{
  "cutoff": "2026-10-13",
  "note": "Selected publication milestones, not an exhaustive history or discovery priority claim.",
  "milestones": [
    {
      "pmid": "29537989",
      "year": "2018",
      "title": "Psilocin and ketamine microdosing: effects of subchronic intermittent microdoses in the elevated plus-maze in male Wistar rats.",
      "doi": "10.1097/FBP.0000000000000394",
      "url": "https://pubmed.ncbi.nlm.nih.gov/29537989/",
      "interpretation": "Intermittent rodent psilocin/ketamine anxiety-proxy study gives modest possible anxiogenic boundary rather than clinicalLSD evidence."
    },
    {
      "pmid": "30357434",
      "year": "2018",
      "title": "Exploring the effect of microdosing psychedelics on creativity in an open-label natural setting.",
      "doi": "10.1007/s00213-018-5049-7",
      "url": "https://pubmed.ncbi.nlm.nih.gov/30357434/",
      "interpretation": "Open-label microdose-event creativity tasks supply early quantitative exploratory support without placebo isolation."
    },
    {
      "pmid": "30478716",
      "year": "2019",
      "title": "The effects of microdose LSD on time perception: a randomised, double-blind, placebo-controlled trial.",
      "doi": "10.1007/s00213-018-5119-x",
      "url": "https://pubmed.ncbi.nlm.nih.gov/30478716/",
      "interpretation": "Controlled low-dose LSD alters interval timing without robust subjective effects; acute pharmacology becomes experimentally testable."
    },
    {
      "pmid": "31331617",
      "year": "2019",
      "title": "Acute Subjective and Behavioral Effects of Microdoses of Lysergic Acid Diethylamide in Healthy Human Volunteers.",
      "doi": "10.1016/j.biopsych.2019.05.019",
      "url": "https://pubmed.ncbi.nlm.nih.gov/31331617/",
      "interpretation": "Healthy acute dose-response study shows measurable subjective action while most cognition and mood outcomes remain unchanged."
    },
    {
      "pmid": "30726251",
      "year": "2019",
      "title": "A systematic study of microdosing psychedelics.",
      "doi": "10.1371/journal.pone.0211023",
      "url": "https://pubmed.ncbi.nlm.nih.gov/30726251/",
      "interpretation": "Six-week naturalistic tracking reports symptom declines and mainly dose-day changes, motivating controlled repeat-dose studies."
    },
    {
      "pmid": "32108529",
      "year": "2020",
      "title": "Microdosing psychedelics: Demographics, practices, and psychiatric comorbidities.",
      "doi": "10.1177/0269881120908004",
      "url": "https://pubmed.ncbi.nlm.nih.gov/32108529/",
      "interpretation": "Microdosing demographic/diagnosis survey identifies self-selection and concurrent-drug differences."
    },
    {
      "pmid": "32975835",
      "year": "2021",
      "title": "Pharmacokinetics and Pharmacodynamics of Lysergic Acid Diethylamide Microdoses in Healthy Participants.",
      "doi": "10.1002/cpt.2057",
      "url": "https://pubmed.ncbi.nlm.nih.gov/32975835/",
      "interpretation": "Verified base-dose pharmacokinetics show5microgram subjective-null versus10/20microgram perception, defining a dose-dependent boundary."
    },
    {
      "pmid": "33648632",
      "year": "2021",
      "title": "Self-blinding citizen science to explore psychedelic microdosing.",
      "doi": "10.7554/eLife.62878",
      "url": "https://pubmed.ncbi.nlm.nih.gov/33648632/",
      "interpretation": "Citizen self-blinding separates randomized capsule exposure from guessed allocation and reports no accumulated between-group benefit."
    },
    {
      "pmid": "33479342",
      "year": "2021",
      "title": "Positive expectations predict improved mental-health outcomes linked to psychedelic microdosing.",
      "doi": "10.1038/s41598-021-81446-7",
      "url": "https://pubmed.ncbi.nlm.nih.gov/33479342/",
      "interpretation": "Prospective baseline expectations predict later wellbeing improvement, strengthening a competing explanation."
    },
    {
      "pmid": "33860175",
      "year": "2021",
      "title": "Low Doses of LSD Acutely Increase BDNF Blood Plasma Levels in Healthy Volunteers.",
      "doi": "10.1021/acsptsci.0c00099",
      "url": "https://pubmed.ncbi.nlm.nih.gov/33860175/",
      "interpretation": "Acute plasmaBDNF positive is reported; it remains a peripheral biomarker rather than validated treatment mediation."
    },
    {
      "pmid": "35106880",
      "year": "2022",
      "title": "Repeated low doses of LSD in healthy adults: A placebo-controlled, dose-response study.",
      "doi": "10.1111/adb.13143",
      "url": "https://pubmed.ncbi.nlm.nih.gov/35106880/",
      "interpretation": "Repeated controlled10/20base-equivalent LSD produces subjective effects but no residual mood or cognitive advantage."
    },
    {
      "pmid": "34915762",
      "year": "2022",
      "title": "Psilocybin microdosing does not affect emotion-related symptoms and processing: A preregistered field and lab-based study.",
      "doi": "10.1177/02698811211050556",
      "url": "https://pubmed.ncbi.nlm.nih.gov/34915762/",
      "interpretation": "Preregistered psilocybin microdose crossover is symptom-null with later blind breaking."
    },
    {
      "pmid": "35918311",
      "year": "2022",
      "title": "Microdosing with psilocybin mushrooms: a double-blind placebo-controlled study.",
      "doi": "10.1038/s41398-022-02039-0",
      "url": "https://pubmed.ncbi.nlm.nih.gov/35918311/",
      "interpretation": "Psilocybin mushroom microdose subjective recognition andEEG effects coexist with wellbeing/cognition nulls."
    },
    {
      "pmid": "36322843",
      "year": "2022",
      "title": "Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression.",
      "doi": "10.1056/NEJMoa2206443",
      "url": "https://pubmed.ncbi.nlm.nih.gov/36322843/",
      "interpretation": "Full-doseCOMP360TRDprimaryweek-three positive has dose and sustained-response limits distinct from microdosing."
    },
    {
      "pmid": "36997080",
      "year": "2023",
      "title": "Acute Mood-Elevating Properties of Microdosed Lysergic Acid Diethylamide in Healthy Volunteers: A Home-Administered Randomized Controlled Trial.",
      "doi": "10.1016/j.biopsych.2023.03.013",
      "url": "https://pubmed.ncbi.nlm.nih.gov/36997080/",
      "interpretation": "Six-week home LSD trial separates transient dose-day mood elevation from no persistent pre/post change."
    },
    {
      "pmid": "38042914",
      "year": "2024",
      "title": "Greater subjective effects of a low dose of LSD in participants with depressed mood.",
      "doi": "10.1038/s41386-023-01772-4",
      "url": "https://pubmed.ncbi.nlm.nih.gov/38042914/",
      "interpretation": "Restricted high-BDI acute low-dose crossover positive raises a symptomatic-population question without testing sustained treatment."
    },
    {
      "pmid": "38622150",
      "year": "2024",
      "title": "LSD increases sleep duration the night after microdosing.",
      "doi": "10.1038/s41398-024-02900-4",
      "url": "https://pubmed.ncbi.nlm.nih.gov/38622150/",
      "interpretation": "Same home-trial wearable sleep analysis identifies a delayed measurable effect rather than clinical symptom efficacy."
    },
    {
      "pmid": "40105807",
      "year": "2025",
      "title": "Safety and Efficacy of Repeated Low-Dose LSD for ADHD Treatment in Adults: A Randomized Clinical Trial.",
      "doi": "10.1001/jamapsychiatry.2025.0044",
      "url": "https://pubmed.ncbi.nlm.nih.gov/40105807/",
      "interpretation": "Two-center six-week ADHD clinical primary fails despite drug perception and measured allocation guesses."
    },
    {
      "pmid": "40251818",
      "year": "2025",
      "title": "Pharmacokinetics and pharmacodynamics of sublingual microdosed lysergic acid diethylamide in healthy adult volunteers.",
      "doi": "10.1177/02698811251330747",
      "url": "https://pubmed.ncbi.nlm.nih.gov/40251818/",
      "interpretation": "Same home-trial PK analysis finds no peripheralBDNF alteration, limiting uniform plasticity-marker claims."
    },
    {
      "pmid": "41789300",
      "year": "2025",
      "title": "Assessing the Potential Cardiovascular Risk of Microdosing the Psychedelic LSD in Mice.",
      "doi": "10.1021/acsptsci.5c00202",
      "url": "https://pubmed.ncbi.nlm.nih.gov/41789300/",
      "interpretation": "Positive-controlled chronic mouse cardiac study finds no observedLSD remodeling, with human rare/longterm risk unresolved."
    },
    {
      "pmid": "41202873",
      "year": "2026",
      "title": "LSD microdosing in major depressive disorder: results from an open-label trial.",
      "doi": "10.1016/j.neuropharm.2025.110762",
      "url": "https://pubmed.ncbi.nlm.nih.gov/41202873/",
      "interpretation": "Direct eight-week open-label MDD improvement is published, furnishing exploratory clinical support requiring causal isolation."
    },
    {
      "pmid": "41529826",
      "year": "2026",
      "title": "Reward-related neural activity after low doses of LSD in participants with depressed mood.",
      "doi": "10.1177/02698811251405686",
      "url": "https://pubmed.ncbi.nlm.nih.gov/41529826/",
      "interpretation": "Same depressed-mood crossover reward analysis relates neural changes to48hour symptoms without mediator manipulation."
    },
    {
      "pmid": "41110634",
      "year": "2026",
      "title": "Cognitive and subjective effects of psilocybin microdosing: Results from two double-blind placebo-controlled longitudinal trials.",
      "doi": "10.1016/j.neuropharm.2025.110722",
      "url": "https://pubmed.ncbi.nlm.nih.gov/41110634/",
      "interpretation": "Later effectively blinded psilocybin longitudinal trials report no corrected emotional/cognitive benefit."
    },
    {
      "pmid": "41187880",
      "year": "2026",
      "title": "Microdosing psilocybin and its effect on creativity: Lessons learned from three double-blind placebo controlled longitudinal trials.",
      "doi": "10.1016/j.neuropharm.2025.110732",
      "url": "https://pubmed.ncbi.nlm.nih.gov/41187880/",
      "interpretation": "Pooled original truffle creativity trials retain a restricted guess-adjusted originality positive."
    },
    {
      "pmid": "41848690",
      "year": "2026",
      "title": "Efficacy and Safety of Psilocybin in Treatment-Resistant Major Depression: The EPISODE Randomized Clinical Trial.",
      "doi": "10.1001/jamapsychiatry.2026.0132",
      "url": "https://pubmed.ncbi.nlm.nih.gov/41848690/",
      "interpretation": "Full-doseEPISODEprimaryresponse null preserves endpoint hierarchy despite favorable exploratory scales and safety signals."
    }
  ],
  "gaps": [
    "Complete outcome-paper methods, analyzed sample, missing-data handling, dose distribution and comparator/rater masking for the completed LSDDEP2 trial; additional independent symptomatic trials and anxiety-specific estimates.",
    "Dose/base-tartrate normalization and individual perceptibility measured before declaring a regimen subperceptual.",
    "Independent expectancy manipulation and safe interpretation of postdose allocation-guess adjustment.",
    "Clinical relevance of reward/connectivity/EEG/BDNF signals rather than assumed plasticity-mediated therapy.",
    "Longerterm, uncommon and cardiovascular harms; small trial echo/mouse nulls do not quantify rarehuman risk.",
    "Regimen-specific comparative efficacy, support intensity and function without transferring full-dose/ketamine positives ornulls."
  ],
  "decisive_experiment": "Registered symptomatic-MDD trial of titrated 5–20 microgram base-equivalentLSD twiceweekly for 8 weeks versus credible sensory-matched active comparator, with equalcontact/co-care and an expectancy-factor manipulation or prespecified sensitivity analyses; follow throughwithdrawal and relapse."
}