Semaglutide (sold under brand names like Ozempic, Wegovy, and Rybelsus) has become one of the most talked-about medications of the decade. Originally developed to treat Type 2 diabetes, it is now widely taken for weight management and has shown promise in reducing cardiovascular risk. Clinical trials confirm it can produce significant weight loss and improve a range of metabolic markers. But with that popularity has come a growing conversation about its side effects, from the expected to the surprising to the still-unknown.
"When both our parents were diagnosed prediabetic (and our mother being a very healthy dance teacher of 30+ years), we began to explore our own blood sugar challenges and history. Many of the markers of insulin resistance can be misinterpreted as hormone issues, thyroid issues, etc. After trying every diet and weight loss strategy under the sun, our fears were confirmed - we are both insulin resistant with additional, individual health challenges to boot. That's when we decided to try semaglutide."
- Natalie Peluso, Co-Founder of Lean On
How Semaglutide Works
Semaglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist. It mimics a hormone your body naturally produces to regulate blood sugar and appetite. A weekly dose not only suppresses appetite but also slows the rate at which food leaves the stomach, a process called gastric emptying. This is central to how it helps with weight loss, but it is also the root cause of many of its most common side effects.
The Most Common Side Effects: Gastrointestinal Issues
Across multiple clinical trials, gastrointestinal (GI) problems are consistently the most frequently reported side effects of semaglutide. These include:
- Nausea (the most common complaint)
- Vomiting
- Diarrhea
- Constipation
- Abdominal pain or bloating
- Fatigue and headache
- Burping and flatulence
The good news is that for most people, these effects are manageable and tend to diminish as the body adjusts. Research presented at the American Diabetes Association's 2025 Scientific Sessions confirmed that gastrointestinal adverse events were most common during the dose-escalation phase and decreased over time for the majority of participants.
That said, for a meaningful portion of patients, nausea and vomiting are severe enough to affect daily life or prompt discontinuation of the medication.
"The weight loss was immediate. What also was immediate was the side effects. Nausea, vomiting in the morning if my stomach was too empty, diarrhea... It was rough going at first, and while those were very persistent short term affects, the long term affects were more worrysome."
- Alesha Peluso, Co-Founder of Lean On
Muscle Loss: A Less-Talked-About Risk
One of the more concerning emerging findings around semaglutide is the extent to which weight lost on the drug can come from lean muscle mass rather than fat alone. Research suggests that up to 39% of weight lost during semaglutide treatment may come from lean muscle mass, which can affect metabolism, physical function, injury risk, and long-term independence.
A study published in Clinical Infectious Diseases in early 2025 specifically examined semaglutide's effects on muscle structure and function, finding that muscle loss often accompanies the drug's weight-loss effects. Research from ScienceDaily in 2025 noted this risk appears particularly pronounced in women and older adults.
This is not purely a cosmetic concern. Loss of muscle mass (sarcopenia) has downstream consequences for bone health, balance, and metabolic rate, which may also make it harder to keep weight off long term.
What you can do: Many clinicians now recommend combining semaglutide with resistance training and adequate protein intake to help preserve lean muscle during treatment.
"I'm a 5 days a week HIIT workout kind of gal, so when I started having to drop my weights by over half what I normally lift, I knew the side effects weren't just gastrointestinal. I was seeing the numbers on the scale go down, yes, and so was my strength and energy. I didn't have the appetite to eat all the protein I needed and protein powder would wreck my stomach. It was a depressing spiral."
- Natalie Peluso, Co-Founder of Lean On
Mental Health: An Evolving Picture
The relationship between semaglutide and mental health is one of the most actively debated areas in current research and one where personal experience can diverge sharply from the clinical data.
What the research says: Early clinical trials did not flag mood changes as a common side effect, and a preliminary FDA evaluation did not find evidence that these medications cause suicidal thoughts or actions. The European Medicines Agency similarly reported no confirmed causal link between GLP-1 agonists and suicidal behavior. Some studies have even found that GLP-1 medications are correlated with a lower likelihood of anxiety and depression diagnoses.
What some patients report: Despite this, thousands of users have come forward with experiences of emotional changes such as crying more often, unexplained anxiety, or a sense of emotional detachment. A 2024 cohort study published in Nature involving more than 300,000 patients found a slightly elevated risk of depression and suicidal ideation in semaglutide users compared to non-users. More than 500 reports of psychiatric symptoms (ranging from anxiety to thoughts of self-harm) have appeared in adverse event databases. The FDA and EMA have both launched ongoing reviews.
Researchers note that it is difficult to untangle the effects of the medication from other factors, including the psychological weight of living with obesity, rapid body changes, and pre-existing mental health conditions.
On the more positive side: A randomized controlled trial published in JAMA Psychiatry in early 2025 found that people with alcohol use disorder who took low doses of semaglutide had fewer heavy drinking days, fewer cravings, and reduced alcohol consumption overall, suggesting the drug's effects on the brain's reward pathways may have some beneficial applications.
"In my own experience, one of the best upsides of semaglutide was the positive impact in had on my mental health. I had long wondered if I needed anti-anxiety medicine however my mood significantly improved after starting semaglutide, even before making significant progress in weight loss."
- Alesha Peluso, Co-Founder of Lean On
Serious but Rarer Side Effects
Clinical research and the FDA have identified a number of serious adverse effects that, while uncommon, warrant awareness:
Pancreatitis
Inflammation of the pancreas occurs in fewer than 1% of people who take semaglutide, but it can be severe. Symptoms include intense abdominal pain, with or without vomiting, and require immediate medical attention.
Gallbladder Disease
Acute gallbladder disease, including gallstones, has been reported in association with semaglutide use, likely related to the effects of rapid weight loss on bile composition.
Kidney Problems
Severe dehydration from vomiting or diarrhea can lead to acute kidney injury. Staying well hydrated is especially important for people on this medication.
Thyroid Concerns
Semaglutide carries an FDA black box warning regarding a rare type of thyroid cancer (medullary thyroid carcinoma) because it caused thyroid tumors in long-term animal studies. To date, studies in humans have not confirmed this risk, but as a precaution, semaglutide is not recommended for people with a personal or family history of medullary thyroid cancer or Multiple Endocrine Neoplasia type 2. Symptoms to watch for include a lump in the neck, hoarseness, difficulty swallowing, or shortness of breath.
Eye Problems
A study published in December 2025 by researchers analyzing FDA Adverse Event Reporting System data found a potential association between semaglutide and a range of eye disorders, from swelling to, in rare cases, vision problems. Researchers caution that a causal link has not been established and further study is needed.
Increased Heart Rate
Some users experience a slight increase in resting heart rate. This should be monitored, especially in people with underlying heart conditions, though the drug has also been shown in large trials (the SELECT trial) to reduce major adverse cardiovascular events in people with obesity and existing heart disease.
"While my sister and I haven't experienced any major side effects, we have been extremely careful to support the areas of our health that are most affected by GLP1, such as stacking extra vitamins (B12/Folate/D3K2 + Digestive Enzymes/Protein/BCAA/Biotin)
Hair Loss
Hair loss (telogen effluvium) has been reported by a notable number of semaglutide users. This appears to be linked less to the medication itself and more to rapid weight loss and potential nutritional deficits, particularly if caloric intake drops significantly. It is usually temporary and resolves as the body stabilizes.
What Happens When You Stop
One important and often under-discussed reality of semaglutide is what happens after stopping the medication. Research has shown that weight regain is common after withdrawal. In some cases, a significant portion of lost weight returns within a year. This has led many clinicians to characterize semaglutide as a long-term or lifelong medication, similar to how blood pressure or cholesterol medications are approached.
This is not a personal failing. It reflects the drug's mechanism. Once appetite suppression is removed, hunger signals return, often strongly.
"When I stopped taking semaglutide for a season (actually, to prepare for the launch of DeepSculpt so I could test it on myself for the earliest side effects) I was prepared for the return of the hunger cravings. What I wasn't prepared for was the return of my anxiety, inflammation throughout my body, and the bloating. After 6 months of being off GLP1, those side effects were more challenging to me than any weight gain, which was substantial despite my efforts to maintain my same eating habits."
- Alesha Peluso, Co-Founder of Lean On
Managing Side Effects: Practical Tips from Research
Clinicians and researchers have identified several strategies that can help reduce the burden of side effects:
- Go slow on dose escalation. Taking longer to increase the dose gives the body time to adjust and significantly reduces GI distress.
- Eat smaller, more frequent meals and avoid high-fat, spicy, or heavily processed foods, especially early on.
- Stay hydrated, particularly if experiencing nausea or vomiting.
- Prioritize protein and resistance exercise to help protect lean muscle mass.
- Track mood changes and discuss them with your provider — especially if symptoms of depression, anxiety, or unusual emotional shifts emerge.
- Don't skip follow-up appointments. Blood sugar, kidney function, thyroid, and gallbladder health should all be monitored regularly.
"The side effects of semaglutide is why we started Lean On. We create new formulas that work to protect your body while improving the experience of taking semaglutide. We believe everyone deserves to feel their best, and while the world is making it harder and harder for us to achieve that goal, we believe in the power of our bodies to restore our own health with the right support. And we hope that Lean On is that support."
- Alesha Peluso, Co-Founder of Lean On
The Bigger Picture
Semaglutide is a genuinely powerful medication with real, research-backed benefits for blood sugar control, cardiovascular risk reduction, and weight management. Clinical trials, including those commissioned by the World Health Organization and published in journals like The Lancet and the New England Journal of Medicine, consistently demonstrate its effectiveness.
But powerful medications come with trade-offs. The side effect profile is real, individual experiences vary widely, and much is still unknown about long-term use, particularly for people who have been on it only a few years. The researchers themselves acknowledge that most studies to date have been funded by Novo Nordisk, semaglutide's manufacturer, and that independent, long-term data in broader populations is still needed.
What is most important is that patients feel equipped to make informed decisions — and that they don't feel alone when their experience doesn't neatly match the clinical trials.
Sources
- Medical Research Archives (2025): Semaglutide in Adults with Overweight or Obesity and Diabetes Type 2 — A Narrative Review
- Cochrane Review, commissioned by the WHO (December 2024): Semaglutide for Adults Living with Obesity
- The Lancet SELECT Trial analysis (2025): Semaglutide and Cardiovascular Outcomes by Baseline Adiposity
- New England Journal of Medicine SELECT Trial (2023): Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes
- JAMA Psychiatry (February 2025): Hendershot et al., randomized controlled trial on semaglutide and alcohol use disorder
- Clinical Infectious Diseases (February 2025): Ditzenberger et al., Effects of Semaglutide on Muscle Structure and Function
- ScienceDaily (2025): reporting on Lancet Diabetes & Endocrinology Phase 3 trials, semaglutide 7.2 mg
- ScienceDirect (November 2025): Comparative Safety and Side Effects of Semaglutide and Tirzepatide
- BBC Science Focus Magazine (January 2026): We're Finally Learning the True Side-Effects of Weight-Loss Drugs
- GoodRx Health (2026): Can Ozempic Cause Depression or Mood Changes?
- American Psychological Association Monitor (2025): A New Era of Weight Loss: Mental Health Effects of GLP-1 Drugs
- FDA Adverse Event Reporting System data (December 2025): semaglutide and eye disorders
This article is intended for informational purposes and reflects publicly available research as of 2025–2026. It is not a substitute for medical advice. Please consult your healthcare provider before making any changes to your medication. The stories and experiences shared by the founder are their own and do not impress or reflect on the experiences of others on semaglutide.
