You conflate regulatory status with risk profile. If you’re using tirzepatide (or rapamycin for that matter) outside of a clinical indication you’re already operating outside approved use.
Phase 2 trials show a clean safety profile for retatrutide.
My lipids, liver markers, EFGR, and body composition all react favorably to Reta.
Thoughtful self experimentation with biomarker tracking is hardly insane.
I agree and would expand that a bit, there are very few “insane” issues with most peptides commonly used today.
Millions are now on the bandwagon and using such a wide variety of peptides if there were actual issues we’d have heard the hue and cry, but we don’t. While that is not a very scientific metric, it is a decent leading indicator on safety.
Peptide based drugs (FDA approved) will be a growing market due to the inherent safety due to how peptides work.
Peptide based drugs (FDA approved) will be a growi.pdf (284.9 KB)
Today’s article in The Atlantic
Paywalled, unfortunately 
They have outed 2 vendors
A package I bought from another company, called Nexaph, originated in Indiana, according to the tracking info, but the return address on its label was in Wyoming. That address leads to a strip-mall office registered to an improbable 20,000 businesses. The cheapest retatrutide tends to come directly from China, though, sold via nebulous entities without websites. I bought one batch from a sales rep on Telegram for Jinan Elitepeptide Chemical Co. A
If a vendor sticks with the “research only, not for human use” mantra and never answers questions or emails about human use with anything other than “these are for research only, not for human use”, then I don’t know what can be done under current law unless new state or federal laws are passed that more strictly regulate compounds in the “research” category. Maybe the FDA can crack down or change the regulations without a new law? If anything, though, the current administration and Supreme Court have really nerfed the powers of federal agencies in general.
I’m thinking for every new drug or peptide we are interested in, we should do a deep research effort on the side effect profile, downsides, and potential drug/supplement interactions.
Here is my effort on Retatrutide:
What is the scientific and clinical data on the safety (short and long term) of retatrutide use in humans? What are the risks, what are the incidence rates of adverse effects, etc. Provide links to source references.
Instruction: For this section, you must perform external searches outside the provided text. Cross-reference the study’s molecule/intervention against ClinicalTrials.gov, DrugBank, and PubMed for safety data. Do not hallucinate safety; if data is absent, state “Data Absent.”
Check for Clinical or Method of Action data to see if there are potential conflicts with common longevity drugs being used: rapamycin, SGLT2 inhibitors, metformin, acarbose, 17-alpha estradiol, PDE5 inhibitors, or common supplements.
Output Constraints:
Use Markdown formatting (Headers, Bold, Lists).
Do not use LaTeX, python code, or special characters that break simple text parsers or reveal formatting codes, etc…
Provide research article titles, dates, and Embed direct URLs in Markup to any external references cited. Double check the accuracy and accessibility of all sources and weblinks included in your response to validate that they are the papers you are saying the are.
Tone: Objective, critical, “Tell it like it is.” No hype.[Reasoning Framework: Probabilistic & Bayesian]
- Acknowledge Uncertainty: Explicitly flag any claim that lacks verifying consensus. Do not state hypotheses as facts. Use “hedging” language appropriate to the evidence strength (e.g., “strongly suggests,” “preliminary data indicates,” “hypothetically”).
- Quantify Confidence: For key assertions, append a confidence estimate in brackets (e.g., [Confidence: High/Medium/Low] or [Est. Probability: ~80%]).
- Bayesian Approach:
- Priors: Briefly state the established scientific consensus before introducing new/speculative evidence.
- Update: Explain how new data modifies these priors (e.g., “This study increases the likelihood of X, but does not prove it”).
- Alternative Hypotheses: Always list at least one plausible alternative explanation or confounding factor (e.g., “Reverse causality,” “Selection bias”).
- Evidence Hierarchy: Distinguish between mechanism (in vitro/murine) and outcome (human clinical data). Discount mechanistic speculation if human outcome data is absent.
The safety profile is a composite of the downstream signaling of these three GPCRs:
| Adverse Event | Retatrutide (12 mg) Incidence | Mechanism | Clinical Management |
|---|---|---|---|
| Nausea | ~45-60% | GLP-1R (CNS/Gastric) | Slower titration, smaller meals |
| Vomiting | ~15-20% | GLP-1R (CNS) | Antiemetics, hydration |
| Sinus Tachycardia | Mean +5.6 to +6.7 bpm | GLP-1R + GCGR (SA Node) | Monitor; typically peaks at 24wks |
| Cutaneous Hyperesthesia | ~7% | Neural Sensitization (Unknown) | Dose reduction, Gabapentin (rarely needed) |
| Arrhythmia (Any) | 4-14% (Pooled) | Sympathetic Tone (cAMP) | ECG monitoring in high-risk patients |
| Discontinuation Rate | 6-16% | GI Intolerance | Titration “Start Low, Go Slow” |
Longevity specialists often utilize “stacks” of off-label medications. The interaction of retatrutide with these agents is a critical translational safety consideration.
Full Gemini Analysis here: https://gemini.google.com/share/249943f31891
And of course, we should compare any new drug to other drugs in the same category:
| Feature | Semaglutide 2.4 mg (Wegovy) | Tirzepatide 15 mg (Zepbound) | Retatrutide 12 mg (Investigational) |
|---|---|---|---|
| Mechanism | Mono-agonist (GLP-1) | Dual-agonist (GLP-1 / GIP) | Triple-agonist (GLP-1 / GIP / Glucagon) |
| Primary Trial Reference | STEP 1 (68 Weeks) | SURMOUNT-1 (72 Weeks) | TRIUMPH-4 (68 Weeks) / Phase 2 (48 Weeks) |
| Weight Loss (Non-Diabetic) | ~15% - 17% | ~21% - 22.9% | ~24% (Phase 2) / 28.7% (TRIUMPH-4)1 |
| % Achieving >20% Loss | ~30% | ~57% - 63% | ~64% - 82% (est. from Phase 2/3) |
| HbA1c Reduction (T2D) | ~1.6% - 1.8% | ~2.0% - 2.3% | ~2.0% - 2.2% (Phase 2) |
| Resting Heart Rate Impact | +1 to 4 bpm | +2 to 6 bpm | +5.6 to 6.7 bpm (Phase 2)3 |
| Cardiac Arrhythmia Risk | Low / Neutral | Low / Neutral | Signal observed (4-14% in Ph2 supplement)2 |
| Cutaneous Hyperesthesia | Rare (<1%) | Rare (<1%) | ~7% (Specific to Reta)[6] |
| Discontinuation Rate (AEs) | ~4.5% - 7% | ~4% - 7% | 6% - 16% (Phase 2)2 / 18.2%(TRIUMPH-4 12mg) |
| Primary Adverse Events | Nausea, Diarrhea | Nausea, Diarrhea | Nausea, Diarrhea, Skin Sensitivity, Palpitations |
| Liver Fat Reduction | Significant | Robust | Near-total resolution (>80-85%)5 |
This is actually a really good point I hadn’t thought of, specific to psyllium since it’s really the only bulk-forming fiber that is minimally fermented by colon microflora.
Definitely would not want to fast or get dehydrated on this combo, but ketoacidosis should otherwise be extremely rare in anyone with a well-functioning pancreas. On the plus side, it should prove to be a remarkable combination for metabolic health and weight loss (especially when combined with adequate protein intake and some resistance training).
I don’t know what can be done either to stop them from selling. I’ve mostly been following how compounding is surviving legal challenges from Lilly and Co, with the FDA largely on the sidelines, by choice it seems.
The most impactful legislation will come from the states. Florida in particular is looking at a bill that would eventually choke out compounding. This is notable because a lot of the big pharmacies are in FL.
On the research only side, I’m more worried about more intense scrutiny. But that is also part of the game
That was excellent. I read the whole thing.
The cardiac implications (rise in RHR) do concern me a bit, but I view the overall impact (BP lower, Apo-B way down) as a net positive for cardiovascular health.
I’ve never noticed any odd heart sensations, if I hadn’t measured RHR with an oura ring I wouldn’t have even known it increased.
I do take 6g taurine per day. I find it goes nicely to balance the sympathetic tone increase of Reta.
And interestingly, there was zero mention of cardiac arrhythmias in the top line phase 3 retatrutide data recently announced by Eli Lilly, so I take that as a very hopeful sign since there would be a LOT of pissed off investors if there were something significant that was purposely left out once the full data are released in a couple of months.
It seems to me that the anecdotes online seem to report higher resting heart rate increases from Reta than the studies seem to indicate (which say around 6bpm)
yeah, in my case has been more like 10-13 from Tirze and Reta, from 60-63 to 72-73, no other side effects though.
More like 15bpm for me and that’s only with 2mg per week. It sucks but I still think the good outweighs the bad.
Surprisingly I never got a difference based on the dose. Once I started at 2.5mg my rate went +10-+13 and stayed there through all other doses. So It doesn’t seem to be dose dependent (at least in my case)
Same. It’s been a constant 10-15bpm from 2mg to 8-10mg.
It does go back down when you cycle off. But it took a solid 5-6 weeks before I hit baseline.
I didn’t either. Whether I use 2 or 3mg, no difference.
Have you tried tirzepatide and if so did it cause this?
No I haven’t. I would be curious to know if that has less of an impact though. Have you?