What They Are
GLP-1 (glucagon-like peptide-1) is a gut hormone released after eating. It does several things:
- Stimulates insulin secretion (glucose-dependent, so it won't cause hypoglycemia alone)
- Inhibits glucagon release
- Slows gastric emptying
- Activates brain GLP-1 receptors to promote satiety
The drugs are synthetic versions that resist the enzyme (DPP-4) that normally destroys natural GLP-1 in minutes. The result: hours of activity instead of seconds. Natural GLP-1 has a half-life of about 2 minutes. Semaglutide's half-life is approximately 7 days.
The Main Agents
| Drug | Brand | Route | Frequency | Mechanism |
|---|---|---|---|---|
| Semaglutide | Ozempic / Wegovy | SC weekly or oral daily | Weekly / Daily | GLP-1 only |
| Liraglutide | Victoza / Saxenda | SC daily | Daily | GLP-1 only |
| Dulaglutide | Trulicity | SC weekly | Weekly | GLP-1 only |
| Tirzepatide | Mounjaro / Zepbound | SC weekly | Weekly | Dual GIP + GLP-1 |
Weight Loss Numbers
- Liraglutide 3.0mg (Saxenda): ~5-8% body weight
- Semaglutide 2.4mg (Wegovy): ~15-17%
- Tirzepatide (Zepbound): ~20-22%
Tirzepatide wins because it hits two receptor types (GIP + GLP-1) instead of one. GIP (glucose-dependent insulinotropic polypeptide) has its own set of metabolic effects, and the dual agonism produces additive weight loss beyond what either pathway achieves alone.
For context, lifestyle intervention alone typically produces 3-5% weight loss, and most people regain it within 2-3 years. These drugs represent a different order of magnitude.
The Muscle Problem
About 25-40% of weight lost on GLP-1 agonists is lean mass. Not fat. Without intervention, people on these drugs get smaller and weaker, not leaner.
This matters more than most people realise. Lean mass is metabolically active tissue. Losing it drops your basal metabolic rate, makes weight regain easier after discontinuation, and accelerates sarcopenia in older adults.
The fix:
- Protein: 1.6-2.2g/kg bodyweight daily (this alone significantly reduces lean mass loss)
- Resistance training (non-negotiable - 2-3 sessions per week minimum)
- Some evidence for growth hormone secretagogue co-administration
- Creatine monohydrate may help preserve muscle during caloric deficit
If you're on a GLP-1 and not lifting, you're solving one problem and creating another.
The Rebound Problem
Weight regain after discontinuation is significant. The STEP 1 extension trial showed that one year after stopping semaglutide, participants regained approximately two-thirds of their lost weight. Appetite suppression disappears within weeks of stopping. This positions GLP-1 agonists as chronic therapy for most patients, not a temporary fix.
The implications are financial and practical. These drugs cost $800-1300/month without insurance. Lifetime use is expensive, and supply constraints remain an issue in many countries.
Addiction and Mental Health (BMJ, 2025)
This is the part that doesn't make it into the ads. A cohort study tracked 606,434 US veterans for 3 years. People on GLP-1 agonists showed:
- 14% lower composite substance use disorder risk
- 18% lower alcohol use
- 25% lower opioid use
- 20% lower nicotine use
For people who already had a substance use disorder: 31% fewer ER visits, 50% lower SUD-related mortality.
The mechanism is plausible. GLP-1 receptors exist in the mesolimbic dopamine system - the same reward circuitry that alcohol, opioids, and nicotine hijack. The drugs cross the blood-brain barrier at therapeutic doses and modulate the rewarding properties of addictive substances. Animal studies show semaglutide reduces alcohol self-administration in rodents and attenuates dopamine release in the nucleus accumbens in response to addictive substances.
This is not yet an approved indication. But the signal is strong enough that multiple clinical trials are underway for alcohol use disorder specifically.
Schizophrenia Risk (Mendelian Randomization, 2025)
A two-sample MR study (eQTLGen + PGC + FinnGen) found genetically proxied GLP1R activation associated with 16% lower schizophrenia risk (OR 0.84, 95% CI 0.71-0.98).
Key finding: the effect is mediated by weight loss, not blood sugar control. The pathway is: weight loss -> reduced systemic inflammation -> neuroprotective effect.
The implication for people on antipsychotics that cause weight gain is worth tracking. Olanzapine and clozapine are the worst offenders for metabolic syndrome, and GLP-1 agonists may address both the weight gain and potentially some of the neuroinflammatory burden.
Neuroprotection and Neuroinflammation
GLP-1 receptors are expressed in the hippocampus, cortex, and hypothalamus. Beyond the metabolic effects, there's growing evidence for direct neuroprotective properties:
- Reduced microglial activation and neuroinflammation in animal models
- Improved BDNF (brain-derived neurotrophic factor) expression
- Reduced amyloid-beta plaque deposition in Alzheimer's disease models
- Ongoing Phase III trials for semaglutide in early Alzheimer's disease (EVOKE and EVOKE+)
The neuroinflammation angle connects to multiple psychiatric conditions. Chronic low-grade inflammation is elevated in depression, ADHD, and schizophrenia. Whether GLP-1 agonists have meaningful psychiatric applications beyond weight management is an open question, but the biological plausibility is there.
Cardiovascular Outcomes
The SELECT trial (semaglutide 2.4mg, n=17,604 with overweight/obesity and established cardiovascular disease) showed a 20% reduction in major adverse cardiovascular events (MACE) over a median follow-up of 39.8 months. This was independent of diabetes status, meaning the cardiovascular benefit isn't just about blood sugar control.
This was the data that shifted GLP-1 agonists from "weight loss drug" to "cardiometabolic drug" in clinical framing.
Side Effects
Common (usually transient): nausea (30-50%), vomiting (10-20%), diarrhea or constipation.
Serious (rare): pancreatitis (debated - epidemiological data suggests no higher than baseline diabetes risk), gallbladder disease (likely secondary to rapid weight loss), hypoglycemia when combined with insulin or sulfonylureas.
Practical notes: titrate slowly over 4-8 weeks, stay hydrated, high-fat meals worsen nausea. Most GI side effects diminish after 4-8 weeks at a stable dose.
Oral vs Injectable
- Semaglutide oral (Rybelsus): requires empty stomach + 30 min wait before eating, lower bioavailability (~1% absorption), higher dose needed (14mg oral vs 1mg injectable)
- Injectable: more reliable absorption, once-weekly convenience
- Orforglipron (in development): oral nonpeptide GLP-1 agonist, no fasting requirement, potentially cheaper to manufacture since it's a small molecule rather than a peptide
Orforglipron Phase III data is expected in 2025-2026. If it works as well as injectable semaglutide without the fasting requirement, it could significantly expand access.
References
- Collins, R. & Costello, M. (2024). GLP-1 Receptor Agonists. StatPearls
- BMJ (2025). GLP-1 agonists and substance use disorders. https://www.bmj.com/content/392/bmj-2025-086886
- Xiang, Y. & Peng, L. (2025). GLP-1 RA and Mental Illness. International Journal of Molecular Sciences. https://pmc.ncbi.nlm.nih.gov/articles/PMC11942543/
- Lincoff, A.M. et al. (2023). Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes (SELECT). NEJM
- Wilding, J.P.H. et al. (2022). Weight regain and cardiometabolic effects after withdrawal of semaglutide (STEP 1 extension). Diabetes, Obesity & Metabolism