An experimental weight-loss drug that has not yet received regulatory approval is already attracting users willing to obtain unapproved versions online. Now, scientists are using artificial intelligence to investigate their experiences, uncovering unexpected symptom reports that differ from those documented in clinical trials.
The drug, retatrutide, belongs to a new generation of GLP-1 medications designed to help regulate appetite and body weight. Although it remains under investigation and is not approved for use, people are purchasing unapproved formulations that are not intended for human consumption and discussing their experiences on internet forums.
Researchers at the University of Pennsylvania analyzed nearly 150,000 Reddit posts and comments from approximately 40,000 users to investigate these accounts. Their study, published in JAMA Network Open, provides the first systematic examination of potential side effects reported by people claiming to use unapproved retatrutide.
One finding stood out. Among users whose reported symptoms could be classified, increased appetite was the most common complaint. That was particularly unexpected because retatrutide is designed to suppress hunger, and its Phase 2 clinical trials primarily identified digestive problems as the most frequent side effects.
AI Uncovers Unexpected Weight-Loss Drug Reports
“Our goal is to identify hypotheses in online conversations that we could test. AI helps us find recurring patterns in people’s self-reports, including experiences that may be missed by conventional drug-safety monitoring,” says Sharath Chandra Guntuku, Research Associate Professor in Computer and Information Science (CIS), Director of Penn’s Computational Social Listening Lab and senior author of the study.
However, the researchers emphasize that the findings should not be interpreted as proof of previously unknown side effects. Reddit users represent a very different population from clinical trial participants, and their accounts cannot establish whether the drug caused the symptoms they described.
There is also considerable uncertainty about what these individuals are actually taking. Products sold outside regulated medical channels may differ from the genuine experimental medication in their ingredients, purity, and dosage.
“We can’t say that retatrutide is causing these symptoms, or even that Reddit users are actually taking genuine retatrutide, since the drug is not legally available, and gray market formulations vary,” says Lyle Ungar, Professor in CIS and a co-author of the study.
Rather than confirming new risks, the research offers scientists an opportunity to identify questions that warrant more rigorous investigation.
“This is the first glimpse into the experiences of a population that is otherwise outside conventional drug safety monitoring because they are taking unapproved versions of a drug that has yet to finish clinical trials,” says Neil Sehgal, the study’s first author and a doctoral student in CIS.
How Researchers Analyzed 150,000 Reddit Posts
The project builds on previous research by the University of Pennsylvania team. In that earlier investigation, scientists used large language models (LLMs), the type of artificial intelligence that powers many modern chatbots, to examine more than 400,000 Reddit posts discussing semaglutide and tirzepatide.
That analysis revealed reports of possible side effects, including menstrual irregularities, that may not have been fully documented in clinical trials or official drug safety records.
“We wanted to apply the same methodology to gray-market retatrutide,” says Sehgal.
Retatrutide is particularly interesting because it works differently from existing GLP-1 medications. Semaglutide acts on one hormone receptor involved in blood sugar control and appetite regulation, while tirzepatide targets two. Retatrutide activates three receptors, potentially producing a different combination of effects throughout the body.
To investigate what people were experiencing, the researchers used AI to examine nearly 150,000 Reddit posts and comments. They identified approximately 14,000 users who claimed to have personally taken an unapproved version of retatrutide.
The AI systems then extracted descriptions of symptoms that users associated with the medication and translated those descriptions into standardized medical terminology. This allowed researchers to compare reports even when different people used different words to describe similar experiences.
After excluding expected effects such as weight loss and reduced appetite, the team identified 7,823 users who reported at least one symptom that could be medically classified.
“A researcher might be able to examine a few thousand Reddit posts by hand, but looking at nearly 150,000 would be an enormous undertaking,” says Sehgal. “AI makes it possible to analyze these conversations at scale, identifying patterns in what people are sharing that would otherwise be difficult to recognize.”
A Surprising Appetite Paradox Emerges
The most striking difference involved hunger.
In retatrutide’s Phase 2 clinical trials (the drug is currently in Phase 3 trials, the final step before FDA approval), participants most commonly experienced gastrointestinal complaints, including nausea. These effects are familiar concerns with medications that influence appetite and digestion.
But among Reddit users who reported taking unapproved retatrutide, the pattern looked different. Increased appetite emerged as the most frequently described classifiable symptom, despite the substantial weight-loss effects demonstrated in clinical testing.
The researchers also compared the new findings with their earlier analysis of semaglutide and tirzepatide.
Compared with those earlier Reddit reports, discussions involving unapproved retatrutide contained proportionally more mentions of appetite-related changes, sleep disturbances, increased heart rate, and muscle-related symptoms. Reports of nausea and other digestive complaints were proportionally less common.
These differences could reflect how retatrutide interacts with the body. However, they could also result from differences between the groups of people discussing the medications, their other drug use, or the contents of the unapproved products.
“Retatrutide works differently from existing GLP-1 drugs, so it’s possible that its effects on the body are different, too,” says Jena Shaw Tronieri, Senior Research Investigator at Penn’s Center for Weight and Eating Disorders and a co-author of the study.
“But the people discussing it on Reddit also may be different,” she notes. “Users willing to obtain an unapproved medication on the gray market likely differ from other clinical populations. Some may be taking multiple experimental peptides, and we can’t verify exactly what they’re taking. We need more research to understand what, if anything, these differences in self-reported symptoms mean.”
Can AI Detect Drug Safety Concerns Earlier?
Beyond the findings about retatrutide, the study demonstrates how AI could potentially improve the early detection of drug safety concerns.
Traditional monitoring systems depend heavily on clinical trials, reports submitted to regulators, and information collected by healthcare professionals. People obtaining experimental medications through unapproved channels may not be represented in those systems.
Social media offers another source of information, allowing researchers to identify recurring experiences that might otherwise escape attention. However, these reports must be independently investigated before they can be considered reliable evidence of a drug-related problem.
The Penn team has already seen an example of how this approach can help guide further research.
In their previous investigation of semaglutide and tirzepatide, researchers identified online reports of menstrual irregularities. Those findings subsequently encouraged another scientific team to examine similar symptoms using the FDA’s database of reported adverse drug events.
The follow-up study, published in Obstetrics & Gynecology, also detected disproportionate reports of certain menstrual changes. Although those findings did not establish causation, they provided additional reasons to investigate the potential connection.
The researchers hope their retatrutide findings will lead to similar independent studies, particularly as the drug advances through clinical development.
“That’s what we hope will happen with this study,” says Sehgal. “Other researchers can take what we find on Reddit and look for the same patterns in other datasets, using entirely different methods. Whether those signals hold up or not, the goal is to build a better understanding of what people are actually experiencing.”
The research was conducted through the University of Pennsylvania’s School of Engineering and Applied Science and Perelman School of Medicine. Benjamin Rader of Boston Children’s Hospital also contributed as a co-author. Funding was provided in part by the University of Pennsylvania’s Penn Medical Communication Research Institute. Tronieri disclosed receiving an investigator-initiated grant from Novo Nordisk on behalf of the University of Pennsylvania, along with consulting fees from Currax Pharmaceuticals, LLC. No conflicts of interest were reported by the other authors.
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