Retatrutide belongs to a new generation of GLP-1 drugs designed to regulate appetite and support weight loss. Although the drug remains under investigation and is not approved for use, some people are purchasing unapproved preparations not intended for human consumption and discussing their experiences on internet forums.

Researchers at the University of Pennsylvania analyzed approximately 150,000 Reddit posts and comments from about 40,000 users. Their study, published in JAMA Network Open, provides the first systematic investigation of potential side effects reported by people who claim to be using unapproved retatrutide.

One finding stood out: Among users who categorized their symptoms, increased appetite was the most common complaint. This was unexpected because retatrutide is designed to suppress hunger, while its Phase 2 clinical trial primarily identified gastrointestinal problems as the most frequent side effect.

AI identifies unexpected weight-loss drug reports

“Our goal is to identify hypotheses that can be tested in online conversations. AI can help find recurring patterns in people’s self-reports, including experiences that may be missed by traditional drug safety monitoring,” said Sharath Chandra Guntuk, research associate professor in the Department of Computer and Information Sciences at the University of Pennsylvania, director of the Computer Social Listening Lab, and lead author of the study.

However, the researchers emphasized that the finding should not be interpreted as evidence of previously unknown side effects. Reddit users represent a different population from clinical trial participants, and their accounts cannot prove that retatrutide caused the symptoms they described.

There is also considerable uncertainty about what these individuals actually ingested. Products sold outside regulated medical channels may differ from genuine experimental drugs in their composition, purity, and dosage.

“We cannot say that retatrutide is causing these symptoms, nor can we say that Reddit users are actually taking real retatrutide, because the drug is not legally available and gray-market formulations vary,” said Lyle Unger, a professor in the Department of Computer and Information Sciences and co-author of the study.

Rather than confirming new risks, the research gives scientists questions that can be examined through more rigorous studies.

“This is our first glimpse into the experience of a population that is not subject to traditional pharmacovigilance because they are taking unapproved versions of drugs that have not yet completed clinical trials,” said Neil Sehgal, lead author of the study and a doctoral student in the Department of Computer and Information Sciences.

How researchers analyzed 150,000 Reddit posts

The project builds on previous research by the University of Pennsylvania team. In an earlier study, scientists examined more than 400,000 Reddit posts discussing semaglutide and tirzepatide using large language models, or LLMs—a form of artificial intelligence that powers many modern chatbots.

That analysis identified reports of possible side effects, including menstrual irregularities, that may not be well documented in clinical trials or official drug-safety records.

“We wanted to apply the same methodology to gray-market retatrutide,” Sehgal said.

Retatrutide is of particular interest because it works differently from existing GLP-1 drugs. Semaglutide acts on one hormone receptor involved in blood-sugar control and appetite regulation, while tirzepatide targets two. Retatrutide activates three receptors and may produce different combinations of effects throughout the body.

To examine people’s experiences, researchers used AI to analyze 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 system extracted the symptoms users associated with the drug and translated their descriptions into standardized medical terminology. This allowed researchers to compare reports even when users employed different words to describe similar experiences.

After excluding possible effects such as weight loss and loss of appetite, the researchers identified 7,823 users who reported at least one medically classifiable symptom.

“Researchers may be able to manually examine thousands of Reddit posts, but examining nearly 150,000 posts would be a daunting task,” Sehgal said. “AI allows us to analyze these conversations at scale, identifying patterns in what people share that are otherwise difficult to recognize.”

A surprising appetite paradox

The most notable difference concerned hunger.

In Phase 2 clinical trials of retatrutide, the most common experience was gastrointestinal distress, including nausea. The drug is currently in Phase 3 trials, the final stage before potential FDA approval. Gastrointestinal effects are a well-known concern with drugs that affect appetite and digestion.

However, the pattern appeared different among Reddit users who reported taking unapproved retatrutide. Despite the drug’s significant weight-loss effects in clinical trials, increased appetite was the most frequently reported classifiable symptom in the Reddit analysis.

The researchers also compared the findings with previous analyses of semaglutide and tirzepatide.

Compared with earlier Reddit reports, discussions about unapproved retatrutide included proportionately more mentions of appetite changes, sleep disturbances, increased heart rate, and muscle-related symptoms. Reports of nausea and other gastrointestinal disorders were proportionately less common.

These differences may reflect how retatrutide interacts with the body. They may also result from differences between the groups discussing each drug, the use of other medications, or the contents of unapproved products.

“Retatrutide works differently from existing GLP-1 drugs, so it may have different effects on the body,” said Jenna Shaw Toronieri, senior research scientist at the Pennsylvania Center for Weight and Eating Disorders and a co-author of the study.

“But the people discussing it on Reddit may also be different,” she added. “Users who seek to obtain unapproved drugs on the gray market are likely to differ from other clinical populations. Some may be taking multiple experimental peptides, but we cannot be sure exactly what they are taking. Further research is needed to understand what, if anything, these differences in self-reported symptoms mean.”

Can AI detect drug-safety concerns earlier?

Beyond the findings involving retatrutide, the study demonstrates how AI could support the early detection of potential drug-safety concerns.

Traditional monitoring systems rely heavily on clinical trials, reports submitted to regulatory authorities, and information collected by medical professionals. People who obtain experimental drugs through unapproved channels may not be represented in these systems.

Social media provides another potential source of information, allowing researchers to identify repeated experiences that might otherwise escape attention. However, these reports must be independently investigated before they can be considered reliable evidence of drug-related problems.

The University of Pennsylvania team has already seen how this approach can guide further research.

In a previous study of semaglutide and tirzepatide, researchers identified online reports of menstrual irregularities. The findings later encouraged another scientific team to investigate similar conditions using the FDA database of reported adverse drug events.

The follow-up study, published in Obstetrics & Gynecology, also detected disproportionate reporting of certain menstrual changes. Although the findings did not establish a causal relationship, they provided additional reasons to investigate potential associations.

Researchers hope the retatrutide findings will lead to similar independent studies as the drug advances through clinical development.

“That’s what we hope will happen with this study,” Sehgal said. “Other researchers can take what we found on Reddit and look for the same patterns in other datasets using completely different methods. Whether those signals hold or not, the goal is to build a better understanding of what people are actually experiencing.”

This 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. Part of the funding was provided by the University of Pennsylvania Penn Medical Communication Institute. Toronieri disclosed receiving an investigator-initiated grant from Novo Nordisk on behalf of the University of Pennsylvania and consulting fees from Currax Pharmaceuticals, LLC. No conflicts of interest were reported by the other authors.