19 compounds were read against these 3 conditions; 8 produced a graded row. The other 11 are named further down.

The ranking, and the key it uses

Ordered by the best rung the compound holds anywhere in this goal; then by what that study measured; then by how many graded rows it holds here, as a tie-break only; then by name. There is no blended score — one number mixing the rung and what was measured would invent a third scale nothing was graded against. Every rung links to the rubric that assigned it.

1. 01

   ARA-290

   human RCT · direct outcome · 2 graded rows across 2 of 3 conditions

   Pain · Neuropathic pain

   2 graded rows, 1 source

   1. Pain

      human RCT Direct outcome In registered trials

      Who was studied

      patients with sarcoidosis and symptoms of small-fibre neuropathy, n=22 (12 on ARA 290, 10 on placebo), 2 mg intravenously three times weekly for 4 weeks

      A randomised, double-blind placebo-controlled pilot trial measured the Small Fibre Neuropathy Screening List, the SF-36 pain dimension and the Brief Pain Inventory. SFNSL and the SF-36 pain dimension improved more on ARA 290 than on placebo, but Brief Pain Inventory scores fell equivalently in both arms. The population is sarcoidosis-associated small-fibre neuropathy only; no trial of ARA 290 in pain of other causes is on file, and it has no regulatory approval anywhere.

      Source PubMed Central 2 primary sources read for this row

   2. Neuropathic pain

      human RCT Direct outcome In registered trials

      Who was studied

      patients with sarcoidosis and symptoms of small-fibre neuropathy, n=22 (12 on ARA 290, 10 on placebo), 2 mg intravenously three times weekly for 4 weeks

      A randomised, double-blind, placebo-controlled pilot trial measured the Small Fibre Neuropathy Screening List, the SF-36 pain dimension and the Brief Pain Inventory. SFNSL and the SF-36 pain dimension improved more on ARA 290 than on placebo, but Brief Pain Inventory scores fell equivalently in both arms, so the trial's general pain measure did not separate from placebo. The population is sarcoidosis-associated small-fibre neuropathy only, n=22; no trial in diabetic, chemotherapy-induced or post-herpetic neuropathy is on file, and ARA 290 has no regulatory approval anywhere.

      Source PubMed Central 2 primary sources read for this row

2. 02

   PEA

   human RCT · direct outcome · 2 graded rows across 2 of 3 conditions

   Pain · Neuropathic pain

   2 graded rows, 2 sources

   1. Pain

      human RCT Direct outcome Not approved for this condition

      Who was studied

      adults with chronic pain of mixed cause, pooled n=774 (383 on PEA, 391 controls) across 11 double-blind randomised trials; conditions included spinal cord injury and diabetic neuropathic pain, knee osteoarthritis, temporomandibular joint arthritis, carpal tunnel syndrome, endometriosis-related pelvic pain, dysmenorrhoea, vestibulodynia, irritable bowel syndrome and burning mouth syndrome; durations 10 days to 12 months, most 8-12 weeks

      A 2023 systematic review and meta-analysis of 11 double-blind randomised trials pooled pain intensity measured on visual analogue, numeric rating or Likert scales and reported a standardised mean difference of 1.68 (95% CI 1.05 to 2.31) favouring oral palmitoylethanolamide over comparator. The pooled population is heterogeneous - neuropathic, musculoskeletal and gynaecological pain were combined - so the estimate is not specific to any one pain type, and PEA is sold as a food supplement rather than approved by any regulator for pain.

      Source PubMed Central 2 primary sources read for this row

   2. Neuropathic pain

      human RCT Direct outcome Not approved for this condition

      Who was studied

      adults with type 1 or type 2 diabetes (62 of 65 type 2) and diabetic peripheral neuropathic pain confirmed by DN4 >4 or S-LANSS >12, n=66 analysed (33 palmitoylethanolamide, 33 placebo), mean age 63.5 years; 600 mg oral PEA daily (Levagen+ formulation) for 8 weeks

      A single-centre, quadruple-blinded, randomised placebo-controlled trial measured the Brief Pain Inventory for Diabetic Peripheral Neuropathy and the Neuropathic Pain Symptom Inventory. BPI-DPN pain severity and pain interference both fell more on PEA than placebo (p <= 0.001), and most NPSI domains improved, but the evoked-pain domain reached only a trend (p = 0.09). The population is diabetic peripheral neuropathy alone; the wider PEA meta-analyses pool neuropathic with musculoskeletal and gynaecological pain and report no separate neuropathic subgroup estimate, and PEA is sold as a food supplement with no regulatory approval for neuropathic pain.

      Source PubMed Central 3 primary sources read for this row

3. 03

   Collagen Peptides

   human RCT · direct outcome · 1 graded row across 1 of 3 conditions

   Pain

   1 graded row, 1 source

   1. Pain

      human RCT Direct outcome Not approved for this condition

      Who was studied

      adults aged 40-75 with mild to moderate knee osteoarthritis (Kellgren-Lawrence grade I-III), pooled n=507 across 4 randomised placebo-controlled trials; oral doses of 2-10 g daily for 90-180 days

      A meta-analysis of four randomised placebo-controlled trials pooled 100 mm visual analogue scale pain scores in knee osteoarthritis and reported a standardised mean difference of -0.58 (p = 0.004) favouring oral collagen peptides, graded moderate quality. The population is knee osteoarthritis specifically; no trial in neuropathic, post-operative or generalised chronic pain is on file, and collagen peptides are a food ingredient with no regulatory approval for pain.

      Source PubMed Central 1 primary source read for this row

4. 04

   Oxytocin

   human RCT · direct outcome · 1 graded row across 1 of 3 conditions

   Migraine

   1 graded row, 1 source

   1. Migraine

      human RCT Direct outcome In registered trials

      Who was studied

      adults 18-65 with chronic migraine (with or without aura) by ICHD-3, n=88 randomised, 12 weeks; intranasal oxytocin 30 IU once daily or 30 IU twice daily versus placebo nasal spray, quadruple-blinded (TNX-1900, NCT05679908)

      This is the one compound here that was given as a candidate treatment, and it was measured directly: mean change in monthly migraine headache days over 12 weeks. Posted registry results show no separation from placebo - placebo -8.17 days, oxytocin 30 IU once daily -7.78 days, oxytocin 30 IU twice daily -5.77 days. No regulator has approved oxytocin for migraine.

      Source ClinicalTrials.gov 1 primary source read for this row

5. 05

   PACAP (Pituitary Adenylate Cyclase-Activating Peptide)

   human RCT · direct outcome · 1 graded row across 1 of 3 conditions

   Migraine

   1 graded row, 1 source

   1. Migraine

      human RCT Direct outcome Not approved for this condition

      Who was studied

      adults with migraine without aura and headache-free healthy controls; PACAP-38 10 pmol/kg/min IV over 20 min, n=12 migraine + 12 healthy (Schytz 2009); PACAP-27 10 pmol/kg/min IV over 20 min, n=20 migraine without aura (Ghanizada 2020). People with migraine with aura were not the studied group in either trial.

      In both randomised, double-blind, placebo-controlled crossover trials PACAP was infused in order to TRIGGER attacks, not to treat them: PACAP-38 provoked migraine-like attacks in 7 of 12 migraine patients and none on placebo, and the shorter isoform PACAP-27 provoked attacks in 11 of 20 and 2 of 20 on placebo. This is evidence that PACAP causes migraine attacks in susceptible people; no study has administered PACAP-38 or PACAP-27 as a migraine treatment, and the drug programmes built on this work develop antibodies and receptor antagonists that BLOCK PACAP - those are different molecules and their evidence does not belong to PACAP itself.

      Source DOI 2 primary sources read for this row

6. 06

   Substance P

   human RCT · mechanistic only · 1 graded row across 1 of 3 conditions

   Migraine

   1 graded row, 1 source

   1. Migraine

      human RCT Mechanistic only Not approved for this condition

      Who was studied

      healthy adults with no headache disorder, n=21, double-blind placebo-controlled two-way crossover; substance P 1.5 pmol/kg/min IV over 20 min. People with migraine were not enrolled.

      Recorded, and not evidence for this condition

      Substance P was infused in order to PROVOKE headache, and it did: headache within 12 hours in 15 of 21 healthy participants versus 2 of 21 on placebo, with dilation of the superficial temporal artery. No study measured any migraine outcome - the participants did not have migraine, and migraine attack frequency, severity and duration were not measured, so the link from this result to migraine is an argument from mechanism rather than a result. A provocation trial in people with migraine without aura is registered (NCT06959004) and has not reported.

      Source DOI 1 primary source read for this row

7. 07

   Nociceptin

   human observational · mechanistic only · 1 graded row across 1 of 3 conditions

   Migraine

   1 graded row, 1 source

   1. Migraine

      human observational Mechanistic only Not approved for this condition

      Who was studied

      adults with migraine without aura, n=18, headache-free at sampling, versus n=24 controls; a further 6 sampled within the first 3 hours of an attack. Migraine with aura was not studied.

      Recorded, and not evidence for this condition

      This study MEASURED circulating nociceptin; it did not administer it to anyone. Interictal plasma nociceptin was lower in migraineurs than controls (5.79 vs 9.74 pg/mL) and lower still during attacks, which is an association between a blood marker and having migraine. No study has given nociceptin to people with migraine, so no migraine outcome has ever been measured for this compound, and nothing here shows that raising or lowering nociceptin changes attacks.

      Source DOI 1 primary source read for this row

8. 08

   Cartilage Peptides

   human case series · direct outcome · 1 graded row across 1 of 3 conditions

   Pain

   1 graded row, 1 source

   1. Pain

      human case series Direct outcome Not approved for this condition

      Who was studied

      adults with moderate knee joint discomfort and loss of function, n=33, 1000 mg fish cartilage hydrolysate orally once daily for 3 months; no control group

      An exploratory, non-comparative, multi-centre study measured the Knee injury and Osteoarthritis Outcome Score and reported improvement in the knee pain and function subscales. There was no placebo arm and no randomisation, so improvement cannot be separated from natural course or expectation; the authors state the result needs confirmation in a randomised controlled trial. The population is knee joint pain, not pain generally.

      Source PubMed Central 1 primary source read for this row

Checked, and nothing on file

11 compounds were read against these conditions and produced no gradeable row. They are named here rather than left off, because a list of 8 reads identically whether 8 survived 19 or 8 were all anyone thought of.

1. Bradykinin

   No rung — nothing on file to grade

   Checked against pain, migraine. No study meeting the rubric was found for any of them.

2. Cartalax

   No rung — nothing on file to grade

   Checked against pain. No study meeting the rubric was found for any of them.

3. CRH (Corticotropin-Releasing Hormone) on pain

   No rung — nothing on file to grade Not approved for this condition

   Nothing located with an administered dose and a pain outcome.

4. Dynorphin A

   No rung — nothing on file to grade

   Checked against pain. No study meeting the rubric was found for any of them.

5. Endothelin-1 on pain

   No rung — nothing on file to grade Not approved for this condition

   Intradermal or perineural ET-1 is used experimentally to PROVOKE pain and mechanical hyperalgesia in animals and human skin. A provocation model is not a treatment outcome.

6. Galanin

   No rung — nothing on file to grade

   Checked against pain. No study meeting the rubric was found for any of them.

7. IGF-1 on neuropathic pain

   No rung — nothing on file to grade Not approved for this condition

   Only animal and in-vitro work on nerve degeneration is on file (PMID 10023126, a review). The neurotrophic factor that reached phase 3 in diabetic peripheral neuropathy was nerve growth factor, not IGF-I; no IGF-I trial measured pain.

8. Leu-Enkephalin

   No rung — nothing on file to grade

   Checked against pain. No study meeting the rubric was found for any of them.

9. Met-Enkephalin

   No rung — nothing on file to grade

   Checked against pain. No study meeting the rubric was found for any of them.

10. Neurotensin

    No rung — nothing on file to grade

    Checked against pain. No study meeting the rubric was found for any of them.

11. β-Endorphin

    No rung — nothing on file to grade

    Checked against pain. No study meeting the rubric was found for any of them.

Browse by goal

• Weight loss — 29 compounds with a graded row, from 48 checked
• Anti-ageing & metabolic — 16 compounds with a graded row, from 30 checked
• Muscle growth — 9 compounds with a graded row, from 20 checked
• Infection & immunity — 23 compounds with a graded row, from 30 checked
• Cardiovascular — 29 compounds with a graded row, from 33 checked
• Healing & recovery — 16 compounds with a graded row, from 29 checked
• Sexual health & fertility — 13 compounds with a graded row, from 28 checked
• Skin & hair — 9 compounds with a graded row, from 33 checked
• Brain & nerve recovery — 7 compounds with a graded row, from 15 checked
• Mood & anxiety — 3 compounds with a graded row, from 12 checked
• Sleep — 9 compounds with a graded row, from 30 checked
• Cognition — 8 compounds with a graded row, from 43 checked
• Inflammation — 5 compounds with a graded row, from 23 checked
• Biological ageing — 8 compounds with a graded row, from 30 checked
• Gut health — 12 compounds with a graded row, from 27 checked