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Grout, M.M.; Mitchell, K.B. Disulfiram. Encyclopedia. Available online: https://encyclopedia.pub/entry/43736 (accessed on 18 August 2024).
Grout MM, Mitchell KB. Disulfiram. Encyclopedia. Available at: https://encyclopedia.pub/entry/43736. Accessed August 18, 2024.
Grout, Martha M., Kenneth B. Mitchell. "Disulfiram" Encyclopedia, https://encyclopedia.pub/entry/43736 (accessed August 18, 2024).
Grout, M.M., & Mitchell, K.B. (2023, May 04). Disulfiram. In Encyclopedia. https://encyclopedia.pub/entry/43736
Grout, Martha M. and Kenneth B. Mitchell. "Disulfiram." Encyclopedia. Web. 04 May, 2023.
Disulfiram
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This entry is adapted from the peer-reviewed paper 10.3390/antibiotics12020262

The literature has suggested that disulfiram (DSM) may be a potent drug in the armamentarium of physicians who treat chronic Lyme disease. The use of disulfiram in the treatment of Lyme disease started with a researcher who determined that DSM is bactericidal to spirochete. 

Lyme disease treatment disulfiram toxicity

1. Introduction

Disulfiram (DSM) may serve as a potent addition to the armamentarium of physicians who treat chronic Lyme disease. Vector-borne diseases can, in theory, be treated in the early stages using a relatively short course of antibiotics, often doxycycline, amoxicillin or azithromycin, for a period of four to six weeks [1].
DSM is a thiuram derivative that blocks the oxidation of alcohol at the acetaldehyde stage, causing an elevation of aldehyde levels. Resulting symptoms due to excessive acetaldehyde may include flushing, nausea, vomiting, palpitations, chest pain, tachycardia, air hunger, weakness, hypotension, confusion and even death. Emergency physicians are warned to consider disulfiram overdose in alcoholic patients with unexplained symptoms [2].
When alcohol is consumed in the presence of DSM, serum acetaldehyde levels become elevated, causing a myriad of unpleasant and occasionally fatal symptoms [3]. In theory, in the absence of alcohol, these symptoms do not occur. Nevertheless, the literature on disulfiram describes both predictable and potentially avoidable adverse effects which may occur even in the absence of readily identifiable alcohol consumption. This research paper arises out of a desire to mitigate the adverse effects of DSM while still utilizing the benefits of the drug for Lyme disease patients.

2. History of Disulfiram

The use of DSM in treatment of Lyme disease started with the discovery that disulfiram is bactericidal to the Borrelia spirochete [4]. The drug had been used in the past to treat parasitic infections, such as tuberculosis and malaria [5][6][7], so its use for Lyme disease does not require a huge stretch of the imagination.
The first recorded case reports using DSM for the treatment of Lyme disease were published in 2019 [8].
Off-label use of commonly prescribed drugs is not unusual in the practice of medicine. Having used disulfiram in the past for alcoholics who had a desire to stop drinking made it seem reasonable to try something with prior history of success in our difficult-to-treat Lyme patients who were willing to experiment with a different approach.
It also seemed reasonable to conclude that if we could safely give the drug to alcoholics, there should be no problem giving it to patients with an infectious disease who were not alcoholics, in whom the possibility of adverse effects seemed remote. However, the onset of symptoms such as psychosis, uncontrollable babbling, uncontrollable dark thoughts, debilitating neuropathy and unexpected pain began to be reported in the Lyme chat groups. These symptoms had been reported in the earlier literature on disulfiram, associated with alcohol ingestion but not with the treatment of infectious diseases [3][9][10][11][12].
The history of DSM [13] starts with its synthesis by a German chemist M Grodzki in 1881, for reasons lost to the obscurity of history. A metabolite of DSM, carbon disulfide, was used in the rubber industry to hasten vulcanization—the cross-linking between rubber molecules through the sulfide bond improved the strength and consistence of the rubber. An article by an industrial physician, EE Williams, published in the JAMA in 1937 [12] noted the distressing effects of alcohol on workers in the rubber industry. In the 1940s, it was discovered that DSM was effective in the treatment of scabies and other parasites [13]. The drug was used to treat animals at first. Then, Dr. Jacobsen decided to take it himself, and very quickly realized that when he took the drug and drank any amount of alcohol, the effects were extraordinarily unpleasant. Thus, Antabuse® was born. In the meantime, a large body of literature was published on the effect of disulfiram on multiple parasites, such as malaria and tuberculosis, as well as intestinal parasites.
In 2016, a group of researchers looking for new drugs to treat Lyme disease discovered the bactericidal effects of DSM [14]. One published case series used the drug for Lyme disease with good success [8]. Since then, the drug has been used in many patients who were previously not responsive to other commonly used antibiotics, such as doxycycline, azithromycin, metronidazole, amoxicillin/clavulanate, cephalosporins and others. There have been some successes, but the toxicity of DSM has become abundantly clear.
This toxicity may occur with or without the ingestion of alcohol, although certainly patients who do imbibe any form of alcohol find treatment with any dosage of disulfiram to be extremely unpleasant.
As such, if we are going to use DSM for its pathogen-killing effects, we need to be especially careful to inform our patients of the alcohol-containing (or even alcohol-like) supplements or drugs that they may already be taking. Homeopathic tinctures are often alcohol-preserved. Sugar alcohols (sorbitol, xylitol, erythritol, etc.) are still alcohols. Hand sanitizers are an especially ubiquitous source of hidden alcohol [15].

3. Mechanism of Action

The biochemical effects of DSM are excellently described in an article on Medscape, freely available for download [16]. DSM irreversibly inhibits the oxidation of acetaldehyde by competing with the cofactor nicotinamide adenine dinucleotide (NAD) for binding sites on aldehyde dehydrogenases [ALDH] [17]. The graphic for alcohol/NAD should be placed in this section. Uploaded already. If it needs a credit, that should be “Lucretia Alexandre”. An increased serum acetaldehyde concentration is thought to be responsible for the unpleasant symptoms of treatment with disulfiram, including:
  • Headache,
  • Tachycardia and palpitations,
  • Hypertension,
  • Nausea and vomiting,
  • Anxiety and shortness of breath.
The directly toxic effects of DSM include neurologic [18], cutaneous [19] and hepatotoxic [20] sequelae. Indirect toxic effects may occur due to DSM’s inhibition of cytochrome P450 enzymes, resulting in a decreased clearance of drugs such as warfarin, phenytoin, benzodiazepines and some tricyclic antidepressants [21].
Approximately 20% of the drug remains in the body for 1–2 weeks post ingestion, significantly prolonging its effects due to the irreversible inhibition of ALDH and the body’s need to synthesize new stores of the enzyme.
DSM serves as a prodrug for diethyldithiocarbamate (DDC). DDC chelates copper, impairing the activity of dopamine beta-hydroxylase, an enzyme that catalyzes the metabolism of dopamine to norepinephrine, depleting presynaptic norepinephrine and causing an accumulation of dopamine. In the end, an accumulation of copper and oxidation of lipid membranes can result in myelin damage due to oxidative stress [22][23][24].
Nerve damage may be irreversible. In a rat study, peripheral nerve changes returned to control levels within a few weeks. However, the myelin changes in the brain were much more prolonged, perhaps because of continued accumulation of copper or changes in the levels of detoxifying proteins, such as superoxide dismutase 1 [25].
Neurotoxic effects associated with DSM include extrapyramidal symptoms. DSM administration to mice has resulted in lesions of the basal ganglia [26].
DDC inhibits superoxide dismutase (SOD), thereby impairing the ability to eliminate free radicals. DDC-induced methemoglobinemia can also occur secondary to the impairment (consumption) of glutathione-dependent methemoglobin reduction [23].
DSM can produce irreversible injury to the mitochondria by the oxidation of both glutathione and NAD [24], resulting in damage mainly to the organs with large numbers of mitochondria, i.e., brain, heart, muscle.
Given all the negative factors, does DSM have sufficient anti-spirochetal activity to warrant its use in Lyme patients? It appears that many microorganisms are susceptible to DSM. One hypothesis [27] attributes the immediate in vitro deceleration observed in bacterial growth to the cleavage of DSM by thiophilic components of intracellular metal ions, intracellular cofactors, such as coenzyme A reductase, and other enzymes within the microorganisms causing the depletion of glutathione and abrupt cessation of growth. This effect is seen in multiple microorganisms including giardia, mycobacteria, and staphylococci.
For many patients with chronic Lyme disease, the effects of the disease are worse than the more remote possibility of injury from a new and potentially helpful treatment.
As such, it behooves us, as their treating physicians, to ensure that such disulfiram treatment is as non-toxic as possible in the hopes that it will relieve patients of their intolerable symptoms of chronic Lyme disease.

4. Symptoms of Disulfiram Toxicity

It is important to distinguish disulfiram toxicity symptoms from symptoms of active neurologic infection and from Herxheimer reactions due to successful therapy.
Catatonia is reported in several articles [28][29][30]. Disulfiram-induced catatonia can be reversed simply by removing disulfiram from the system. Catatonia appears to be an idiosyncratic reaction because it does not occur in all patients and may recur when disulfiram is re-introduced.
Cytolytic hepatitis [31], ophthalmologic problems [32], cardiac abnormalities [33] peripheral neuropathy and encephalopathy [34][35][36][37] and even male sexual dysfunction and semen quality are reported to be toxic effects [32]. Hepatitis has been reported to progress to liver failure requiring transplantation [38][39].
Disulfiram is known to cause mitochondrial injury by inducing irreversible oxidation of both NAD (vitamin B3 derivative, nicotinamide adenine dinucleotide) and GSH (glutathione). Without these two crucial nutrients, mitochondria lose their transmembrane potential and become incapable of oxidative phosphorylation and energy generation [24].
Toxic effects may be delayed. One patient developed both neuropathy and encephalopathy after uneventful treatment with disulfiram for thirty years [34][35].
As always, drug–drug interactions may cause significant adverse effects [39].
Disulfiram metabolites may be at least partly to blame for some of the toxic effects. Cardiac abnormalities are described [33], as well as neuropsychiatric [37], ophthalmologic [32], sexual [40] and hormonal [41] adverse reactions.
Any symptoms arising in the liver, the heart or the nervous system (central or peripheral) after the institution of disulfiram therapy must be viewed through the lens of toxic suspicion, recognizing the difficulty of determining whether a symptom is due to Herxheimer reaction or DSM toxicity.

References

  1. ILADS Treatment Guidelines. Available online: https://www.ilads.org/patient-care/ilads-treatment-guidelines/ (accessed on 1 January 2023).
  2. Segher, K.; Huys, L.; Desmet, T.; Steen, E.; Chys, S.; Buylaert, W.; De Paepe, P. Recognition of a disulfiram ethanol reaction in the emergency department is not always straightforward. PLoS ONE 2020, 15, e0243222.
  3. Chick, J. Safety issues concerning the use of disulfiram in treating alcohol dependence. Drug Saf. 1999, 20, 427–435.
  4. Custodio, M.M.; Sparks, J.; Long, T.E. Disulfiram: A Repurposed Drug in Preclinical and Clinical Development for the Treatment of Infectious Diseases. Anti-Infect. Agents 2022, 20, 34–45.
  5. Maitra, A.; Bates, S.; Kolvekar, T.; Devarajan, P.V.; Guzman, J.; Bhakta, S. Repurposing—A ray of hope in tackling extensively drug resistance in tuberculosis. Int. J. Infect. Dis. 2015, 32, 50–55.
  6. Scheibel, L.W.; Adler, A.; Trager, W. Tetraethylthiuram disulfide (Antabuse) inhibits the human malaria parasite Plasmodium falciparum. Proc. Natl. Acad. Sci. USA 1979, 76, 5303–5307.
  7. Phillips, M.; Malloy, G.; Nedunchezian, D.; Lukrec, A.; Howard, R.G. Disulfiram inhibits the in vitro growth of methicillin-resistant Staphylococcus aureus. Antimicrob. Agents Chemother. 1991, 35, 785–787.
  8. Liegner, K.B. Disulfiram (Tetraethylthiuram Disulfide) in the Treatment of Lyme Disease and Babesiosis: Report of Experience in Three Cases. Antibiotics 2019, 8, 72.
  9. Dupuy, O.; Flocard, F.; Vial, C.; Rode, G.; Charles, N.; Boisson, D.; Flechaire, A. Disulfiram (Esperal) toxicity. Apropos of 3 original cases. La Rev. Med. Interne 1995, 16, 67–72.
  10. Larson, E.W.; Olincy, A.; Rummans, T.A.; Morse, R.M. Disulfiram treatment of patients with both alcohol dependence and other psychiatric disorders: A review. Alcohol. Clin. Exp. Res. 1992, 16, 125–130.
  11. Pattanayak, R.D.; Sagar, R.; Pal, A. Tracing the journey of disulfiram: From an unintended discovery to a treatment option for alcoholism. J. Ment. Health Hum. Behav. 2015, 20, 41.
  12. Williams, E.E. Effects of alcohol on workers with carbon disulfide. JAMA 1937, 109, 1472–1473.
  13. Landegren, J.; Borglund, E.; Storgårds, K. Treatment of scabies with disulfiram and benzyl benzoate emulsion: A controlled study. Acta Derm.-Venereol. 1979, 59, 274–276.
  14. Pothineni, V.R.; Wagh, D.; Babar, M.M.; Inayathullah, M.; Solow-Cordero, D.; Kim, K.-M.; Samineni, A.V.; Parekh, M.B.; Tayebi, L.; Rajadas, J. Identification of new drug candidates against Borrelia burgdorferi using high-throughput screening. Drug Des. Dev. Ther. 2016, 10, 1307.
  15. Ghosh, A.; Mahintamani, T.; Balhara, Y.P.S.; Roub, F.E.; Basu, D.; Bn, S.; Mattoo, S.K.; Mishra, E.; Sharma, B. Disulfiram Ethanol Reaction with Alcohol-Based Hand Sanitizer: An Exploratory Study. Alcohol Alcohol. 2020, 56, 42–46.
  16. Medscape Article. Available online: https://emedicine.medscape.com/article/814525-overview (accessed on 1 January 2023).
  17. Hassinen, I. Effect of disulfiram (tetraethylthiuram disulfide) on mitochondrial oxidations. Biochem. Pharmacol. 1966, 15, 1147–1153.
  18. Hayman, M.; Wilkins, P.A. Polyneuropathy as a Complication of Disulfiram Therapy of Alcoholism. Q. J. Stud. Alcohol 1956, 17, 601–607.
  19. Haddock, N.F.; Wilkin, J.K. Cutaneous reactions to lower aliphatic alcohols before and during disulfiram therapy. Arch. Dermatol. 1982, 118, 157–159.
  20. Verge, C.; Lucena, M.I.; López-Torres, E.; Puche-García, M.J.; Fraga, E.; Romero-Gomez, M.; Andrade, R.J. Adverse hepatic reactions associated with calcium carbimide and disulfiram therapy: Is there still a role for these drugs. World J. Gastroenterol. WJG 2006, 12, 5078.
  21. Frye, R.F.; Branch, R.A. Effect of chronic disulfiram administration on the activities of CYP1A2, CYP2C19, CYP2D6, CYP2E1, and N-acetyltransferase in healthy human subjects. Br. J. Clin. Pharmacol. 2002, 53, 155–162.
  22. Viquez, O.M.; Valentine, H.L.; Amarnath, K.; Milatovic, D.; Valentine, W.M. Copper accumulation and lipid oxidation precede inflammation and myelin lesions in N, N-diethyldithiocarbamate peripheral myelinopathy. Toxicol. Appl. Pharmacol. 2008, 229, 77–85.
  23. Kelner, M.J.; Alexander, N.M. Inhibition of erythrocyte superoxide dismutase by diethyldithiocarbamate also results in oxyhemoglobin-catalyzed glutathione depletion and methemoglobin production. J. Biol. Chem. 1986, 261, 1636–1641.
  24. Valentine, H.L.; Viquez, O.M.; Amarnath, K.; Amarnath, V.; Zyskowski, J.; Kassa, E.N.; Valentine, W.M. Nitrogen substituent polarity influences dithiocarbamate-mediated lipid oxidation, nerve copper accumulation, and myelin injury. Chem. Res. Toxicol. 2009, 22, 218–226.
  25. Menon, R.N.; Jagtap, S.; Thakkar, R.; Narayanappa, G.; Nair, M. Bilateral symmetrical globus pallidus lesions following disulfiram ingestion. Neurol. India 2013, 61, 539–540.
  26. Balakirev, M.Y.; Zimmer, G. Mitochondrial injury by disulfiram: Two different mechanisms of the mitochondrial permeability transition. Chem. Biol. Interact. 2001, 138, 299–311.
  27. Potula, H.H.S.; Shahryari, J.; Inayathullah, M.; Malkovskiy, A.V.; Kim, K.M.; Rajadas, J. Repurposing disulfiram (Tetraethylthiuram Disulfide) as a potential drug candidate against Borrelia burgdorferi in vitro and in vivo. Antibiotics 2020, 9, 633.
  28. Fisher, C.M. Catatonia’due to Disulfiram Toxicity. Arch. Neurol. 1989, 46, 798–804.
  29. Nayak, V.; Chogtu, B.; Virupaksha, D.; Bhandary, P.V. Disulfiram induced catatonia. Case Study Case Rep. 2011, 1, 6–8.
  30. Balaban, Ö.D.; Atagün, M.İ.; Alpkan, L.R. A case of catatonia induced by disulfiram. Dusunen Adam J. Psychiatry Neurol. Sci. 2010, 23, 215.
  31. Schade, R.R.; Gray, J.A.; Dekker, A.; Varma, R.R.; Shaffer, R.D.; Van Thiel, D.H. Fulminant Hepatitis Associated with Disulfiram: Report of a Case. Arch. Intern. Med. 1983, 143, 1271–1273.
  32. Wang, C.; Tan, X.; Bi, Y.; Su, Y.; Yan, J.; Ma, S.; He, J.; Braeckman, L.; De Bacquer, D.; Wang, F.; et al. Cross-sectional study of the ophthalmological effects of carbon disulfide in Chinese viscose workers. Int. J. Hyg. Environ. Health 2002, 205, 367–372.
  33. Kuo, H.W.; Lai, J.S.; Lin, M.; Su, E.S. Effects of exposure to carbon disulfide (CS2) on electrocardiographic features of ischemic heart disease among viscose rayon factory workers. Int. Arch. Occup. Environ. Health 1997, 70, 61–66.
  34. Borrett, D.; Ashby, P.; Bilbao, J.; Carlen, P. Reversible, late-onset disulfiram-induced neuropathy and encephalopathy. Ann. Neurol. Off. J. Am. Neurol. Assoc. Child Neurol. Soc. 1985, 17, 396–399.
  35. Frumkin, H. Multiple system atrophy following chronic carbon disulfide exposure. Environ. Health Perspect. 1998, 106, 611–613.
  36. Hotson, J.R.; Langston, J.W. Disulfiram-induced encephalopathy. Arch. Neurol. 1976, 33, 141–142.
  37. Krstev, S.; Perunicić, B.; Farkić, B.; Banićević, R. Neuropsychiatric effects in workers with occupational exposure to carbon disulfide. J. Occup. Health 2003, 45, 81–87.
  38. Mohanty, S.R.; LaBrecque, D.R.; Mitros, F.A.; Layden, T.J. Liver transplantation for disulfiram-induced fulminant hepatic failure. J. Clin. Gastroenterol. 2004, 38, 292–295.
  39. Masiá, M.; Gutiérrez, F.; Jimeno, A.; Navarro, A.; Borrás, J.; Matarredona, J.; Martín-Hidalgo, A. Fulminant hepatitis and fatal toxic epidermal necrolysis (Lyell disease) coincident with clarithromycin administration in an alcoholic patient receiving disulfiram therapy. Arch. Intern. Med. 2002, 162, 474–476.
  40. Ma, J.Y.; Ji, J.J.; Qing Ding Liu, W.D.; Wang, S.Q.; Ning Wang Chen, G.Y. The effects of carbon disulfide on male sexual function and semen quality. Toxicol. Ind. Health 2010, 26, 375–382.
  41. Sieja, K.; von Mach-Szczypiński, J.; von Mach-Szczypiński, J. Health Effect of Chronic Exposure to Carbon Disulfide (CS2) on Women Employed in Viscose Industry. Med. Pract. 2018, 69, 329–335.
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Martha M. Grout
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