A real skinny pill emerges

In an ironic twist of science and history, people once had access to the most coveted of all medicines – the ultimate skinny pill. This chemical could shed pounds without so much as lifting a finger. It was so effective that it was eventually banned by the FDA. Now researchers are on the brink of introducing a new “skinny pill” – one that eliminates the ability to overdose.

It is a classic story in the medical field-

“If one pill is good for me, aren’t two going to be twice as good?”

This simple assumption by patients has spurred the FDA to ban a number of drugs because of a narrow therapeutic index or one too close to the LD50.

These terms, such as LD 50 and therapeutic index, are technical proxies used to describe a simple reality- drug dosing is difficult, and otherwise effective drugs have been banned because patients could not be trusted to use them correctly.

Nowhere was this phenomenon better observed than in the meteoric rise and fall of the first “skinny pill,”  or 2,4-Dinitrophenol (DNP).

First described in 1931, DNP found success even during the depression era, with approximately  100,000 patients treated within one year of commercialization.

DNP was effective for a broad spectrum of people, from wrestlers to sedentary suburbanites. The success of DNP owed the fact that is is very simple medicine with an even simpler mechanism of action:

Within each of our cells, three main biochemical pathways are used to create energy. The first two, glycolysis and the citric acid cycle, create chemical intermediates used by the third process, the electron transport chain, to make energy.

By analogy, the electron transport chain creates energy the same way that a dam generates hydroelectric power. In the case of a dam, a reservoir of water at the top flows through a turbine to transform gravitational energy into electric power. The electron transport chain similarly uses a molecular reservoir that flows through a turbine to transform chemical potential into usable energy.

DNP works by poking a hole in the the dam. Instead of flowing through the turbine, the chemical reservoir can freely flow through. This is known as a mitochondrial uncoupling.

Free-flowing water does two things to the body – first, it creates an energy debt that must be compensated for. The body realizes that the chemical reservoir is draining, so it works extra hard by burning more and more fat to achieve the same energy yield. Increased lipid oxidation, or fat burning, is responsible for the weight loss effects of DNP.

The second effect of DNP is that the fuel normally used to create energy is instead converted to heat.

This second effect was the one that proved lethal.

Moderate DNP consumption paired with careful observation was the standard practice for administering DNP, yet for several people, this approach was not fast enough. Several deaths due to hyperthermia, or internal overheating, were reported soon after the release of DNP. These patients had consumed a lethal dose of DNP that led to an uncoupled energy generation system.

These people cooked themselves from the inside out.

Even though it was soon banned, the death toll continues to climb every year as DNP is still available from online pharmacies.


The narrow therapeutic index for DNP, or range within which it is effective, has prompted research in creating new mitochondrial uncouplers with the same mechanism but better safety profiles than DNP.

Furthermore, recent trends in Type 2 Diabetes and obesity are making pharmacological approaches to weight loss even more appealing as conventional approaches, such as exercise and education, are failing.

A recent report, published in Nature, describes a new drug that might just make it to the shelves, or internet pharmacies should it fail FDA approval. This new drug is a derivative of the anti-Tapeworm medicine, niclosamide.

Niclosamide functions as a mitochondrial uncoupler in worms, but cannot shuttle protons through the human mitochondrial membrane.

By modifying this drug into Niclosamide-ethanolamine and feeding it to mice, these scientists discovered that the drug worked to combat weight gain and the onset of diabetes. It has a good safety profile with limited side effects.

How far this derivative makes it will depend on the efficacy in humans. However given the adverse health effects of obesity and diabetes, such as increased cancer risk, demand for the drug will not be an issue.

However, like DNP, the potential side effects of this new derivative may not come to light until it reaches the hands of weight-loss fanatics.

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