{
  "generated_from": "index.html",
  "count": 49,
  "verified_against_source": 16,
  "not_re_checked": 33,
  "verification_note": "Only entries with a 'reverified' date were opened and checked against the primary source. The rest carry figures compiled without a second pass.",
  "references": [
    {
      "id": 1,
      "evidence_type": "primary",
      "authors": "Nutt DJ, King LA, Phillips LD.",
      "title": "Drug harms in the UK: a multicriteria decision analysis.",
      "journal": "The Lancet",
      "reverified": null,
      "verification_status": "not independently re-checked",
      "note": "The load-bearing calibration reference — not an external check, see section 02. Expert panel scored 20 drugs on 16 weighted criteria. Overall harm: alcohol 72, heroin 55, crack 54, meth 33, cocaine 27, tobacco 26, cannabis 20, benzodiazepines 15, ketamine 15, MDMA 9, LSD 7, mushrooms 5. Harm-to-others part-scores: alcohol 46, heroin 21, crack 17. Harm-to-individual: crack 37, heroin 34, meth 32. Meth's harm-to-others is not published separately but follows from the additive model — overall 33 minus harm-to-user 32 leaves roughly 1, which rescales against alcohol's 46 to about 2.",
      "url": "https://pubmed.ncbi.nlm.nih.gov/21036393/"
    },
    {
      "id": 2,
      "evidence_type": "primary",
      "authors": "Lopez-Quintero C, Pérez de los Cobos J, Hasin DS, Okuda M, Wang S, Grant BF, Blanco C.",
      "title": "Probability and predictors of transition from first use to dependence on nicotine, alcohol, cannabis, and cocaine: results of the NESARC.",
      "journal": "Drug and Alcohol Dependence",
      "reverified": "2026-07 — all four percentages and all four sample sizes exact",
      "verification_status": "checked against source",
      "note": "Re-verified against the published record, July 2026 — every figure exact. Drug and Alcohol Dependence 2011;115(1–2):120–30. Cumulative probability of transition from first use to dependence: nicotine 67.5%, alcohol 22.7%, cocaine 20.9%, cannabis 8.9%. Subsamples of lifetime users: nicotine n=15,918, alcohol n=28,907, cannabis n=7,389, cocaine n=2,259. Half of dependence cases appeared roughly 27, 13, 5 and 4 years after first use for nicotine, alcohol, cannabis and cocaine respectively — the source of the onset-speed figures quoted on this page. Population: US civilian non-institutionalised adults 18+, which excludes incarcerated and unsheltered people and so undercounts the heaviest use. Source of every dependence percentage in this table. Lifetime transition: nicotine 67.5%, alcohol 22.7%, cocaine 20.9%, cannabis 8.9%. Ten-year: nicotine 15.6%, cocaine 14.8%, alcohol 11.0%, cannabis 5.9%. Median time to half of all cases: ~27, 13, 5 and 4 years for nicotine, alcohol, cannabis and cocaine respectively.",
      "url": "https://pubmed.ncbi.nlm.nih.gov/21145178/"
    },
    {
      "id": 3,
      "evidence_type": "primary",
      "authors": "Wagner FA, Anthony JC.",
      "title": "From first drug use to drug dependence: developmental periods of risk for dependence upon marijuana, cocaine, and alcohol.",
      "journal": "Neuropsychopharmacology",
      "reverified": null,
      "verification_status": "not independently re-checked",
      "note": "National Comorbidity Survey, n=8,098, ages 15–54, survival analysis. The independent replication that NESARC's ten-year figures agree with. Speed-of-progression ranges (heroin median ~0 months; cocaine 0–4 yrs; cannabis 1–6; tobacco 1–27; alcohol 3–15) are a synthesis across this and later cohorts, not a single study's output.",
      "url": "https://pubmed.ncbi.nlm.nih.gov/11927172/"
    },
    {
      "id": 4,
      "evidence_type": "review",
      "authors": "Johnson MW, Griffiths RR, Hendricks PS, Henningfield JE.",
      "title": "The abuse potential of medical psilocybin according to the 8 factors of the Controlled Substances Act.",
      "journal": "Neuropharmacology",
      "reverified": null,
      "verification_status": "not independently re-checked",
      "note": "Anchors the psychedelic floor. Limited reinforcing effects; only marginal, transient non-human self-administration. Names the real harms too: dangerous behavior in unprepared or unsupervised users, and exacerbation of illness in those predisposed to psychotic disorders.",
      "url": "https://pubmed.ncbi.nlm.nih.gov/29753748/"
    },
    {
      "id": 5,
      "evidence_type": "primary",
      "authors": "Carbonaro TM, Johnson MW, Griffiths RR, et al.",
      "title": "Subjective features of the psilocybin experience that may account for its self-administration by humans.",
      "journal": "Psychopharmacology 2020;237(8)",
      "reverified": null,
      "verification_status": "not independently re-checked",
      "note": "Supports the \"not addictive\" claim in detail: NIDA does not consider psilocybin addictive as it doesn't produce uncontrollable drug-seeking; not reliably self-administered by monkeys; tolerance occurs but no evidence of a withdrawal syndrome after chronic administration. Also the ARCI euphoria/dysphoria scale point.",
      "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC10013695/"
    },
    {
      "id": 6,
      "evidence_type": "clinical",
      "authors": "Alcohol Withdrawal Syndrome.",
      "title": "",
      "journal": "StatPearls",
      "reverified": null,
      "verification_status": "not independently re-checked",
      "note": "Withdrawal delirium historically carried mortality as high as 20%, now around 1% with critical care and prompt treatment. Also documents withdrawal seizures at 8–48 hours and warns that patients with prior complicated withdrawal should not reduce intake without clinical consultation.",
      "url": "https://www.ncbi.nlm.nih.gov/books/NBK441882/"
    },
    {
      "id": 7,
      "evidence_type": "clinical",
      "authors": "Delirium Tremens: Practice Essentials, Pathophysiology, Etiology.",
      "title": "",
      "journal": "Medscape / eMedicine",
      "reverified": null,
      "verification_status": "not independently re-checked",
      "note": "The higher end of the mortality range: 5–15% despite appropriate treatment, closer to 5% with modern ICU management, versus as high as 35% before intensive care. Most common causes of death are respiratory failure and cardiac arrhythmias. Included precisely because it disagrees with [6].",
      "url": "https://emedicine.medscape.com/article/166032-overview"
    },
    {
      "id": 8,
      "evidence_type": "review",
      "authors": "Delirium tremens — overview and cohort data.",
      "title": "",
      "journal": "ScienceDirect Topics",
      "reverified": null,
      "verification_status": "not independently re-checked",
      "note": "Cohort detail behind the range: in 200 consecutive alcohol-dependent admissions at an inner-city US hospital, 24% developed DTs and 8% of those died of complications. Risk concentrated among the unemployed, homeless, and those with more severe end-organ disease — a reminder these averages hide steep social gradients.",
      "url": "https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/delirium-tremens"
    },
    {
      "id": 9,
      "evidence_type": "clinical",
      "authors": "Mader EC Jr, Rathore SH, England JD, Branch LA, Copeland BJ.",
      "title": "Benzodiazepine withdrawal catatonia, delirium, and seizures in a patient with schizoaffective disorder.",
      "journal": "J Investig Med High Impact Case Rep 2020;8:2324709620969498",
      "reverified": null,
      "verification_status": "not independently re-checked",
      "note": "Documents the full severity span — withdrawal ranging from mild anxiety to life-threatening delirium or seizures — in a case where lorazepam cessation triggered convulsive seizures and nonconvulsive status epilepticus. Concrete grounding for the benzodiazepine withdrawal score of 90.",
      "url": "https://pubmed.ncbi.nlm.nih.gov/33138643/"
    },
    {
      "id": 10,
      "evidence_type": "primary",
      "authors": "Winstock AR, Mitcheson L, Gillatt DA, et al.",
      "title": "The prevalence and natural history of urinary symptoms among recreational ketamine users.",
      "journal": "BJU International",
      "reverified": null,
      "verification_status": "not independently re-checked",
      "note": "The prevalence study behind ketamine's elevated organ score — urinary symptoms among recreational users, rather than inference from clinical case series alone.",
      "url": "https://pubmed.ncbi.nlm.nih.gov/22416998/"
    },
    {
      "id": 11,
      "evidence_type": "review",
      "authors": "Jhang JF, Birder LA, Kuo HC.",
      "title": "Pathophysiology, clinical presentation, and management of ketamine-induced cystitis. (PMC10399845); with Shahani R, et al., Urology 2007;69(5):810-12, first describing ketamine-associated ulcerative cystitis.",
      "journal": "Tzu Chi Medical Journal 2023;35(3)",
      "reverified": null,
      "verification_status": "not independently re-checked",
      "note": "Mechanism and progression: irritable bladder symptoms advancing to painful ulcerated bladder, reduced capacity, detrusor overactivity and contracture; metabolites drive urothelial inflammation, barrier deficits, oxidative stress and wall fibrosis.",
      "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC10399845/"
    },
    {
      "id": 12,
      "evidence_type": "review",
      "authors": "Ketamine-induced uropathy: clinical recognition, epidemiology, and multisystem effects.",
      "title": "",
      "journal": "Cureus (PMC12276041, Shkoukani et al. 2025; PMC12828242, Nazir et al. 2025)",
      "reverified": null,
      "verification_status": "not independently re-checked",
      "note": "Progression to hydronephrosis and renal impairment; ketamine-induced cholangiopathy with concomitant hemorrhagic cystitis as an emerging cause of cholestasis; UK misuse and related uropathy among 16–24 year-olds doubled 2010–2020.",
      "url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12276041/"
    },
    {
      "id": 13,
      "evidence_type": "primary",
      "authors": "Gable RS.",
      "title": "Comparison of acute lethal toxicity of commonly abused psychoactive substances.",
      "journal": "Addiction",
      "reverified": "2026-07 — all plotted values inside published bands; caffeine 100 and nitrous 150 NOT in the 2004 paper",
      "verification_status": "checked against source",
      "note": "Re-verified against the published abstract, July 2026. Bands as published: below 10 — GHB oral, heroin intravenous, isobutyl nitrite. 10–20 — alcohol oral, cocaine intranasal, codeine, dextromethorphan, MDMA oral, methadone, methamphetamine oral. Above 20–80 — DMT, flunitrazepam oral, ketamine inhaled, mescaline, phenobarbital. 100 or above — fluoxetine, LSD oral, marijuana oral, nitrous oxide inhaled, psilocybin oral. Every figure used here falls inside its published band, and Gable reports ratios varying by more than a factor of 100, which is the source of the hundredfold claim in section 03. Two figures could not be confirmed from the 2004 paper: caffeine at 100 and nitrous oxide at 150 are not among the substances its abstract names and appear to come from Gable's 2006 book chapter; both are now marked estimated on the chart. Method: LD50 estimated from postmortem blood concentrations, reported overdose doses and pharmacokinetic modelling; fatalities involving co-intoxicants or trauma excluded, though Gable notes those are the majority of published cases. Values assume a healthy 70 kg adult with no tolerance and no residue from prior use. For six substances (DMT, ketamine, LSD, marijuana, mescaline, psilocybin) fewer than three human fatality reports existed, so the lethal dose is extrapolated from animal studies — marked \"?\" in the chart. Gable warns the ratios are ordinal and must not be arithmetically manipulated, and that tolerance narrows them.",
      "url": "https://pubmed.ncbi.nlm.nih.gov/15139867/"
    },
    {
      "id": 14,
      "evidence_type": "review",
      "authors": "Sellman D.",
      "title": "If alcohol was a new drug.",
      "journal": "New Zealand Medical Journal 2009;122(1303):6-8 (editorial)",
      "reverified": null,
      "verification_status": "not independently re-checked",
      "note": "States the comparison directly: alcohol's safety ratio of 10 places it nearer heroin (6) and GHB (8) for overdose danger than MDMA (16), and far above LSD (1000) or cannabis (>1000). Draws its ratios from Gable (Addiction 2004).",
      "url": "https://nzmj.org.nz/media/pages/journal/vol-122-no-1303/4a415421eb-1696469507/vol-122-no-1303.pdf"
    },
    {
      "id": 15,
      "evidence_type": "primary",
      "authors": "Gable RS.",
      "title": "Toward a comparative overview of dependence potential and acute toxicity of psychoactive substances used nonmedically.",
      "journal": "American Journal of Drug and Alcohol Abuse",
      "reverified": null,
      "verification_status": "not independently re-checked",
      "note": "The earlier study combining dependence potential with acute lethality across 20 substances. Intravenous heroin carried the greatest combined risk; oral psilocybin the least. Explicitly excludes behavioural deficits, perceptual distortion and chronic illness — the route-of-administration point.",
      "url": "https://pubmed.ncbi.nlm.nih.gov/8213692/"
    },
    {
      "id": 16,
      "evidence_type": "primary",
      "authors": "Wood AM, Kaptoge S, Butterworth AS, et al.",
      "title": "Risk thresholds for alcohol consumption: combined analysis of individual-participant data for 599,912 current drinkers in 83 prospective studies.",
      "journal": "The Lancet",
      "reverified": null,
      "verification_status": "not independently re-checked",
      "note": "40,310 deaths over 5.4 million person-years. All-cause mortality showed a positive curvilinear association with consumption; minimum mortality risk around or below 100 g of alcohol per week — about five to six UK glasses or pints as the paper frames it, or roughly seven US standard drinks at 14 g each. HRs corrected for long-term variability using 152,640 serial assessments.",
      "url": "https://www.thelancet.com/article/S0140-6736(18)30134-X/fulltext"
    },
    {
      "id": 17,
      "evidence_type": "review",
      "authors": "Stockwell T, Zhao J, Panwar S, et al.",
      "title": "Do \"moderate\" drinkers have reduced mortality risk? A systematic review and meta-analysis.",
      "journal": "J Stud Alcohol Drugs",
      "reverified": null,
      "verification_status": "not independently re-checked",
      "note": "Meta-analysis of 87 studies. Unadjusted, it reproduces the classic J-shaped curve — low-volume drinkers at 1.3–24.9 g/day showed reduced mortality (RR 0.86). The paper's contribution is showing how much of that apparent benefit is study-design artefact, notably sick-quitter bias.",
      "url": "https://pubmed.ncbi.nlm.nih.gov/26997174/"
    },
    {
      "id": 18,
      "evidence_type": "primary",
      "authors": "GBD 2016 Alcohol Collaborators.",
      "title": "Alcohol use and burden for 195 countries and territories, 1990–2016.",
      "journal": "The Lancet",
      "reverified": null,
      "verification_status": "not independently re-checked",
      "note": "Concluded the level minimising individual risk is zero, as estimated protective effects for ischaemic heart disease and diabetes in women are offset by monotonic associations elsewhere. Alcohol was the seventh leading risk factor for deaths and DALYs in 2016 — 2.2% of female and 6.8% of male deaths.",
      "url": "https://www.thelancet.com/article/S0140-6736(18)31571-X/fulltext"
    },
    {
      "id": 19,
      "evidence_type": "primary",
      "authors": "GBD 2020 Alcohol Collaborators.",
      "title": "Population-level risks of alcohol consumption by amount, geography, age, sex, and year.",
      "journal": "The Lancet",
      "reverified": "2026-07 — paper fetched; TMREL/NDE figures confirmed",
      "verification_status": "checked against source",
      "note": "Included because it disagrees with [18]. Bryazka D, Reitsma MB, Griswold MG, et al; Lancet 2022;400:185–235. Burden-weighted dose–response curves across 22 outcomes, for 21 regions and 204 countries, by 5-year age group, sex and year, ages 15–95+, 1990–2020. Source of every figure in the age explorer above; one standard drink = 10 g ethanol. Global TMREL: 0.136 (males) and 0.273 (females) at 15–39, 0.527 and 0.562 at 40–64, 0.636 and 0.656 at 65+. NDE: 0.249/0.546, 1.69/1.82, 3.19/3.51. Across all regions the TMREL spans 0–0.603 at 15–39 and 0.114–1.87 at 40+. Differences between males and females were not statistically significant in any age band, and the authors explicitly recommend guidelines differentiate by age rather than by sex. Of those consuming harmful amounts in 2020, 59.1% were aged 15–39 and 76.9% were male.",
      "url": "https://www.thelancet.com/article/S0140-6736(22)00847-9/full"
    },
    {
      "id": 20,
      "evidence_type": "primary",
      "authors": "Arendt M, Munk-Jørgensen P, Sher L, Jensen SO.",
      "title": "Mortality among individuals with cannabis, cocaine, amphetamine, MDMA, and opioid use disorders: a nationwide follow-up study of Danish substance users in treatment.",
      "journal": "Drug and Alcohol Dependence",
      "reverified": null,
      "verification_status": "not independently re-checked",
      "note": "20,581 individuals in treatment 1996–2006; 1,441 deaths over 111,445 person-years. SMRs: heroin 9.1 (CI 8.5–9.8), other opioids 7.7 (6.6–8.9), cocaine 6.4 (3.9–10.0), amphetamine 6.0 (4.2–8.3), cannabis 4.9 (4.2–5.8). MDMA crude rate 1.7/1000 person-years, SMR not significantly elevated. Injection use raised hazard ratios significantly. Treatment-population sample — does not generalise to casual users.",
      "url": "https://pubmed.ncbi.nlm.nih.gov/20971585/"
    },
    {
      "id": 21,
      "evidence_type": "clinical",
      "authors": "Garnett MF, Miniño AM.",
      "title": "Drug Overdose Deaths in the United States, 2003–2023.",
      "journal": "NCHS Data Brief no. 522, December 2024",
      "reverified": null,
      "verification_status": "not independently re-checked",
      "note": "105,007 overdose deaths in 2023; age-adjusted rate 31.3 per 100,000, down from 32.6 in 2022 after nearly quadrupling from 8.9 in 2003. Note deaths involving multiple drugs are counted in each category, so drug-specific rates are not mutually exclusive.",
      "url": "https://www.cdc.gov/nchs/products/databriefs/db522.htm"
    },
    {
      "id": 22,
      "evidence_type": "primary",
      "authors": "Ágoston C, Urbán R, Richman MJ, Demetrovics Z.",
      "title": "Caffeine use disorder: an item-response theory analysis of proposed DSM-5 criteria.",
      "journal": "Addictive Behaviors",
      "reverified": null,
      "verification_status": "not independently re-checked",
      "note": "Caffeine dependence is not negligible. Studies across countries put caffeine use disorder at roughly 8–20% of consumers; the Iranian cross-sectional study (n=1,228) estimated CUD at 19.5% and caffeine withdrawal at 46.6%. Caffeine withdrawal is a formal DSM-5 diagnosis; caffeine use disorder remains in Section 3, \"conditions for further study.\"",
      "url": "https://pubmed.ncbi.nlm.nih.gov/29454178/"
    },
    {
      "id": 23,
      "evidence_type": "clinical",
      "authors": "Caffeine Withdrawal.",
      "title": "",
      "journal": "StatPearls",
      "reverified": null,
      "verification_status": "not independently re-checked",
      "note": "Headache is reported in up to 50% of people who stop, and roughly 13% experience clinically significant distress or functional impairment - the same figures as [40]. Onset 12-24 hours, peak 20-51 hours, resolution 2-9 days. Real syndrome, no mortality — which is exactly why caffeine scores low on withdrawal danger despite scoring non-zero on withdrawal frequency.",
      "url": "https://www.ncbi.nlm.nih.gov/books/NBK430790/"
    },
    {
      "id": 24,
      "evidence_type": "primary",
      "authors": "Marconi A, Di Forti M, Lewis CM, Murray RM, Vassos E.",
      "title": "Meta-analysis of the association between the level of cannabis use and risk of psychosis.",
      "journal": "Schizophrenia Bulletin",
      "reverified": null,
      "verification_status": "not independently re-checked",
      "note": "Dose-response, pooled across 10 studies: odds of psychosis 1.97 (CI 1.68–2.31) at median use, rising to 3.90 (CI 2.84–5.34) among the heaviest users. Independently corroborated by Moore et al. 2007 (AOR 2.09) and Kiburi et al. 2021 in adolescents (OR 2.7).",
      "url": "https://pubmed.ncbi.nlm.nih.gov/26884547/"
    },
    {
      "id": 25,
      "evidence_type": "primary",
      "authors": "Di Forti M, Quattrone D, Freeman TP, et al.",
      "title": "The contribution of cannabis use to variation in the incidence of psychotic disorder across Europe (EU-GEI).",
      "journal": "Lancet Psychiatry",
      "reverified": null,
      "verification_status": "not independently re-checked",
      "note": "The potency/dose finding, and a direct illustration of the \"how much\" point: irregular low-potency use roughly doubles psychosis odds, daily use raises it to 3.2 (CI 2.2–4.1), and daily high-potency use to 4.8 (CI 2.5–6.3). The 2015 south London study found daily high-potency users about five times more likely than non-users to have a psychotic disorder.",
      "url": "https://www.thelancet.com/article/S2215-0366(19)30048-3/fulltext"
    },
    {
      "id": 26,
      "evidence_type": "primary",
      "authors": "Henry JA, Jeffreys KJ, Dawling S.",
      "title": "Toxicity and deaths from 3,4-methylenedioxymethamphetamine (\"ecstasy\").",
      "journal": "The Lancet",
      "reverified": null,
      "verification_status": "not independently re-checked",
      "note": "The foundational MDMA toxicity series. Among 7 fatalities the pattern was fulminant hyperthermia, convulsions, disseminated intravascular coagulation, rhabdomyolysis and acute renal failure — following recreational misuse of small amounts, which is the key point for the acute column.",
      "url": "https://pubmed.ncbi.nlm.nih.gov/1353554/"
    },
    {
      "id": 27,
      "evidence_type": "review",
      "authors": "Hall AP, Henry JA.",
      "title": "Acute toxic effects of ecstasy (MDMA) and related compounds.",
      "journal": "British Journal of Anaesthesia",
      "reverified": null,
      "verification_status": "not independently re-checked",
      "note": "Mechanism and environment-dependence: severe serotonin syndrome has historically been quoted at 10–15% mortality — a claim about the syndrome at its most severe rather than the fatality risk of MDMA use, and reported MDMA-associated cases usually involve another serotonergic drug; MDMA hyperthermia is amplified by high ambient temperature and crowding (\"aggregation toxicity\"). Also documents dose-nonlinearity — a small dose increase can produce a large plasma-level jump. Directly supports treating MDMA's risk as dose- and setting-dependent rather than fixed.",
      "url": "https://www.bjanaesthesia.org/article/S0007-0912(17)35084-5/fulltext"
    },
    {
      "id": 28,
      "evidence_type": "clinical",
      "authors": "Johnson B, Streltzer J.",
      "title": "Risks associated with long-term benzodiazepine use.",
      "journal": "American Family Physician 2013;88(4):224-6",
      "reverified": null,
      "verification_status": "not independently re-checked",
      "note": "Beyond withdrawal: many of the ~4 million US daily benzodiazepine users meet DSM-IV dependence criteria. Driving risk comparable to a blood alcohol level of 0.05–0.079%; hip-fracture risk in older people raised by at least 50%; cognitive decline that did not resolve three months after discontinuation. Withdrawal symptoms are possible after only a month of daily use.",
      "url": "https://www.aafp.org/pubs/afp/issues/2013/0815/p224.html"
    },
    {
      "id": 29,
      "evidence_type": "clinical",
      "authors": "Tobacco-Related Mortality; Diseases and Death.",
      "title": "",
      "journal": "CDC",
      "reverified": null,
      "verification_status": "not independently re-checked",
      "note": "More than 480,000 US deaths a year including ~41,000 from secondhand smoke — about one in five deaths. Overall mortality among smokers is roughly three times that of never-smokers. Smokers die about 10 years earlier on average.",
      "url": "https://www.ncbi.nlm.nih.gov/books/NBK294316/"
    },
    {
      "id": 30,
      "evidence_type": "primary",
      "authors": "Doll R, Peto R, Boreham J, Sutherland I.",
      "title": "Mortality in relation to smoking: 50 years' observations on male British doctors.",
      "journal": "BMJ",
      "reverified": null,
      "verification_status": "not independently re-checked",
      "note": "The independent long-run cohort behind the CDC figures. About half of persistent cigarette smokers are eventually killed by smoking; the higher \"two-thirds\" figure comes from later cohorts (Pirie 2013, Banks 2015) and is not this paper’s; continuous smokers born 1900–1930 died about 10 years younger than lifelong non-smokers. Stopping at 60, 50, 40 or 30 regained about 3, 6, 9 and 10 years respectively — the strongest dose/duration-response evidence in the whole table.",
      "url": "https://pubmed.ncbi.nlm.nih.gov/15213107/"
    },
    {
      "id": 31,
      "evidence_type": "review",
      "authors": "Schwartz BG, Rezkalla S, Kloner RA.",
      "title": "Cardiovascular effects of cocaine.",
      "journal": "Circulation",
      "reverified": null,
      "verification_status": "not independently re-checked",
      "note": "Anchors cocaine's acute score. Reviews Mittleman 1999 (Circulation 1999;99(21):2737–41), whose case-crossover design put risk 23.7-fold above baseline in the first hour on a very wide interval — 95% CI 8.5–66.3, from nine exposed cases — falling to about 4-fold in the second and third hours. Cocaine users have 3.8–6.9 times the overall MI incidence of non-users, and cocaine contributes to roughly one in four MIs in people aged 18–45.",
      "url": "https://www.ahajournals.org/doi/10.1161/circulationaha.110.940569"
    },
    {
      "id": 32,
      "evidence_type": "primary",
      "authors": "Anthony JC, Warner LA, Kessler RC.",
      "title": "Comparative epidemiology of dependence on tobacco, alcohol, controlled substances, and inhalants: basic findings from the National Comorbidity Survey.",
      "journal": "Experimental and Clinical Psychopharmacology",
      "reverified": null,
      "verification_status": "not independently re-checked",
      "note": "The source that extends dependence coverage beyond NESARC's four drugs. Americans aged 15–54: about 24% had a history of tobacco dependence, 14% alcohol, 7.5% dependence on an inhalant or controlled drug. Among users, roughly a third of tobacco smokers became dependent and about 15% of drinkers. Anthony's later per-class summary gives heroin 23%, cocaine 17%, alcohol 15%, stimulants 11%, cannabis 9%, psychedelics 5%, tobacco 32%.",
      "url": "https://pure.johnshopkins.edu/en/publications/comparative-epidemiology-of-dependence-on-tobacco-alcohol-control/"
    },
    {
      "id": 33,
      "evidence_type": "primary",
      "authors": "Grant BF, Saha TD, Ruan WJ, Goldstein RB, Chou SP, Jung J, et al.",
      "title": "Epidemiology of DSM-5 drug use disorder: results from NESARC-III.",
      "journal": "JAMA Psychiatry",
      "reverified": null,
      "verification_status": "not independently re-checked",
      "note": "Establishes what the modern survey does and does not measure. 36,309 adults; 3.9% had a 12-month drug use disorder and 9.9% a lifetime diagnosis. Use disorders are assessed for amphetamine, cannabis, club drugs, cocaine, hallucinogens, heroin, non-heroin opioids, sedatives/tranquilizers and inhalants — but as prevalence of disorder, not as a use-to-dependence transition probability, which is why MDMA and ketamine have no comparable figure in the table above.",
      "url": "https://pubmed.ncbi.nlm.nih.gov/26580136/"
    },
    {
      "id": 34,
      "evidence_type": "clinical",
      "authors": "Drug overdose deaths by substance, 2022–2023.",
      "title": "",
      "journal": "CDC / NCHS",
      "reverified": null,
      "verification_status": "not independently re-checked",
      "note": "Per-drug US death counts: synthetic opioids (mostly fentanyl) 74,702; psychostimulants including methamphetamine 36,251; cocaine 29,918; natural/semisynthetic opioids 10,171; heroin about 4,000. Roughly 76% of 2023 overdose deaths involved an opioid. CDC states explicitly that deaths involving multiple drugs are counted in every applicable category, so these figures must not be summed.",
      "url": "https://www.cdc.gov/overdose-prevention/about/index.html"
    },
    {
      "id": 35,
      "evidence_type": "clinical",
      "authors": "Esser MB, et al.",
      "title": "Deaths from excessive alcohol use — United States, 2016–2021.",
      "journal": "MMWR",
      "reverified": null,
      "verification_status": "not independently re-checked",
      "note": "Average annual deaths from excessive alcohol use rose 29.3%, from 137,927 in 2016–2017 to 178,307 in 2020–2021 — about 5% of all US deaths. The earlier 2011–2015 ARDI estimate was 95,158 per year with 29 years of life lost per death. Leading causes: alcohol-associated liver disease, heart disease and stroke, poisonings, accidents, and alcohol-related cancers.",
      "url": "https://www.cdc.gov/alcohol/facts-stats/index.html"
    },
    {
      "id": 36,
      "evidence_type": "primary",
      "authors": "Zhu DT, Bajaj SS, Sen A.",
      "title": "Methamphetamine and cocaine overdose deaths in the United States, 1999-2023.",
      "journal": "Substance Use & Misuse",
      "reverified": null,
      "verification_status": "not independently re-checked",
      "note": "Why single-drug death counts mislead. Methamphetamine-involved deaths rose from 547 in 1999 to 34,855 in 2023; cocaine-involved from 3,822 to 29,449. Critically, stimulants were involved in about 8% of fentanyl overdoses in 1999 but 56.67% by 2023 — the \"fourth wave\" of the overdose crisis is largely a polysubstance phenomenon, so attributing a death to one drug is increasingly artificial.",
      "url": "https://pubmed.ncbi.nlm.nih.gov/40509756/"
    },
    {
      "id": 37,
      "evidence_type": "clinical",
      "authors": "Garnett MF, Miniño AM.",
      "title": "Drug Overdose Deaths in the United States, 2023–2024.",
      "journal": "NCHS Data Brief",
      "reverified": "2026-07 — NCHS Data Brief 549 PDF fetched; all tables confirmed",
      "verification_status": "checked against source",
      "note": "Supersedes [21] and [34] for 2024. Final NVSS counts: 79,384 overdose deaths in 2024, age-adjusted rate 23.1 per 100,000, down 26.2% from 31.3 — the largest single-year fall in the 2014–2024 series. By sex: male 44.3→32.2, female 18.3→14.1. By age (2023→2024): 15–24 13.5→8.5, 25–34 45.6→30.4, 35–44 60.8→44.2 (highest), 45–54 53.3→41.0, 55–64 49.2→38.6, 65+ 14.7→13.4. By drug: synthetic opioids 22.2→14.3, psychostimulants 10.6→8.5, cocaine 8.6→6.3, heroin 1.2→0.8. Race rates are not adjusted for death-certificate misclassification, which understates American Indian and Alaska Native rates by about 34%. Deaths involving multiple drugs are counted in every applicable category.",
      "url": "https://www.cdc.gov/nchs/products/databriefs/db549.htm"
    },
    {
      "id": 38,
      "evidence_type": "primary",
      "authors": "Crépault JF, Russell C, Asbridge M, et al.",
      "title": "Drug harms in Canada: a multi-criteria decision analysis.",
      "journal": "Journal of Psychopharmacology 2026;40(2):286-95",
      "reverified": "2026-07 — scores confirmed; Nutt and Phillips co-authorship confirmed",
      "verification_status": "checked against source",
      "note": "The nearest thing to a holdout this page has. Twenty experts from six provinces, 16 drugs, 16 harm dimensions — ten to the person using, six to others — scored 0–100 at a two-day decision conference, then swing-weighted. Alcohol 79, tobacco 45, nonprescription opioids 33, cocaine 19, methamphetamine 19, cannabis 15. The authors are explicit that these are population-level harms reflecting Canadian prevalence and policy context, not individual-level harmfulness — which is why tobacco ranks far higher there than here. Independence is partial: David Nutt and Lawrence Phillips co-author this paper as well as [1], and the method is the same MCDA tradition.",
      "url": "https://journals.sagepub.com/doi/10.1177/02698811251409147"
    },
    {
      "id": 39,
      "evidence_type": "primary",
      "authors": "SAMHSA, Center for Behavioral Health Statistics and Quality.",
      "title": "Key Substance Use and Mental Health Indicators in the United States: Results from the 2024 National Survey on Drug Use and Health.",
      "journal": "HHS Publication PEP25-07-007, NSDUH Series H-60",
      "reverified": "2026-07 — NSDUH 2024 prevalence figures confirmed",
      "verification_status": "checked against source",
      "note": "Source of every prevalence figure in the per-drug panels. Past year, aged 12+, 2024: marijuana 64.2M, hallucinogens 10.4M, prescription opioid misuse 7.6M, tranquilliser/sedative misuse 4.6M, cocaine 4.3M, methamphetamine 2.4M (0.8%, flat since 2021), heroin ~556,000. Past month: alcohol 134.3M, tobacco products 48.0M, marijuana 44.3M, nicotine vaping 27.7M. 73.6M (25.5%) used any illicit drug; 48.4M had a substance use disorder; 10.2M received treatment. Three limitations matter for this page. Counts are not mutually exclusive — polysubstance use is counted in every applicable row. LSD, psilocybin, MDMA and ketamine are pooled into one \"hallucinogens\" figure and cannot be separated, so four of the thirteen rows here have no drug-specific prevalence. And NSDUH samples the civilian non-institutionalised population, excluding people who are incarcerated or unsheltered — which systematically undercounts the heaviest use. The 2024 overall response rate was 11.3%, with a weighted interview response rate of 45.3%.",
      "url": "https://www.samhsa.gov/data/data-we-collect/nsduh-national-survey-drug-use-and-health/national-releases/2024"
    },
    {
      "id": 40,
      "evidence_type": "review",
      "authors": "Juliano LM, Griffiths RR.",
      "title": "A critical review of caffeine withdrawal: empirical validation of symptoms and signs, incidence, severity, and associated features.",
      "journal": "Psychopharmacology",
      "reverified": "2026-07 — PDF fetched; 50% headache / 13% impairment confirmed",
      "verification_status": "checked against source",
      "note": "The reason caffeine is no longer the thinnest row here. Systematic review of 57 experimental and 9 survey studies. Of 49 candidate symptom categories, 10 met validity criteria — headache, fatigue, decreased energy, decreased alertness, drowsiness, decreased contentedness, depressed mood, difficulty concentrating, irritability, and feeling foggy. Headache incidence 50%; clinically significant distress or functional impairment 13%. Onset 12–24 hours after abstinence, peak at 20–51 hours, duration 2–9 days. Symptoms appeared at habitual doses as low as 100 mg/day — roughly one cup of coffee. Expectancy was found not to be a prime determinant, which rules out the obvious placebo explanation, and avoidance of withdrawal was central to habitual use. The review concluded the syndrome was well enough characterised to warrant inclusion in the DSM; caffeine withdrawal is now a DSM-5 diagnosis, with caffeine use disorder listed as a condition for further study.",
      "url": "https://link.springer.com/article/10.1007/s00213-004-2000-x"
    },
    {
      "id": 41,
      "evidence_type": "primary",
      "authors": "Duke AN, Johnson MW, Reissig CJ, Griffiths RR.",
      "title": "Nicotine reinforcement in never-smokers.",
      "journal": "Psychopharmacology",
      "reverified": "2026-07 — confirmed",
      "verification_status": "checked against source",
      "note": "Eighteen never-smokers (fewer than 50 lifetime nicotine exposures), double-blind oral nicotine against placebo. The first demonstration that nicotine functions as a reinforcer in people who have never smoked. The result that matters for this table is the variability: nicotine is a weak and inconsistent reinforcer in non-humans, and in never-smokers some individuals chose it reliably while others avoided it. Nicotine carries the highest population dependence rate of any drug measured [2] while being, in controlled conditions, an unreliable reinforcer — a combination Griffiths described as making it a very unusual drug from an addiction standpoint.",
      "url": "https://link.springer.com/article/10.1007/s00213-015-4053-4"
    },
    {
      "id": 42,
      "evidence_type": "primary",
      "authors": "Jones HE, Griffiths RR.",
      "title": "Oral caffeine maintenance potentiates the reinforcing and stimulant subjective effects of intravenous nicotine in cigarette smokers.",
      "journal": "Psychopharmacology",
      "reverified": "2026-07 — confirmed",
      "verification_status": "checked against source",
      "note": "A measured interaction between two rows of this table. Double-blind, within-subject: chronic oral caffeine (200 mg/70 kg three times daily for at least 12 days) against placebo, then intravenous nicotine. Caffeine maintenance significantly increased subjective drug effect, stimulation, and willingness to pay for nicotine. Cited here not for the caffeine row or the nicotine row but because it belongs to neither — this model scores thirteen drugs independently and has no structure that can hold a result like this.",
      "url": "https://link.springer.com/article/10.1007/s00213-002-1262-4"
    },
    {
      "id": 43,
      "evidence_type": "primary",
      "authors": "Carbonaro TM, Bradstreet MP, Barrett FS, MacLean KA, Jesse R, Johnson MW, Griffiths RR.",
      "title": "Survey study of challenging experiences after ingesting psilocybin mushrooms: acute and enduring positive and negative consequences.",
      "journal": "Journal of Psychopharmacology",
      "reverified": "2026-07 — all percentages confirmed",
      "verification_status": "checked against source",
      "note": "The evidence behind psilocybin's acute-crisis score, which was previously the thinnest-supported non-zero cell on the page. 1,993 respondents (mean age 30, 78% male) described their single worst psychologically difficult experience. 39% rated it among the five most challenging experiences of their life; 11% put themselves or others at risk of physical harm; 2.6% behaved aggressively or violently; 2.7% sought medical help. Among those whose experience was over a year earlier, 7.6% had sought treatment for enduring psychological symptoms, with three cases linked to onset of persisting psychotic symptoms and three to attempted suicide. Read the denominator carefully: this is a self-selected online sample recalling their worst experience, so these are proportions of people who had a difficult trip and chose to report it — not rates among psilocybin users. The risk factors identified are the useful part: dose, duration, difficulty, and absence of physical comfort and social support.",
      "url": "https://journals.sagepub.com/doi/abs/10.1177/0269881116662634"
    },
    {
      "id": 44,
      "evidence_type": "review",
      "authors": "Johnson MW, Richards WA, Griffiths RR.",
      "title": "Human hallucinogen research: guidelines for safety.",
      "journal": "Journal of Psychopharmacology",
      "reverified": "2026-07 — screening protocol confirmed",
      "verification_status": "checked against source",
      "note": "Source for the screening advice in the safety notice at the top of this page. Classical hallucinogens are described as relatively safe physiologically and not drugs of dependence, with the risk being specifically psychological: the most likely adverse event is overwhelming distress during drug action, which can lead to dangerous behaviour such as leaving the session; prolonged psychoses are less common. The safeguards are exclusion of anyone with a personal or family history of psychotic or other severe psychiatric disorder, rapport with monitors established beforehand, careful preparation, a safe physical setting, and interpersonal support from at least two monitors throughout, with follow-up probing for hallucinogen persisting perception disorder. Persisting adverse reactions are rare when these conditions hold — which is the point: the risk is largely a property of the circumstances, not the molecule.",
      "url": "https://journals.sagepub.com/doi/10.1177/0269881108093587"
    },
    {
      "id": 45,
      "evidence_type": "primary",
      "authors": "Johnson MW, Garcia-Romeu A, Cosimano MP, Griffiths RR.",
      "title": "Pilot study of the 5-HT2AR agonist psilocybin in the treatment of tobacco addiction.",
      "journal": "Journal of Psychopharmacology",
      "reverified": "2026-07 — 12 of 15 at six months confirmed",
      "verification_status": "checked against source",
      "note": "Open-label pilot, psilocybin within a 15-week structured smoking-cessation protocol: 12 of 15 participants were abstinent at six-month follow-up, a rate well above those usually reported for behavioural or pharmacological treatments. Small, uncontrolled and unblinded, so it proves little on its own. It is cited here for a structural reason rather than a clinical one — like [42] it is one row of this table acting on another row, but in the opposite direction. This model has no way to represent either.",
      "url": "https://journals.sagepub.com/doi/10.1177/0269881114548296"
    },
    {
      "id": 46,
      "evidence_type": "meta",
      "authors": "Bahji A, Stephenson C, Tyo R, Hawken ER, Seitz DP.",
      "title": "Prevalence of cannabis withdrawal symptoms among people with regular or dependent use of cannabinoids: a systematic review and meta-analysis.",
      "journal": "JAMA Network Open",
      "reverified": "2026-07 — 47% pooled / 17% population-based, 95% CI confirmed",
      "verification_status": "checked against source",
      "note": "Upgrades cannabis withdrawal from a judgment cell to a measured one. Eight databases, 3,848 citations screened, 47 studies, 50 cohorts, 23,518 participants. Pooled prevalence of cannabis withdrawal syndrome 47% (95% CI 41–52) — but the stratification is what matters here: 17% (13–21) in population-based samples, against 54% in outpatient and 87% in inpatient groups. Since this page scores harm per person using rather than per person in treatment, 17% is the applicable figure and the widely quoted 47% is treatment-skewed. Heterogeneity was extreme (I² = 99.2%), and prevalence rose with daily use and with concurrent tobacco or other substance use. Note the limit: this establishes that the syndrome is real and common, not that it is dangerous — which is what the quitting column actually measures.",
      "url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7146100/"
    },
    {
      "id": 47,
      "evidence_type": "primary",
      "authors": "US Centers for Disease Control and Prevention; Office of the Surgeon General.",
      "title": "Secondhand smoke: health problems, and tobacco-related mortality.",
      "journal": "CDC; The Health Consequences of Smoking — 50 Years of Progress",
      "reverified": "2026-07 — 41,000 adult deaths confirmed",
      "verification_status": "checked against source",
      "note": "Upgrades tobacco's damage-to-others from judgment to a counted figure, which it should have been from the start. CDC attributable-mortality modelling estimates more than 40,000 deaths a year among US adults who do not smoke — about 33,951 from heart disease and 7,333 from lung cancer — plus roughly 400 infant deaths. Around 58 million non-smoking Americans are exposed, and living with a smoker raises a non-smoker's lung cancer risk by 20–30%. Since 1964 about 2.5 million non-smokers have died from secondhand exposure. One of very few harm-to-others values in this table derived from mortality surveillance rather than inferred from an expert part-score — though these are modelled attributable estimates, not individually counted deaths.",
      "url": "https://www.cdc.gov/tobacco/secondhand-smoke/health.html"
    },
    {
      "id": 48,
      "evidence_type": "pooled cohort",
      "authors": "Byhamre ML, Araghi M, Alfredsson L, et al.",
      "title": "Swedish snus use is associated with mortality: a pooled analysis of eight prospective studies.",
      "journal": "International Journal of Epidemiology",
      "reverified": "2026-07 — aHR 1.28 (1.20-1.35) confirmed",
      "verification_status": "checked against source",
      "note": "The organ-harm anchor for the nicotine row, and the best long-run evidence on nicotine without combustion anywhere. Eight prospective Swedish cohorts. Exclusive current snus users, against never-users of any tobacco: all-cause mortality aHR 1.28 (95% CI 1.20–1.35), cardiovascular mortality 1.27 (1.15–1.41), other-cause mortality 1.37 (1.24–1.52), cancer mortality 1.12 (1.00–1.26). Risk rose with duration of use but not with weekly amount. Read it carefully in both directions: smokeless nicotine is clearly not harmless, and it is just as clearly nowhere near cigarettes, which carry two to three times all-cause mortality. A separate cohort of 41,162 adults found no association with major heart disease after adjustment, but did find raised stroke risk in never-smokers (HR 1.52, 1.01–2.30).",
      "url": "https://academic.oup.com/ije/article/49/6/2041/6042990"
    },
    {
      "id": 49,
      "evidence_type": "review",
      "authors": "Clarke E, Thompson K, Weaver S, Thompson J, O'Connell G.",
      "title": "Snus: a compelling harm reduction alternative to cigarettes.",
      "journal": "Harm Reduction Journal",
      "reverified": "2026-07 — Swedish prevalence and mortality position confirmed",
      "verification_status": "checked against source",
      "note": "The population-level counterpart to [48]. Sweden reports the lowest daily cigarette prevalence in the EU at around 5%, alongside roughly 20% daily oral tobacco use, and the lowest tobacco-related mortality and male lung cancer incidence in Europe. Comparative reviews find lower risks of lung cancer, COPD, mouth cancer and heart disease for smokeless products than for cigarettes. Two cautions. The Valen systematic review reports raised risks of oesophageal, pancreatic, stomach and rectal cancer among snus users, rating confidence in those estimates from moderate down to very low. And this literature attracts industry funding, so it should be read as a set of contested estimates rather than a settled conclusion \\u2014 which is why the nicotine row's organ score leans on the independent cohort pooling in [48].",
      "url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6882181/"
    }
  ]
}