A study in mice has found that off-label use of the drug disulfiram (DSF)—more commonly known as Antabuse—which has been used for fifty years to treat chronic alcohol addiction, consistently normalized body weight and reversed metabolic damage in obese middle-aged mice of both sexes. The international research team, headed by Michel Bernier, PhD, staff scientist and Rafael de Cabo, PhD, senior investigator, both at the National Institute on Aging (NIA), say their results suggest that the drug could potentially be repurposed to treat obesity and related metabolic comorbidities in humans. Reporting their findings in Cell Metabolism, they concluded, “Overall, our results indicate that DSF normalizes body weight both prophylactically and therapeutically while reversing metabolic abnormalities commonly associated with diet-induced obesity … Given the potent anti-obesogenic effects in rodents, repurposing disulfiram in the clinic could represent a new strategy to treat obesity and its metabolic comorbidities.” Their published paper is titled, “Disulfiram Treatment Normalizes Body Weight in Obese Mice.”
Obesity has reached epidemic proportions in developed countries and represents a major public health challenge, the authors wrote, and many obese individuals can’t achieve consistent weight loss by changing their diet and lifestyle. “For many individuals with obesity, behavioral and lifestyle modifications are insufficient for long-term weight-loss maintenance and, therefore, depend on surgical procedures and/or pharmacological interventions that alter either appetite or absorption of calories.” While there are a number of FDA-approved weight-loss medications, the authors continued, “… battling obesity requires long-term use of safe and effective drugs, and ideally ones that can alleviate its comorbidities, such as improving systemic glucose and lipid homeostasis.”
DSF (tetraethyl thiuramdisulfide) is an FDA-approved drug for treating alcohol misuse, that is well tolerated, with few side effects. The drug is effective in combating inflammation in vivo, and a related compound, pyrrolidinedithiocarbamate (PDTC), has been shown to lower fasting blood glucose in a rat model of type 2 diabetes, the investigators noted. There are also 44 clinical studies listed in the clinicaltrials.gov database in which DSF has been used for various conditions, including alcohol- and cocaine-use disorders, cancer, and HIV, but, they continued, “… none of the trials monitor weight loss as an outcome.”
Bernier and de Cabo collaborated with the NIH and external researchers on studies that investigated how changes in dietary patterns like intermittent fasting could lead to cognitive and physical health benefits. They first became interested in disulfiram after reading about the benefits that this class of drug has shown in treating type 2 diabetes in rats, coupled with the growing interest in repurposing drugs that may also improve healthy aging.
For their newly reported study, the team wanted to investigate the effects of long-term, off-label use of DSF in the prevention and treatment of diet-induced obesity in mice. The scientific team first studied groups of nine-month-old animals that had been fed a high-fat diet (HFD) for 12 weeks. As expected, the mice became overweight and started to show signs of pre-diabetes-like metabolic dysfunction, such as insulin resistance and elevated fasting blood sugar levels. The scientists then divided these mice into four groups, each of which was fed a different diet for an additional 12 weeks. One group was fed a standard diet (SD) alone, another group was given a high-fat diet alone, while the third and fourth groups received a high-fat diet with either a low amount of disulfiram, or a higher amount of disulfiram.
As expected, mice that remained on the high-fat diet alone continued to gain weight and show metabolic problems. Mice that were switched to a standard diet alone gradually showed normalization of body weight, fat composition, and blood sugar levels. The mice in the remaining two groups, with either a low or high dose of disulfiram added to their high-fat diet, showed a dramatic decrease in their weight and related metabolic damage. Mice on the high dose of disulfiram lost as much as 40% of their body weight in just four weeks, effectively normalizing their weight to that of the obese mice that were switched back to standard diet. Mice in either of the disulfiram dose HFD groups became leaner and showed significant improvement in blood glucose levels, again, equivalent to that of the mice who were returned to standard diet.
“When we first went down this path, we did not know what to expect, but once we started to see data showing dramatic weight loss and leaner body mass in the mice, we turned to each other and couldn’t quite believe our eyes,” Bernier said.
The investigators’ analyses indicated that the positive results stemmed from disulfiram’s anti-inflammatory properties, which helped to prevent imbalances in fasting glucose and protected the animals from the damage of a fatty diet and weight gain, while improving metabolic efficiency. DSF also helped restore insulin sensitivity in the HFD cohorts to the same level as in SD-fed mice, they wrote. “It would appear that the observed improvement in insulin sensitivity evoked by DSF stemmed from the lowering in ß–cell hyperplasia and correction of diet-induced dysregulation in insulin secretion.”
None of the obese mouse (control and disulfiram) cohorts was subjected to any form of exercise, nor did the DSF-treated animals demonstrate noticeable spontaneous behavioral changes that might relate to the observed improvements. “There was no alteration in locomotor activity between DSF-treated mice and controls regardless of the diet,” the scientists wrote. “These results indicate that long-term treatment with DSF leads to body weight regulation through lower feeding efficiency and improved energy expenditure without impacting fuel selection or voluntary locomotor activity.”
Disulfiram treatment also appeared to protect the pancreas and liver from damage caused by prediabetic-type metabolic changes and fat build-up that are commonly caused by eating a high-fat diet. “ … the study results also indicated that long-term use of DSF maintained hepatic homeostasis by preventing diet-induced liver dysfunction and injury.” Based on their collective observations and analyses, the researchers reason that the beneficial effects stemmed solely from the drug, which also had no apparent adverse side effects in the treated mice.
They next carried out a series of tests in rats that are predisposed to develop obesity. The three-month-old animals were maintained on a standard diet either alone, or supplemented with high or low doses of DSF, for 12 weeks. The results showed that in the DSF-treated animals “a significant reduction in fat mass and increase in lean tissue mass translated into higher lean-to-fat ratio.”
“Overall, our results demonstrate that DSF treatment initiated at early adulthood triggers a range of health benefits culminating in improvements in whole body physiology and metabolism in mice and rats,” they concluded. “… besides, the drug provides benefits by reversing diet-induced metabolic dysfunction in middle-aged male and female obese mice partly via the normalization of body weight, loss in adiposity, and reduction in fasting blood glucose.”
The research team pointed out both strengths and limitations of their study, and stressed that the results of adding DSF to rodents can’t be extrapolated to any potential benefits for humans at this point. They say disulfiram should not be used off-label for weight management outside of the context of clinical trials. Nevertheless, the team is planning future steps for studying disulfiram’s potential, including a controlled clinical study to test if it could help individuals with morbid obesity lose weight, as well as deeper investigation into the drug’s molecular mechanisms and potential for combining with other therapeutic interventions.
