enough much about the language, someone knowledgable about clinical trials would know and the notion of a randomised withdrawal trial according to the link above indeed seems similar (though not quite the same) but in that case the nomenclature of "placebo-controlled trial" still seems fitting to me.

The issue isn’t that they did not have a placebo-control group (because they technically did), but that the placebo arm was designed so that they got the treatment first. Therefore, you can’t properly isolate the effect of the treatment because it might have a long-lasting or permanent effect.

Yes, a long-lasting effect or permanent effect would confuse the picture but as with many other things that would depend entirely on the study goals and observations. One might think that the authors will have had suspicions about whether there is a long-lasting or permanent effect and one might think they are more so looking at the scenario I initially described and the reader would understand that it's those things that are being controlled for rather than anything else. Who knows. The trial design is anyways probably not of particular relevance here given the results.

So it seems to me like their two statements are contradictory, and that the last statement is wrong.

My reading is that it's fine as it is. We seem to agree that it's a placebo-controlled trial (although not in the "placebo vs drug sense" but rather that there is a placebo that offers some control) and I think saying that there is no placebo-control group is also fine (because there is no placebo-group that would offer control, of course reading things differently one can argue that there is a control group and that the control is afforded by a placebo, but I find the other reading more natural).

In any case we're just discussing nomenclature here so the discussion is probably not very fruitful.

 

[Arnie Pye]

For info on Disulfiram.

Disulfiram : link to the wikipedia page

Disulfiram : link to the BNF page

According to the wiki article above, Disulfiram is used to try and stop alcoholics and heavy drinkers from drinking alcohol. One of the main ways to achieve this apparently is for the drug to deliberately make people feel very unwell if they consume alcohol. I'm not clear on how the people who are teetotal feel while taking Disulfiram. If they feel awful as well it does sound as if the people being offered it are being punished for something.

 

[richie]

Careful about doses and beware of liver, neurological and psychiatric side effects. Avoid alcohol. Also chelates heavy metals and has been used to reduce nickel sensitivity be reducing overall burden. Liberated both nickel and lead in me, still elevated in urine 7 weeks after quitting DS in 2021.
Inhibits transformation of retinol to retinoic acid. hits on thiols and methylation. Very versatile drug with possible applications against cancer where it can deliver hit of metals to cancer cells.
Irreversibly affects some mitochondrial enzymes in plants. I presume fresh enzymes will not be affected after DS removed.
Long half life.
Psychiatric effects may be caused by carbon disulfide which was a biproduct of rubber manufacture and cellulose production and associated with mental illness in workers. A probable case was featured in an Episode of "A House in Time" on the BBC about the history of a house in Leeds and the case involved the suicide of the worker. Serious stuff.
It does however have a long history of safe usage in compliant alcoholics and I would not like it to be summarily dismissed by those whose main "argument" - in face mere assertion - is not aboutn danger but that "there is no chronic Lyme". Dose reduction can limit/abolish side effects.

 

[duncan]

Kenneth Liegner made news with this five or six years ago:
https://pubmed.ncbi.nlm.nih.gov/31151194/