The commercially-available drink has gotten the attention of amateur and professional athletes, including two who are competing in the Rio Olympics.

Many an athlete—from Olympic competitors to the hoi polloi of the workout world—has been felled by debilitating muscle spasms. British runner Paula Radcliffe, the world record holder in the women’s marathon, cramped during the 2008 Summer Olympics competition in Beijing and finished the race in 23rd place. Cleveland Cavaliers basketball player and NBA champion LeBron James had to leave a playoff game because of severe leg cramps. Cathy Ellis, a long distance cyclist who won the Race Across America in 1991, had a hard time training because of frequent leg cramps.

The cause of cramps is a matter of some debate. The field of sports medicine has long theorized that microscopic muscle tears, improper hydration and electrolyte imbalances is behind the condition, and many athletes down Gatorade or Powerade before and during a competition hoping to ward off spasms.

But Harvard neurobiologist Bruce Bean and molecular neurobiologist Rod MacKinnon of Rockefeller University think the underlying cause of cramping might be more related to misfiring alpha-motor neurons that cause our motor circuit to become hyper-excitable. Furthermore, they think that by stimulating TRPV1 and TRPA1 ion channels to strongly activate sensory nerve fibers in the mouth and gut, it is possible to modify activity of the neural circuits that cause motor neuron hyperexcitability and thereby inhibit cramping.

It’s not all that surprising that Bean and MacKinnon zeroed in on a neurobiological solution to an age-old complaint. What is unusual is how they are applying the idea outside the laboratory. The two spent several years testing ways of inhibiting cramps by inducing cramps in themselves using external electrical stimulation of nerves. This led them to develop a formulation of TRP activator ingredients that stimulate TRP ion channels in the mouth, esophagus and stomach to regulate nerve function. That eventually helped MacKinnon and Bean develop HOTSHOT™, a commercially available drink for muscle cramps that has gotten the attention of amateur and professional athletes, including two who are competing in the Rio Olympic Games. Boston-based biotech Flex Pharma launched HOTSHOT™ in June. The product is available at www.TeamHOTSHOT.com and at selected retailers in Boston, Boulder and Los Angeles.

Flex Pharma concocted the blend of ingredients and flavoring that make up HOTSHOT™, says Bean. “They did a tremendous job of developing a combination of ingredients that works well to activate TRPV1 and TRPA1 channels but also tastes quite good,” he said. “Much better than the prototypes that Rod and I had, which some people described as disgusting.”

The story behind HOTSHOT™  has appeared in the Wall Street Journal, Nature, The Boston Globe, Outside Magazine and Runners World Online, and Bean, who oversees a lab focused on the biophysics of sodium, calcium and potassium ion signaling in relation to pain processing, spoke about HOTSHOT™ last November at the Ion Channels in Drug Discovery symposium organized by Charles River. Eureka caught up with Bean on Friday, just as the Olympics were getting going, to talk about the science behind the product and what it’s like to navigate the world of business when your orientation is the bench.

What is in HOTSHOT™?

BB: It’s a combination of plant extracts designed to produce a powerful stimulation of TRPV1 and TRIPA1 ion channels topically in the mouth and yet still be palatable. The hardest part was getting it to taste OK.

How did you end up achieving that?

BB: The people at Flex Pharma developed the combination of ingredients in HOTSHOT™. They don’t like to say exactly what the ingredients are, but it’s all from natural plants. I use it a lot, and I like it, actually. They did a tremendous job of making something that tastes good. It’s much better than our earlier prototypes, which some people described as disgusting. At one point early on, an outside firm specializing in taste formulation came back and said “we can’t even work with this”. But ultimately the team at Flex managed to combine effectiveness and taste.  

What did they like about the earlier prototype?

BB: Well, the prototype worked, even if it didn’t taste good. In our first meeting with the first person to join the company, Jennifer Cermak, we demonstrated the prototype to her in my kitchen by electrically stimulating her toe to induce a cramp and then gave her the prototype. It worked perfectly, and that convinced her to leave her job in big pharma and help us work on commercializing our prototype.

What other products is Flex Pharma developing?

BB: A candidate drug molecule called FLX-787 is being designed for patients who suffer from muscle cramps. There is a Phase II study in multiple sclerosis patients that has started in Australia and there is a planned study in patients with amyotrophic lateral sclerosis that will be starting in a month or so. We are very excited about the possibility that we can use the insights from developing the athletic drink to make a drug to help people with cramps associated with disease.    

Which athletes are using the energy drink?

BB: In terms of Olympic athletes, Shalane Flanagan and Amy Cragg, who are members of the women’s marathon team in Rio, are enthusiastic about  HOTSHOT™. It’s also being used by several other Olympic athletes who have asked not to have their names made public because they regard the drink as a secret weapon. A number of NFL teams are using it. The long-distance cyclist Cathy Ellis heard about it even before we launched. She was having so many problems with cramping that she had trouble training and she got a beta version. She has said HOTSHOT™ changed her life.

What makes your beverage different from other energy drinks?

BB: It’s totally different. The point of HOTSHOT™ is not to provide glucose or electrolytes but to stimulate the TRP channels in the mouth and esophagus. This is based on the observation we made that by doing that, we could effectively inhibit cramping. We first tested it on electrically-induced cramping, first on ourselves and then in a series of controlled blinded trials on volunteers. Now we are hearing from many athletes that it works quite well in exercise-induced cramps. A lot of athletes are telling us that just being relieved of the fear of cramping can enhance their performance. We’re also hearing people say that it reduces soreness after strenuous training.

Have you been able to determine the precise mechanism that makes it work?

BB: We have a hypothesis but we don’t really know for sure. What we do know is that cramping almost always comes from the nerves and not the muscles. It’s almost undoubtedly hyperactivity of the motor neurons that are controlling the muscles that gives you the cramp. We think that by strongly stimulating sensory neurons in the mouth and esophagus, which go via the vagus nerve to the brainstem, we modify the activity of descending modulatory pathways to the spinal cord involving transmitters like serotonin, which then inhibit the hyperexcitability of the motor neurons. One of the problems with understanding cramping is that there is no good animal model, which is why the mechanism is hard to test.

Are there any side effects?

BB: Really, nothing. You feel a definite kick to your sensory nerves from the TRP channels being activated, followed by a glow. You feel it in your esophagus and stomach. Most people find that pleasant. A few people don’t like the taste. Surprisingly, there have been very few people reporting any issues with GI disturbances.

Finally, as a neurobiologist, what’s been the most interesting part of developing and testing a product for consumers?

BB: Well, it’s been a huge amount of fun developing something that people actually use and like. Originally we were just developing this for ourselves. Then we realized that there might be a lot of athletes interested in it. As you know, if you are starting off with a discovery in basic science, the chances you will end up with a drug that people take and get benefit from is pretty slim. And even if successful, the process takes an incredibly long time. Being able to develop a consumer product that benefits people in just a few years was a huge thrill. And it’s been eye-opening to see how much hard work and how many different skills of a big team it took to do it. 

How to Cite: 

McEnery, Regina. Got Cramps? Scientists Find a New Way to Attack an Old Problem. Eureka blog. Aug. 9, 2016. Available: http://eureka.criver.com/scientists-find-a-new-way-to-attack-an-old-problem/