DISULFIRAM Off Label Use in Post-Treatment Lyme Disease Syndrome 10 04 19
The following is for your information only, and is not intended to replace your practitioners medical advice. Please consult your health care practitioner before implementing any medical treatments.
Disulfiram (tetraethylthiuram), also known as Antabuse was first synthesized in 1881 and licensed by the FDA in 1951 as an enzyme inhibitor to treat alcoholism but recently in a 2016 Stanford study it was found to be highly effective against both active spirochetes and dormant antibiotic tolerant borrelia persister cells in culture and in mice. The research team searched four chemical libraries containing 4,366 compounds to identify novel drug candidates that might be repurposed to effectively treat Lyme borreliosis. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4827596/
Dr. Kim Lewis of Northeastern University was interviewed at the 1st Annual Lyme Disease in the Era of Precision Medicine Conference in 2016. He discussed his research on disulfiram’s surprising ability to kill Borrelia burgdorferi persister cells in the lab https://www.youtube.com/watch?v=KCxA0Vmqb2o
In 2018 multiple trials were started on disulfiram. A small human study on disulfiram has recently been approved. https://clinicaltrials.gov/ct2/show/NCT03891667 Some of the studies doses were at 500mg a day, which can be difficult to tolerate.
Dr Liegner’s article: https://www.mdpi.com/2079-6382/8/2/72/htm shows chronically ill patient response to Disulfiram. “Disulfiram (Tetraethylthiuram Disulfide) in the Treatment of Lyme Disease and Babesiosis: Report of Experience in Three Cases” Kenneth B. Liegner Most of the information in this note is taken from this paper.
THINGS TO KNOW ABOUT DISULFIRAM:
o It’s inexpensive with a coupon from https://www.goodrx.com/ but you cannot buy it with your insurance unless you are an alcoholic in recovery with proper supervision.
o It is not an antibiotic, it is not likely to disrupt the gut microbiome.
o It can trigger Mast Cell Activation with redness and puffiness.
HOW DOES IT WORK?
o Mechanism of action is unknown. Dr. Kim Lewis had wondered if it inhibits an unidentified enzyme.
o Treatment with disulfiram causes the Borrelia cells to develop misshapen cell walls and those that survived had misshapen walls and failed to replicate in the lab.
o Disulfiram has been reported to inhibit the enzyme LDH which helps the human body detoxify, which is required by borrelia to synthesize its proteins.
o Disulfiram is a metal chelator that has an affinity for copper, forming a complex that enters into the bacterial cells. It also chelates manganese, the trace metal borrelia uses instead of iron (most bacteria use iron).
o One 2016 study looked at disulfiram’s identified antibacterial action against 9 virulent bacteria (including in vitro and in vivo Staph aureus) hypothesized that disulfiram acts as a growth inhibitor, causing abrupt halt to the metabolic activity of susceptible bacteria. The antagonistic effects may be due to the compounds in disulfiram having antagonistic actions against glutathione, which exists in abundance in the affected bacteria….glutathione is the most potent natural antioxidant, the best instrument of cellular defense guaranteeing health for an organism.
o It has wide distribution in tissues, getting into lipids and the central nervous system. (good)
o It has a long half-life, so if you do not tolerate it, it will still be in your body for 1-2 weeks. (not so good)
o It causes a severe reaction if you have any alcohol exposure less than 12 hours before starting, and up to 2 weeks after you stop treatment.
o No one knows if disulfiram completely eradicates Borrelia.
o If it cannot get rid of all the Borrelia, periodic doses may need to be given just like those with HIV are treated (with other drugs) on a periodic basis.
DRUG INTERACTIONS: Many, see references:
The PDR is one source, along with another excellent source provided:
One source for drug/herbal interactions:
Trazadone, Imipramine and desipramine levels may increase when taking disulfiram.
Concurrent use of the imidazoles metronidazole and tinidazole is contraindicated.
Disulfiram can also inhibit the enzyme dopamine β-hydroxylase (DBH), which converts dopamine to norepinephrine, leading to buildup of dopamine and deficiency of norepinephrine. High dopamine may lead to mania, low noepinephrine may lead to depression.
It’s active metabolites irreversibly inhibit the action of Aldehyde Dehydrogenase (ALDH). This means it can take up to 14 days to reach steady-state plasma levels, and 14 days to be eliminated from the body.
HERBALS: It interacts with passion flower, valerian or yarrow (herbs typically used in some herbal sleep preparations.
TREATMENT WITH DISULFIRAM 10 01 19 version
Blood counts may become abnormal, and frequent monitoring is medically necessary.
CBC and CMP(comprehensive metabolic profile) including liver panel (to include AST, ALT, alk phos, bilirubin), creatinine week 1, 2, 4 and then every 2 weeks.
DOSING AND DURATION OF TREATMENT:
No one knows for certain the minimum or maximum length of treatment needed. Physicians generally increase slowly up to the right dose for the patient’s weight and detoxification potential, then stay at the highest tolerated dose for 1-3 months. Neuropathy seems to develop the longer one is on treatment.
No alcohol for at least 12 hours before beginning treatment and for 2 weeks after stopping treatment.
Patients not responsive to long term combinations of antibiotics have responded to 2-3 months of treatment with disulfiram 250-500mg a day. Sometimes a much lower dose is effective.
Typical dosing suggestion: 100 lbs or less 250 mg; (101)-150 lbs. 375 mg; 200 lbs. 500 mg. > 200 lbs. ? 750 mg?
o Dosing should start low (1/4 every 1-3 days,) and increase every 14 days as tolerated up full dose.
Here is one sample treatment plan, each individual would have dose set for their own circumstances.
1st week 62.5 to 125mg, every third day. Don't increase if your herxes are unmanageable- work on detoxing.
-2nd week 62.5 every day.
-3rd and 4th week: 125mg daily. (1/2 tablet).
-5th and 6th week 375 mg daily (1/2 tablet a day + ¼ tablet )
-7th and 8th week 250 mg daily.
-9th and 10th week 250 mg plus 125 mg. (250 mg tab 1 and 1/2 daily)
And so on, increase if herx is manageable, or take a break if herx is active or extreme until it resolves.
o IF YOU ARE FRAGILE, START AT ¼ TABLET TWICE A WEEK. Some may need to start even lower at 25mg tablet from a compounding pharmacy every other day or every third day.
o Go slow do not increase too quickly. Sometimes the body cannot handle the herx cannot detox and the reaction can persist for weeks.
o Some patients are only able to tolerate 125mg every 3rd day but steady improvement is being seen. They may not reach their target dose, and may be on disulfiram for 6 months or longer if tolerated and if improving.
o Nickel allergic patients may do best and avoid liver damage by going on low nickel diet 6 weeks before starting treatment. This is because disulfiram chelates (or binds) out nickel, and if you are nickel allergic, all this nickel passing through the liver may damage the liver, causing the AST/ALT liver enzymes to rise. There are many references and iPhone APPs that can help guide a low nickel diet. A point system is generally assigned and one tries to stay at under 15 points. Be aware that region that plants are grown may matter a lot.
Here is one reference:
LOW NICKEL DIET:
1. NO foods high in nickel: cocoa, chocolate, soya beans, oatmeal, nuts, almonds and fresh and dried legumes.
2. NO drinks and vitamin supplements with nickel.
3. NO canned food. Nickel dissociates from the can and increases the total nickel content you ingest.
4. NO fishes that show high concentration of nickel such as tuna, herring, shellfish, salmon and mackerel.
5. OK Meat, poultry and eggs are fine
6. OK Nickel content of cereals is low. Foods prepared from rice (polished).
7. OK Vegetables such as potatoes (small portions see above), cabbage and cucumber can be used.
8. USE IN MODERATION: onion and garlic, should be used in moderation.
9. USE SPARINGLY: Green leafy vegetables are an inseparable part of Indian food; if desired, they may be taken sparingly due to the possibility of high concentration of nickel. Young leaves are preferred than older leaves as they contain relatively lower concentration of nickel. Mushroom can be used.
10. OK bananas (in moderation ½ and NOT too ripe as that will contain more natural sugar, which supports yeast), apples (up to 3-4 times a week) and citrus fruits (up to 3-4 times a week).
11. OK Tea and coffee in moderation (up to 2 cups a day).
12. AVOID: While cooking, nickel-plated utensils should not be used and should be replaced. Acidic food should not be cooked in stainless steel utensils as the acids may lead to the dissociation nickel from the utensils and it may increase the nickel content of the food. The initial water flow from the tap in the morning should not be drunk or used for cooking as nickel may be released from the tap during night.
o Although generally safe, it has had adverse effects: including encephalopathy, convulsion, cranial and peripheral neuropathy, permanent neurological deficits, hypertension, drug-induces psychosis and has been known to cause liver injuries which have required liver transplantation and/or resulted in death.
o Disulfiram adverse effects; please read this paper: https://www.glowm.com/resources/glowm/cd/pages/drugs/d053.html
o Severe Jarisch-Herxheimer reactions, can be intolerable even on doses as low as 125mg per day. This can last for days or weeks after the disulfiram is discontinued. A few days of low dose oral steroids may help, however steroid use is contraindicated in those with a history of psychosis as steroids can promote psychosis if you are on disulfiram.
o LIVER: Symptoms of hepatotoxicity usually develop within 2-12 weeks of initiation of therapy, but can develop later or even after therapy has been discontinued. Hepatotoxicity is rare (1 in 10,000-30,000) however, when it occurs, it can be severe, it has been reported that some patients needed a liver transplant. If you are on disulfiram you need to have labs done before you start and then week 1, 2, 4 and every 2 weeks thereafter during treatment and every 3 months after.
Intermittent therapy is reported to have a higher incidence of liver toxicity. This may be due to an idiosyncratic drug hypersensitivity.
An excellent review of disulfiram-induced hepatotoxicity is provided by NIH.
Stinky odor: You may stink because of the sulfur molecules breathed out from the lungs.
Feeling weird Lyme patients report feeling weird on disulfiram. It could be due to increased dopamine in the brain. Vitamin C helps with breakdown of dopamine. Some people report Boardroom VitC 1-3 TBS 1-3 times daily is really helpful.
Psychosis: If you develop racing thoughts and delusions, you would need to be seen by a psychiatrist. IF you already have a history of psychosis disulfiram may not be a good fit for you.
o Neurotoxicity to the basal ganglia causing Parkinson’s like symptoms:
o Peripheral neuropathy: (This may respond to Lion’s Mane or Benfotiamine.)
o Optic neuritis:
o Organic brain syndrome: https://www.ncbi.nlm.nih.gov/pubmed/472804
o De novo seizures: https://www.ncbi.nlm.nih.gov/pubmed/6632888
Disulfiram inhibits the enzyme beta hydroxylase in the brain, which turns dopamine into norepinephrine with the aid of Vitamin C. A deficiency of this enzyme causes postural hypotension and peripheral neuropathy and may be responsible for most toxic neuro side effects that disulfiram causes.
o AVOID ANY ALCOHOL: cough syrup, herbals in alcohol, aftershave, perfumes, homeopathic doses in alcohol, hairsprays, hair dyes, lotions, sunscreen moisturizers, liniments, skin toners, back rub preparations can cause a severe reaction if you have any alcohol exposure less than 12 hours before starting, and for 2 weeks after you stop treatment. Avoid make up, use beet juice and vitamin E oil. The reaction can be life threatening, resulting in seizures, loss of consciousness or loss of life. All alcoholic beverages including beer. Nothing out of a bottle unless you know for certain it does not contain acyl or acetyl alcohol. Beware of occupational solvent exposures.
o AVOID FOODS containing alcohol, any type of vinegar (includes condiments like ketchup, mustard, mayonaise, worcestershire sauce), sugar alcohols (sorbitol, mannitol, isomalt, maltitol, lactitol, xylitol and erythritol), caffeine/coffee , green tea including green tea extract supplements, vanilla in alcohol, stevia in alcohol.
Anything fermented: (kombucha, hard apple cider, fermented veggies like sauerkraut).
o AVOID HERBALS/SUPPLEMENTS: passion flower, valerian or yarrow (read your tea ingredients carefully). NO alpha lipoic acid (ALA), copper, herbal antimicrobials in alcohol base.
o PRESCRIPTION MEDICATIONS INTERACTIONS: Metronidazole or steroids (increased risk psychosis), paraldehyde, isoniazide. Phenytoin (Dilantin). Warfarin (coumadin). Monitor PT and INR as it may increase anticoagulant effects. Barbiturates, amphetamines, methylphenidate, diazepam, midazolam, Clonazepam, Buspirone. Marijuana (synergistic CNS stimulation). Imipramine/amitriptyline and desipramine may cause transient delirium.
o SUGAR and anything that feeds yeast (which can make acetaldehyde, a form of alcohol).
o NO SUGAR ALCOHOLS: sorbitol, mannitol (Alka Seltzer Gold), isomalt, maltitol, lactitol, xylitol and erythritol)
o MARIJUANA OR MEDICAL THC can induce psychosis.
WHAT HELPS TO TOLERATE TREATMENT:
o Dean Ornish Lifestyle Medicine is VERY helpful: https://www.ornish.com It will give you healing tools and help improve your immune system.
o You will feel tired and spacey on treatment.
§ Rest (often as needed) + Meditate (20 minutes twice a day)
§ Visualize a return to Good Health.
o Luteolin Bioflavonoids will help you to feel better (antioxidant, anti-inflammatory) and prevents Mast Call Activation which causes sudden burning hot flushing and gurgley voice.
Juice organic in horizontal auger style juicer: Make fresh every 1-2 days.
Drink 16 ounces every morning
o Eat fresh foods, nothing out of a box, can or package. Nothing processed.
o Gentle exercise if tolerated.
Some supplements some people use to help with the herx.
o TriSalts 1/2 tsp in 8 ounces water three times daily as needed (avoid or limit in case of renal insufficiency).
o Boardroom brand liposomal vitamin C 1/2-1 ounces once or twice daily.
Prescriptions from your doctor that may be helpful:
o For dizziness: Meclizine/Antivert.
o For nausea Zofran.
Who would qualify?
o Anyone who has been on antibiotics for over 1 year with mixed results.
o Particularly those who have not been able to get off of antibiotics without return of symptoms.
Who would not qualify?
· Allergic to disulfiram.
· Sulfa allergy is not an issue.
· Allergies to vulcanized rubber.
· Children: no studies, and severe permanent neurological injury reported in accidental disulfiram poisoning in children. But it has been used safely in adolescents (16-19yo)
· Those who will not stop drinking. THE REACTION WITH ALCOHOL CAN BE LIFE THREATENING. IT COULD CAUSE SEIZURE OR SYNCOPAL EPISODE (passing out). Go to the emergency room if you have a reaction.
· Those without lab access. I will not prescribe disufiram for those unable to have labs done prior to starting disulfiram and then Week 1, 2, 4 and every 2 weeks until the end of treatment, then every 3-6 months after. Labs: CBC with dif, Liver panel including AST, ALT, alkaline phosphatase, bilirubin (and creatinine if you have chronic kidney disease).
· Caution is recommended when there is hepatic insufficiency or disease.
· Caution if you are sensitive to nickel as those who are seem to have more issues with hepatotoxicity (toxic liver).
· Caution if you have a history of psychosis or a family history of psychosis. Best if you are followed by a psychiatrist during treatment.
What are the biggest risks?
· Accidentally getting exposed to alcohol. Depending on the dose this reaction could be severe.
· Next would be elevated liver enzymes.
· Psychosis is a possibility but rather remote, Dr Liegner said there was 8 reported cases between 1996 and 2016.
What is its regular use in treatment of alcoholism?
o Disulfiram works to help alcoholics cease drinking by causing a reaction if the person has any alcohol for 14 hours prior to 14 days after taking the pill.
o Disulfiram reactions can involve severe headaches, skin redness, anxiety and feeling awful. Anything containing alcohol can bring on an intense reaction which can cause seizures or loss of consciousness.
Are there any other uses for disulfiram?
· It is known to have anti-parasitic properties: giardia, malaria, leishmaniasis and trypanosomiasis.
· It has anti-cancer properties. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5730499/?tool=pmcentrez
· It has been reported to have anti-babesia properties.
· It has been shown to reduce plaque burden in a mouse model of Alzheimer’s disease.
· It has been shown to have antimycobacterial properties.
· HIV and retrovirus:
DSF in combination research for HIV: