Encyclopedia of mechanisms

A triple GIP, GLP-1 and glucagon agonist — the only one in this group that genuinely raises energy expenditure instead of merely suppressing appetite.

What the data say: Phase 2 (NEJM 2023). Phase 3 is under way; the long-term profile is UNKNOWN.

• Tolerability is decided by the PACE of escalation, not the dose: a fast start at 4 mg gave 50% nausea, while a slow start to the same target dose was far better tolerated
• It raises resting heart rate (a glucagon effect) — monitor pulse and blood pressure
• In some people it transiently raises blood sugar at the start
• An unapproved compound, in clinical trials

A long-acting amylin analogue — it acts on satiety through a different axis than GLP-1 (area postrema, amylin receptors 1 and 3), which is why it is combined with semaglutide (CagriSema).

What the data say: Phase 3 RCTs in combination: REDEFINE-1 (3,417 people) −20.4% vs −3.0% at 68 weeks, REDEFINE-2 in type 2 diabetes −13.7%. Cagrilintide alone: phase 2 (706 people, −6.0 to −10.8% vs −3.0%); the monotherapy arm of REDEFINE-1 −11.8%. Not approved; the CagriSema application is with the FDA according to the manufacturer, no decision yet.

• Combined with GLP-1 it adds to the slowing of gastric emptying — never raise both doses in the same week
• Nausea and vomiting are intensified in combination

A GLP-1 receptor agonist — it acts on the satiety centre in the hypothalamus and brainstem and slows gastric emptying.

What the data say: Phase 3 RCT (STEP-1); an approved medicine.

• Up to 40% of the mass lost can come from muscle — without protein and resistance training you lose the tissue you did not want to lose
• Nausea and constipation depend on the PACE of escalation, not the final dose
• After stopping, about two thirds of the lost weight returns within a year — this is not a cycle but chronic therapy
• Contraindications: medullary thyroid carcinoma or MEN2 in the history, previous pancreatitis, pregnancy

A dual GIP and GLP-1 agonist — the GIP component adds insulin sensitisation of the adipocyte and eases the nausea typical of GLP-1 alone.

What the data say: Phase 3 RCT (SURMOUNT-1); an approved medicine.

• Still about 25% of the mass lost is lean tissue — resistance training and protein are mandatory
• Gallstones and a risk of dehydration with vomiting
• Contraindications as for semaglutide (MEN2 / medullary thyroid carcinoma)

Fragment 176-191 of growth hormone — in the literature and in anti-doping analysis it is the same molecule as AOD-9604 (177-191 with an added tyrosine). It curbs fat storage in animals; despite the 'lipolytic' label it did not significantly break fat down in the early studies.

What the data say: No peer-reviewed efficacy studies in humans. The AOD-9604 programme (same molecule): 6 RCTs, ~900 people, safety only in print; the phase IIb result and the 2007 termination are known solely from the sponsor's announcement.

• Rapid breakdown in the body and no material standardisation — reagent quality is the main real risk here
• Do not combine with AOD-9604 — functionally the same compound

A growth-hormone fragment (aa 177-191) with an added tyrosine — meant to curb fat storage without affecting IGF-1 or glucose; the effect persisted in mice lacking the beta3 receptor, so the mechanism is not directly beta3.

What the data say: Six RCTs, about 893 participants (2001–2006) — safety only in print. The phase IIb trial (24 weeks, 502 people) showed no advantage over placebo and development stopped in 2007 — a result known solely from the sponsor's announcement, never published in a journal.

• This is not uncertainty — it is documented lack of efficacy in humans. The mechanism works in animals and did not carry over to people
• Do not combine with HGH Fragment 176-191 — practically the same compound

A dual GLP-1 and glucagon agonist, an oxyntomodulin analogue — it combines appetite suppression with thermogenesis and hepatic fat metabolism.

What the data say: Phase 3 in China: GLORY-1/GLORY-2 (obesity) and DREAMS-1/DREAMS-2 (type 2 diabetes); meta-analysis of 9 RCTs (2,292 people). Approved in China (June 2025 obesity, September 2025 diabetes); no EU/US approval — Lilly's US programme is phase 2. No abstract reports >20% weight loss.

• Raises heart rate by 5–9 bpm (phase 2, vs +4.8 on placebo); 20% discontinued on 16 mg in the US phase 2
• No approval in Europe

A dual glucagon/GLP-1 agonist with a strong glucagon component — a two-track programme: obesity (SYNCHRONIZE) and steatotic liver disease (LIVERAGE).

What the data say: Phase 3 SYNCHRONIZE-1 (725 people) and SYNCHRONIZE-MASLD (216 people); meta-analysis of 6 RCTs (1,272 people): −6.7 kg, HbA1c −0.66 points, more discontinuations. Not approved anywhere (as of September 2026, no Drugs@FDA record).

• Long escalation — 20 weeks in the phase 2 obesity trial, 24 weeks in the liver trials; in phase 3 discontinuations 41% vs 40% (MASLD)
• Raises heart rate by 2–7 bpm (phase 2 in type 2 diabetes)

A small-molecule NNMT inhibitor (not a peptide) — it raises NAD+ in the fat cell and boosts its metabolism without touching appetite.

What the data say: No published human studies (PubMed: 4 records on the compound, all laboratory; ClinicalTrials.gov: 0). Oral bioavailability 38.4% in the RAT; the key experiments used injections. Circulating dosing schemes are conversions from mg/kg in mice.

• No data on effective dose, bioavailability or safety in humans
• Long-term modulation of the methylome has not been studied
• Do not combine with AICAR — both target the same cellular energy axis

An AMPK activator called an exercise mimetic — in mice it raised endurance by 45% without training.

What the data say: Oral absorption is <5%, and after intravenous dosing it does not reach the AMPK-activation threshold in muscle (three human studies; in one, glucose uptake still doubled). As acadesine it was tested in >7,000 people in cardiac surgery: a 1997 meta-analysis (4,043 people) showed 27% fewer infarcts, but RED-CABG 2012 (3,080 people) was stopped for futility (5.0% vs 5.1%). 'Weak' refers to the AMPK/endurance goal — for the cardiac indication the evidence is extensive and negative.

• Banned by WADA (on the Prohibited List since 2009) — relevant for doping control; AICAR is also an endogenous metabolite (urine of 499 athletes)
• Most of the dose is taken up by erythrocytes and endothelium; only a negligible amount reaches muscle
• Hyperuricaemia (the metabolite enters the purine pathway)
• Do not combine with 5-Amino-1MQ — the same energy axis

A GHRH analogue bound to albumin — it keeps GH and IGF-1 elevated for many days from a single injection.

What the data say: Pharmacokinetic studies in humans; no data beyond a year of use.

• A constant GHRH background weakens the response to subsequent pulses — you lose the advantage of physiological pulsatility
• Water retention, joint pain and carpal tunnel syndrome at higher doses
• Chronically raised IGF-1 requires monitoring

The most selective ghrelin receptor agonist — it releases GH without touching cortisol or prolactin.

What the data say: In preclinical studies it did not raise ACTH or cortisol even at doses over 200x the GH-effective one.

• Do not combine with GHRP-2, GHRP-6 or hexarelin — the same receptor, no gain, more side effects
• Possible water retention at higher doses combined with GHRH

Recombinant human growth hormone — it acts directly on the GH receptor, bypassing the pituitary.

What the data say: Systematic reviews in healthy adults (Liu 2007/2008): +2.1 kg lean mass WITHOUT any gain in strength, more adverse events; RCT in athletes: sprint +3.9% only. Long-term safety from the SAGhE registry (23,984 patients treated in childhood).

• It builds the collagen matrix, NOT myofibrils — which explains the real recovery effect alongside the absence of strength gain
• Type 2 diabetes six times more frequent in CHILDREN treated with GH (34.4 per 100,000 treatment-years); in healthy older adults reviews only report 'somewhat more frequent' glucose intolerance
• Joint pain, carpal tunnel syndrome, gynaecomastia, water retention
• More adverse events (oedema, joint pain, carpal tunnel) as the dose rises — in the SAGhE registry mortality and cancer tracked the underlying diagnosis, not the dose
• It shuts down your own GH secretion for the duration of use

An IGF-1 analogue that binds the carrier proteins poorly — it circulates in free form; more potent than IGF-1 only where IGFBP proteins bind the native hormone (it binds the receptor itself about 3× more weakly).

What the data say: No human studies at all (PubMed 66 records — in vitro and animal; ClinicalTrials.gov — 0; 2026 review: tier D). The only window on risks is mecasermin (rhIGF-1): hypoglycaemia, tonsillar hypertrophy. In pigs LR3 switched off endogenous GH and IGF-1 and SLOWED growth.

• Risk of hypoglycaemia — at high concentrations it stimulates the insulin receptor; 49% of children treated with recombinant IGF-1 (mecasermin) reported hypoglycaemia
• Individual-data meta-analysis: higher IGF-1 is associated with higher prostate-cancer risk (OR 1.29 for extreme quintiles); the mitogenic mechanism is biologically coherent
• Absolute contraindication: active or previous malignancy
• Do not combine with HGH or the GH axis — it is the terminal effector of the same pathway

A second-generation ghrelin agonist — a stronger GH release than GHRP-6 at a lower dose, at the cost of raising cortisol.

What the data say: Human pharmacodynamic studies (small groups, single doses); the only long-term data are 8 months in 6 children — IGF-I unchanged.

• Raises ACTH and cortisol to a degree comparable with CRH (single-dose human studies)
• Evening dosing raises night-time cortisol, but in the only sleep study it did not change slow-wave sleep
• A moderate rise in prolactin

The first ghrelin agonist described — it stimulates appetite (in rats after central administration; not studied in humans), which is sometimes the goal rather than a side effect.

What the data say: Human pharmacodynamic studies (single doses, small groups); the GHRH+GHRP-6 diagnostic test validated in 250 people.

• Raises ACTH and cortisol (night-time human RCT: cortisol 56 vs 25 ng/ml); no head-to-head comparison within the class exists
• In the only sleep study stage-2 sleep lengthened and slow-wave sleep was unchanged — the effect on sleep is not established

A potent GH releaser (similar to GHRP-2 in head-to-head comparison) that additionally binds the CD36 protein in the heart — but the GH response partly fades with continuous use.

What the data say: Desensitisation documented in humans: GH AUC 19.1 → 12.3 (week 4) → 10.5 (week 16) → 19.4 after a 4-week break; after 16 weeks the cortisol response was SMALLER than at baseline.

• Partial desensitisation: after 16 weeks the GH response is about 45% smaller, recovering after a 4-week break
• It raises cortisol and prolactin much like GHRP-2
• The CD36 mechanism is unconfirmed in humans; in the isolated heart it constricts coronary vessels

A GHRH analogue stimulating your own pulsatile growth-hormone secretion — the only one in the catalogue that selectively reduces VISCERAL fat while protecting muscle mass.

What the data say: Two phase 3 RCTs (412 and 404 patients with HIV): visceral fat −15.2% and −10.9%; FDA-approved in 2010 (Egrifta) for HIV lipodystrophy; meta-analysis of 5 RCTs (2026).

• It raises IGF-1 — monitoring is required
• Growth hormone worsens insulin sensitivity, working against incretin drugs — if you combine them, monitor glucose and HbA1c
• The visceral-fat effect was measured at 26 weeks; after stopping, the fat returns within months
• Contraindications: active malignancy, pregnancy, pituitary disease

The native GHRH fragment — the gentlest entry into the growth-hormone axis, working through your own pituitary.

What the data say: Historically a medicine (Geref: diagnostic test 1990, paediatric treatment 1997; withdrawn 2008–2009 for non-clinical reasons — FDA 2013). In adults, studies of 10–19 people from 1992–1997.

• Cleared from blood in about 4 minutes (half-life 4.3 min); the GH pulse lasts about 2 h
• Facial flushing, pain at the injection site

A short-acting GHRH analogue — it triggers a single, physiological growth-hormone pulse instead of a sustained elevation.

What the data say: No human studies of the no-DAC version (PubMed 33 records — DAC only; ClinicalTrials.gov — one DAC trial, terminated); 2026 review: tier D. Pharmacodynamic data concern CJC-1295 WITH DAC or plain GRF 1-29.

• Dosing schemes circulating online (per-injection ceiling, fasted dosing) have no studies behind them — they come from forums
• Transient facial flushing and drowsiness after injection (data for GRF 1-29)

It acts at the very top of the reproductive axis — on hypothalamic neurons releasing GnRH, above both the pituitary and the gonads.

What the data say: Research protocols only (small groups, Imperial College). Subcutaneous dosing works dose-dependently (2026 RCT in 15 men). GnRH is about 3× more potent in head-to-head comparison. The 'minutes' half-life (4 min) comes from MICE — there is no human pharmacokinetics for KP-10.

• A continuous 5-day infusion returns gonadotropins to control levels, yet a 22-hour infusion did not desensitise GnRH neurons and 8–16 h/day dosing held the effect for 12 days — 'pulsatility as a prerequisite' is an oversimplification
• Combining with HCG/HMG has no study behind it — this is methodological caution (bypassing feedback from two sides confuses hormone readings), not a documented interaction

An LH analogue — it stimulates Leydig cells directly to produce testosterone inside the testis.

What the data say: A licensed medicine with an extensive andrology literature (meta-analysis of 44 studies: gonadotropins restore sperm in 75% of men with HH). Fertility preservation during testosterone therapy — only a retrospective series of 26 men.

• Intratesticular testosterone is 50-100x higher than in blood and it is what determines fertility — which is why on testosterone therapy you can have a normal blood result and zero spermatogenesis
• Low doses maintain intratesticular testosterone (250 IU every other day: −7% after 3 weeks); whether higher doses improve semen was not measured in the Coviello study
• Gynaecomastia with excessive aromatisation, water retention
• Does not replace FSH — with HCG alone sperm counts in healthy men fell to about 25% of normal; in childhood-onset hypogonadism HCG alone usually does not normalise semen

A mixture of FSH and LH — only together with HCG does it fully restore spermatogenesis quantitatively.

What the data say: Clinical literature in hypogonadotropic hypogonadism (meta-analysis of 44 studies; Finkel 1985 NEJM). In IVF two conflicting Cochrane versions: 2011 no difference versus rFSH, 2026 — HMG more live births and less OHSS.

• Therapy is long: median 5.5 months to the first sperm, 12.4 to >5 million/ml and 29 months to >20 million/ml (Liu 2002, 29 men)
• Requires endocrinologist supervision and oestradiol monitoring
• Prior testosterone therapy does not hinder recovery (Liu 2002, Rastrelli 2014); there are no studies of testosterone given CONCURRENTLY with HMG

A melanocortin agonist acting centrally on MC4R — it raises desire in the brain rather than through the blood vessels as PDE5 inhibitors do.

What the data say: An approved medicine (Vyleesi, 2019).

• Nausea in about 40% of people, mostly on the first dose — which is why one starts below the approved dose
• A transient rise in blood pressure: contraindicated in uncontrolled hypertension and cardiovascular disease
• Acute liver injury has been reported (a LiverTox database entry)
• A maximum of one dose a day and eight a month
• It does not raise testosterone and does not replace investigation for hypogonadism

A melanocortin-receptor agonist favouring MC1R (pigmentation) — cryo-EM structures show it also binds and activates MC4R; yet the central effects typical of MT-II have not been reported in its clinical trials.

What the data say: Two NEJM RCTs (74 and 94 EPP patients; Langendonk 2015): USA 69.4 vs 40.8 pain-free hours, EU 6.0 vs 0.8 h; safety follow-up of up to 8 years (115 patients, 1,023 implants). Approved by the EMA on 22 Dec 2014 and the FDA on 8 Oct 2019.

• Requires dermatological monitoring of moles — dermoscopic changes at 5 months reversed by 12 months, with no malignant features (103 nevi)
• Nausea — the most frequent adverse event over up to 8 years of follow-up, not just at the start; redness and pain at the implant site
• It does not remove the need for sun protection

It stimulates the formation of new vessels (the VEGFR2 and nitric oxide axis), delivering blood and oxygen where tissue is damaged. Resistant to stomach acid, so it works orally on the gut.

What the data say: Hundreds of preclinical papers, but dominated by a single research group. NO published phase 2/3 human trials.

• The route decides: for the gut ORALLY (it resists acid), for a tendon SUBCUTANEOUSLY near the injury — oral bioavailability to peripheral tissue is low
• The key contraindication: active or undiagnosed malignancy — the pro-angiogenic mechanism is exactly what a tumour needs
• Effective doses in rats convert to about 110 µg for 70 kg, so protocols found online are sometimes several times higher than the research implies
• Banned by WADA since 2022 (category S0) — with no exemption available for athletes
• Caution with blood-pressure-lowering drugs (additive nitric oxide effect)

It maintains a pool of actin ready for use, so repair cells can migrate quickly to the site of injury. It acts systemically, not locally.

What the data say: The biochemical mechanism is very well documented crystallographically, but clinical translation is weak — there are no approvals.

• It acts SYSTEMICALLY — injecting it into a painful knee makes no pharmacokinetic sense
• A long tissue half-life: dosing more often than twice a week has no justification
• A serious oncological contraindication: in an animal model, overexpression of thymosin beta-4 produced an average of 46.7 lung metastases against 10.9 in controls — the same migration and angiogenesis mechanism we use for healing
• Drowsiness and mental fog in the first days are the commonest complaint
• Banned by WADA (S2)

Two pro-angiogenic peptides with overlapping mechanisms (BPC-157: VEGFR2/NO; TB-500: a thymosin β4 fragment) — sold together as 'Wolverine'. The only study of the pair (rats, Achilles tendon, 2026) showed no benefit of the combination over either agent alone.

What the data say: No human studies — neither of the blend nor of the components (2026 reviews: 67% of papers are animal; both banned in sport). The only study of the blend: 32 rats, 4 weeks — 'combined treatment did not confer additional benefits compared to either agent alone'. This conflicts with the synergy narrative.

• Contains BPC-157 and TB-500 — do not add them separately
• Inherits the oncological contraindication of both components

Three peptides with overlapping mechanisms (all pro-angiogenic, matrix remodelling) in one vial; GHK-Cu is about 70% of the mass, so copper (≈ 8 mg per 50 mg vial) is the main safety variable. There are no studies of the blend itself.

What the data say: No paper with all three components together; the only study of two (BPC-157 + TB-500, rats) — no additive effect. 2026 reviews name 'combination therapy effects' as a knowledge gap. EFSA 2023: copper ADI 0.07 mg/kg (oral route).

• GHK-Cu makes up about 70% of the blend by mass — the copper load is the main safety variable here
• Do not add GHK-Cu, BPC-157 or TB-500 separately — all three are already in it
• Do not combine with KLOW: KLOW is the same composition plus KPV

This is exactly GLOW with KPV added — the same recovery set reinforced with an anti-inflammatory component. A typical vial: 50 mg GHK-Cu plus 10 mg each of BPC-157, TB-500 and KPV.

What the data say: No studies of the blend; KPV in humans: 0 (PubMed + ClinicalTrials.gov). The best argument for complementarity (GHK-Cu and KPV at different stages of healing — 2025 review) comes from separate papers, not from the combination.

• Contains FOUR substances — do not add KPV, GHK-Cu, BPC-157 or TB-500 separately
• KPV has no human studies at all, so there are no 'studied ranges' to refer to
• Do not combine with GLOW — an almost identical composition, the only difference is KPV

The C-terminal fragment of alpha-MSH that carries its anti-inflammatory action without any effect on pigmentation. It most likely does not act through melanocortin receptors (the effect persists in mice lacking MC1R, with no cAMP rise). It enters gut cells through the PepT1 transporter, which is UP-regulated in inflammation — the inflamed gut draws it in.

What the data say: Three independent mouse colitis models plus a clear transport mechanism (the effect disappears in PepT1-knockout mice). No human studies of any kind (PubMed, ClinicalTrials.gov — September 2026).

• For the gut the best-documented route is oral (the PepT1 transporter in the epithelium), but an effect was also seen after intraperitoneal dosing in mice — no head-to-head comparison of routes exists
• Caution during active infection: suppressing NF-kB means suppressing the innate response
• If KLOW is in the protocol, separate KPV is redundant — KLOW already contains it

The only human cathelicidin — it disrupts bacterial membranes and biofilms while acting as an alarm signal for the immune system.

What the data say: Three RCTs of TOPICAL application to wounds (34, 148 patients and diabetic foot) — the largest null; no studies of systemic dosing in humans. Autoantigen role in psoriasis confirmed (T cells in 2/3 of patients).

• THE MOST SERIOUS WARNING ON THE LIST: LL-37 is an autoantigen. It binds the body's own DNA and triggers type I interferon — a documented INITIATING mechanism in psoriasis and lupus
• Contraindications (mechanistic caution, not trial data): psoriasis, lupus, rosacea, RA and other autoimmune diseases
• Opposite directions to KPV (stimulating vs. damping innate immunity) — combining them has no basis in research

It drives T-lymphocyte maturation and REVERSES their exhaustion — restoring reactivity instead of suppressing it.

What the data say: Approved in over 35 countries (Zadaxin; hepatitis B/C, vaccine adjuvant), but hard endpoints disappoint: TESTS 2025 (1,106 sepsis patients) null, COVID-19 meta-analysis no effect on deaths, Cochrane 2026 in hepatitis B — very low certainty of evidence.

• Contraindications: autoimmune disease (the Th1 direction may aggravate it), post-transplant status and immunosuppressive treatment (a risk of rejection)
• A possible transient flare of autoimmune thyroid disease
• Do not combine with LL-37 — double stimulation towards autoimmunity

A thymic nonapeptide that is completely inactive WITHOUT zinc — binding the zinc ion is a condition of its action, not an extra.

What the data say: The least documented compound in terms of practical use: no clinical protocols and no established human dosing.

• With zinc deficiency, giving thymulin alone is pointless — conversely, repleting zinc raises the activity of your own thymulin. Start by measuring zinc, not by buying a peptide
• The dose relationship is biphasic: LOW doses cause pain hypersensitivity, higher ones reduce it — here less does NOT mean safer
• Copper peptides antagonise zinc status and may therefore lower thymulin activity

It induces regulatory lymphocytes and mucosal tolerance while strongly dilating blood vessels.

What the data say: Strong mechanism; in two RCTs of respiratory failure in COVID-19 aviptadil (synthetic VIP) failed the primary endpoint (Youssef 2022, n=196; TESICO 2023, n=461 — stopped for futility).

• Plasma half-life is about ONE MINUTE — clinical trials used intravenous infusion, nebulisation or intracavernosal injection; intranasal dosing has not been studied
• Low blood pressure, dizziness and facial flushing are a direct consequence of vasodilation
• Contraindications: low blood pressure, ischaemic heart disease, antihypertensive drugs and PDE5 inhibitors
• Secretory diarrhoea at higher doses

A natural tripeptide whose level falls with age (about 200 ng/ml at 20, about 80 ng/ml at 60). It directs the FULL skin-remodelling cycle — raising collagen and, at the same time, the enzymes that break down the old matrix.

What the data say: Strong in-vitro and model data, moderate for topical use; weak for subcutaneous administration in humans.

• A countable copper load: GHK-Cu is about 15% copper by mass, so 2 mg of peptide subcutaneously is about 0.3 mg of copper BYPASSING intestinal regulation — it accumulates with daily use over months
• Absolute contraindication: Wilson's disease and disorders of copper metabolism
• Antagonism with zinc — long courses may lower zinc status
• Very painful injections and prolonged redness are the most common complaint
• Active cancer — pro-angiogenic action

A GHK-Cu analogue differing by one amino acid. The only dedicated paper (Pyo 2007): elongation of human hair follicles ex vivo and stimulation of dermal papilla cells; the TGF-β1/VEGF mechanisms attributed online come from the GHK-Cu literature.

What the data say: One in vitro / ex vivo paper (Pyo 2007). No human studies (PubMed 1 record; ClinicalTrials.gov 0 for AHK-Cu, 'copper tripeptide-3', alanyl-histidyl-lysine). Clinical trials of a 'copper peptide' (e.g. QR678) concern GHK-Cu — a different molecule. Catagen in the human follicle is triggered by TGF-β2, not β1.

• Topical to the scalp only — the target is anatomically local, and subcutaneous injection only adds copper load without benefit
• Allow at least 12-16 weeks before judging the effect, because that is how long the hair cycle takes
• Wilson's disease — a contraindication
• Adds to the copper load from GHK-Cu, GLOW and KLOW

A mixture of pig-brain peptides with a proposed neurotrophic action; in mouse microglia fewer pro-inflammatory genes (the 'M1→M2 switch' framing is a simplification).

What the data say: The only preparation on the list with a drug licence in some countries, yet Cochrane 2023 (7 RCTs, 1,773 people) found no benefit in stroke and showed MORE non-fatal serious adverse events (RR 2.39). Manufacturer-linked meta-analyses are more favourable. PubMed flags 10 preclinical Cerebrolysin papers as retracted (2025–2026, figure concerns) — the mechanistic literature needs caution.

• A preparation of animal origin (porcine brain) — a real risk of anaphylaxis, which sets it qualitatively apart from synthetic peptides
• Contraindication: epilepsy — it lowers the seizure threshold
• Requires intramuscular or intravenous administration under supervision; there is no form for self-administration

An ACTH-fragment analogue stripped of action on the adrenal cortex — it raises BDNF and modulates the dopamine system without touching cortisol.

What the data say: A real medicine registered in Russia since 1994, but the studies are small, single-country, often unblinded and without Western replication. The nootropic use in healthy people is the least studied of all.

• Intranasal is the only route with a rationale — the plasma half-life is measured in minutes, and transport to the brain runs along the olfactory route
• Doses of 6-18 mg a day are HOSPITAL protocols in acute stroke, not an advanced tier of biohacking
• It amplified amphetamine-induced dopamine release — caution with stimulants
• Nasal irritation, agitation and insomnia with late dosing

Mimics the erythropoietin fragment that binds the innate repair receptor (EPOR/βcR) — tissue-protective WITHOUT stimulating red-cell production; anti-inflammatory action 'possibly also within the CNS' (rats).

What the data say: Five randomised human trials (sarcoidosis, type 2 diabetes), small, with objective endpoints (corneal nerve fibres). Not approved anywhere, phase 2b at most; a diabetic macular oedema trial (NCT06626971) was terminated after 9 participants because the study drug expired.

• Caution in cancer — a theoretical activation of cell-survival pathways
• As an EPO derivative it is treated restrictively by anti-doping bodies

A mimetic of the active CNTF fragment — it unlocks neurogenesis through LIF antagonism and lowers tau hyperphosphorylation.

What the data say: A strong rodent base, but almost entirely from one laboratory (Iqbal, NYS IBR; patents, Phanes Biotech). The only outside paper — Bologna 2024 (Cdkl5 model): worked in vitro, BDNF did NOT rise in vivo. No human data, not even a registered trial (PubMed, ClinicalTrials.gov).

• The rodent protocol is ORAL dosing in the diet for 6–18 months; the adamantyl group was added to improve blood–brain-barrier penetration (gut-fluid stability is a separate property) — injection has no basis in any study
• A negative result worth recording: in the Cdkl5 model P021 did NOT raise BDNF — the mechanism is model-dependent, not universal
• LIF antagonism has consequences outside the brain: haematopoiesis, embryo implantation, stem-cell maintenance

A tuftsin analogue acting anxiolytically by modulating GABA-A receptor expression and serotonergic tone — without sedation and without dependence.

What the data say: The better documented of the Russian pair, but the trials had 30-60 participants, one centre, usually without placebo. The oft-repeated figure of over 800 patients comes from sales pages, not from a meta-analysis.

• Sellers describe this as benzodiazepine-like action ON THE RECEPTOR — that is untrue: what was shown was a change in subunit gene expression, not receptor binding
• Immunomodulatory activity is a genuine unknown in autoimmune disease
• Theoretically additive central depression with alcohol and benzodiazepines

A truncated spadin analogue blocking the TREK-1 potassium channel — an antidepressant mechanism faster than SSRIs, with neurogenesis visible after four days.

What the data say: Effectively one laboratory. Zero human data, zero pharmacokinetics, zero safety studies. Even the parent compound never entered clinical trials.

• TREK-1 is not a brain-only, mood-only channel: it takes part in protection against ischaemia and seizures. Mice lacking TREK-1 are MORE susceptible to both, so chronic blockade is plausibly pro-convulsant
• Do not treat it as a mild sedative
• Intranasal administration has never been studied for this peptide
• Interactions with SSRIs: a converging mechanism, unstudied
• Biphasic action (Pietri 2019, mice after stroke): small amounts OPEN TREK-1 (neuroprotection), larger ones close it — the direction of the effect depends on dose

A nonapeptide with a proposed influence on slow-wave sleep. Its receptor and gene are unknown (2006 review); no paper reports a human half-life.

What the data say: Human studies from 1987–1995, small and conflicting: Schneider-Helmert 1987 (double-blind, 14 people, 7 nights) positive but never replicated; Bes 1992 (16 patients) and Monti 1987 (crossover) without clinical benefit. ClinicalTrials.gov: 0 trials. No gene and no receptor — the 'sleep peptide' hypothesis is weak (Kovalzon 2006).

• BUSTING A POPULAR NARRATIVE: controlled studies showed that DSIP does NOT lower cortisol or ACTH and does NOT raise growth hormone or prolactin (Bjartell 1989 saw a drop in an ACTH marker with cortisol unchanged)
• The claim that 'the effect lasts for days' has no source — the furthest observation is one night after dosing ended
• Theoretically additive sedation with alcohol and hypnotics

A peptide that binds cardiolipin in the inner mitochondrial membrane — it organises cristae and the respiratory-chain supercomplexes. Described in 2004 as a 'peptide antioxidant' (dimethyltyrosine scavenges radicals); cardiolipin is now considered the main mechanism.

What the data say: The clinical record is a series of missed primary endpoints: MMPOWER-3 (218 patients) −3.2 m on the 6MWT, PROGRESS-HF (71) no effect. Barth syndrome: the blinded part of TAZPOWER (12 patients) did NOT meet its primary endpoints, improvement came only in the open-label extension — yet the FDA approved the drug in 2025 under accelerated approval.

• Extrapolating from Barth syndrome to 'mitochondrial optimisation' in healthy people is a very long leap with no data at all
• Efficacy signals in humans came from short intravenous infusions (5 days, p = 0.053; a single infusion in 39 older adults: ATPmax yes, fatigue no); 24 weeks of subcutaneous dosing in phase 3 did not work
• Frequent injection-site reactions, sometimes dose-limiting

A peptide encoded in mitochondrial DNA — it activates AMPK through the folate pathway, mimicking the signal of physical exercise.

What the data say: ZERO published data from giving native MOTS-c to humans. The only clinical study (the analogue CB4211, 88 people) exists as a company announcement only: liver fat fell about as much as on placebo. Since February 2026 the first phase 2a trial of native MOTS-c is recruiting (NCT07505745, 120 people with prediabetes; results no earlier than 2027).

• The analogue CB4211: a phase 1b study in 88 people ended in 2021 with no published results; reports of injection-site nodules come solely from company announcements
• It acts through the folate cycle and AMPK — interactions with methotrexate, folate status, metformin or berberine are PLAUSIBLE but unstudied; avoid in pregnancy as a precaution

A precursor of the coenzyme consumed by sirtuins, DNA-repair enzymes and CD38. This is a supply-side intervention — it provides substrate rather than activating an enzyme.

What the data say: The key distinction: BIOMARKER YES, FUNCTION NO. A meta-analysis of 10 RCTs in adults 60+ (6 NMN + 4 NR): muscle mass, grip strength, gait speed, chair rise — no effect. A meta-analysis of 8 NMN RCTs (342 people): glucose, insulin, HbA1c, lipids — no effect. Yoshino 2021 (positive) vs Dollerup 2018 (null) — conflicting.

• INTRAVENOUS INFUSION REACTION: chest tightness, tachycardia and gastrointestinal symptoms in all 6 subjects studied (Reyna 2026); resolves once the infusion stops, the dependence on infusion speed is anecdotal
• Home infusions without supervision are a bad idea — the symptoms during infusion are unpleasant and hard to tell apart from dangerous reactions
• The dominant driver of the NAD+ decline in ageing is the CD38 enzyme, not a lack of supply — adding precursor targets the secondary problem
• High doses impose a methyl tax on the body
• Caution with active malignancy — the data run both ways and are unresolved

A pineal tetrapeptide; a claimed telomerase activator and regulator of the melatonin rhythm.

What the data say: The source paper on telomerase is ONE small in-vitro study from one laboratory, never independently replicated. No study shows that systemic administration lengthens telomeres in healthy people. The mortality studies were run unblinded and without placebo, and used a pineal extract rather than synthetic Epitalon.

• A theoretical concern worth recording: telomerase activation is exactly the mechanism cancer cells use to immortalise themselves. No long-term oncological data
• Caution with active or previous malignancy
• The rationale for twice-yearly courses is institutional practice, not the result of a dose-response study

A tripeptide of the Khavinson school; postulated modulation of gene expression through direct interaction with DNA. No receptor has been identified.

What the data say: No randomised trial has ever been completed (ClinicalTrials.gov 0). In humans only open-label work from one research network (Adv Gerontol): 32 people on Pinealon + Vesugen — with a PRO-OXIDANT signal and a drop in CD34+; drivers (150+150) without placebo. Everything else is cells and rodents (two papers with errata). No genotoxicity data. Telomerase belongs to Epitalon, not Pinealon.

• BEWARE A COMMON MISATTRIBUTION: the telomerase claims belong to Epitalon, not Pinealon — sellers routinely transfer them
• Circulating oral and injectable protocols differ many-fold in dose while claiming the same effect — the sources are vendors, not studies; a sign that dosing is convention, not pharmacology
• Given that the claimed mechanism is modulation of gene expression, the absence of genotoxicity and oncology data is a significant gap

The main intracellular antioxidant and a cofactor in hepatic detoxification. It is not a signalling peptide but a substrate in redox reactions.

What the data say: Human data are sparse and conflicting: a 4-week RCT was null, a 6-month RCT positive (biomarkers, not clinical outcomes). Intravenous GSH had no effect in Parkinson's disease. Oral bioavailability was described as "negligible" after a single dose (n=7), with no reliable percentage figure.

• Oral glutathione: two RCTs disagree — 4 weeks changed no markers (Allen 2011), 6 months raised GSH stores by 30–35% (Richie 2015); the liposomal form has only an open-label pilot in 12 people, the precursors (glycine + NAC) have an RCT
• Caution around training if endurance adaptations are the goal — this is an extrapolation from a vitamin C and E study (Ristow 2009), not from glutathione itself

The 'bonding' neuropeptide — in animals and imaging studies it lowers amygdala reactivity; in human clinical trials the psychological effects of intranasal dosing are non-significant when pooled.

What the data say: The human evidence is EXTENSIVE and mostly negative: 42 RCTs, g = 0.17 (non-significant). The regenerative effect is shown only in animals; central bioavailability after intranasal dosing is disputed (blood levels do not reflect brain levels, r = 0.08).

• The 'inverted-U' curve (higher doses worse) is not established — no head-to-head dose comparisons, and the meta-analysis found no moderation by dose
• Antidiuretic effect: an oxytocin surge was linked to falling sodium in 31% of subjects (without the hormone being given) — hyponatraemia risk at high doses adds to GH-related water retention