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.
The Main Agents
| Drug | Brand | Route | Frequency |
|---|---|---|---|
| Semaglutide | Ozempic / Wegovy | SC weekly or oral daily | Weekly / Daily |
| Liraglutide | Victoza / Saxenda | SC daily | Daily |
| Dulaglutide | Trulicity | SC weekly | Weekly |
| Tirzepatide | Mounjaro / Zepbound | SC weekly (dual GIP+GLP-1) | Weekly |
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.
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.
The fix:
- Protein: 1.6-2.2g/kg bodyweight daily
- Resistance training (non-negotiable)
- Some evidence for growth hormone secretagogue co-administration
If you're on a GLP-1 and not lifting, you're solving one problem and creating another.
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, which is 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.
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.
Side Effects
Common (usually transient): nausea (30-50%), vomiting (10-20%), diarrhea or constipation.
Serious (rare): pancreatitis (debated - may be no higher than baseline), gallbladder disease, hypoglycemia when combined with insulin.
Practical notes: titrate slowly, stay hydrated, high-fat meals worsen nausea.
Oral vs Injectable
- Semaglutide oral (Rybelsus): requires empty stomach + 30 min wait before eating, lower bioavailability, higher dose needed
- Injectable: more reliable absorption
- Orforglipron (in development): oral nonpeptide, no fasting requirement
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/