2,4-dinitrophenol (DNP) is an old chemical with a long history, used in explosives since WWI. In the 1930’s it had a short-lived use as a weight loss drug, and was banned. A generally well written and researched summary aticle on DNP can be found via Jessica Wapner published in the Daily Beast of all places. The article also mentions how Dan Duchaine resurrected it in the public sphere to the bodybuilding/fitness community in the 90’s. Unfortunately, DNP continues to survive via the ‘net. As I knew Dan well, and he’d told me about his interests in DNP at the time, I was on the ground floor of the emergence of DNP. Here’s my summary:
Everything negative you have heard about DNP is true. Everything positive you have heard about DNP is true.
How is that possible?
DNP is the poster child for the expression used in medical/science circles “the dose makes the poison.”
More succinct, known as the three D’s: Drug, Dose, Duration.
What Is DNP? As it’s easy to Google up the basics of DNP as it pertains to weight loss, mechanisms, etc, a short summery:
“2-4-Dinitrophenol (DNP) was one of the first antiobesity therapy used in the 1930s. Its effect was first noticed among factory workers who were exposed to this and lost weight. It was shown to cause weight loss by uncoupling oxidative phosphorylation, leading to a heightened metabolic rate and increased fat metabolism. The rapid consumption of calories was thought to occur because of the shift in the proton electrochemical gradient, which results in potential energy dissipating as heat, instead of being converted to ATP. This mechanism of action also leads to an accumulation of pyruvate and lactic acids. Unlike thyroid hormone, which was used for weight loss, it did not impact on nitrogen excretion and thus was postulated to cause fat rather than lean muscle mass loss…” – https://www.sciencedirect.com/topics/neuroscience/2-4-dinitrophenol
While DNP has been given a bad rap as a toxic drug, studies suggest it has potential medical benefits, and increases the longevity of animals and indicators or metabolic health at low doses. (1,2,3). Again, the dose makes the poison. This is actually a common phenomena with many compounds, at one dose/schedule it’s a benefit, at another, it’s toxic. For example, the cancer drug Dasatinib is a Senolytic Drug that is highly toxic at one dose/schedule, has shown great promise as drug for anti-aging and disease prevention by removing “Zombie cells.” Zombie cells are senescent cells that survive by evading apoptotic mechanisms the body normally uses to eliminate them and they accumulate as we age.
Another is the Rapamycin, used to prevent organ rejection and suppresses the immune system and highly toxic at one dose/schedule, extends lifespan and improves metabolic health at a lower dose/schedule.
Both those drugs, Dasatinib and Rapamycin are receiving a great deal of interest and focus among researchers for their potential medical/anti-aging uses, are dangerous and toxic if not used under strict medical supervision, which brings us back to DNP…
Is DNP a viable fat loss drug under proper supervision? Yes it is. Does it have potential anti-aging/medical benefits? Yes again. Does it require more research as to how the Three D’s apply to humans? VERY much so. As always, there’s a risk to benefit issue that must be considered, and as obesity, and diseases related to it, such as heart disease, diabetes, and others are the top causes of premature death, simply ignoring DNP, leaving it to be sold via the net, is illogical and poor science. Sadly, even among some with the education to know better, understanding the concepts of the risk/benefit (vs “bad” or “good” dichotomy) and the Three D’s, is often lost on people.
The Real Problem With DNPThe real issue with DNP is that the therapeutic dose and the toxic dose/LD50* is close enough that even minor mistakes in dosing can be dangerous, and in rare cases, fatal, and that’s no BS. While I’m in favor of pursuing DNP as a viable weight loss drug and or its other potential benefits that deserves more research and interest by the medical/science community, self-administration of DNP via ‘net based sources is a VERY bad idea. Under no circumstances would I ever recommend the use of DNP, unless under medical supervision using a known source. I don’t know how to make that any clearer to readers. Unfortunately, taking the “more is better” approach so common among people looking to lose some fat or gain some muscle, will not end well as it applies to DNP.
Back In The Day
In the 90’s, I knew some physique athletes that were using DNP. What was interesting was how they almost universally reported how truly terrible they felt, like they had the flu and a fever. That’s not far off as DNP does raise body temp (to the point it can kill you…) and metabolic rate, and so not surprising at all they reported feeling terrible. But bodybuilders especially, but other athletes too, often conflate feeling terrible and suffering as it must be working and par for the course with achieving their goals and what all the “hard core” types do to succeed. It disappeared off my radar until recently when articles started popping up about its use a diet drug (see article linked in the intro) in the general population and I started receiving emails with “What do you know about this ‘new’ diet drug DNP Will?” type Qs. That prompted me to write an article and set the record straight on the topic of DNP.
While the science suggests DNP may be an effective and viable fat loss drug, that may also have other possible benefits, the narrow margins of safety/benefit ratio – due to the fact the therapeutic dose so close to the dose that can send people to the ER or worse – means it’s:
- A very bad idea to self-administer using questionable sources
- It needs more research in humans
- Must be administered under medical supervision for an acceptable risk/benefit
(1) Mild mitochondrial uncoupling in mice affects energy metabolism, redox balance and longevity. Aging Cell. 2008 Aug;7(4):552-60.
Caloric restriction is the most effective non-genetic intervention to enhance lifespan known to date. A major research interest has been the development of therapeutic strategies capable of promoting the beneficial results of this dietary regimen. In this sense, we propose that compounds that decrease the efficiency of energy conversion, such as mitochondrial uncouplers, can be caloric restriction mimetics. Treatment of mice with low doses of the protonophore 2,4-dinitrophenol promotes enhanced tissue respiratory rates, improved serological glucose, triglyceride and insulin levels, decrease of reactive oxygen species levels and tissue DNA and protein oxidation, as well as reduced body weight. Importantly, 2,4-dinitrophenol-treated animals also presented enhanced longevity. Our results demonstrate that mild mitochondrial uncoupling is a highly effective in vivo antioxidant strategy, and describe the first therapeutic intervention capable of effectively reproducing the physiological, metabolic and lifespan effects of caloric restriction in healthy mammals.
(2) The Mitochondrial Uncoupling Agent 2,4-Dinitrophenol Improves Mitochondrial Function, Attenuates Oxidative Damage, and Increases White Matter Sparing in the Contused Spinal Cord. J Neurotrauma. 2004 Oct;21(10):1396-404
The purpose of this study was to investigate the potential neuroprotective efficacy of the mitochondrial uncoupler 2,4-dinitrophenol (DNP) in rats following a mild to moderate spinal cord contusion injury. Animals received intraperitoneal injections of vehicle (DMSO) or 5 mg/mL of DNP prior to injury. Twenty-four hours following surgery, mitochondrial function was assessed in mitochondria isolated from spinal cord synaptosomes. In addition, synaptosomes were used to measure indicators of reactive oxygen species formation, lipid peroxidation, and protein oxidation. Relative to vehicle treated animals, pretreatment with DNP maintained mitochondrial bioenergetics and significantly decreased reactive oxygen species levels, lipid peroxidation, and protein carbonyl content following spinal cord injury. Furthermore, pretreatment with DNP significantly increased the amount of remaining white matter at the injury epicenter 6 weeks after injury. These results indicate that treatment with mitochondrial uncoupling agents may provide a novel approach for the treatment of secondary injury following spinal cord contusion.
(3) Additional sources HERE
*= “In toxicology, the median lethal dose, LD₅₀, LC₅₀ or LCt₅₀ is a measure of the lethal dose of a toxin, radiation, or pathogen. The value of LD₅₀ for a substance is the dose required to kill half the members of a tested population after a specified test duration.”
Will Brink is the owner of the Brinkzone Blog. Will has over 30 years experience as a respected author, columnist and consultant, to the supplement, fitness, bodybuilding, and weight loss industry and has been extensively published. Will graduated from Harvard University with a concentration in the natural sciences, and is a consultant to major supplement, dairy, and pharmaceutical companies.
His often ground breaking articles can be found in publications such as Lets Live, Muscle Media 2000, MuscleMag International, The Life Extension Magazine, Muscle n Fitness, Inside Karate, Exercise For Men Only, Body International, Power, Oxygen, Penthouse, Women’s World and The Townsend Letter For Doctors.
He’s also been published in peer reviewed journals.
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