{
  "cutoff": "2026-10-12",
  "note": "Selected publication milestones, not an exhaustive history or discovery priority claim.",
  "milestones": [
    {
      "pmid": "14281087",
      "year": "1965",
      "title": "LAETRILE: A STUDY OF ITS PHYSICOCHEMICAL AND BIOCHEMICAL PROPERTIES.",
      "doi": "",
      "url": "https://pubmed.ncbi.nlm.nih.gov/14281087/",
      "interpretation": "chemical comparison documents nonidentical formulations and tests the proposed biological rationale."
    },
    {
      "pmid": "1060511",
      "year": "1975",
      "title": "Experimental studies of the antitumor activity of amygdalin MF (NSC-15780) alone and in combination with beta-glucosidase (NSC-128056).",
      "doi": "",
      "url": "https://pubmed.ncbi.nlm.nih.gov/1060511/",
      "interpretation": "controlled tumour models test amygdalin with enzyme activation near tolerated doses and find no activity with increased toxicity."
    },
    {
      "pmid": "683212",
      "year": "1978",
      "title": "Special report on Laetrile: the NCI Laetrile Review. Results of the National Cancer Institute's retrospective Laetrile analysis.",
      "doi": "10.1056/NEJM197809072991013",
      "url": "https://pubmed.ncbi.nlm.nih.gov/683212/",
      "interpretation": "selected retrospective case submissions include judged responses but no definite attribution."
    },
    {
      "pmid": "7005480",
      "year": "1981",
      "title": "A pharmacologic and toxicological study of amygdalin.",
      "doi": "",
      "url": "https://pubmed.ncbi.nlm.nih.gov/7005480/",
      "interpretation": "human pharmacology maps oral/IV and interacting-food differences."
    },
    {
      "pmid": "7033783",
      "year": "1982",
      "title": "A clinical trial of amygdalin (Laetrile) in the treatment of human cancer.",
      "doi": "10.1056/NEJM198201283060403",
      "url": "https://pubmed.ncbi.nlm.nih.gov/7033783/",
      "interpretation": "nonrandomized human metabolic-regimen trial finds no substantive benefit and toxicity hazards."
    },
    {
      "pmid": "28912981",
      "year": "2017",
      "title": "Physician Beware: Severe Cyanide Toxicity from Amygdalin Tablets Ingestion.",
      "doi": "10.1155/2017/4289527",
      "url": "https://pubmed.ncbi.nlm.nih.gov/28912981/",
      "interpretation": "prescribed oral tablets precede a clinically documented poisoning syndrome with antidote response."
    },
    {
      "pmid": "32636623",
      "year": "2020",
      "title": "Magnetically Directed Enzyme/Prodrug Prostate Cancer Therapy Based on β-Glucosidase/Amygdalin.",
      "doi": "10.2147/IJN.S242359",
      "url": "https://pubmed.ncbi.nlm.nih.gov/32636623/",
      "interpretation": "engineered magnetic-enzyme activation tests a different tumour-delivery platform in mice."
    },
    {
      "pmid": "36355478",
      "year": "2022",
      "title": "In Vitro and In Vivo Evaluation of the Effectiveness and Safety of Amygdalin as a Cancer Therapy.",
      "doi": "10.3390/ph15111306",
      "url": "https://pubmed.ncbi.nlm.nih.gov/36355478/",
      "interpretation": "niosomal-gel study measures restricted rat skin-tumour volume and local histology."
    },
    {
      "pmid": "41882653",
      "year": "2026",
      "title": "Targeted nanocomposite delivery system of amygdalin using chitosan/reduced graphene oxide-zinc oxide/hyaluronic acid for treatment of head and neck squamous cell carcinoma.",
      "doi": "10.1186/s12903-026-07943-1",
      "url": "https://pubmed.ncbi.nlm.nih.gov/41882653/",
      "interpretation": "nanocomposite cell assays explore uptake and delivery; human-regimen validation remains absent."
    }
  ],
  "gaps": [
    "Bridge cell concentrations to measured tumour and normal-organ exposure rather than equating plasma peak with sustained tumour concentration.",
    "Separate free compound, historical products and new carrier/enzyme platforms.",
    "Verify actual normal-tissue comparators and systemic cyanide margins for modern selectivity claims.",
    "Resolve route, foods and microbial activation without assuming everyIVdose is safe or everyoral exposure is lethal.",
    "Retain the difference between178 treated and175 evaluable, and label the temporary response detail as secondary-source verification until original body is obtained.",
    "Do not use generic alternative-care mortality coding as a laetrile-specific causal estimate.",
    "Audit current retractions before reusing older positive cell papers."
  ],
  "decisive_experiment": "First characterize formulation identity, parent/metabolite kinetics and cyanide generation with clinically anchored exposure in matched malignant and normal systems. Establish selective functional activity, normal-organ margin and pharmacodynamic tumour exposure in controlled relevant models using carrier/enzyme-only and route-matched controls. A future new-platform add-on trial would require those preclinical criteria and independent review; it must preserve effective cancer care and is not a recommendation to revive the historical unbeneficial regimen."
}