Pic Source: Autoinjector with Trulicity (0.75mg) by Lilly (Dulaglutide)

Dulaglutide is built differently from every other GLP-1 you've heard about.

TL;DR: Once-weekly GLP-1 receptor agonist that does not use the albumin-binding fatty-acid trick. Instead, two GLP-1 analog chains are fused to a human IgG4 Fc fragment, giving it a roughly 60 kDa molecular weight and a half-life around five days. Sold as Trulicity. REWIND showed cardiovascular benefit in primary-prevention T2D, which was a meaningful expansion for the class. Weight loss is real but lower than the fatty-acid GLP-1s (and well below tirzepatide).

Quick facts

• Aliases: LY2189265, Trulicity
• Origin: Eli Lilly; an Fc-fusion approach to half-life extension (rather than the Novo albumin-binding playbook)
• Structure: Two modified GLP-1(7-37) analog chains, each linked through a small spacer to a human IgG4 Fc heavy chain. ~60 kDa total — orders of magnitude larger than liraglutide or semaglutide
• Class: GLP-1 receptor agonist (Fc-fusion biologic)
• Route: SC weekly, prefilled single-use pen
• Half-life: ~5 days
• Dose: 0.75 mg/wk start, escalation up to 4.5 mg/wk
• Regulatory status:
• FDA-approved 2014 (T2D)
• Approved cardiovascular risk reduction in T2D (post-REWIND label update)
• Same class thyroid C-cell tumor black-box warning

Mechanism(s)

• GLP-1R agonism on pancreatic beta cells, gastric smooth muscle, and CNS satiety circuits — same axis, different scaffold
• The IgG4 Fc dimer drives FcRn-mediated recycling, the same mechanism that gives therapeutic antibodies their long half-lives
• Reduced renal clearance compared to small peptide GLP-1s (the Fc moiety is too large to filter)
• Modified GLP-1 sequence resists DPP-4 cleavage at position 8

Research highlights

• Gerstein HC et al. 2019 (Lancet, PMID 31189511): REWIND — 12% relative risk reduction in major adverse cardiovascular events over a median 5.4 years, with about half the cohort being primary prevention
• Dungan KM et al. 2016 (Diabetes Obes Metab, PMID 26799540): AWARD-8 added dula to glimepiride; HbA1c reduction held against the active comparator
• The AWARD program (notably, sometimes inconsistently, occasionally compared head-to-head against liraglutide and exenatide) consistently showed dula matching or beating the older agents on glycemic control with weekly dosing
• Weight loss is in the 3-5 kg range at higher doses, lower than sema and far below tirz

Side effects (reported)

• Nausea, diarrhea, vomiting (less intense than the daily/weekly small-peptide GLP-1s in some head-to-heads, possibly because of the slower exposure ramp)
• Injection site reactions
• Pancreatitis (rare)
• Gallbladder events
• Black-box thyroid C-cell tumor warning (class)
• Anti-drug antibodies are detectable but rarely clinically meaningful

Bottom line:

Dulaglutide is the structural outlier in the GLP-1 family. Liraglutide, semaglutide, and tirzepatide all use the same fatty-acid-binds-albumin engineering trick to extend half-life. Trulicity uses a totally different approach (an antibody Fc) and gets to the same once-weekly dosing window from the other direction. That makes it useful as a clean comparison point: when sema 1.0 mg outperformed dula 1.5 mg in head-to-head T2D trials, it was a real receptor-level efficacy comparison rather than a half-life artifact. The weekly-dosing convenience is real and the cardiovascular benefit in primary prevention (REWIND) is one of the strongest pieces of long-term safety data in the class. Whether it survives the tirzepatide tide commercially is a different question.

ENTRY #20 of 100+ Peptides

Semagutide before semaglutide.

TL;DR: 31-aa GLP-1 analog with a C16 fatty acid that binds albumin and stretches the half-life from minutes to about half a day. Daily injection. Sold as Victoza for T2D and Saxenda for obesity. The weight-loss number was the pre-semaglutide ceiling: roughly 5-8% at a year, which felt impressive in 2014 and looks modest now. LEADER cemented the cardiovascular benefit. If you read entry #1 on semaglutide, this is its older, shorter-half-life sibling.

Quick facts

• Aliases: NN2211, Saxenda, Victoza
• Origin: Novo Nordisk; first GLP-1 analog using the albumin-binding fatty-acid trick that later carried sema and tirz
• Structure: 31-aa GLP-1 analog with a C16 palmitic diacid attached at Lys26 via a glutamic acid spacer. ~3751 Da
• Class: GLP-1 receptor agonist
• Route: SC daily
• Half-life: ~13 hrs (the reason it's daily and not weekly)
• Dose: 0.6-1.8 mg/day for T2D (Victoza); 3.0 mg/day for obesity (Saxenda), titrated weekly
• Regulatory status:
• FDA-approved 2010 (Victoza, T2D), 2014 (Saxenda, chronic weight management)
• Class thyroid C-cell tumor black-box warning
• Generic liraglutide approved in the U.S. in 2024

Mechanism(s)

• GLP-1R agonism: insulin secretion, gastric emptying delay, central satiety signaling, glucagon suppression
• C16 fatty diacid drives reversible albumin binding, slowing renal clearance and DPP-4 access
• Receptor occupancy is essentially continuous on a daily schedule, but the trough vs. peak swing is wider than the weekly agents

Research highlights

• Pi-Sunyer X et al. 2015 (NEJM, PMID 26132939): SCALE Obesity and Prediabetes — 8.0% mean weight loss at 56 weeks on 3 mg vs. 2.6% on placebo
• Marso SP et al. 2016 (NEJM, PMID 27295427): LEADER — 13% relative risk reduction in major adverse cardiovascular events in T2D over a median 3.8 years
• Dungan KM et al. 2016 (Diabetes Obes Metab, PMID 26799540): AWARD-8 / glimepiride add-on data
• The 5-8% weight-loss ceiling is exactly what made the SUSTAIN-6 and STEP-1 numbers feel like a category jump, not an iteration

Side effects (reported)

• Nausea, vomiting, diarrhea, constipation (the GI quartet, dose-dependent)
• Pancreatitis (rare, listed)
• Gallbladder disease at higher cumulative exposure
• Injection site reactions
• Black-box: thyroid C-cell tumors (class warning, rodent finding, no human signal yet)
• Hypoglycemia when stacked with insulin or sulfonylureas

The interesting part mechanistically:

Liraglutide is the proof-of-concept that the C16 albumin-binding chemistry works. The same idea, scaled up to a C18 diacid with two extra amino-acid substitutions, became semaglutide and pushed the half-life from 13 hours to about a week. That single chemistry change is the difference between a daily injection with 5-8% weight loss and a weekly injection with 15%+ weight loss, even though the receptor target is identical. There is a lesson in there about how much of a drug's clinical profile is pharmacokinetics rather than pharmacology. Liraglutide didn't get worse when sema landed; it just stopped being the version anyone reached for first. Generic launch may give it a second life as the cheap entry-tier GLP-1 once the patent dust settles.

FS-344: the long-form precursor that's actually inside the gene-therapy construct

TL;DR: Follistatin precursor isoform with an additional N-terminal signal peptide. After secretion and cleavage it mostly produces FS-315. The reason FS-344 has its own identity in research-chemical land is that the AAV-delivered constructs in the muscular dystrophy trials encoded FS-344, and the supplier ecosystem followed the literature. The peptide labeled FS-344 sold for SC injection has even less direct evidence than FS-315.

Quick facts

• Aliases: FS-344
• Origin: Long-form follistatin precursor; processed intracellularly to FS-315 after signal peptide cleavage
• Structure: 344-aa precursor isoform
• Class: Follistatin isoform / myostatin-activin antagonist (precursor form)
• Route: SC injection (research-chemical use); AAV gene therapy delivers the FS-344 cDNA
• Half-life: Hours after secretion-and-cleavage
• Dose (anecdotal): 100-500 mcg SC daily, identical to FS-315 community protocols
• Regulatory status:
• No approved peptide product
• Gene therapy: the Mendell et al. 2015 Becker muscular dystrophy trial (PMID 25322757) used AAV-FS344. That's where the "344" identity acquired its clinical pedigree
• SC peptide sold as research-chemical only

Mechanism(s)

• After cleavage, functionally equivalent to FS-315 in the systemic compartment
• Same myostatin-neutralizing mechanism as parent follistatin
• The pharmacologically interesting form, in vivo, is mostly FS-315 — FS-344 is the precursor that gets you there

Research highlights

• Mendell JR et al. 2015 (Mol Ther, PMID 25322757): the AAV-FS344 Phase 1/2a in Becker muscular dystrophy. This is the only follistatin clinical trial with a registered FS-344 identity
• Kota J et al. 2009 (Sci Transl Med): preclinical AAV-FS344 in DMD model, proof of concept for the gene-therapy approach
• Amthor H et al. 2004 (Dev Biol, PMID 15136138): parent follistatin/myostatin biology; the FS-isoform-specific data for the SC peptide use case does not exist as a separate paper
• The structural reason this matters: the gene-therapy program chose FS-344 because the cDNA encodes a real translatable transcript that gets correctly processed in the muscle cell. SC injection of pre-made FS-344 peptide bypasses that processing logic entirely and is essentially a distinct pharmacological intervention from the AAV approach

Side effects (reported)

• For the AAV gene therapy in dystrophy populations: localized to injected muscles, no major systemic adverse events
• For the SC peptide: anecdotal injection-site reactions; long-term safety not characterized
• The activin-mediated fertility/fluid-balance concerns apply to any sustained systemic follistatin exposure

Where FS-344 sits in the practical hierarchy:

If you compare the three follistatin entries (parent, FS-315, FS-344), the gene-therapy literature is doing essentially all of the credibility work. Mendell 2015 and Kota 2009 are real human and primate data — but they used AAV vectors, not SC peptide. The community decision to map "FS-344" labeling onto an SC peptide product is a marketing artifact, not a science one.

For a normal person actually evaluating these past three: they are functionally the same bet on the same evidence base, with branding that mirrors the published trial constructs. If any of the three works clinically (well, if any of the three produces a measurable effect in healthy adults), the others probably do too at the same dose (Of course, not medical advice just some speculation). If none of them work in healthy adults, the gene-therapy data probablwon't rescue the SC peptide story. That's the honest framing.

Find more information about Follistatin 344 and potential interactions with other peptides here.

FS-315: the circulating follistatin isoform that the heparin-binding question is built around

TL;DR: Alternative splicing of the FST gene produces several follistatin isoforms. FS-315 is the longer circulating form that lacks the heparin-binding C-terminus, so it stays soluble in plasma rather than sticking to extracellular-matrix proteoglycans. Functionally: same myostatin-binding pocket as parent follistatin, different tissue distribution. Marketed in research-chemical channels as a more "systemic" follistatin choice. There is no human-data justification for that distinction at the SC peptide level — only the parent-protein biology.

Quick facts

·         Aliases: FS-315

·         Origin: Major circulating follistatin isoform; product of alternative splicing of the FST gene

·         Structure: 315-aa circulating isoform (lacks the heparin-binding C-terminus that anchors FS-288 to ECM)

·         Class: Follistatin isoform / myostatin-activin antagonist

·         Route: SC injection

·         Half-life: Hours (rough estimate; no published PK in healthy humans for the SC recombinant peptide)

·         Dose (anecdotal): 100-500 mcg SC daily

·         Regulatory status:

·         No approved product

·         Sold as a research chemical

·         WADA-banned as part of the myostatin-pathway class

Mechanism(s)

·         Binds and neutralizes myostatin (GDF-8) and activin A in the systemic circulation

·         Lacks the heparin-binding C-terminus of FS-288, so stays in plasma rather than tethering to extracellular matrix

·         Theoretical advantage: more even systemic exposure

·         Same off-target binding to activin A as parent follistatin, with the same fertility and fluid-balance considerations

Research highlights

·         Amthor H et al. 2004 (Dev Biol, PMID 15136138): the parent paper covering follistatin/myostatin biology. There is no isoform-specific Phase 1/2 clinical trial for FS-315

·         Hill JJ et al. 2003 (Mol Endocrinol): characterization of the circulating myostatin-follistatin complex; FS-315 is the dominant carrier in serum

·         Schneyer AL et al. 2003 (Endocrinology): comparative receptor binding between FS-288 and FS-315; FS-288 binds with higher affinity to ECM proteoglycans, FS-315 with comparable affinity to myostatin

Crucial POint: the published research-chemical sourcing of FS-315 SC peptide does not have any clinical-trial evidence for the bodybuilding use case. The isoform distinction is real biochemistry; the dosing intuition is community-derived.

Side effects (reported)

·         Injection-site irritation

·         Theoretical: same activin-mediated fertility and fluid-balance concerns as parent follistatin

·         Long-term safety completely uncharacterized

Why pick FS-315 over the parent follistatin product ??

This is the question without a satisfying answer. In endogenous physiology, FS-315 and FS-288 are real isoforms with different tissue distributions and different roles. In a vial labeled "follistatin," what you're getting depends entirely on what the supplier produced. Some suppliers are selling FS-288 under "follistatin," some are selling FS-315 under "follistatin," and the FS-315 specifically labeled product is sometimes effectively the same molecule as the next-shelf-over follistatin.

If you take the biology at face value, FS-315 should produce more systemic myostatin antagonism and less ECM-bound local activity. Whether that translates to a meaningful clinical difference in a 200-kg human is unstudied. For practical purposes, follistatin / FS-315 / FS-344 sold as SC research peptides are all taking the same bet on the same evidence base, with isoform labels that may or may not correspond to what's actually in the bottle.

Follistatin: the myostatin sponge

TL;DR: A 288-aa glycoprotein that binds and neutralizes myostatin (the muscle-growth brake gene) and several other TGF-beta family members. The fascination is mechanistic: myostatin loss-of-function in animals (Belgian Blue cattle, the famous "Mighty Mouse" knockouts, the German "myostatin baby" case report) produces dramatic muscle hypertrophy. The clinical question is whether you can pharmacologically reproduce that without taking out the rest of TGF-beta signaling. The honest answer so far is: no, not really, not yet.

Quick facts

·         Aliases: FS, FST

·         Origin: Originally purified from ovarian follicular fluid in 1987. Got reframed as a muscle-growth target after the myostatin field exploded in the late 1990s

·         Structure: 288-aa glycoprotein with multiple isoforms (FST-288, FST-315, FST-344)

·         Class: Myostatin/activin-binding antagonist

·         Route: SC for the recombinant peptide; intramuscular AAV gene therapy in clinical trials

·         Half-life: isoform-dependent; FST-288 is short and tissue-bound, FST-315 is longer and circulating

·         Dose (anecdotal SC): 100-500 mcg SC daily — very rough; almost no human PK data on the recombinant peptide

·         Regulatory status:

·         No approved follistatin product

·         Gene therapy programs: Phase 1/2a follistatin AAV trials in Becker muscular dystrophy and inclusion body myositis. Mendell et al. 2015 (PMID 25322757) was the first published Phase 1/2a result

·         The recombinant peptide form sold as a research chemical has very different pharmacology from the gene-therapy approach

Mechanism(s)

·         High-affinity binding to myostatin (GDF-8), neutralizing its action at the activin receptor

·         Also binds activin A and several BMPs — this is the off-target problem. Activin signaling matters for fertility, fluid balance, and inflammation

·         Net result of muscle-cell myostatin sequestration: increased satellite cell activation, increased myocyte protein synthesis, decreased atrophy signaling

·         The Belgian Blue / Piedmontese cattle phenotype, and the human myostatin loss-of-function case report, are the natural-experimnet evidence that the pathway controls a meaningful fraction of muscle mass

Research highlights

Amthor H et al. 2004 (Dev Biol, PMID 15136138): foundational paper showing follistatin complexes myostatin and antagonizes its inhibition of myogenesis

Mendell JR et al. 2015 (Mol Ther, PMID 25322757): Phase 1/2a follistatin AAV gene therapy in Becker muscular dystrophy. Modest functional improvement at 6 months, six-minute walk test gains, well tolerated

Moore U et al. 2023 (PMID: 36689846) Myostatin and follistatin as monitoring and prognostic biomarkers in dysferlinopathy

Honest caveat: every published clinical follistatin program (I could find at least) has been gene therapy in muscular dystrophy populations, not the recombinant SC peptide that bodybuilders inject. There is no human RCT for the SC peptide use case

Side effects (reported)

·         For the SC peptide: injection-site reactions; the rest is mostly anecdotal

·         For the gene therapy: localized to the injected muscles, no major systemic adverse events at the doses tested

·         Theoretical and biologically plausible: activin off-target effects (fertility, hormone regulation), edema, immune dysregulation if systemic exposure is sustained

·         The cancer concern is less about follistatin specifically and more about chronic suppression of TGF-beta-family tumor surveillance

Why "follistatin" is a category, not a drug:

The peptide labeled "follistatin" sold for SC injection is not the same thing as the AAV-delivered follistatin in the muscular dystrophy trials. They share a sequence; they don't share pharmacology. SC peptide is a glycoprotein cleared in hours. Gene therapy puts a continuous local source inside the target muscle. The "muscle hypertrophy in healthy adults" use case has neither evidence nor a sensible delivery method, which is why this peptide is more famous in forums than in pharmacies. The next two entries (FS-315 and FS-344) are the specific isoforms.

Find more information about Follistatin and potential interactions with other peptides here.

Same MGF molecule, with a polyethylene glycol leash that makes it last days instead of minutes

TL;DR: PEG-MGF is MGF (the IGF-1Ec C-terminal E-domain peptide) with polyethylene glycol covalently attached, which extends the plasma half-life from ~5 minutes to ~2-3 days. The pitch: get the MGF effect systemically without injecting locally before every workout. The trade: no independent primary literature exists for the pegylated form. The pegylation is a community-engineered modification, not a drug-development program. You are extrapolating from MGF's mechanism and PEG-conjugation's general pharmacokinetics.

Quick facts

·         Aliases: Pegylated Mechano Growth Factor

·         Origin: Community/research-supplier produced; not a registered drug development program

·         Structure: MGF (24-aa E-domain peptide) covalently conjugated to polyethylene glycol

·         Class: Pegylated IGF-1 splice-variant peptide

·         Route: SC or IM

·         Half-life: ~2-3 days (vs. native MGF's ~5 min)

·         Dose (anecdotal): 200-400 mcg SC, 1-2x weekly

·         Regulatory status:

·         No human approvals; no investigational program

·         Research-chemical sourcing only

·         WADA-banned

Mechanism(s) (extrapolated from MGF)

·         Same satellite cell signaling premise as native MGF

·         The pegylation is intended to allow systemic, non-local dosing — which fundamentally changes the pharmacology of a peptide whose endogenous role is local and pulsatile

·         Whether systemic PEG-MGF reproduces local MGF's satellite-cell activation, or just produces a sustained IGF-1Ec signal that satellite cells weren't evolved to respond to chronically, is genuinely an open question

Research highlights

McKoy G et al. 1999 (J Physiol, PMID 10087355): the original MGF paper, the same citation that grounds native MGF. PEG-MGF has no independent indexed primary literature

Honest caveat: the entire body of pharmacokinetic, safety, and efficacy data for PEG-MGF specifically is community-anecdotal. Pegylation can change immunogenicity (anti-PEG antibody formation in a non-trivial percentage of the population) and alter receptor pharmacology in ways that don't always match the parent peptide

Side effects (reported)

·         Injection-site reactions

·         Possible immunogenicity / anti-PEG antibodies in a subset of users (PEG sensitization is a well-documented phenomenon across pegylated drugs)

·         Theoretical cancer concerns, same IGF-1 axis caveats as LR3 / DES / MGF

·         Long-term safety: completely uncharacterized

Why this peptide is on a different evidence tier than the rest of the IGF-1 family:

LR3 has cell-culture and cattle data. DES has biochem and oncology cell-line data. MGF has the McKoy/Goldspink rabbit-muscle work. PEG-MGF has none of those — it has the conceptual logic of "extend MGF's half-life" and that's it. The community has been using it for years without obvious disasters, which is real-world Bayesian evidence of a kind, but it's not the same evidence that you'd want to see before a drug enters an IND.

If you're going to use a peptide in this family, MGF (local, post-workout, with the McKoy paper as the mechanistic basis) is the most defensible choice. PEG-MGF is the one where the gap between "what bodybuilders do" and "what has been studied" is widest. That doesn't mean it doesn't work. It means there is no honest answer to the question "does it work" that doesn't come down to anecdote.

Find more information about PEG-MGF and potential interactions with other peptides here.

Long R3 IGF-1: what bodybuilders use when they want IGF-1's effects without IGF-1's plasma kinetics

TL;DR: 83-aa modified version of IGF-1 with two changes: a 13-aa N-terminal extension and an Arg3 substitution. Both modifications dramatically reduce binding to IGF-binding proteins (IGFBP-3 in particular). Results in much more free IGF-1 floating around, way longer half-life (20-30 hours vs. native IGF-1's 10-15 minutes), and a level of receptor agonism that pushes muscle hyperplasia in animal models. There is essentially no controlled human data for the bodybuilding use case.

Quick facts

·         Aliases: Long R3 IGF-1, LR3-IGF-1

·         Origin: Originally a research reagent for cell-culture work. The Arg3 substitution was designed to study IGFBP-independent IGF-1 signaling. The bodybuilding repurposing came later

·         Structure: 83-aa modified IGF-1; ~9111 Da; Arg3 substitution plus N-terminal 13-aa extension

·         Class: IGF-1 receptor agonist (long-acting analog)

·         Route: SC or IM

·         Half-life: ~20-30 hours, the central design feature

·         Dose (anecdotal): 20-100 mcg SC daily, often timed post-workout

·         Regulatory status:

·         Not approved for any human indication anywhere

·         Sold as a cell-culture research reagent; the bodybuilding use is off-label diversion

·         WADA-banned as part of the IGF-1 / GH axis class

Mechanism(s)

·         Direct IGF-1 receptor agonism on muscle, bone, and most other tissues

·         Reduced IGFBP binding means more of the molecule is bioavailable at any given time

·         Drives satellite cell proliferation, differentiation and protein synthesis simultaneously; that combination is the muscle hyperplasia story

·         Crosses the insulin receptor at high doses, which is the hypoglycemia risk

Research highlights

·         Hammon H et al. 1997 (Am J Physiol, PMID 9252489): the foundational paper on Long R3-IGF-1 modulating the somatotropic axis in neonatal calves. Most LR3 dosing intuition comes from cattle and cell culture work, not human RCTs

·         Cell-culture work, the original use case: LR3 is the standard reagent for studying IGF-1 signaling without IGFBP confounders

·         Honest caveat: there is no published Phase 1/2 in humans for the bodybuilding indication. Everything written about LR3 dosing in humans is anecdotal or extrapolated from cattle physiology

Side effects (reported)

·         Hypoglycemia, especially at higher doses or fasted states. This is the most common acute adverse event

·         Disproportional tissue growth (the "IGF-1 gut" rumor in bodybuilding circles, which has not been formally documented but is consistent with prolonged IGFR agonism on visceral organs)

·         Theoretical cancer-progression risk via IGF-1 axis

·         Injection site irritation

·         Tachyphylaxis after weeks of continuous daily use, which is why most users cycle

The unresolved tension:

LR3 is doing something IGF-1 in your body normally cannot do. Native IGF-1 is bound to IGFBP-3 and the acid-labile subunit ~99% of the time, with the binding proteins acting as a slow-release reservoir and keeping the bioactive fraction in a narrow physiologic window. LR3 broke that ratio on purpose to make a useful research tool. The acute effects are well characterized in cell culture and short animal studies. The chronic systemic consequences in healthy adults are not.

Find more information about IGF-1 LR3 and potential interactions with other peptides here.

TL;DR: 191-amino-acid recombinant human growth hormone, identical to pituitary-secreted GH. Sold under a long list of brand names (Humatrope, Genotropin, Norditropin, Saizen, etc.). FDA-approved for pediatric and adult GH deficiency, Turner, Prader-Willi, idiopathic short stature, AIDS wasting, and short bowel. Schedule III in the U.S. for non-medical use, illegal to distribute off-label. Every other peptide in this cluster (sermorelin, CJC-1295, ipamorelin, tesamorelin, MK-677) is either a workaround for the legal status or an attempt to drive GH the body's own way instead of bypassing the pituitary.

Quick facts

• Aliases: Recombinant hGH; Humatrope, Genotropin, Norditropin, Saizen, Omnitrope, etc.
• Origin: Recombinant E. coli expression (Genentech, 1985; replaced cadaver-derived hGH after the CJD contamination crisis)
• Structure: 191-aa recombinant hGH, MW ~22 kDa
• Class: Direct growth hormone receptor agonist
• Route: SC daily (some protocols 6/7 days, weekend off)
• Half-life: 2-5 hours subcutaneous; effective biological half-life longer due to IGF-1 induction
• Dose: 0.15-0.3 mg/day SC for adult GHD on label; 1-2 IU/day off-label "anti-aging"; 4-12 IU/day in performance use (well outside any therapeutic range)
• Regulatory status:
• FDA-approved for multiple indication above
• Schedule III for off-label distribution (a felony in the U.S.)
• Banned in WADA-tested sport
• Long-acting weekly versions (lonapegsomatropin/Skytrofa, somatrogon/Ngenla) recently approved

Mechanism(s)

• Direct GH receptor agonism on hepatocytes leading to IGF-1 production
• Direct GHR signaling on muscle, adipose, bone via the JAK2/STAT5 pathway
• Lipolysis (fat loss) and protein anabolism (lean mass) at supraphysiologic doses; that's the cosmetic appeal
• Chronic dosing down-regulates pulsatile endogenous secretion. This is the central pharmacological difference from sermorelin or ipamorelin: HGH replaces the system, GHRH/GHRP analogs work with it

Research highlights

• Foundational pediatric GHD trials, 1980s-1990s; established efficacy of replacement therapy
• Liu H et al. 2007 (Ann Intern Med): systematic review of HGH in healthy older adults. Modest body comp changes, no proven functional benefit, increased rates of edema/joint pain/glucose intolerance
• Rudman D 1990 (NEJM): the famous 12-man pilot in elderly men that launched the entire anti-aging-HGH industry. The trial was tiny, the effect size was overstated by the secondary literature, and the safety follow-through never matched the hype

Side effects (reported)

• Edema, carpal tunnel, arthralgia (the classic dose-dependent triad)
• Insulin resistance, frank type 2 diabetes at high chronic doses
• Acromegaly features (jaw, hands, feet, organomegaly) at sustained supraphysiologic dosing
• Theoretical and somewhat-supported cancer-progression risk (IGF-1 axis)
• In children with GHD, generally well tolerated; in non-deficient adults, the risk-benefit gets steeply worse with dose

Find more information about Somatropin (HGH) and potential interactions with other peptides here.

TL;DR

GHRP-6 is the original growth hormone releasing peptide. It was developed in 1984 by Cyril Bowers' group at Tulane University and became the first strong proof that an unknown growth hormone secretagogue receptor existed. That receptor was later identified as GHS-R1a, now known as the ghrelin receptor.

Modern compounds like GHRP-2, hexarelin, and ipamorelin all descend from this discovery. GHRP-6 was effectively the prototype for the entire GHRP class.

Quick Facts

• Full name: Growth Hormone Releasing Peptide-6
• Developed by: Cyril Bowers et al., Tulane University
• First described: 1984
• Structure: His-D-Trp-Ala-Trp-D-Phe-Lys-NH2
• Class: GHRP / ghrelin receptor agonist
• Administration: Primarily subcutaneous injection; intranasal routes appeared in older studies
• Half-life: Approximately 15 to 30 minutes
• Common anecdotal dosing: 100 to 300 mcg SC, 2 to 3 times daily

Regulatory Status

• Never FDA approved
• Studied experimentally in cardiac and inflammatory settings
• Listed in FDA 503A Category 2, alongside compounds such as BPC-157

Mechanism of Action

GHRP-6 acts primarily as a GHS-R1a agonist, stimulating pulsatile growth hormone release while also strongly increasing appetite. The hunger effect is one of its most recognizable characteristics and separates it from newer compounds like ipamorelin.

Unlike more selective modern secretagogues, GHRP-6 can also increase cortisol and prolactin levels in a dose-dependent manner. Those hormonal spillover effects were one of the reasons later compounds were developed.

Researchers have also explored possible cardioprotective effects in animal models. Some evidence suggests these actions may involve receptor subtypes outside the pituitary pathway.

Synergy With Other GH Pathway Compounds

GHRP-6 is commonly discussed alongside GHRH analogs because the pathways complement each other.

Examples include:

• Sermorelin
• CJC-1295
• Tesamorelin

Using both pathways together generally produces a stronger GH pulse than either pathway alone.

Key Research

Bowers et al. (1984)

Endocrinology | PMID: 6714155

This was the foundational paper for the entire class. The study demonstrated that a synthetic hexapeptide could trigger potent GH release in rat and ovine somatotrophs through a receptor distinct from the GHRH receptor.

Wu et al. (1996)

Journal of Endocrinology | PMID: 8699133

Compared GHRP-6 and GHRP-2 in terms of cAMP signaling and GH secretion dynamics.

Granado et al. (2008)

Journal of Endocrinology

Investigated cardioprotective effects in rodent ischemia-reperfusion models.

Important Caveat

Like most GHRPs, the modern recreational use of GHRP-6 rests heavily on mechanistic studies, animal data, and small human trials. Large-scale clinical success never materialized. One major failed postoperative ileus trial also contributed to the collapse of corporate development for related compounds such as ipamorelin.

Reported Side Effects

The defining side effect is rapid appetite stimulation, often occurring within 20 to 40 minutes after administration.

Other commonly reported effects include:

• Increased hunger
• Mild cortisol elevation
• Mild prolactin elevation
• Water retention
• Temporary tingling or numbness near the injection site
• Fatigue or heavy eyelids after dosing

These effects appear dose dependent in many users.

Why People Still Use It

Despite newer and cleaner compounds existing, GHRP-6 still has a niche.

The main reasons are straightforward:

• It is relatively inexpensive
• It is widely available in research markets
• Some users specifically want the appetite stimulation

That appetite effect makes it appealing in certain contexts, including:

• Bulking phases in bodybuilding
• Medically supervised recovery from appetite suppression
• Cachexia-related experimentation

For users focused purely on cleaner GH signaling with fewer side effects, compounds like ipamorelin or hexarelin are generally considered more refined tools.

Historical Significance

The importance of GHRP-6 goes beyond its current use.

Bowers' group was originally attempting to create a cholecystokinin-related analog. Instead, they accidentally discovered a compound that revealed an entirely new endocrine signaling pathway. That observation eventually led to the identification of the ghrelin receptor and the development of the entire GHRP category.

Pretty much every modern ghrelin receptor agonist traces back to this discovery. No exxageration.

Learn more, as always, here.

Synthetic GHRH analog (44-aa peptide) that stimulates pituitary release of endogenous growth hormone.

Quick facts

• Class: GHRH receptor agonist
• Route: SC daily injection
• Regulatory status:
• Not approved for general anti-aging or weight loss
• Available by prescription; reformulated as Egrifta SV in

Mechanism(s)

• Spares peripheral subcutaneous fat in trial data; thatselectivity is what made the HIV-lipodystrophy approval possible

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Research highlights

• Faulk - Metabolic effects of a growth hormone-releasing factor in patients with HIV

• Stanley TL et al. Reduction in visceral adiposity with tesamorelin and improved metabolic profile in HIV-infected patients. Clin Infect Dis 2012. PMID 22495074

• ⁠What we don't have: any large RCT outside HIV lipodystrophy. The off-label "tesamorelin for visceral fat in metabolic syndrome" use is mostly extrapolation

Side effects (reported)

• Injection site reactions (the most common reason for trial dropout)
• Joint pain, edema, hyperglycemia
• Glucose intolerance, especially in pre-diabetic patients
• Class warning shared with all GH-axis stimulators: any active malignancy is a hard contraindication

The interesting part mechanistically:

Tesamorelin's whole identity is seemingly a paradox in review. GH and IGF-1 are generally lipolytic but also generally diabetogenic; push the GH axis hard and you usually trade fat loss for worse glucose control. The HIV lipodystrophy trials showed the opposite: VAT dropped, triglycerides dropped, and metabolic markers actually improved.

The leading explanation is that visceral adipose in HIV lipodystrophy is inflammatory and is GH-resistant before treatment, so a GHRH-stimulated pulse re-sensitizes it to lipolysis without the expected insulin-resistance downside you'd see in a metabolically healthy person.

This is dense as hell though. So if you're still interested you can find more information about Tesamorelin and potential interactions with other peptides here.

No video is going to be perfect, but at least this is a break from the massive info dumps I usually post! Same as always, please check out more than one source before making any decisions about research for your lab rat.

This is different and important since we haven’t discussed stacking these two yet. Plus I think it’s easier to digest than reading dense academic research sometimes.

BPC-157: the "body protection compound"

TL;DR: 15-amino-acid fragment of a stomach-juice protein. Wildly popular for tendon, ligament, and gut healing. Almost zero human data. Compounding pharmacies were hit hard by FDA's 2023 categorization. Pivot from the GLP-1 hype-train to something with a very different evidence story.

Quick facts

• Structure: Synthetic pentadecapeptide (sequence: GEPPPGKPADDAGLV)
• Class: Cytoprotective peptide
• Studied administration routes: Subcutaneous (SC), intramuscular (IM), oral, intranasal

Regulatory status:

• Not approved by the U.S. FDA for any medical indication
• Continues to be marketed online as a “research chemical”

Mechanism(s)

• Growth factor signaling: Associated with increased expression of growth hormone receptors and fibroblast growth factors in connective tissue
• Nitric oxide modulation: Demonstrates bidirectional interaction with nitric oxide pathways in preclinical models
• Dopaminergic effects: Animal studies suggest modulation of dopamine-related responses
• Gastrointestinal protection: Appears to support mucosal integrity and reduce NSAID-induced damage in rodent models

Research highlights

Honest caveat: The vast majority of citations are animal models from a single Croatian research group (Sikiric et al.). Independent replication is thin. There is no published Phase 2/3 human trial.

Side effects (reported)

• Injection site irritation
• No notable systemic toxicity in rodent studies even at high doses
• Theoretical concerns: pro-angiogenic activity raises a tumor-growth question. This has not been evaluated in human trials.

The interesting part mechanistically:

BPC-157 is notable for being derived from a protein naturally present in gastric juice, which underlies the rationale for oral administration—unusual for peptides, which are typically degraded in the digestive tract. The central question remains whether systemic administration (e.g., subcutaneous injection) produces the same effects as its proposed local activity in the gastrointestinal environment, or whether it behaves as a distinct pharmacological agent.

Find more information about BPC-157 and potential interactions with other peptides here. There are also some tools for comparing these peptides given how dense all of the information can be!

***The site included above is my personal passion project and includes NO suppliers, and every tool/resource is totally free. Please check if you need. It is just a reference/toolkit that beginners can use to get educated and understand their peptides before beginning their research.

Tirzepatide: the dual agonist that beat semaglutide head-to-head TL;DR: 39-amino-acid dual agonist at the GIP and GLP-1 receptors. SURMOUNT-1 reported ~22.5% mean weight loss at 72 weeks at the 15 mg dose — meaningfully higher than semaglutide's ~15%. SURPASS-2 beat semaglutide head-to-head on HbA1c and weight in T2D. Same C20 fatty diacid albumin-binding trick as semaglutide, with one extra receptor everyone used to think was the wrong one to target.

Quick facts • Aliases: LY3298176, Mounjaro, Zepbound

• Origin: 39-aa synthetic peptide based on the GIP backbone, engineered for dual GIP-R + GLP-1R activity, with a C20 fatty diacid for albumin binding

• MW: ~4813 Da • Class: GIP / GLP-1 dual receptor agonist (the first approved dual incretin) • Route: SC weekly injection

• Half-life: ~5 days • Doses: 2.5 mg start, titrated to a max of 15 mg weekly

Regulatory status:

• FDA-approved: Mounjaro (T2D, 2022), Zepbound (chronic weight management, 2023)

• Same thyroid C-cell tumor black-box warning as the GLP-1 class

Mechanism(s)

• GLP-1R agonism: same axis as semaglutide — insulin secretion, gastric emptying delay, central satiety, glucagon suppression

• GIP receptor agonism: the differentiator. GIP-R activation enhances insulin secretion and appears to improve adipose tissue insulin sensitivity. Centrally, GIP-R neurons in the hypothalamus suppress food intake through pathways distinct from GLP-1

• Synergy, not additivity: in head-to-head trials the dual agonist outperforms maximal-dose GLP-1 monotherapy by more than the GIP arm alone would predict

• Albumin binding: C20 diacid (one carbon longer than semaglutide's C18) extends half-life similarly

Research highlights

• Jastreboff AM et al. 2022 (NEJM, PMID 35658024): SURMOUNT-1 — 20.9% (10 mg) and 22.5% (15 mg) weight loss at 72 weeks in obesity without diabetes

• Frias JP et al. 2021 (NEJM): SURPASS-2 — head-to-head vs. semaglutide 1 mg in T2D; tirzepatide superior on HbA1c reduction and weight loss across all doses

• SURMOUNT-2 (PMID 37385275): efficacy in T2D with obesity • SURMOUNT-3 / SURMOUNT-4: durability and lifestyle-intervention combinations

Side effects (reported)

• Nausea, vomiting, diarrhea (dose-dependent, titrate to mitigate)

• Constipation

• Pancreatitis (rare, listed)

• Gallbladder events

• Black-box warning: thyroid C-cell tumors (same class warning as semaglutide)

• Hypoglycemia when combined with insulin or sulfonylureas

The interesting part mechanistically:

For decades GIP was considered the wrong incretin to target for obesity. Older receptor-knockout work in mice suggested that knocking out GIP signaling protected against diet-induced obesity, which read as: GIP agonism would make people fatter. Tirzepatide is the result of someone at Lilly betting the opposite — that chronic GIP-R agonism, paired with GLP-1, would amplify weight loss rather than blunt it. They were right, but the mechanistic explanation is still being argued. The leading hypothesis: sustained GIP-R agonism functionally desensitizes the receptor in adipose tissue (so the "stores fat" signal blunts) while preserving the pancreatic insulinotropic effect — and centrally, GIP-R activation suppresses appetite through a hypothalamic neuron population separate from GLP-1's. The SURMOUNT-1 vs. STEP-1 delta is one of the cleanest "second receptor matters" demonstrations in modern incretin pharmacology. It's also exactly why retatrutide (next entry) bolted on a third.

Find more information about Tirzepatide and potential interactions with other peptides here.

***The site included above is my personal passion project and includes NO suppliers, and every tool/resource is totally free. Please check if you need. It is just a reference/toolkit that beginners can use to get educated and understand their peptides before beginning their research.

Semaglutide: the molecule that turned GLP-1 into a household word

TL;DR: 31-amino-acid modified GLP-1 with a C18 fatty diacid linker that latches onto serum albumin and stretches a 1-2 minute native peptide into a 7-day weekly drug. Marketed as Ozempic (T2D), Wegovy (obesity), Rybelsus (oral T2D). The SELECT trial established cardiovascular benefit in non-diabetic obesity — that's the result that pushed it from "diabetes drug" to "category-defining weight-loss drug."

Quick facts

·  Aliases: NN9535, Ozempic, Wegovy, Rybelsus

·  Origin: Modified human GLP-1(7-37); two amino acid substitutions (Aib8, Arg34) plus a glutamic acid spacer + C18 fatty diacid attached at Lys26

·  MW: ~4114 Da

·  Class: GLP-1 receptor agonist

·  Routes: SC weekly injection (Ozempic / Wegovy); oral daily (Rybelsus, with SNAC absorption enhancer)

·  Half-life: ~7 days

Regulatory status:

·  FDA-approved: Ozempic (T2D, 2017), Rybelsus (T2D, 2019), Wegovy (obesity, 2021)

·  Black-box warning for thyroid C-cell tumors (rodent finding)

·    Intermittent shortages on FDA's drug shortage list during the obesity boom — drove the compounded-semaglutide market

Mechanism(s)

·  GLP-1R agonism on pancreatic β-cells: glucose-dependent insulin secretion (insulin only releases when glucose is elevated, which limits hypoglycemia risk vs. insulin/sulfonylureas)

·  Gastric emptying delay: slower glucose appearance, prolonged satiety

·  Central appetite suppression: hypothalamic and brainstem GLP-1R activation → reduced food intake, reduced food reward

·  Glucagon suppression: lowers hepatic glucose output

·  Albumin binding via the C18 linker: the actual half-life trick — non-covalently anchors to albumin in serum and rides around for a week

Research highlights

·  Wilding JPH et al. 2021 (NEJM, PMID 33567185): STEP 1 — 14.9% weight loss at 68 weeks in adults with overweight/obesity (the headline obesity result)

·  Lincoff AM et al. 2023 (NEJM, PMID 37952131): SELECT — 20% reduction in major adverse cardiovascular events in obese non-diabetic patients; established the cardiovascular indication

·  Marso SP et al. 2016 (NEJM): SUSTAIN-6 — earlier T2D cardiovascular outcomes trial; basis of the original CV label

Side effects (reported)

·  Nausea (most common, dose-related, usually decreases over weeks)

·  Vomiting, constipation, diarrhea

·  Pancreatitis (rare)

·  Gallbladder disease (cholelithiasis / cholecystitis)

·  Black-box warning (Serious Side-Effect): Thyroid C-cell tumors are possible based on rodent data, although it's uncertain if this has any relevance to humans yet. Contraindicated in MEN2 / personal or family history of medullary thyroid carcinoma

·  Injection-site reactions (ya feel itching/redness)

The interesting part mechanistically:

Native GLP-1 has a half-life of 1-2 minutes. DPP-4 protease snips off the N-terminus almost as fast as the gut secretes it. Every GLP-1 drug since exenatide has been an answer to "how do you keep the molecule alive long enough to dose practically." Semaglutide's answer is the cleanest version of the playbook: protect the N-terminus from DPP-4 (Aib substitution at position 8), block another cleavage site (Arg at 34), then dangle a C18 fatty diacid off the side that quietly binds albumin in serum.

Find more information about Semaglutide and potential interactions with other peptides here.

***The site included above is my personal passion project and includes NO suppliers, and every tool/resource is totally free. Please check if you need. It is just a reference/toolkit that beginners can use to get educated and understand their peptides before beginning their research.