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Weight Loss, But at What Cost?
Sure, use a chemical used in insecticides and the preservation of wood for weight loss. What could go wrong? Info here.
A pound of fat a day. That’s how much some people have allegedly lost while using inordinately large amounts of the metabolism booster, 2,4, dinitrophenol, or DNP. Unfortunately, many people get seriously sick within just a few hours, and some have died.
This is why DNP is illegal (at least in the U.S.) and has been illegal for a long time. Like most things, though, it’s still available online, usually in the form of a yellow powder, capsules, or even creams. But the government has little interest in enforcing the laws, probably because they don’t know much about it.
DNP was once very popular in bodybuilding circles. You could easily spot users because they were always covered with a patina of sweat, regardless of temperature. However, as adverse effects and the occasional death became more publicized, the drug’s popularity faded.
However, as with many things in human history, what’s old often becomes new again, and sweaty men and women are once again easy to spot.
A Brief History of DNP
DNP existed long before World War I, but it hadn’t been used on a wide scale where many people would come into contact with large amounts of it (e.g., a manufacturing floor).
In France, other nitrated phenol-type compounds like picric acid (2,4,6-trinitrophenol or TNP) were used in munitions factories without any noticeable issues, so they thought they could use DNP without any problems as part of a filling mixture that contained picric acid and TNT (1,2).
Boy, were they wrong. Workers suffered adverse effects such as nausea, vomiting, malaise, headache, fever, sweating, and in some cases, death (1,2). While some workers complained of becoming thin after working in the factory for several months, this aspect didn’t receive much attention.
These deaths prompted Maurice Tainter and colleagues at Stanford University to do animal and human experiments in 1931. They wanted to determine the mechanism behind DNP’s fever-producing effects and if there might be any potential therapeutic uses (4,5).
In 1933, they published their findings. They noted that DNP produced impressive weight loss and was (according to them) safe. They used 100 mg three times daily for around three months. Subjects lost 2-3 pounds per week (1,4).
The 100 mg dosage increased metabolic rate a little over 10% (6,7). Of course, even under the care of these physicians, a follow-up report revealed that 9 patients out of 113 had to stop taking DNP due to “undesirable reactions” (1).
The publication by Tainter et al. caused an explosion in the popularity of DNP as a weight-loss drug. Within two years, reports of various adverse effects surfaced, including cataracts, nausea, vomiting, skin lesions, agranulocytosis (when the body stops making a certain type of white blood cell), damage to the heart, liver and kidneys, and of course, death (1).
By 1938, DNP was deemed unfit for human consumption and banned (7). It wasn’t as if Tainter’s group hadn’t issued any cautions, though. They said they’d only studied DNP in certain subjects under close supervision, and they’d only administered the compound for a short period of time (1). They warned against taking large doses and noted that some people might experience adverse effects even at doses they’d deemed safe.
None of that stopped a huckster named Dr. Nicholas Bachynsky from relabeling DNP as “Mitcal” in the 1980s. Bachynsky claimed Mitcal had multiple health benefits and began treating patients with it. Soon after, the FBI initiated an investigation of him, code-named “Stopdoc,” which resulted in 87 counts of racketeering, conspiracy, mail fraud, bankruptcy fraud, and money laundering.
After he served his time, he ran to Italy and began to market DNP as a cure for cancer, which led to another conviction of fraud. Anyhow, Bachynsky may well be responsible for the interest in DNP that’s continued on and off until today.
How Does DNP Work?
DNP works by uncoupling oxidative phosphorylation from electron transport, leading to potential energy being lost as heat (thermogenesis) instead of being used to make more ATP (7). Our body has uncoupling proteins that do this to a limited extent, but in the case of DNP, it’s substantial and uncontrolled. The term “cooked alive” comes up often.
The mechanism for death is usually elevated body temperature, although the uncoupling of oxidative phosphorylation itself may be harmful via ATP depletion (leading to hypoxic and chemical injury).
The Problems with DNP (Other Than, You Know, Death)
The main issue with DNP? It has a narrow therapeutic index/ratio – the difference between a dose that allows for a desired therapeutic effect and a dose that causes toxicity is small (8,9). But there are other issues too.
First, the available data on DNP’s safety in humans is derived from a time when many aspects of drug safety were still in their infancy. Modern clinical chemistry vastly differs from what was available in the early 1930s (10). The common and sensitive assays used to assess organ function today were, for the most part, not available back then. They also lacked modern-day study designs that use randomized controlled trials with statistical analyses (9).
Second, people are different. Tainter et al. referred to “idiosyncrasies” among individuals (1). Today, we know there can be significant inter-individual differences regarding pharmacokinetics (how your body handles a given compound) and pharmacodynamics (how a compound affects your body).
This may be the case with DNP. A recent study in mice determined that DNP exhibited non-linear pharmacokinetics, which they suspected may be attributable to non-linear protein binding and tissue partitioning (8).
If this turns out to be the case in humans, a combination of a narrow therapeutic index with non-linear pharmacokinetics and potentially significant inter-individual differences in the pharmacokinetics/pharmacodynamics puts DNP in a very risky category. That would explain why there’s so much variation in adverse effects.
The authors (Meyer, et al.) also indicated that DNP appears to have limited tissue partitioning and is mainly confined to the blood (8). When evaluating the distribution to different tissue types, adipose tissue experienced comparatively lower levels of DNP.
This may be why a dose that can allow for an adequate, effective concentration to be reached in fat will lead to much higher levels in other tissues, such as the kidney, liver, and heart. This may partially explain the narrow therapeutic index of DNP.
Is There a Safe Dose?
It would be a disservice to suggest that any molecule that follows a monotonic (neither increasing nor decreasing) dose-response curve with a threshold effect can’t be free of toxic effects at a low enough dose. Conversely, even molecules considered harmless will cause toxicity if the dose is high enough. This is the founding principle of toxicology from our old pal Paracelsus, “the father of toxicology.”
Risk assessments can utilize a point of departure or POD – often a dose in humans or animals that either shows no observed adverse effects or the lowest dose showing an observed adverse effect). That can then be divided by one or more uncertainty factors (UFs) meant to account for inter-individual variation, interspecies differences, differences in duration of exposure, etc.
One example is the minimal risk level (MRL) of DNP – a level of exposure that isn’t expected to cause adverse noncancerous health effects; cancerous effects aren’t considered in the analysis. According to a 2021 Agency for Toxic Substances and Disease Registry assessment, it’s 0.00007 mg/kg/day or 0.07 micrograms/kg/day for an intermediate duration (15-364 days) (9).
In this case, the MRL was derived from a study on mice starting with a lowest observed adverse effect level (LOAEL) of 0.07 mg/kg/day and then performing serial dilutions. Of course, you have to account for individual human variability, interspecies extrapolation (mouse to human), and using a LOAEL instead of a “no observed adverse effect level” (NOAEL) as the point of departure.
This level is also unlikely to have any weight loss effects because it’s far lower than the 1 mg/kg/day dose used for that purpose.
While all this is an interesting exercise to demonstrate a general toxicological tenet (i.e., the dose makes the poison), the purpose of these published values is to act as a screening guide for professionals to determine if exposure to DNP under certain circumstances (like at a hazardous waste site or contaminated drinking water or food) may or may not be likely to cause harm (9), rather than a dare to go out and experiment.
So, while these doses are unlikely to cause adverse effects, they still shouldn’t be ingested… and they’d be ineffective for weight loss anyhow. The use of DNP should be restricted to manufacturing: pesticides, dyes, and wood preservation.
Take Home Points
DNP can’t be safely managed, even under the care of a physician.
The difference between toxic and fatal doses versus a dose that causes weight loss is very small.
The data from the 1930s is crude and shouldn’t be relied on for the determination of a safe dose.
Adverse effects from DNP may not be exclusively from pyrexia but other potential mechanisms such as ATP depletion. In that case, simply monitoring yourself for fever wouldn’t provide sufficient protection from potentially serious adverse effects.
With current research, there may eventually come a day when a molecule – one likely inspired by DNP – may be able to target adipose tissue nearly exclusively while minimizing the risk of adverse effects. Until then, please don’t use DNP.
The only “safe dose” is one so low as to not have any effects at all, making it pointless to use DNP in the first place.
Editor’s Note: Other weight loss drugs, such as this one, appear to be safer.
ReferencesReferences
Horner WD. A Study of Dinitrophenol and Its Relation to Cataract Formation. Trans Am Ophthalmol Soc. 1941;39:405-37. PMID: 16693262; PMCID: PMC1315023.
Perkins RG. Public Health Weekly Reports for OCTOBER 24, 1919. Public Health Rep (1896). 1919 Oct 24;34(43):2335-2430. PMID: 19314692; PMCID: PMC1996938.
Rabinowitch IM, Fowler AF. DINITROPHENOL. Can Med Assoc J. 1934 Feb;30(2):128-33. PMID: 20319386; PMCID: PMC403212.
Tainter ML, Cutting WC, Stockton AB. Use of Dinitrophenol in Nutritional Disorders: A Critical Survey of Clinical Results. Am J Public Health Nations Health. 1934 Oct;24(10):1045-53. doi: 10.2105/ajph.24.10.1045. PMID: 18014064; PMCID: PMC1558869.
Cutting WC, Tainter ML. Actions of Dinitrophenol. Proceedings of the Society for Experimental Biology and Medicine. 1932;29(9):1268-1269. doi:10.3181/00379727-29-6315
Dunlop DM. The Use Of 2:4-Dinitrophenol As A Metabolic Stimulant. Br Med J. 1934 Mar 24;1(3820):524-7. doi: 10.1136/bmj.1.3820.524. PMID: 20778151; PMCID: PMC2444737.
Grundlingh J, Dargan PI, El-Zanfaly M, Wood DM. 2,4-dinitrophenol (DNP): a weight loss agent with significant acute toxicity and risk of death. J Med Toxicol. 2011 Sep;7(3):205-12. doi: 10.1007/s13181-011-0162-6. PMID: 21739343; PMCID: PMC3550200.
Meyer LF, Rajadhyaksha PM, Shah DK. Physiologically-based pharmacokinetic model for 2,4-dinitrophenol. J Pharmacokinet Pharmacodyn. 2022 Jun;49(3):325-336. doi: 10.1007/s10928-022-09806-y. Epub 2022 Jan 28. PMID: 35089483.
Agency for Toxic Substances and Disease Registry (ATSDR). 2021. Toxicological profile for Dinitrophenols. Atlanta, GA: U.S. Department of Health and Human Services, Public Health Service.
Rosenfeld L. A golden age of clinical chemistry: 1948-1960. Clin Chem. 2000 Oct;46(10):1705-14. PMID: 11017957.
EPA. Provisional Peer Reviewed Toxicity Values for 2,4-Dinitrophenol. 2007. Available from: https://cfpub.epa.gov/ncea/pprtv/documents/Dinitrophenol24.pdf
Thank you for taking the time to produce this excellent article.
Some additional comments and historical data here:
weight loss product based on dnp-int Sorry they want to sell me a weight loss product, designed on dnp-int, but you know if it has any side effects you can take; has anyone heard of it?
See Fig. 1 and Table 1. Interesting max temperatures in the case studies (don’t necessarily die of overheating).
Thank you! I’m glad you found it useful.
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