Risk/Reward Profile (tradeoff considerations) for the use of 2,4-dinitrophenol (DNP)

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Title: Risk/Reward Profile (tradeoff considerations) for the use of 2,4-dinitrophenol (DNP):
Author: Type-IIx


Compound:
Caswell No. 392; Sulfo Black B; Nitro Kleenup

DNP (2,4-dinitrophenol):
protonophore; mitochondrial uncoupler of phosphorylative oxidation and ATPase.

Risk/Reward Profile (tradeoffs):
The use of 2,4-dinitrophenol ("DNP") may be rational dependent upon whether:

+ ↑↑↑BMR/RMR dose-dependently (to the tune of 300 mg ⇒ ~33% ↑BMR [mean])

+ Relative (i.e., muscle) protein sparing (preferentially oxidizes fat mass [FM])

+ Improved blood lipids

+ Improved glucose tolerance (but unclear and disparate effects on blood glucose levels or hyperglycemia)

* outweighs the risks & direct drug effects:

- (high probability, low - moderate severity; 15 - 23.4% prevalence) Skin rash... ranging in severity from mild (e.g., pruritis) to severe (e.g., urticaria, generalized: "...tremendous urticarial lesions appeared... The hands and feet were immensely swollen and intensely hot and red. Practically the entire body was covered with large wheals. The temperature was 100° F, the pulse 112, the respiration 28, and the blood pressure 112 systolic, 64 diastolic... Epinephrine gave prompt relief... New lesions cropped up intermittently for three weeks thereafter, though they were so scattered as to cause very little discomfort." [13]

- (low probability, extremely high severity, permanent but usually operable; 0.1 - 1% prevalence) Cataracts... No case has shown spontaneous resolution. The shortest time reported for the development of cataracts is one month. In nearly all cases, cataract development occurs exclusively in those who had more than one course of DNP. It is during the second or subsequent course that dimness of vision begins. One anecdote concerned a 48 year old woman that ran two DNP courses of 300 - 400 mg daily x 9 weeks first, separated by 9 weeks, and again resuming DNP at 300 - 400 mg daily x 4 weeks. After complete cessation from the drug, 3 weeks later, while at a seaside resort, she "became cold and complained of marked chilliness. Within a few minutes, huge urticarial wheals covered the entire body with the exception of the face. The urticaria disappeared within an hour. Three hours later she developed diplopia when she closed her left eye. The condition became gradually worse until [1 month later], when an opthalmologist discovered bilateral cataracts. Shortly afterward, dimness of vision began to develop and grew rapidly wose...The diplopia persisted until vision was completely lost at the end of December 1935." [13]

- (low probability, high severity) Peripheral neuritis... The striking symptoms are practically always sensory, the legs and feet being affected first, the arms and hands next. Various paresthesias, such as numbness and "pins and needles" develop and after the drug is stopped clear up slowly, within three weeks to two months. Cases of motor weakness, such as drop foot, are rare. The weakness disappears when the drug is stopped, usually within a week... n a few patients, disturbance of the sensation of taste (dysgeusia) developed that disappeared spontaneously with continuation of DNP. [13]

- (high probability, low severity) Susceptibility to colds, especially to upper respiratory infections, is increased, fairly traceable to excessive sweating.

- (low probability, low severity) Generalized toxic effects. Though DNP is not cardio-, hepato-, nor reno- toxic, it may present generalized toxic effects not traceable to any particular etiology. To illustrate, one patient was prostrated for several days after ingesting a single 100 mg capsule, and another developed extreme generalized aches and pains after the ingestion of three 100 mg capsules (300 mg). Another experienced acute cystitis. Another marked dizziness. [13]

- direct effects (assured, 100% probability, low severity):

- ↑body temperature (thermogenesis) ⇒ excessive sweating

- ↑O₂ consumption (hyperventilation; respiratory minute-volume) ⇒ ergolytic (performance worsening) for cardiorespiratory fitness & worsened ability to perform aerobic endurance activities (O₂ consumption approaching VO₂max at rest)

- ↓ATPase substrate availability ⇒ worsened ability to perform muscular contractions (ergolytic for resistance training)

* in consideration of:

+ availability of incretins (e.g, GLP-1 & GIP agonists, that improve insulin sensitivity, alter food preference, reduce hunger/appetite, etc.) & statins

+ ability to restrict energy intakes & manipulate nutrient intakes, in conjunction with aerobic endurance and resistance training, to improve body composition, and even effect rapid fat loss (and actually save money insodoing)

Mechanisms of action

During oxidative phosphorylation, DNP's primary target of action is on the proton pump, where the mitochondrial matrix actively (endergonically) pumps protons into the intermembrance space- DNP "sabotages" this by allowing the protons to leak back into the mitochondrial matrix. Rather than permitting potential energy to form via an electrochemical gradient of protons with a lower concentration in the mitochondrial matrix versus the intermembrane space (natural state), a higher concentration build in the mitochondrial matrix and energy must be dissipated as heat (increase in core temperature). [1]

Decreases efficiency of (catabolic) energy metabolism ⇒ heat

- Complete nutrient catabolism is between 30 and 40 percent efficient, and some of the energy is therefore released as heat. Heat is a vital product of nutrient catabolism and is involved in maintaining body temperature. If cells were too efficient at transforming nutrient energy into ATP, humans would not last to the next meal, as they would die of hypothermia.

Additional aspects of DNP's mechanisms:

- Ca²⁺ release from mitochondria & SR into the cytosol -- which subsequently must be pumped back (caused by effects on membrane potential from oxidative phosphorylation) [6]

- Interferes with Pᵢ groups' uptake into the mitochondrial matrix, thereby reducing substrates for ATPase [7]

Dosing methods

dose-response: average BMR ↑ 11% * 100mg⁻¹ [3] [12]... but varies widely between individuals [12] (in some cases, DNP alone, without dietary modifications, results in no significant weight loss) [13]
* 4 mg/kg results in ~40% increase to RMR (mean)

The method employed consisted of the administration of one capsule (100 mg of sodium dinitrophenol) the first day, two capsules the second day, and three capsules daily thereafter (preferably after meals)... Thereafter the dose was regulated by... [A] rule was followed invariably that, when the temperature rose as high as 99.2° F (37.33° C) [indicative of acute toxicity], the drug was either discontinued or the dosage sharply reduced... [12]

With long-term administration (> 7 weeks), two factors lead to sudden cessation of weight loss (after weeks of steady, rapid weight loss):

1. Factor 1: rapidly acquired tolerance to the drug. EX:

* One patient, on a daily dose of 320 mg, resulting in a RMR ↑26%, lost weight at an average rate of 1.4 kg (3 lb) weekly x 7 weeks. Then, for 6 weeks, she lost no weight even though the dose was raised to 400 mg daily. A RMR determination at this time showed that RMR ↑ by a mere 6% (relatively rare)

2. Factor 2: Edema (profound); DNP promotes water storage in the tissues of the body. EX:

* Another patient, on a daily dose of 300 mg, resulting in a RMR ↑46%, lost an average of 0.9 kg (2 lb) weekly x 8 weeks. Then, she suddenly stopped losing weight. The dosage was increased to 400 mg daily x 4 weeks with no resultant weight loss. A RMR determination at this time showed that RMR ↑ by a considerable 62% (common)

- Naturally, cessation from DNP at such a time results in dramatic water, and therefore weight, loss.
[12]

Seasonal phenomenon

In climates subject to warm and cold months, a seasonal phenomenon is observed:


> As summer passes into fall, it is found that the patient suddenly ceases to lose weight, although the weight loss before may have been very satisfactory and steady. That the mechanism involved is not the development of tolerance is attested by the fact that a considerable group of patients exhibit this phenomenon simultaneously. In the case of dinitrophenol it may be partly accounted for, but only partly, by the diminution of sweating that accompanies the colder weather. In the hot summer months, small doses of dinitrophenol will produce a weight loss that will be matched in the cold winter months only by considerably larger doses.
[12]

Effects on the heart

Myocardial effects; EKG changes

Changes that may occur (moderate likelihood), indicate per Taussig (56) the development of a "prolongation of the recovery time of the heart muscle together with a decrease in the voltage initiated by ventricular contraction and suggest that some alteration in the metabolism of the myocardium has resulted from dinitrophenol... There is no evidence that dinitrophenol causes death through a toxic action on the heart." [12]

Blood glucose modulating effects

DNP, by uncoupling of oxidative phosphorylation ⇒ ↑↑O₂ consumption (reflects ↑RMR) & ADP:ATP ratio, ↑lactate synthesis (the latter due to a compensatory ↑glycolysis due to low ATP, thereby ↑pyruvate [glycolysis end-product]) & ↓glucose (due to the ↑glycolysis) [8]... therefore, hyperlactacidemia is a serious concern with chronic DNP use.

Less practically useful as an antidiabetes agent than aspirin [9].

Time-course dependent (bimodal effects)

From [12]:


Apparently the conclusions to be drawn are that, with short courses of dinitrophenol (e.g., 5 days) administration in normal individuals, there is moderate elevation of the fasting blood sugar (though not hyperglycemia) and a moderate impairment of carbohydrate tolerate (i.e., GTT), in the majority of cases. With prolonged administration (e.g., 21 - 420 days) there is no change in the fasting blood sugar and a marked increase of carbohydrate tolerance... With prolonged administration in cases of diabetes there is apparently an increase of carbohydrate tolerance.
Interactions with thyroid hormones

No significant effect on thyroid function


DNP is known to occupy thyroid binding proteins in blood. That leaves less of the binding protein to bind to thyroid, which can increase free thyroid levels. In the short term, that can result in higher serum levels of thyroid and accelerated clearance from the body. However, a new steady state is soon reached in which thyroid function will be normal, despite potentially reduced serum levels of total T4 and total T3. As one paper on DNP explained, "this action could lower the total hormone concentration in serum but should have no persistent effect on thyroid function". This means that even though the level of thyroid hormones in the blood can be lower than normal while on DNP, thyroid function will still be normal. So if you're seeing a doctor and having blood work done to determine your correct thyroid dose, you would not want to be taking DNP, since it could alter your numbers. Only after your dose has been set and no blood work is planned would you want to take DNP, during which time you'd stay on your thyroid medication.
Conciliator @ MesoRx Oct 9 2009

It's not quite clear that DNP decreases T3 levels in practice. Theres a case study that's often posted as evidence for this, but I'm of the opinion that the bodybuilders in question had low thyroid levels not because of the DNP, but because they were taking T3 during their cycle. Exogenous T3 definitely will suppress endogenous production. I had a Norwegian translate the paper for me and it was unclear why they had low thyroid levels. They didn't test for reverse thyroid when they could have, which would have made the cause clearer.

I also have a friend who's a doctor of internal medicine who ran 600mg/day for 3-4 months (went from 320 lbs down to the mid 200's). He gave himself frequent blood tests and said his thyroid didn't budge. I'm just not convinced that DNP lowers thyroid levels. Even if it did, you can simply bump up your DNP dosage to keep weight loss humming along. This is what they did in the original research after they found that there was a rapidly developing tolerance to the drug in the first couple of weeks. They just upped the dosage a little to overcome the tolerance. No one was given thyroid, even though subjects were kept on the drug for many months at a time to over a year. I like this option because thyroid is notoriously catabolic. I think it's generally best to just leave it alone.
Conciliator @ Steroid.com May 14 2007

Ketogenic diet

Practically, my view is that if you're using DNP, the objective cannot be to build new muscle tissue (as ATP is going to be dramatically reduced: thus the energy state of the cell directs energy metabolism to catabolic processes).

As such, just use a - here we go again - minimal effective dose. So that means, don't go under 100 mg daily (no real justification; even at 100 - 200 mg daily, DNP is less efficacious as an insulin sensitizing/antidiabetic agent than aspirin in humans; and at 100 mg, expect a modest ~10% RMR increase [less in heavy bodybuilders]).

Certainly, a keto diet can rationally serve this objective: in an individual with a low b.f.%, with the use of MCTs, et cetera, keto can be used to really reduce those difficult to reduce fat depots like the lower back in men & the hips/thighs in women. DNP will make this all the more attainable (and we can "get in and get out," staving off longer-term muscle catabolism).

Theoretically the reason that DNP does lower blood glucose concentrations (but remember, it's a minor effect in humans) is by uncoupling of oxidative phosphorylation ⇒ ↑↑O₂ consumption (reflects the increase in RMR) & ADP:ATP ratio, ↑lactate synthesis (the latter due to a compensatory ↑glycolysis due to low ATP, thereby ↑pyruvate [gycolysis end-product]) & ↓glucose (due to the ↑glycolysis): hence hyperlactacidemia is a serious concern with DNP use.

So yes: with DNP, keto makes sense (i.e., entering ketosis); anticatabolic agents that are selective in the intracellular compartment (androgens) make sense as well; the utility of rhGH here is complicated by its hyperglycemic and insulin resistance effects, but it certainly makes sense for longer-term adaptations to caloric restriction (i.e., ↓IGF-I): but again, the use of a burst or plateau busting tactic for short term "diet sprints" at already low body fat seems the most logical approach for DNP & keto.

Muscle protein sparing

> The extra energy of metabolism is derived mainly from fat and practically not at all from protein or carbohydrate. Consequently, dinitrophenol in therapeutic dosage produces no breakdown of significant amounts of body protein, even with patients on an inadequate protein intake. This is in marked contrast with the very consdierable increase in nitrogen excretion observed in patients undergoing treatment with thyroid. The fat is used completely and satisfactorily broken down, as no ketone bodies are found in urine. There is a no hyperlipidemia or constant change in the fixed and fatty acids of the blood.
[12]

Human toxicity values


Lethal doses for orally ingested 2,4-dinitrophenol in humans have been reported to be 14 to 43 mg/kg ...
National Research Council. Drinking Water & Health, Volume 4. Washington, DC: National Academy Press, 1981., p. 237

Fatal dose in adults is about 1 to 3 g by mouth; 3 g has also proved fatal in divided doses over a period of 5 days. /Dinitrophenol/
Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984., p. III-157

Pharmacokinetics
The PK/PD of DNP in humans is considered unknown

elimination half-life

Assumption: single dose pharmacokinetics describe a 36 h elimination half-life.

Subject to multi-dose & dose-dependent pharmacokinetics:


The elimination half-life (t1/2) of 2,4-DNP was (88.78 ± 14.66) h in the routine HP group, while the t1/2 was only (54.58 ± 12.92) h in the intensive HP group.

The t1/2 of 2,4-DNP in the intensive HP group was apparently shorter than that in the routine HP group, with statistical significance (t=4.535, P=0.001).
[11]

Absorption, Distribution, Excretion (ADE):

A single oral dose of from 3 to 5 mg per kilogram of body weight (3 - 5 mg/kg b.w.) produces an increase in RMR of from 20 to 30 percent within the first hour. This level is maintained for 24 hours and then falls gradually to normal on the third day. With daily administration there is a rapid rise of the RMR on the first day, a slight additional rise on subsequent days, and the maximum on the fourth day. [12]

After discontinuation, the RMR falls to normal within three to fourteen days. [12]

The response to a given dose may vary considerably from day to day. [12]

If the RMR rises less than 30 or 40 percent, there is little reaction except peripheral vasodilation, and a slight increase in respiratory minute-volume. A greater elevation produces uncomfortable heat and sweating. [12]

______________________
References:

[1] Bond, P. Article: How Does DNP (2,4-dinitrophenol) Work? Oct 2021. Article: https://thinksteroids.com/articles/how-does-dnp-24-dinitrophenol-work/
[2] Cutting, W. C., H. Gr Mehrtens, and M. L. Tainter. “Actions and uses of dinitrophenol: promising metabolic applications.” Journal of the American Medical Association 101.3 (1933): 193-195.
[3] Tainter, M. L., A. B. Stockton, and W. C. Cutting. “Dinitrophenol in the treatment of obesity.” Journal of the American Medical Association 105.5 (1935): 332-337.
[4] BARBE, P., LARROUY, D., BOULANGER, C., CHEVILLOTTE, E., VIGUERIE, N., THALAMAS, C., … LANGIN, D. (2001). Triiodothyronine-mediated up-regulation of UCP2 and UCP3 mRNA expression in human skeletal muscle without coordinated induction of mitochondrial respiratory chain genes . The FASEB Journal, 15(1), 13–15. doi:10.1096/fj.00-0502fje
[5] De Lange, P., Lanni, A., Beneduce, L., Moreno, M., Lombardi, A., Silvestri, E., & Goglia, F. (2001). Uncoupling Protein-3 Is a Molecular Determinant for the Regulation of Resting Metabolic Rate by Thyroid Hormone. Endocrinology, 142(8), 3414–3420. doi:10.1210/endo.142.8.8303
[6] Hudman, D., Rainbow, R. D., Lawrence, C. L., & Standen, N. B. (2002). The Origin of Calcium Overload in Rat Cardiac Myocytes Following Metabolic Inhibition With 2,4-Dinitrophenol. Journal of Molecular and Cellular Cardiology, 34(7), 859–871. doi:10.1006/jmcc.2002.2024
[7] Grundlingh, J., Dargan, P. I., El-Zanfaly, M., & Wood, D. M. (2011). 2,4-Dinitrophenol (DNP): A Weight Loss Agent with Significant Acute Toxicity and Risk of Death. Journal of Medical Toxicology, 7(3), 205–212. doi:10.1007/s13181-011-0162-6
[8] Liangyou Rui; New Antidiabetes Agent Targeting Both Mitochondrial Uncoupling and Pyruvate Catabolism: Two Birds With One Stone. Diabetes 1 December 2019; 68 (12): 2195–2196. doi:10.2337/dbi19-0024
[9] Dinitrophenol and Diabetes. (2009). Nutrition Reviews, 17(3), 81–83. doi:10.1111/j.1753-4887.1959.tb06405.x
[10] Perry RJ, Zhang D, Zhang XM, Boyer JL, Shulman GI. Controlled-release mitochondrial protonophore reverses diabetes and steatohepatitis in rats. Science. 2015 Mar 13;347(6227):1253-6. doi: 10.1126/science.aaa0672. Epub 2015 Feb 26. PMID: 25721504; PMCID: PMC4495920.
[11] Zhao, X., Jiang, J., & Lu, Y. (2015). Evaluation of efficacy of resin hemoperfusion in patients with acute 2,4-dinitrophenol poisoning by dynamic monitoring of plasma toxin concentration. Journal of Zhejiang University-SCIENCE B, 16(8), 720–726. doi:10.1631/jzus.b1500101
[12] Simkins, S. (1937). Dinitrophenol and dessicated thyroid in the treatment of obesity. Journal of the American Medical Association, 108(25), 2110. doi:10.1001/jama.1937.02780250024006
[13] Simkins, S. (1937). Dinitrophenol and dessicated thyroid in the treatment of obesity. Journal of the American Medical Association, 108(26), 2193. doi:10.1001/jama.1937.02780260021007
 

Kraken

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What s this giant copy / paste from?
 

Thrawn

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What s this giant copy / paste from?
Looks like Messo, still good info if accurate I haven't read it over completely.
I am aware of 4 documented fatalities since I've been around the boards so since 1998/99. Could be more.
 
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I wrote this. It’s a risk reward profile I built before deciding not to use DNP myself. You won’t find this on Meso.

I built these out for a lot of compounds that I was uncertain whether I should use, to weigh the considerations involved.
 
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I honestly look at dnp like insulin. 99% of the information online is total bs. I don’t think fat people should use it as a means to get lean. However I feel it’s a great tool for those of us that are having a hard time getting the last 1 to 2%!bf off
 

CJ

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I honestly look at dnp like insulin. 99% of the information online is total bs. I don’t think fat people should use it as a means to get lean. However I feel it’s a great tool for those of us that are having a hard time getting the last 1 to 2%!bf off

That's the problem. 99.9% of the people who ask about it have absolutely no business using it. Their nutrition and training is subpar, they're merely looking for a shortcut.
 

Send0

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I honestly look at dnp like insulin. 99% of the information online is total bs. I don’t think fat people should use it as a means to get lean. However I feel it’s a great tool for those of us that are having a hard time getting the last 1 to 2%!bf off
Actually the leaner you are it becomes significantly less and less effective, to the point of not really working much anymore aside from feeling side effects. So it's pretty pointless for the last 1-2% of bf you're referring to.
 
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