Increased appetite, fatigue, increased energy, and insomnia were among the retatrutide side effects reported in an analysis of close to 10,000 users commenting about the drug on the social media site Reddit.

These effects differed from the main side effects reported during clinical trials, according to the study authors.

“Even though retatrutide is still in clinical trials and not approved anywhere in the world, untold numbers of people are purchasing unapproved versions of the drug not intended for human consumption and posting about their experiences online,” lead author Neil Sehgal, ME, University of Pennsylvania, Philadelphia, told Medscape Medical News.

“We wanted to understand what people in these communities were reporting because their experiences may otherwise remain largely invisible to clinicians and traditional safety monitoring systems,” he said.

“The biggest surprise was that gastrointestinal symptoms were common but did not dominate the reports, unlike the pattern in the phase 2 trial,” he added. “The appetite findings were especially interesting given that retatrutide is being studied for weight loss.”

The study was published online on October 14 in JAMA Network Open.

Did Reta Cause These Side Effects?

Sehgal’s team previously conducted a study examining Reddit users’ experiences of adverse effects with tirzepatide and semaglutide. Reported side effects were similar to those in clinical trials, he said, but some effects that were identified, such as reproductive symptoms, had not been well captured in the trials.

The researchers took a similar approach for the current study. They conducted a cross-sectional analysis of 148,640 retatrutide-related Reddit posts and comments from 38,936 users across 27 retatrutide, peptide, and weight management communities from 2021 to 2025.

A large language model (gpt-5.4-nano) classified self-disclosed retatrutide use, extracted dose and demographic information, identified user-attributed symptoms, and mapped these to Medical Dictionary for Regulatory Activities Preferred Terms. Manual validation of 100 posts showed high precision and recall for use classification and symptom extraction.

Among 148,640 retatrutide-related posts and comments, the classifier identified 45,592 posts and comments from 13,589 users reporting current retatrutide use during the study period.

After excluding prespecified weight-related and appetite-suppression preferred terms, 7823 users (57.6%) formed the analytic denominator for symptom frequencies.

The most common reported symptoms were increased appetite (17.1%) fatigue (15.2%), increased energy (12.4%), nausea (11.6%), food craving (7.3%), insomnia (6.1%), and increased heart rate (4.8%).

Compared with those in the prior semaglutide and tirzepatide social media study, retatrutide discussions were more concentrated in appetite, general-system, muscle-related, sleep, and heart rate or pulse categories. By contrast, semaglutide and tirzepatide discussions were more concentrated in nausea and vomiting and gastrointestinal motility categories.

The reports of increased appetite were unexpected, given mean weight losses of up to 17.5% at 24 weeks in initial 12-mg/wk trials, the authors wrote.

“A key limitation is that we cannot determine whether retatrutide caused these experiences,” Sehgal acknowledged. “We could not verify what products people actually took, their purity, or the doses they took. The patterns we observed could reflect the drug’s unique pharmacology, variable product quality, concurrent use of other peptides or medications (‘stacking’ multiple peptides is a common practice in these online communities), differences in the users themselves (Redditors are a different population than those in the retatrutide clinical trials), or misattribution of untreated symptoms to the drug.”

For now, the findings should be considered “hypothesis-generating,” he said. Clinicians should consider asking nonjudgmentally about unapproved peptide use and pay attention to symptoms beyond gastrointestinal complaints, he advised.

‘Turning to Social Media for Guidance’

Commenting on the study for Medscape Medical News, Priya Jaisinghani, MD, obesity specialist at NYU Langone Health in New York City, said, “Although there is tremendous excitement surrounding investigational therapies like retatrutide, it is critical to distinguish the drug being studied in clinical trials from non-FDA-approved products sold on the gray market. These products may contain additional substances, or even ingredients that aren’t what they claim to be. This could potentially result in adverse effects that differ from those observed in clinical trials.”

The current study emphasizes that clinicians may encounter patients using a non-FDA-approved drug currently in clinical trials. “Patients may also turn to social media platforms like Reddit for guidance rather than consulting a healthcare professional or reporting adverse events to the FDA,” she said.

“This underscores the importance of nonjudgmental patient discussions, education about potential risks, clinical vigilance, and adverse event reporting through the FDA to strengthen safety surveillance,” she concluded.

Current Status of Retatrutide

Lilly plans to submit a Biologics License Application (BLA) for retatrutide to the FDA in the first quarter of 2027 based on the TRIUMPH trials in obesity, knee osteoarthritis pain, and moderate-to-severe obstructive sleep apnea, a Lilly spokesperson told Medscape Medical News. The company would not disclose which indications the BLA will cover. A submission for type 2 diabetes will follow in 2027.

This project was funded in part by the University of Pennsylvania’s Penn Medical Communication Research Institute. Sehgal reported having no disclosures. Jaisinghani disclosed consulting for Eli Lilly and Company; Novo Nordisk; Madrigal Pharmaceuticals, Inc.; Boehringer Ingelheim; and Corcept Therapeutics.

Marilynn Larkin, MA, is an award-winning medical writer and editor based in New York City whose work has appeared in numerous publications, including Medscape Medical News and its sister publication MDedge, The Lancet (where she was a contributing editor), and Reuters Health.