GLP-1 Medications Beyond Weight Loss: Metabolism, Cravings, and Brain Health
GLP-1 medications are some of the most talked-about drugs today – both in medicine and in mainstream media (and perhaps even your social circles!). Because of the effects on cravings and the brain’s reward system, GLP-1 medications are now being studied for addiction and alcohol use as well.
GLP-1 medications are approved for weight loss and type 2 diabetes, with the first GLP-1 drug being approved for diabetes more than 2 decades ago. So, they are not even close to new, but because of all the new things we are learning about them, their popularity has increased profoundly. A quick search on PubMed will validate this, with only 843 peer-reviewed articles about GLP-1s being published between 2004-2006 and 10,295 between 2024-2026!
Researchers are now studying GLP-1 medications for other conditions like cardiovascular disease, fatty liver disease (MASLD or NAFLD), several types of cancer, dementia, mood disorders, addiction, inflammation, and more. This FAQ explains the basics about GLP-1s in simple terms.
What Are GLP-1 Medications and How Do They Work?
GLP-1 stands for glucagon-like peptide-1, a hormone your body naturally makes. It helps control blood sugar, appetite, and cravings through a variety of mechanisms in the gut and the brain. Technically, GLP-1 medications are called GLP-1 receptor agonists – meaning that they act on the receptor that the endogenous hormone (GLP-1 that our body makes) stimulates in the human body.
Hormone function explained simply. These medications work in a few main ways:
Help your body release insulin when blood sugar is high
Slow down how fast food leaves your stomach
Make you feel full faster (less hunger)
Act on the brain to reduce cravings
Brain and appetite effects. GLP-1 medications also affect the brain’s reward system, which is important for regulating both appetite and addiction.
GLP-1 receptors are found in areas of the brain linked to reward (like dopamine pathways)
When activated, they can lower craving and reduce the “reward” feeling from substances or behaviors
Clinical trials in humans show they may reduce alcohol intake andnicotine intake and relapse. They also are being studied in human studies for cocaine,opioid, and methamphetamineuse disorders
They also impact both GABA and glutamate in the brain modulating excitatory/inhibitory balance, and help reduce neuroinflammation (a factor in neurodegenerative diseases like dementia)
What Conditions Are GLP-1 Drugs Approved For?
Type 2 diabetes. The first GLP-1 drug approved for the treatment of type 2 diabetes was the injection drug exenatide (BYETTA), approved in 2005.
Chronic weight management. The first GLP-1 drug approved for weight loss was liraglutide (SAXENDA), approved in 2014.
Semaglutide vs Tirzepatide: What’s the Difference?
GLP-1 vs dual agonist (GIP/GLP-1). The compound found in semaglutide is only a GLP-1 receptor agonist, while the compound found in tirzepatide is a dual agonist of the GLP-1 receptor as well as GIP (Glucose-dependent Insulinotropic Polypeptide) receptor. Activation of the GIP receptor may additionally promote weight loss, decrease hyperglycemia (elevated blood sugar), and reduce cravings by a variety of mechanisms.
GLP-1 weight loss results. Semaglutide (WEGOVY) was approved for the indication of weight loss and maintaining weight reduction in June of 2021, based on the STEP 1 trial. In this trial, participants with obesity or overweight lost an average of 15% of their body weight over 68 weeks.
Tirzepatide (ZEPBOUND) was approved for the indication of weight reduction and long-term maintenance in November of 2023, based on the findings from the SURMOUNT-1 trial. In this trial, adults who were overweight or obese lost up to 21% of their body weightat the highest dose of the medication (15 mg/week), compared to only 3% in the placebo group, over 72 weeks.
How Are GLP-1 Medications Taken?
Most FDA-approved GLP-1 medications are taken as once-weekly injections and come as prefilled injector pens. The injections are self-administered into the fatty tissue beneath the skin with a small needle. The once-daily oral tablet of semaglutide (WEGOVY) and orforglipron (FOUNDAYO), also a GLP-1 medication, were recently approved by the FDA for weight loss. With oral GLP-1 medications, slightly less weight loss is typically seen.
Through compounding pharmacies, GLP-1 drugs may be available in alternate formats such as flexible-dosing injections, oral suspensions, and troches. Oral suspensions typically use proprietary techniques to enhance absorption and drug bioavailability. Flexible dosing injections are typically taken 1-2x/week while oral suspensions and troches are usually taken daily. Compounded versions are typically more affordable and help make these compounds accessible to more individuals.
Who Qualifies for a GLP-1 Prescription?
In the clinical trials leading to the approval of GLP-1 medications for weight loss, adults age 18 and older were eligible for treatment if they had obesity (BMI ≥ 30 kg/m2) or overweight (BMI ≥ 27 kg/m2) plus the presence of at least one comorbidity (hypertension, dyslipidemia, obstructive sleep apnea, or cardiovascular disease). In clinical trials for alcohol use, adults meeting all inclusion and exclusion criteria with a BMI as low as 23 kg/m2 have been eligible for the study.
What Are the Common Side Effects?
Gastrointestinal (GI) symptoms. GI symptoms are the most common side effects with both semaglutide and tirzepatide. In the pivotal trials leading to the approval of these GLP-1 drugs for weight loss (STEP 1 and SURMOUNT-1), the rate of nausea was seen more often in semaglutide at 2.4 mg (44% of participants) as compared to tirzepatide at 5, 10, or 15 mg (24-33% of participants), although these trials did not compare the drugs head-to-head. Diarrhea and vomiting were the second and third most common side effects in both trials for patients on drug. Side effects were typically Grade 1 or 2.
In practice, side effects like these are seen most often in the days following treatment initiation or a dose increase. Medications such as ondansetron or botanicals like ginger may help reduce or prevent nausea and/or vomiting while fiber and natural or over-the-counter laxatives may help reduce constipation.
Rare but serious risks. In the STEP 1 and SURMOUNT-1 trials, gallbladder-related disorders (cholelithiasis, cholecystitis) occurred in ~2.5–3% and ~1–2% of patients on semaglutide and tirzepatide, respectively. Pancreatitis was very rare in both trials, occurring in less than 0.3% of participants on drug. Side effects leading to discontinuation (mostly due to drug intolerance) occurred in 7% of patients on semaglutide in STEP 1 and 4-7% of patients on tirzepatide (dose-dependent) in SURMOUNT-1.
Slowing the rate of titration or dose and utilizing medications to reduce side effects can improve medication tolerability and reduce discontinuation rates.
Who Should Not Take GLP-1 Medications?
Contraindications. Because a certain type of cancer known as a thyroid-C cell tumor has been seen in clinically relevant doses in rodents, the use of GLP-1 medications is contraindicated in patients with a personal or family history of medullary thyroid cancer and patients with Multiple Endocrine Neoplasia type 2 (MEN2). They should not be taken in individuals who are known to be allergic to the medication, pregnant, trying to conceive, or breast feeding.
Warnings and precautions. Although not absolute contraindications, the medications should be used with caution in individuals with a history of pancreatitis, gallbladder disease, and diabetic retinopathy. They should not be used in combination with insulin or insulin secretagogues. Adequate fluid is important to reduce the risk of kidney injury. Individuals with a history of gastrointestinal issues including nausea, heartburn (GERD), constipation, diarrhea, and gastroparesis should work closely with a provider to help reduce the risk of these and other adverse events during treatment initiation and dosage increases.
What Happens When I Stop a GLP-1 Medication?
Generally speaking, it is medically not contraindicated to abruptly discontinue GLP-1 medications if necessary. The physiological and psychological changes that were achieved with the medication gradually diminish, and one will likely experience an increase in cravings or appetite to what they had at baseline. For this reason, when prescribed for weight loss, the full dose that was needed to achieve the goal weight is sustained or the dose is gradually tapered until one reaches a dosage that is effective for weight maintenance. This is one reason why implementation of lifestyle habits to help sustain positive behavioral changes or a healthy weight such as regular exercise are important. The best outcomes exist when a strong, consistent healthy lifestyle and the underlying drivers of the condition are treated, such as gut health, hormone imbalance, anxiety, and poor sleep.