GLP-1 agonist drugs have seen explosive growth in the U.S., after they were recently approved for weight loss. Researchers and product developers in the nutrition space have naturally had a heightened focus on how natural products may serve as a useful tool for blood sugar management and appetite reduction by way of modulating the GLP-1 hormone.
 
Calocurb, a New Zealand-based dietary supplement brand that recently launched in the U.S., features the active ingredient Amarasate, a bitter extract from a specific New Zealand-grown hops flower.
 
“The discovery of the GLP-1 hormone in 1986 changed the way we understood appetite and the feedback mechanism the body uses to control eating,” said Sarah Kennedy, CEO of Calocurb. “Scientists, both in pharmaceuticals and nutraceuticals, started looking to either increase this release naturally, as Calocurb has done, or through synthetic peptide replacement, with GLP-1 agonist injectables. The discovery of both mechanisms has been a major breakthrough in the management of obesity, weight management, and healthy dieting.” 

The ‘Bitter Brake’ Effect

Amarasate was discovered thanks to the support of a New Zealand government research institute, which invested over $30 million over 14 years of R&D.
 
In New Zealand, nearly all primary research is funded by the government, Kennedy noted. “In 2010, a group of scientists at Plant and Food Research, the largest government-owned research facility, had a hypothesis that they could find a plant-based extract that would control appetite. They named their application ‘Foods for appetite control’ and this was accepted for a $20 million research grant. Contrary to what many people believe, New Zealand has the third highest obesity rate in the world, just behind the U.S. and Mexico. Their rationale was if an affordable food extract was available to assist people in making healthy food choices, this would be a good health and economic decision.”
 
On a broad level, emerging research suggests that bitter compounds can trigger satiety-related hormones such as GLP-1. Researchers narrowed it down to Amarasate after an extensive screening process to find the most suitable candidate for clinical trials on appetite suppression, said Kennedy.
 
“The inspiration to look for a bitter compound to suppress appetite came from history,” she noted. “In the Scottish Highlands in times of famine, Scottish people chewed very bitter berries to suppress appetite. In the Kalahari Desert, tribesmen chew very bitter cactus to suppress hunger on long hunts. So New Zealand scientists set out to find an extract that duplicated this response, which they named the ‘bitter brake.’”
 
In preliminary work, the researchers took 300 biopsies from human intestinal tracts to show that TAS2R bitter receptors line the entero-endothelial cells of the intestine. Then, they built a model using these cells to assess TAS2Rsignaling with over 1,000 extracts.
 
“A specific hop variety was the ‘eureka’ discovery and the only extract that stimulated these receptors to produce significant amounts of appetite-suppressing hormones,” Kennedy said. This finding laid the groundwork for three clinical studies to date on Amarasate, the active ingredient in Calocurb.

Clinical Study Details

With scrutiny toward weight management and blood sugar related dietary supplement claims, it’s important to ensure that products are backed by sound science.
 
Kennedy noted that few supplement brands are up to the task of investing the appropriate amount of time and money into a single ingredient to create the portfolio of science necessary for claims related to weight loss and appetite suppression.
 
“All of Calocurb’s clinical trials are ethics-approved, independent, double-blind, randomized trials that have been published in high-end journals,” said Kennedy. “This commitment to one ingredient and product over 14 years, with $30 million in funding, is unusual in the supplement category.
 
“We not only get a statistically significant result,” she continued, “but a behavioral change, which is shown by our hunger and craving scores (VAS measured) and the average of an 18% drop in calorie intake after 1 hour. It is the only supplement in the world that has been clinically proven to stimulate the release of three important appetite-suppressing hormones at 600% above base level. Other supplements may stimulate some GLP-1 release or create an environment for GLP-1 production, but not at levels required for behavioral change. Literature tells us this needs to be above 400% for this to occur.”
 
Calocurb is also adding to an industry-wide effort to validate results in women across both monthly hormonal cycles and menopause. Despite challenges related to timing treatments at specific times in the menstrual cycle and at the same point each week, while the COVID-19 pandemic was at its height, “the results were stunning,” according to Kennedy.
 
“We showed that women are more sensitive to GLP-1 stimulation with a greater reduction in hunger and craving than men,” she said. “This is thought to be an evolutionary mechanism making women more sensitive to protect their fetus. This result shows that Calocurb can be used at specific times in the menstrual cycle (luteal phase) when women can eat up to 600 calories more per day, and through menopause when women have to eat approximately 200 calories less per day just to stay the same size.” 
 
In three clinical studies to date, the hops extract was shown to reduce subjective feelings of hunger, which translated to real-world, significant reductions in the amount of calories consumed among clinical trial participants.
 
A 2019 randomized, placebo-controlled study in Nutrients, the first human clinical study on the ingredient, evaluated potential impacts on subjective ratings of appetite during a 24-hour water-only intermittent fast. Thirty healthy men fasted on the same day of each week for 3 weeks straight, during which time they were given either a high (250 mg) or low (100 mg) dose of Amarasate twice daily, with both groups showing a significant decrease in self-reported measures of hunger by at least 10%. Reductions in self-reported hunger of 30% were achieved in the high-dose group, with results suggesting that a single dose of the compound can significantly enhance satiety for a 4-hour window.
 
A follow-up study a few years later found that, in a group of healthy men, Amarasate’s impact on the subjective experience of hunger led to real-world calorie intake reductions. Researchers administered either a placebo or 500 mg of the ingredient to 19 healthy-weight men, either in a delayed-release or regular form, and tracked their energy intake at lunch and during an afternoon snack. Blood samples were taken, along with subjective measures of appetite, GI discomfort, vitality, meal palatability, and mood. In addition to being associated with an 18% reduction in calories consumed, the hop extract stimulated ghrelin, CCK, GLP-1, and PYY responses compared to placebo. Both delivery forms of the hop extract resulted in a release of hormones involved in appetite and glycemic regulation, “providing a potential ‘bitter brake’ on energy intake in healthy men,” the authors noted.
 
Earlier this year, a randomized, placebo-controlled human clinical study published in Obesity Pillars found that, in 30 women, those who took either a high- or low- dose of Amarasate twice daily at 16 and 20 hours into a 24-hour fast experienced a significant reduction in appetite, and cravings (roughly -40%), as well as calories consumed during a fast-breaking meal compared to placebo.
 
“These data suggest that appetite suppressant co-therapy may be useful in reducing hunger during fasting in women and shows that gastrointestinal delivery of bitter compounds may also be an effective method of reducing cravings for food,” the authors concluded. “The relative decrease in absolute hunger ratings observed here was a greater magnitude than what was previously seen in males.”
 
Calocurb’s fourth human clinical trial, supported by Plant and Food Research, is currently underway, and will be the largest study to date on the ingredient, Kennedy noted. The study will observe 150 men and women over a 6-month treatment period with 3 months of follow-up, measuring multiple biomarkers alongside changes in weight.
 
“Calocurb can help anyone who is struggling with hunger and cravings, trying to make healthy choices,” Kennedy said, noting that sensations of hunger increase gradually over months after a person’s calorie intake is reduced. “Our primitive hindbrain controls hunger, and if it senses you are going into a famine, or reducing calories, it tells you to go and look for food. This was an essential asset for humans in evolution, but in the modern world where we are surrounded by food, it is a liability.”
 
Kennedy noted that, in addition to serving as a standalone option, “Calocurb is being used by practitioners as patients come off GLP-1 agonists because it restimulates the body’s own production of GLP-1, and CCK/PYY, re-establishing that gut-brain connection. Calocurb can serve as a safety net for people coming off the drugs to start managing their eating and to prevent the weight rebound that’s often reported.”
 

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About the Author: Mike Montemarano has been the associate editor of Nutraceuticals World since 2020. He can be reached at mmontemarano@rodmanmedia.com.