Issues & changes, newest first.

The discovery pass surfaced six useful interventions that were not yet present as database rows. They now have sourced entries, evidence/risk summaries, dose notes, and secondary category visibility where appropriate.

Added:

• CBT-I as a first-line behavioral insomnia protocol, visible under Sleep & Recovery, Mood, and Cognitive.
• Beta-alanine and sodium bicarbonate as evidence-backed ergogenic buffers for high-intensity exercise.
• MCT oil / ketogenic MCT drink for the mild-cognitive-impairment/ketone fuel use case.
• 2’-fucosyllactose (2’-FL) as a targeted HMO prebiotic with early older-adult microbiome/metabolic data.
• Dietary nucleotide supplementation as a promising but early aging/cognition/muscle nutrition entry.

The database now tracks 389 interventions.

A reader caught the pattern: Pinealon was listed only under Longevity even though its own evidence notes include cognitive/neuroprotective claims, and it is commonly searched as a pineal/circadian peptide.

The database already has a mechanism for this. Each intervention keeps one canonical CSV category, while CROSS_CATEGORIES decides where else it appears in the rankings filters. The issue was not duplicate rows or scoring. It was under-listing.

This pass reviewed all 383 rows and expanded secondary category membership where the row already had a credible use case, mechanism, or reader-search reason to appear elsewhere. Examples:

• Pinealon now appears under Longevity, Cognitive, and Sleep & Recovery. The sleep listing is deliberately evidence-weak: it reflects pineal/circadian positioning, not strong human sleep-trial evidence.
• Creatine now appears under Cognitive and Muscle & Strength, not only Essentials/Sleep & Recovery.
• Omega-3, NAC, taurine, GlyNAC, sulforaphane, curcumin, boswellia, SPMs, PEA, thymosin alpha-1, and KPV now show up in the inflammation, detox, mitochondrial, mood, or metabolic lists they logically touch.
• Progesterone, testosterone, HGH and GH secretagogues, resmetirom, and thyroid-support minerals now appear in the endocrine or metabolic lists readers would expect.
• Urolithin A, methylene blue, alpha-lipoic acid, CoQ10, MOTS-c, Humanin, and ALCAR now surface across the mitochondrial, cognitive, metabolic, muscle, or longevity filters where appropriate.

Scores, evidence tiers, doses, notes, and primary CSV categories did not change. This is a visibility correction: the same intervention now appears in every category it has earned, without creating duplicate compound pages.

We audited the site against the WADA 2026 prohibited-list CSV and added coverage for the missing performance-relevant gaps: long-tail anabolic steroids, EPO/HIF oxygen-delivery drugs, myostatin and activin blockers, GH analogs and secretagogues, exercise mimetics, stimulant families, diuretics and masking agents, opioids, THC/cannabinoids, systemic glucocorticoids, beta-blockers, high-volume IV infusions, and gene/cell doping concepts.

The goal was coverage without turning the database into a phone book of obscure near-duplicates. Common compounds still get their own pages; long-tail WADA examples now live inside class-level rows with aliases in the notes.

When an intervention has evidence that varies by use, its database row records that as a multi-part rating — for example Strong (acute poisoning); Very Weak (detox supplement). The score reads the first part. The convention is to lead with the use a reader of this site would actually adopt.

Thirteen rows broke that convention. They led with a narrow emergency-room or clinical indication — and so they scored as if that were the point of taking them.

The clearest case: activated charcoal sat at A+. It earned that on “Strong evidence, high effectiveness” — for treating acute poisoning in an ER. As the “detox” supplement it’s actually sold as, the evidence is Very Weak (it never leaves the gut). The row led with the ER use, so the score followed.

The whole Detox category ran on this pattern — chelators and adsorbents genuinely are strong emergency drugs and inert supplements at the same time.

Each row’s rating clauses were reordered so the reader-relevant use leads. What moved:

• Activated charcoal — A+ → C
• Milk thistle — A+ → C+
• Glutathione — A → B
• NAC (both entries) — A → B+
• Thymosin α-1 — A → C+
• Digestive enzymes — A− → C+
• CBD — B → C+
• HGH — B− → C−
• DMSA / DMPS chelators — B− → D
• IGF-1 LR3 — C → D
• Anti-amyloid antibodies — C− → D−
• EDTA chelation — C+ → F

A note on the last two. Anti-amyloid antibodies were scoring on amyloid clearance shown on PET scans — a surrogate marker; the rating now reflects clinical benefit, which a 2026 Cochrane review found trivial-to-small against a meaningful risk of brain swelling and bleeding. EDTA chelation was scoring on lead-poisoning treatment; marketed as a heart-disease or “detox” therapy it has no demonstrated benefit (the TACT2 trial was negative), and it lands at F.

Nothing about the scoring formula or the grade bands changed — this was a data correction. The authoring convention that prevents it recurring is now written into the data workflow.

A reader pointed out that creatine showed up twice in the rankings — once under Essentials, once under Sleep & Recovery. A full scan of the database turned up 14 compounds with the same problem: a compound that legitimately belongs to two categories had been entered as two separate rows, which meant two ranks, two scores, and two compound pages for one substance.

That is now fixed. Each of these 14 compounds is a single entry:

• Creatine, vitamin D, magnesium, zinc, omega-3, collagen peptides — kept in Essentials, also shown under Sleep & Recovery or Immune & Inflammation.
• Ashwagandha — kept in Mood, Anxiety & Stress, also shown under Essentials.
• Berberine, tesofensine, T3, CoQ10 — consolidated into their primary category, cross-listed under the second.
• Quercetin and lithium — single entries, cross-listed across the Longevity and Immune/Mood lists they each touch.
• GHK-Cu — had two near-identical rows inside Longevity itself; now one.

The surviving entry keeps the fuller of the two write-ups, and any citations that only existed on the other row were carried over, so nothing was lost. When a merge changed the picture — for example, T3’s off-label fat-loss use is now folded into the single thyroid-hormone entry — the notes were updated to say so.

A consolidated compound still appears under every category it earns a place in: filter the rankings by Essentials or by Sleep & Recovery and creatine shows up in both. It is just one row now, ranked once, instead of two competing copies.

One deliberate non-change: glycine is still two entries. The longevity dose (10–15 g/day, as a methionine-restriction mimetic) and the sleep dose (3 g before bed) are different enough in purpose to stand on their own — that is not a duplicate.

NAC (N-acetylcysteine) had two separate database rows — one filed under Essentials, one under Immune & Inflammation — a cross-category duplicate the earlier consolidation pass missed.

They are now a single row. The canonical entry lives in Essentials (where the other daily-supplement staples sit) and is cross-listed under Immune & Inflammation, so it still appears in both category rankings. The merged row keeps the fuller mechanism, risk, legality and notes detail from the two originals and the combined citation list.

The grade is unchanged — NAC was B+ in both rows after the evidence-context correction, and it remains B+.

S-tier had no members. That was a bug, not a verdict.

The composite score runs 0–10, and the letter scale mapped S to 9.4 and up. But the database’s interventions clump near the top — more than a dozen sit at exactly 8.4 — and the single best score anywhere was 8.8. The top grade was, in practice, impossible to earn. A reader’s first question about a tier list is “what’s at the top?”, and the honest answer was “nothing,” which isn’t an answer.

We fixed it in two parts.

The top of the scale was recalibrated. The four highest bands (A− through A+) were tightened to 0.3-point steps, and S now begins at 8.5 — the realistic ceiling of the database rather than a number nothing reaches. Bands B+ and below are untouched, so 245 of 350 interventions keep exactly the grade they had. The composite formula itself — how Evidence, Benefit, and Safety combine — was not changed.

Five interventions were re-graded on the evidence. Sleep, resistance training, protein intake, creatine, and VO2 max / HIIT were carrying “Strong” evidence ratings when their evidence base is genuinely among the most robust of anything in the database — replicated across hundreds of trials and decades of epidemiology. They were moved to “Very Strong.” Sleep’s risk rating was also corrected: a note about the danger of sleep deprivation had been sitting in the risk field, where it doesn’t belong — the act of sleeping 7–9 hours is very low risk.

The new S-tier, eight interventions:

• Sleep — 9.7
• Creatine — 9.7
• Resistance training — 9.3
• Protein intake — 9.3
• Statins (rosuvastatin / atorvastatin) — 8.8
• Tadalafil — 8.8
• PCSK9 inhibitors — 8.7
• VO2 max / HIIT — 8.5

Statins, tadalafil, and PCSK9 inhibitors were not re-rated at all — they already carried top evidence and effectiveness scores and simply landed in S once the band was reachable.

This was a calibration of the letter scale and a correction of five under-rated rows — nothing about the underlying scoring math changed.

The full-table review produced one big access change: orforglipron is no longer a pipeline-only obesity drug. FDA approved it as Foundayo on April 1, 2026, so the row now uses the approved tablet titration schedule and Rx status.

Semaglutide also changed. Wegovy HD adds a 7.2 mg weekly option, with FDA specifically calling out altered skin sensation as more common at the higher dose.

Discovery added FGF21 analogs as a Metabolic Health row. Efruxifermin, pegozafermin, and efimosfermin are still investigational, but the class now has enough human Phase 2 data and Phase 3 MASH programs to belong in the database rather than the watchlist.

The toxins table gained four consumer-channel hazards: DMAA/DMHA stimulant adulterants, yellow oleander-adulterated weight-loss supplements, nitrite poppers, and recreational nitrous oxide inhalation.

This audit fixed a failure mode in the rankings: a large effect size had too much room to pull dangerous interventions upward. That made the score less faithful to an evidence-first, safety-visible product.

The formula still uses Evidence, Benefit, and Safety, but the weights now put more pressure on Evidence and Safety: 0.45·Ev + 0.15·Bn + 0.40·Sf. There are no hidden caps or vetoes. A compound can show high Benefit and terrible Safety at the same time, and the visible breakdown should make that tradeoff obvious.

The row corrections were deliberately focused:

• Caffeine now reflects ordinary dietary use as low risk, with a separate warning for pure or highly concentrated caffeine powders.
• Clomiphene and enclomiphene are now separate entries.
• DNP and several high-risk performance drugs gained clearer warning-only / high-risk framing in their notes and tags.
• BPC-157 and TB-500 now use parser-recognized Unknown-High risk language.
• Fadogia now correctly shows no human efficacy trials.
• PFAS now parses as high-prevalence toxin exposure.
• Duplicate Astaxanthin and Yohimbine rows were consolidated.

This is a correction, not a recommendation. The point is to make the ranking table less gameable by raw efficacy while keeping the component scores honest and visible.

“Protocols” was doing two jobs at once: a category (its own tab in the rankings) and a kind of thing (a class, like Peptide or Hormone). The double duty meant sauna sat in a generic “Protocols” bucket instead of next to the cardiovascular and longevity interventions it actually competes with.

It’s now just a class. Every protocol — sauna, cold plunge, Zone 2, resistance training, time-restricted eating, breathwork — keeps the Protocol class label but is ranked inside its real evidence categories. Resistance training shows up under Muscle Building, Longevity, and CV/Lipid; sauna under CV/Lipid, Longevity, and Recovery. The standalone Protocols tab is gone.

Nothing about the scores changed — only where these rows are filed.

Read Off Label ranks things you take or do — compounds, supplements, and protocols — scored on evidence, benefit, and safety. Diagnostic tests (bloodwork, DEXA, CGM, whole-body MRI, multi-cancer screening, epigenetic age tests) are a different kind of decision: their value depends on what you do with the result, not on a benefit-versus-risk profile. Scoring them on the same rubric was always a stretch, so the category is out.

What changed: 16 diagnostic entries removed. The rankings page drops its Diagnostics mode and is now a two-way Interventions / Toxins view. The database goes from 19 categories to 18, and from 384 to 368 ranked entries.

This narrows the site to what it does best. A dedicated treatment of testing — which tests are worth it, and how to act on the results — may return later as its own format, but not inside the intervention rankings.

First full evidence audit since launch. Worked category by category against PubMed, ClinicalTrials.gov, AdisInsight, and bioRxiv. Net result: the database grew from 357 to 378 interventions across 19 categories, and 31 malformed CSV rows (silent unescaped commas) were repaired.

Score-relevant rerates:

• Rapamycin — downgraded. The PEARL trial (April 2025) missed its primary endpoint of visceral adiposity reduction. Secondary signals on lean mass and well-being held up; the headline longevity claim did not.
• Multi-cancer early detection (Galleri) — downgraded from Moderate to Weak–Moderate. NHS-Galleri 2026 — the first large RCT of MCED — did not reduce late-stage cancer incidence.
• Cagrilintide (CagriSema) — re-framed. REDEFINE 1/2 (NEJM, June 2025) came in below Phase 2 expectations (-20.4% vs ~25% projected) and below tirzepatide 15 mg’s SURMOUNT-1 number. Removed the prior “rivals tirzepatide” framing.
• Tirzepatide — refined with SURMOUNT-5 head-to-head vs semaglutide (-20.2% vs -13.7%) and SURMOUNT-1 176-week extension data.
• Testosterone (TRT) — FDA Feb 2025 label change folded in. Boxed cardiovascular warning removed; class-wide blood pressure warning added; AF / AKI / PE signals from TRAVERSE acknowledged.
• Niacin — Lp(a) niche eclipsed by RNA-targeted agents (olpasiran, pelacarsen, lepodisiran et al). Notes refreshed.
• Retatrutide — TRIUMPH Phase 3 program detail (4 trials + TRANSCEND-CKD + TRIUMPH-Outcomes CVOT) updated.

New entries — Weight loss: orforglipron (Lilly oral small-molecule GLP-1), survodutide (BI/Zealand GLP-1/glucagon), maridebart cafraglutide / MariTide (Amgen monthly peptide-antibody), mazdutide (Innovent dual agonist, approved China 2025).

New entries — CV/Lipid: Lp(a)-lowering therapies (olpasiran / pelacarsen / lepodisiran / zerlasiran / muvalaplin) as a class entry; obicetrapib (next-gen CETP inhibitor).

New entries — Hormones: fezolinetant (Veozah, NK3 antagonist for VMS); elinzanetant (Lynkuet, dual NK1/NK3 antagonist); resmetirom (Rezdiffra, first FDA-approved MASH/NASH drug); romosozumab (Evenity, sclerostin antibody for osteoporosis).

New entries — Mental Health: dextromethorphan-bupropion (Auvelity, oral rapid-acting antidepressant); zuranolone (Zurzuvae, oral PPD); xanomeline-trospium (Cobenfy / KarXT, first new schizophrenia mechanism in 50+ years).

New entries — Cognitive: anti-amyloid mAbs (lecanemab / donanemab / aducanumab) as a class entry, with the 2026 Cochrane meta-analysis showing only trivial cognitive benefit; solriamfetol (Sunosi); pitolisant (Wakix); phenibut (with explicit dependence/withdrawal warning).

New entries — Recovery: suzetrigine (Journavx, first new acute pain mechanism in decades); glucosamine + chondroitin.

New entries — Longevity: pyrroloquinoline quinone (PQQ).

New entries — Immune: bovine lactoferrin.

Minor refreshes: bimagrumab, enclomiphene/clomiphene, estradiol HRT (NK3/NK1 cross-ref), TMS (SAINT clearance), microplastics (2026 Polimeni cardiovascular review).

Full per-row entries with DOIs and PMIDs live in the repo at src/data/audit_log.md. Eight cross-category duplicates (tesofensine, ashwagandha, collagen peptides, quercetin, berberine, astaxanthin, CoQ10, microdose lithium) are flagged for consolidation in a future pass.

First published ranking. 357 compounds and protocols across 19 categories, scored against the composite rubric. Methodology and disclaimer finalised. Weekly newsletter, Off Label Weekly, launching 28 April.

Initial scores are the author’s best synthesis as of this date. Expect movement as readers flag studies I missed. Every subsequent change will land here.