Maricel Maffini, consultant, and Tom Neltner, Chemicals Policy Director
A federal district court this fall ruled that the Food and Drug Administration (FDA) has the authority to allow food companies to make Generally Recognized as Safe (GRAS) safety determinations for novel chemicals added to food without notifying the agency. The decision followed a lawsuit by EDF and others, in which we challenged this practice. The court agreed, in part, with FDA that an uptick in companies voluntarily choosing to send notices to the agency since the 2016 rule went in effect was a sign that the program was working. We disagree with the court’s conclusion but opted not to appeal.
This blog is the second in our Broken GRAS series where we explore how the voluntary notification system works in practice and why it is broken. The first dealt with a synthetic chemical called apoaequorin and marketed as Prevagen, a chemical found in jellyfish and used in protein shakes. The company claims the substance helps memory, but FDA has repeatedly raised serious questions about its safety. Despite the agency’s concerns the company continues to sell the product as GRAS.
In this blog, we examine another voluntary GRAS notice, this one for GABA, a neurotransmitter naturally produced in the brain and known to slow down certain nervous system activities. It is marketed as a food ingredient despite FDA’s serious concerns with the notice that prompted the company to withdraw it. The agency does not make such information publicly available. We were able to learn of FDA’s concerns through a Freedom of Information Act (FOIA).
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Companies have the option to voluntarily notify FDA when they determine that a use of a new chemical or a new use of an existing chemical is Generally Recognized as Safe, or GRAS. When they do notify FDA, agency scientists then review the data and supporting information and can ask additional questions. In most of the cases, FDA agrees with the company’s determination and publishes a “no questions” letter. In roughly 20% of cases, however, companies ask the agency to stop the process after receiving the scientists’ questions. FDA then stops its review and announces a “cease to evaluate” status in the GRAS notification inventory, and that’s the end of it. There is no public record of as to why the company withdrew the notice. In some cases, a brief summary is included in the agency’s response to the cease to evaluate letter published in its website. The company is free to market and sell the substance if it still believes the chemical’s use is GRAS.
This happened with gamma aminobutyric acid (GABA). As you will see, the GABA case is a prime example of the 1) importance of FDA’s scientific review of safety data, and 2) profound implications for health risks when the agency takes no action in response to safety concerns raised by its own experts. A product with the safety concerns we describe below warrants closer examination, regardless of its current market share. Where serious health effects are found, it is important for FDA to act quickly before a specialty product like this one becomes more popular, and its health risks amplified.
What is GABA?
GABA is a neurotransmitter we all have in our bodies. Its primary function is to modulate communications between nerve cells and reduce neuronal activity. The GABA we make helps us fall asleep, reduces mental and physical stress, lowers anxiety, and creates calmness. It is made in the brain from glutamate, an amino acid commonly found in foods like cheese, meats, fish, eggs, tomatoes, walnuts, and broccoli.
Many companies currently manufacture and sell GABA as a dietary supplement and promote it as a sleep-aid. However, it appears that FDA has only reviewed the safety of this use once. That review was in response to a 2016 new dietary ingredient notification – the method FDA employs to evaluate ingredients in dietary supplements not in use before 1994. Minnesota-based Green Rose LLC told FDA that its product, Take5, contains GABA and the amino acid L-theanine. FDA objected to the notification because it “consists of one page that is essentially a cover letter,” and did not include basic information like the conditions of use, safety data, and description of the supplement.
FDA review of GABA uses as food ingredient – Take 1
Japanese company Pharma Foods International (Pharma Foods) submitted the first GABA GRAS safety determination to FDA (GRN 257) in July 2008. The company said GABA would be used as a food ingredient (as opposed to a dietary supplement) added to a “variety of food products including beverages and beverage bases, chewing gum, ready-to-drink coffee and tea products, and candy at concentrations ranging from 0.04 to 4% in various food types.” Pharma Foods hired the consulting firm Cantox, now known as Intertek,[1] to assist with the notification.
The notification states that an expert panel convened by the consulting firm produced a consensus statement concerning the “GRAS status of GABA for use as a food ingredient.” The panel consisted of three university professors, Joseph F. Borzelleca, Ph.D. (Virginia Commonwealth University, School of Medicine), William J. Waddell, M.D. (University of Louisville School of Medicine) and Stephen L. Taylor, Ph.D. (University of Nebraska).
According to the notice submitted to FDA, the expert panel, “independently and collectively, critically evaluated a comprehensive package of scientific information and data” compiled by Cantox. FDA scientists, however, pointed out a series of issues, including:
- the cumulative estimated dietary exposure values were above the toxicology values considered safe, meaning people could consume unsafe levels of GABA under the expected uses;
- failure to discuss absorption, distribution, metabolism, and excretion (ADME) studies, resulting in a lack of information on how the body would process and eliminate GABA;
- relying on unpublished studies, as well as some in Japanese with no English translation.
After FDA’s scientists raised their concerns, Pharma Food withdrew the notification in January 2009. The interactions between the agency and the company’s consultants can be accessed here.
FDA review of GABA uses as food ingredient – Take 2
In August 2015, Pharma Foods submitted a new notification (GRN 595) to FDA to review its revised GRAS safety determination for GABA. This time the company said GABA would be used as “an ingredient in snack bars, breakfast cereals, processed cheese, chewing gum, yogurts, hard and soft candies, chocolate, and beverages and beverage bases including carbonated, energy, flavored, powdered and sports drinks, flavored milk and milk drinks and coffee and tea at a level intended to provide 100 milligrams of GABA per serving”.
Like the first submission, the notification indicated a consensus opinion from the experts, two of whom had been contracted to review the first GRAS notification, plus Dr. John A. Thomas (Indiana Univ. School of Medicine), who replaced Dr. Waddell. The consulting firm handling the data was Intertek.
This time, FDA scientists had more serious questions than in 2008, concluding that “there appear to be critical data gaps that exist to support their GRAS determination under the conditions of their intended use.” Below is a summary of the most troubling concerns expressed by the FDA reviewers. The entire set of documents can be accessed here.
FDA’s scientists said the company’s determination relied on two “critical assumptions”, that oral ingestion of GABA resulted in low absorption into the blood stream and that GABA does not cross the blood-brain barrier. But these assumptions “are not yet validated in several subpopulations that are expected to consume the foods proposed by the notifier for its intended uses,” the agency scientists said.
FDA’s scientists noted several critical data gaps, including:
- Lack of developmental and reproductive toxicity studies, as well as ADME studies to support safety in pregnant or lactating women or in young children. FDA said, “Although there are no specific adverse effects of GABA in pregnant or lactating women and in children reported in the literature, there clearly exists a data gap to effectively assess safety of orally ingested GABA in this vulnerable subpopulation, related to data on uptake across the gastrointestinal tract, crossing the blood brain barrier in fetuses and young children, and whether this causes adverse effects.”
- Insufficient data to rule out potential effects on the pituitary gland. Pharma Food dismissed data suggesting orally administered GABA could affect pituitary and hypothalamic function, arguing such effects only presented in adults at high doses. FDA’s scientists said
“[N]o study has been undertaken to examine dose-effects or whether such high doses are required to elicit pituitary/hypothalamic response in children and pregnant/lactating women. Given such an important role both organs play during pregnancy, lactation, reproduction, and development, we were unable to find sufficient data to evaluate the safety of chronic oral exposure of GABA to these susceptible population groups.”
- Lack of consideration of effects of ingestion of GABA on the gastrointestinal tract, including effects on the gut immune system, “given the developmental importance of gut microflora with respect to allergenicity and oral tolerance in infants”.
- Lack of data addressing concerns regarding GABA effects on individuals with high blood pressure, interference with blood pressure medication, and similarities with GABA derivative drug (Baclofen) with reported adverse effects in pregnant women.
- Cumulative dietary exposure estimate did not include all dietary sources both natural and dietary supplements.
In November 2015, Pharma Foods again asked FDA to cease its evaluation. In an email to FDA, the company said, “we feel we need time to conduct further studies and we would like to withdraw it. We will continue to make efforts to address the concerns raised by you, eventually for our re-application in the future”.
We have not found another GRAS notification for GABA submitted to FDA since 2015.
GABA is marketed for its health benefits
Despite serious safety concerns raised by FDA scientists, PharmaGABA continues to be marketed as “a functional food ingredient in multiple kinds of food products worldwide.” One of these includes chocolate marketed for mental health or as a sleep aid, like Sleepy Chocolate. Others are available on e-commerce sites, in addition to products marketing GABA as a dietary supplement.
Pharma Foods says the ingredient provides “a number of health benefits derived from the natural and safe manufacturing technique.”
Lack of FDA action allows for the proliferation of products with high health risks
The case of GABA illustrates how companies can market products regardless of questions raised by FDA scientists that could have profound consequences on the health and wellbeing of individuals, including children and pregnant women.
PharmaGABA continues to be marketed. We were unable to identify any action the agency may have taken despite the many safety concerns of its own scientists. We have previously reported on this disconnect between agency scientists and agency action in the context of PFAS. GABA is another example of the agency being apparently unable or unwilling to act. At the bare minimum, FDA should publish its safety concerns and warn the public of the health risks of taking dietary supplements and consuming foods with GABA.
[1] Cantox Health Sciences became Intertek in 2010