Cocaine Intoxication — Comprehensive Research Report

1. Disease Information

Overview. Cocaine intoxication is the acute, dose-dependent, transient clinical state produced by cocaine's pharmacological actions during or shortly after use — a sympathomimetic toxidrome combined with disturbances of mood, cognition, perception, and behavior, plus a spectrum of organ-specific toxicity (cardiovascular, cerebrovascular, neurologic, thermoregulatory, gastrointestinal, pulmonary, renal). It is distinct from, but closely tied to, cocaine use disorder (the chronic, compulsive-use condition) — intoxication is what happens pharmacologically to the intoxicated individual, while use disorder is the addictive syndrome.

Key identifiers: - MONDO: MONDO:0019544 (cocaine intoxication) - ICD-10-CM: F14.0/F14.1x2 (cocaine use with intoxication) and T40.5X- (poisoning by cocaine); ICD-11 equivalent under "Disorders due to use of cocaine" 6C24 - ICD-9-CM: 292.89 - Orphanet: ORPHA:90068 (listed for toxic-exposure disorder cross-reference in some aggregator resources, though cocaine intoxication is not a classic Orphanet rare disease and is better sourced from ICD/MeSH than Orphanet) - MeSH: D019966 (Cocaine-Related Disorders), D000079843 relates to Cocaine - DSM-5: Substance Intoxication — Stimulant Intoxication, cocaine type

Common synonyms/alternative names: cocaine toxicity, cocaine poisoning, crack intoxication, cocaine overdose, acute cocaine toxicity, sympathomimetic toxicity (cocaine-type), cocaine-associated agitated delirium (severe form).

Source of information. This entry synthesizes aggregated disease-level knowledge: toxicology/emergency-medicine reviews and guidelines (StatPearls, AHA scientific statements, JACC/Circulation reviews), pharmacology and neuroscience mechanistic literature, population-level surveillance data (CDC NCHS/NVSS, NSDUH), and case-series/case-report literature for organ-specific complications and animal-model work — not primary individual-patient EHR data. Cocaine Toxicity - StatPearls; Management of Cocaine-Associated Chest Pain and MI (AHA); The Cardiovascular Effects of Cocaine (JACC).

2. Etiology

Disease Causal Factor

The single necessary and sufficient causal factor is exposure to cocaine (benzoylmethylecgonine), a tropane alkaloid derived from Erythroxylum coca, via any route (intranasal insufflation of powder cocaine hydrochloride, smoking of freebase "crack" cocaine, intravenous injection, oral ingestion, or mucosal/topical exposure). This is a toxic exposure disorder, not a genetic or infectious disease — there is no disease without the exposure. CHEBI term: CHEBI:27958 (cocaine).

Risk Factors

Genetic risk factors (modify severity/susceptibility, not causation): - BCHE (butyrylcholinesterase) variants — BChE is the primary hydrolytic enzyme clearing cocaine to inactive ecgonine methyl ester; reduced enzymatic activity shunts more cocaine toward hepatic CYP3A4-mediated N-demethylation to the hepatotoxic metabolite norcocaine and prolongs/potentiates cocaine's toxic effects. The common K-variant (rs1803274) is associated with ~33% lower plasma BChE activity in homozygotes (~1/25 people) and heterozygotes (~1/4 people); a study of 1,436 individuals found rs1803274 differed significantly between crack-exclusive and powder-exclusive cocaine users (PMID:24312228). Severe congenital BChE deficiency (atypical/silent alleles) is a described risk factor for markedly prolonged, severe toxicity after cocaine exposure, modeled in Bche/Ces1 (carboxylesterase) double-knockout mice, which show prolonged toxic effects after cocaine challenge as a model for BChE-deficient humans. Butyrylcholinesterase Genetic Variants (PLOS ONE, PMID:24312228); BChE/Ces1 knockout mouse model. - DRD2 splicing polymorphisms — the intronic SNP rs2283265 (altering D2-short/D2-long receptor splice-isoform ratio) confers an odds ratio of ~3 for cocaine overdose/death; this risk is markedly amplified through a gene-gene interaction with the dopamine transporter (SLC6A3/DAT) 3′-UTR VNTR variant rs3836790 — homozygosity for the DAT 6-repeat allele raises the OR to ~7.5 in DRD2 rs2283265 minor-allele carriers, illustrating a gene-gene-environment risk architecture for lethal cocaine toxicity (PMID:23340505, Translational Psychiatry). Dopamine transporter DAT and receptor DRD2 variants affect risk of lethal cocaine abuse. - HLA-B27 — carriage is a reported risk factor for developing agranulocytosis from levamisole-adulterated cocaine (an adulterant-mediated, not cocaine-intrinsic, immunogenetic risk factor — see §5). - CACNB2, GRIN2B, PLXDC2, PKNOX2 — implicated by a meta-analysis of 75 GWAS/2,910 candidate genes in substance-use-disorder/drug-use behavior broadly (not cocaine-specific), relevant to calcium-channel and NMDA-receptor (glutamatergic) signaling pathways engaged by cocaine. - CYP2A6, CYP2D6, ADH1B, ALDH2 — metabolic-gene variation affecting polysubstance toxicity/response, most directly relevant when cocaine is co-used with alcohol (cocaethylene formation, see §4) or nicotine.

Environmental/behavioral risk factors: - Route of administration (smoking/crack and IV produce the most rapid, highest peak plasma concentrations and highest acute toxicity risk vs. intranasal); dose and purity; concurrent alcohol co-use (forms cocaethylene, a longer-half-life active metabolite with independent cardiotoxicity, and synergistically raises risk of sudden death); concurrent opioid (especially fentanyl) co-use/contamination — "fourth wave" polysubstance deaths, with the percentage of U.S. overdose deaths involving both fentanyl and stimulants rising from 0.6% (2010) to 32.3% (2021), and the inverse "cocaine-in-the-dope" adulteration pattern also increasingly recognized (PMID:38829035); ambient heat (hyperthermia risk); underlying cardiovascular disease (accelerates ischemia); pregnancy (fetal/placental exposure, see §5); and structural/demographic disparities — Black/African American persons in the U.S. experienced the steepest rise in cocaine-involved death rates 2018–2023 (9.1 → 24.3 per 100,000). Fourth Wave polysubstance fentanyl deaths (Addiction, 2023); "Coke in the Dope" — cocaine-adulterated fentanyl supply.

Protective Factors

• No pharmacogenomic "protective allele" against acute cocaine toxicity is well established; higher constitutive BChE activity (non-K-variant homozygotes) is protective by accelerating clearance to inactive metabolites.
• Behaviorally: avoidance of concurrent alcohol/opioid use, harm-reduction practices (fentanyl test-strip checking of supply — shown effective at detecting fentanyl contamination before use), supervised-consumption settings, and naloxone co-carriage (protective against the opioid component of a mixed exposure, not against cocaine's own toxicity, since no opioid-receptor mechanism is involved). Fentanyl Test Strip Use and Overdose Risk Reduction (JAMA Network Open).

Gene-Environment Interactions

The clearest documented G×E is the DRD2 rs2283265 × DAT1 rs3836790 × chronic heavy cocaine exposure interaction driving risk of fatal cocaine toxicity (PMID:23340505) — genetic variation in dopaminergic signaling amplifies risk only in the presence of the environmental exposure (repeated/heavy cocaine use), a multiplicative rather than additive interaction. Similarly, BCHE genotype × route of administration interacts, since the K-variant's effect differed specifically between crack (smoked) and powder (intranasal) cocaine users in the case-control study above, suggesting metabolic genotype effects are exposure-route-dependent (peak plasma concentration/kinetics differ by route).

3. Phenotypes

Cocaine intoxication phenotypes span behavioral/psychiatric, cardiovascular, neurologic, thermoregulatory/muscular, respiratory, gastrointestinal, and laboratory domains. All are acute/subacute, dose- and route-dependent, and (for the toxidrome core) resolve as the drug is cleared — but several categories (myocardial infarction, stroke, rhabdomyolysis-associated AKI, bowel infarction) leave permanent sequelae or cause death.

Behavioral/Psychiatric (core toxidrome)

Cardiovascular

Neurologic/Cerebrovascular

Thermoregulatory/Musculoskeletal

Respiratory

Gastrointestinal

Laboratory abnormalities

Elevated creatine kinase (rhabdomyolysis), elevated troponin (myocardial injury), metabolic acidosis, hyperkalemia (rhabdomyolysis/AKI), leukocytosis, and (with levamisole-adulterated product) neutropenia/agranulocytosis and p-ANCA positivity.

Characteristics. Onset is acute (minutes, matching route-specific pharmacokinetics — fastest with smoked/IV, slower with intranasal/oral); severity is broadly dose-dependent but with substantial individual variability (genetic/metabolic factors above); course is typically self-limited over hours as cocaine and active metabolites (cocaethylene, norcocaine) are cleared, though organ injury (MI, stroke, rhabdomyolysis-AKI) can be permanent; frequency of specific phenotypes is highly variable across cohorts and not uniformly reported at the population level (chest pain and agitation are the most common ED-presenting complaints; psychosis in ~30–50% of users at some point; sudden cardiac death and stroke are rare but disproportionate causes of mortality in young cocaine users).

Quality of life impact. Acute intoxication episodes causing MI, stroke, or severe rhabdomyolysis/AKI carry lasting QoL impact (post-MI functional limitation, post-stroke disability, dialysis dependence in severe AKI); psychiatric sequelae (persistent psychosis, anxiety) can also impair daily functioning. Formal EQ-5D/SF-36 disease-specific data for cocaine intoxication specifically (as opposed to cocaine use disorder generally) are not well represented in the literature surveyed.

4. Genetic/Molecular Information

Cocaine intoxication is not a Mendelian genetic disease — there is no single causal gene. The genetic contribution operates entirely at the level of modifier genes affecting susceptibility/severity, and to a lesser extent genes contributing to the separate but related trait of cocaine dependence liability.

• Causal "gene": none (environmental/toxic exposure disorder). No OMIM phenotype entry exists for cocaine intoxication itself.
• Modifier genes (detailed in §2): BCHE (hgnc:983, butyrylcholinesterase — clearance/detoxification), DRD2 (hgnc:3023, dopamine D2 receptor — splicing variant rs2283265 modulates lethality risk), SLC6A3/DAT1 (hgnc:11049 — VNTR modulates lethality risk in combination with DRD2), CYP3A4 (hgnc:2637 — hepatic bioactivation to hepatotoxic norcocaine, and drug-interaction risk with enzyme inducers such as phenytoin/carbamazepine), CES1 (carboxylesterase-1, hgnc:1863 — parallel hydrolytic detoxification pathway to BChE).
• Pathogenic variant classification: Not applicable in the ACMG/AMP sense (this is not a rare Mendelian variant-caused disease); the relevant "variants" are common functional polymorphisms (BCHE K-variant, DRD2 rs2283265, DAT1 VNTR) assessed by population-genetics/pharmacogenomic association studies rather than clinical variant curation (ClinVar has essentially no direct entries framed around "cocaine intoxication" as a phenotype).
• Allele frequency: BCHE K-variant (rs1803274) — approximately 1 in 4 heterozygous, 1 in 25 homozygous in described populations (gnomAD-level population frequency data for rs1803274/rs4263329/rs4680662 would refine this further).
• Somatic vs. germline: All relevant variants are germline; no somatic component.
• Functional consequence: BCHE K-variant → partial loss of enzymatic (esterase) function (~33% reduced activity), shifting cocaine metabolism toward CYP3A4-mediated bioactivation; DRD2 rs2283265 → altered D2S/D2L splice-isoform ratio, altering postsynaptic dopaminergic signaling and mesolimbic circuit sensitivity.
• Epigenetic information: Chronic cocaine exposure (not acute intoxication per se) is associated with altered histone acetylation (e.g., H3/H4 acetylation at fosB, bdnf promoters) and DNA methylation changes in reward-circuit neurons in animal models — mechanistically relevant to the use disorder trajectory rather than to acute intoxication phenotype, but relevant background for a dismech pathophysiology narrative connecting acute exposure to chronic neuroadaptation (sensitization, see §6).
• Chromosomal abnormalities: None relevant; not a chromosomal disorder.

GO/molecular-function terms for the drug's direct targets: - GO:0005329 dopamine transmembrane transporter activity (SLC6A3/DAT — primary high-affinity binding target) - GO:0005335 serotonin:sodium symporter activity (SLC6A4/SERT) - GO:0005326 neurotransmitter transporter activity (SLC6A2/NET, norepinephrine) - GO:0005248 voltage-gated sodium channel activity (SCN5A cardiac isoform — local-anesthetic/Class-I-antiarrhythmic-like blockade) - GO:0005249 voltage-gated potassium channel activity (KCNH2/hERG — QT prolongation) - GO:0005245 voltage-gated calcium channel activity (L-type Ca²⁺ channels — vasospasm/arrhythmia)

5. Environmental Information

• Primary environmental factor: cocaine itself as an exogenous chemical exposure (CHEBI:27958), by any route.
• Adulterants (major independent toxicological contributors):
• Levamisole — an anthelmintic banned in the U.S. since 2000, found in up to 69% of DEA-seized cocaine samples (as of 2009 reporting) — causes a distinctive retiform/stellate purpuric cutaneous vasculitis with or without necrosis, agranulocytosis/severe neutropenia, arthralgias, and leukoencephalopathy, mediated at least partly through an HLA-B27-associated immune mechanism (p-ANCA-positive vasculitis reported). Levamisole-Adulterated Cocaine: Vasculitis and Severe Neutropenia; p-ANCA-Associated Vasculitis (PMID:23476825).
• Fentanyl and fentanyl analogs — increasingly co-present in the cocaine supply ("cocaine-adulterated fentanyl" and the inverse, fentanyl-adulterated cocaine), driving the "fourth wave" of the U.S. overdose crisis; opioid receptor toxicity (respiratory depression) is mechanistically distinct from and additive to cocaine's sympathomimetic toxicity, and naloxone reverses only the opioid component (PMID:38829035).
• Xylazine ("tranq") — an α2-agonist veterinary sedative increasingly found co-adulterating fentanyl/cocaine supplies, contributing sedation and severe skin ulceration, not reversed by naloxone.
• Lifestyle/behavioral factors: route of administration, dose, binge patterns, co-use of alcohol (cocaethylene formation) and tobacco/nicotine, ambient temperature during use (heat-related hyperthermia potentiation), and exertional/agitated state at time of use.
• Infectious agents: Not a direct causal factor for the intoxication itself, but injection-route cocaine use is an established risk factor for bloodborne infections (HIV, HCV, endocarditis) as a downstream consequence of the behavior, and smoked/crack use is associated with increased tuberculosis transmission risk in some population studies — these are comorbidity/complication considerations rather than intoxication mechanisms per se.

6. Mechanism / Pathophysiology

Ordered causal chain (numbered, from exposure to clinical manifestation)

1. Cocaine crosses the blood-brain barrier and enters presynaptic monoaminergic nerve terminals, where it binds with high affinity to the dopamine transporter (DAT/SLC6A3), serotonin transporter (SERT/SLC6A4), and norepinephrine transporter (NET/SLC6A2), acting as a competitive/allosteric transporter blocker ("physical plug") — this directly causes blockade of presynaptic monoamine reuptake (PMID:18568020 structural basis).
2. Reuptake blockade leads to supraphysiologic accumulation of dopamine, serotonin, and norepinephrine in the synaptic cleft, most consequentially in the mesolimbic dopaminergic reward circuit (ventral tegmental area → nucleus accumbens → prefrontal cortex) and in peripheral/central noradrenergic synapses.
3. Excess mesolimbic dopaminergic signaling results in the acute euphoric/reinforcing subjective effect and, at sufficient dose/frequency, drives downstream dopaminergic receptor sensitization (notably via DRD2 splice-isoform dynamics) that underlies the behavioral/psychiatric phenotype spectrum — agitation, hypervigilance, and at the extreme, paranoid psychosis (a documented dopamine-sensitization phenomenon, with 29–53% of users reporting psychotic symptoms).
4. Concurrently, excess glutamate release is triggered in cortical/hippocampal/striatal circuits (partly via cocaine's monoaminergic effects and partly through direct excitatory-amino-acid dysregulation), which leads to NMDA-receptor-mediated excitotoxicity — elevated intracellular Ca²⁺, mitochondrial dysfunction, and oxidative stress in vulnerable neurons — manifesting clinically as seizures and, in chronic/repeated intoxication, contributing to neurotoxic injury.
5. In the periphery, excess norepinephrine at postsynaptic α- and β-adrenergic receptors causes systemic vasoconstriction, tachycardia, and hypertension (the core sympathomimetic toxidrome), which increases myocardial oxygen demand (via increased inotropy/chronotropy) while simultaneously decreasing myocardial oxygen supply through coronary vasoconstriction — a supply-demand mismatch that results in myocardial ischemia/infarction, at times with normal or near-normal coronary arteries on angiography.
6. Coronary vasoconstriction is itself mediated by (a) increased endothelin-1 release, (b) impaired acetylcholine-induced vasorelaxation, (c) blockade of nitric-oxide-synthase-dependent vasodilation, and (d) direct potentiation of L-type calcium-channel-mediated vascular smooth-muscle contraction — together producing a prothrombotic, vasospastic milieu that is further amplified by cocaine-induced platelet activation/aggregation and accelerated endothelial injury/atherosclerosis, jointly leading to intracoronary thrombosis superimposed on vasospasm.
7. The same α-adrenergic-driven vasoconstriction, applied to cerebral vasculature, causes cerebral arterial and microvascular vasospasm (dopamine-mediated) and endothelin-1-dependent vasoconstriction, which results in ischemic stroke; the associated hypertensive surges and endothelial/vessel-wall injury (vasculitis, apoptosis of vascular smooth muscle) independently increase the risk of hemorrhagic stroke (intracerebral and subarachnoid), so the same upstream adrenergic surge branches into two distinct downstream outcomes — ischemic and hemorrhagic cerebrovascular injury — depending on vessel bed and pre-existing vascular integrity.
8. Applied to the splanchnic circulation, norepinephrine-reuptake-blockade-driven mesenteric vasoconstriction causes bowel wall ischemia, which — if sustained — leads to ischemic colitis, bowel infarction, and (in severe cases) perforation and peritonitis.
9. At the cardiac myocyte membrane, cocaine additionally acts as a local-anesthetic-type sodium-channel blocker (Class I antiarrhythmic-like effect on cardiac Naᵥ1.5/SCN5A), which causes delayed ventricular depolarization and QRS widening, and independently blocks cardiac hERG/KCNH2 potassium channels, which causes delayed repolarization and QT prolongation — together resulting in a spectrum of ventricular and supraventricular arrhythmias (including Brugada-pattern ECG changes, wide-complex tachycardia, and torsades de pointes), which can culminate in sudden cardiac death independent of the ischemic mechanism above.
10. Sustained catecholamine excess disrupts intracellular calcium homeostasis in the myocardium and activates NAD(P)H oxidase and xanthine oxidase, generating excess reactive oxygen/nitrogen species that damage the mitochondrial electron transport chain, suppress ATP generation, and overwhelm antioxidant defenses — this oxidative/mitochondrial injury leads to myocardial apoptosis and contraction-band necrosis, which over repeated intoxication episodes results in cocaine-associated cardiomyopathy (a chronic structural sequela of repeated acute mechanistic insults).
11. Centrally, cocaine's monoaminergic and glutamatergic effects, combined with impairment of central thermoregulatory heat-dissipation mechanisms, cause hyperthermia — which is exacerbated by concurrent psychomotor agitation/increased muscular activity and by high ambient temperature, and which, together with (a) intense adrenergic vasoconstriction producing muscle ischemia, (b) direct myotoxic effects of cocaine/metabolites, and (c) sarcoplasmic-reticulum calcium dysregulation increasing intracellular Ca²⁺ in myocytes, converges on rhabdomyolysis — myocyte breakdown releasing myoglobin and intracellular contents, which leads to acute kidney injury (myoglobin-mediated tubular injury) and hyperkalemia. Severe, sustained combination of agitation + hyperthermia + rhabdomyolysis constitutes the clinical entity of cocaine-associated excited/agitated delirium, considered by some authors a chronic-dopamine-dysregulation-driven late-stage manifestation of the same syndrome as rhabdomyolysis, rather than purely an acute dose effect (PMID:10414649).
12. Independent of the mechanisms above, adulterants co-administered with cocaine introduce branch mechanisms not attributable to cocaine itself: levamisole triggers an HLA-B27-associated autoimmune/toxic mechanism causing neutrophil destruction (agranulocytosis) and small-vessel vasculitis; co-administered fentanyl causes μ-opioid-receptor-mediated respiratory depression, additively increasing mortality risk through a mechanistically unrelated pathway.

Molecular pathways

Monoamine-transporter blockade (dopaminergic/serotonergic/noradrenergic signaling), glutamatergic/NMDA-receptor excitotoxic signaling, adrenergic (α1/α2/β) receptor signaling cascades, endothelin-1 signaling, nitric oxide synthase pathway, L-type calcium channel signaling, NAD(P)H oxidase/xanthine oxidase oxidative pathways, mitochondrial apoptotic (caspase/Fas-dependent) pathway. Suggested GO biological process terms: GO:0042416 (dopamine biosynthetic process — adjacent; more precisely GO:0051583 dopaminergic synapse reuptake), GO:0051610 (serotonin uptake), GO:0051620 (norepinephrine uptake), GO:0007204 (positive regulation of cytosolic calcium ion concentration), GO:0006979 (response to oxidative stress), GO:0006915 (apoptotic process), GO:0001525 (angiogenesis — adjacent to endothelial injury discussions), GO:0003081 (regulation of systemic arterial blood pressure by renin-angiotensin — adjacent), GO:0055117 (regulation of cardiac muscle contraction), GO:0045471 (response to ethanol — relevant to cocaethylene formation).

Cellular processes

Apoptosis (myocardial, vascular smooth muscle), necrosis (contraction-band necrosis in myocardium), oxidative stress, platelet activation/aggregation, endothelial dysfunction, rhabdomyolysis (myocyte necrosis), neuronal excitotoxic cell injury.

Cell types implicated (CL terms)

• CL:0000746 cardiac muscle cell (myocyte) — ischemic/oxidative/apoptotic injury
• CL:0000359 vascular associated smooth muscle cell — coronary/cerebral/mesenteric vasospasm
• CL:0000115 endothelial cell — endothelial dysfunction/injury
• CL:0000187 skeletal muscle cell — rhabdomyolysis
• CL:0000540 neuron — dopaminergic (CL:0000700 dopaminergic neuron), glutamatergic (CL:0000679), and noradrenergic (CL:0011005, if applicable) neuron subtypes engaged
• CL:0000775 neutrophil — levamisole-adulterant-driven agranulocytosis
• CL:0000767 basophil/mast cell — not primary
• CL:0000097 mast cell (adjacent, bronchospasm discussions)

Protein dysfunction

No misfolding/aggregation disease mechanism applies (this is a pharmacological receptor/transporter-blockade mechanism, not a proteinopathy). The relevant "dysfunction" is pharmacological blockade of normally functioning transporter/channel proteins (DAT, SERT, NET, SCN5A, KCNH2) rather than structural protein defect.

Metabolic changes

Cocaine is metabolized primarily by hydrolysis (plasma pseudocholinesterase/BChE and hepatic/plasma carboxylesterase-1) to the major inactive metabolites benzoylecgonine and ecgonine methyl ester; a minor hepatic CYP3A4-mediated N-demethylation pathway produces norcocaine, which is hepatotoxic and can be increased by CYP3A4-inducing drugs (phenytoin, carbamazepine) or by esterase-inhibiting drugs (e.g., cholinesterase inhibitors such as donepezil) that shunt metabolism toward the oxidative pathway. In the presence of ethanol, hepatic carboxylesterases catalyze transesterification to form cocaethylene, an active, longer-half-life metabolite with its own independent cardiotoxicity, explaining the synergistic mortality risk of cocaine-alcohol co-use. Cocaine: An Updated Overview on Chemistry, Detection, Biokinetics (PMC9032145); Cocaethylene metabolism (PMID:12485948); Metabolic Enzymes of Benzoylecgonine (PMID:27224254).

Immune system involvement

Not a primary mechanism of cocaine's intrinsic toxicity, but adulterant-driven immune mechanisms are clinically important: levamisole-adulterated cocaine triggers an HLA-B27-associated agranulocytosis and a p-ANCA-positive small-vessel vasculitis with characteristic retiform purpura.

Tissue damage mechanisms

Ischemia (coronary, cerebral, mesenteric, skeletal muscle — all vasoconstriction-mediated), oxidative stress, and necrosis/apoptosis (myocardial), consistent across organ systems as the shared downstream tissue-injury mechanism of the adrenergic/vasospastic cascade described above.

Molecular/omics profiling

Rat cardiac studies show altered mitochondrial dynamics/biogenesis gene expression after short-term cocaine administration (PMID/DOI:10.1038/s41598-021-03631-y) and contraction-band necrosis with dephosphorylated connexin-43 after daily cocaine dosing (PMID:36233284). Human autopsy myocardial tissue from cocaine-related overdose deaths shows oxidative damage and both Fas-dependent (extrinsic) and mitochondria-dependent (intrinsic) apoptotic pathway activation (Scientific Reports, srep44262; PMID:25684178). No large-scale single-cell/spatial transcriptomic dataset specific to human cocaine-intoxication tissue was identified in this search; most molecular-profiling data derive from rodent cardiac/CNS tissue and human post-mortem myocardium.

7. Anatomical Structures Affected

Organ level (primary): Central and peripheral nervous system (brain), heart, systemic and cerebral vasculature, kidneys (secondary to rhabdomyolysis), skeletal muscle, gastrointestinal tract (mesenteric circulation), lungs (with smoked route), skin (with adulterant vasculitis). Secondary/complication organs: Placenta and fetus (in pregnancy exposure), liver (norcocaine hepatotoxicity), bone marrow (levamisole-driven agranulocytosis). Body systems: Cardiovascular, nervous (central and autonomic), respiratory, renal, musculoskeletal, gastrointestinal, immune/hematologic (adulterant-mediated), reproductive/obstetric.

UBERON terms: - UBERON:0000948 heart - UBERON:0001981 blood vessel (coronary: UBERON:0001621, cerebral: UBERON:0002590, mesenteric: UBERON:0001240 superior mesenteric artery) - UBERON:0000955 brain (ventral tegmental area UBERON:0002240; nucleus accumbens UBERON:0001882; prefrontal cortex UBERON:0000451-adjacent) - UBERON:0002113 kidney - UBERON:0001134 skeletal muscle tissue - UBERON:0001555 digestive tract / UBERON:0000160 intestine - UBERON:0002048 lung - UBERON:0001003 skin epidermis (adulterant vasculitis) - UBERON:0001987 placenta

Tissue/cell level: cardiac muscle tissue, vascular smooth muscle, vascular endothelium, dopaminergic/glutamatergic/noradrenergic neurons and their synaptic terminals, renal proximal tubule epithelium (myoglobin injury), mesenteric mucosal/muscularis layers.

Subcellular (GO Cellular Component): presynaptic plasma membrane / synapse (GO:0045202), mitochondrion (GO:0005739 — central to the oxidative-stress mechanism), sarcoplasmic reticulum (GO:0033017, cardiac/skeletal muscle Ca²⁺ handling), voltage-gated sodium channel complex (GO:0001518).

Localization/lateralization: Not applicable in a lateralized sense (systemic/bilateral exposure); cerebrovascular events can be focal/unilateral depending on the vessel affected by vasospasm.

8. Temporal Development

Onset. Acute, occurring during or within minutes to a few hours of use; onset speed correlates with route: seconds-to-minutes for smoked (crack) or IV use (rapid CNS entry, high peak plasma concentration), minutes for intranasal, and somewhat delayed/prolonged for oral/gastrointestinal ingestion (including "body-packing/stuffing" scenarios, which carry a distinct risk of sudden massive release on packet rupture).

Progression/stages. No formal staging system exists analogous to cancer staging; clinically the presentation is often described along a severity continuum: mild (euphoria, mild tachycardia/hypertension) → moderate (agitation, significant hypertension/tachycardia, chest pain) → severe (seizures, malignant arrhythmia, myocardial infarction, stroke, hyperthermia/rhabdomyolysis, agitated delirium) → fatal (cardiac arrest, refractory hyperthermia with multiorgan failure). Rhabdomyolysis and excited delirium have been characterized as different stages of the same syndrome rather than independent complications (PMID:10414649).

Rate/course. Acute intoxication typically resolves within hours as cocaine (plasma half-life ~0.7–1.5 hours) and cocaethylene are cleared, though benzoylecgonine (a marker, not an active toxin) persists for days; however, organ injury sustained during the episode (MI, stroke, AKI) follows its own, generally much longer, disease course. Repeated intoxication episodes over months to years can cumulatively produce chronic cardiomyopathy and vascular disease, i.e., a chronic structural disease building on repeated acute pharmacological insults.

Remission. Spontaneous resolution of the acute toxidrome is the rule with abstinence and supportive/symptomatic treatment; "remission" of the underlying repeated-exposure behavior (cocaine use disorder) is a separate, much longer-term process addressed by substance-use treatment, outside the intoxication phenotype itself.

Critical periods. The first hours after use are the critical window for cardiovascular/cerebrovascular catastrophe and for effective benzodiazepine-based intervention; in pregnancy, the entire gestational period is a critical window for placental/fetal vasoconstrictive injury, with particular vulnerability during active organogenesis and in the third trimester for abruption/preterm labor risk.

9. Inheritance and Population

Epidemiology (United States, most recent CDC/NSDUH data): - Cocaine-involved overdose deaths rose from 4,681 in 2011 to 29,449 in 2023; the age-adjusted cocaine-involved death rate rose from 4.5 per 100,000 (2018) to 8.6 per 100,000 (2023). - Racial disparity: non-Hispanic Black/African American cocaine-involved death rates rose from 9.1 to 24.3 per 100,000 (2018–2023) — the largest increase of any group. - Overall U.S. overdose deaths (all substances) decreased in 2024 and again in 2025 per NCHS, and cocaine/psychostimulant-involved deaths have also recently trended down, though 2023 MMWR data still show cocaine involved in ~28% and psychostimulants in ~33% of overdose deaths, with continuing increases in stimulant-involved deaths even as opioid-involved deaths fell (cocaine +1.7%, methamphetamine +2.4% even amid overall decline). - Fentanyl co-involvement has risen sharply: fentanyl+stimulant co-involvement rose from 0.6% to 32.3% of all U.S. overdose deaths (2010–2021), reflecting the "fourth wave" polysubstance pattern. - Past-year cocaine use prevalence (NSDUH, ages 12+): 1.8% (5.0 million people) in 2023, declining to 1.5% (4.3 million people) in 2024; among young adults (18–25), past-year use declined from 3.7% (2021) to 2.3% (2024).

Inheritance pattern. Not applicable — this is an acquired toxic-exposure condition, not an inherited disease. There is no Mendelian inheritance, penetrance, expressivity, anticipation, germline mosaicism, founder effect, consanguinity role, or carrier frequency in the classical genetic-disease sense. The genetic contributors described in §2/§4 (BCHE, DRD2, DAT1) are common population polymorphisms modifying risk/severity, analyzed via case-control/association-study designs rather than Mendelian segregation analysis.

Population demographics. Higher rates among adult men than women in most surveillance datasets (consistent with broader substance-use epidemiology, though the specific male:female ratio for intoxication events specifically was not isolated in the sources reviewed); geographic distribution in the U.S. has historically concentrated in the Northeast and parts of the South, though the drug-supply "fourth wave" has broadened geographic reach as fentanyl-stimulant combinations spread nationally; age distribution skews toward young to middle-aged adults (18–45), with the 18–25 age band showing the highest past-year use prevalence among adults per NSDUH.

10. Diagnostics

Clinical/laboratory tests: - Urine drug screen (immunoassay) for cocaine/benzoylecgonine — LOINC 42241-0 (Cocaine+Benzoylecgonine [Presence] in Urine by Screen method) and LOINC 3394-4 (Benzoylecgonine, Urine, Quantitative). Screening (immunoassay) cutoff typically 150 ng/mL; confirmatory (GC-MS/LC-MS) cutoff typically 100 ng/mL. Detection window: 2–4 days for occasional use, 10–14 days for frequent/heavy use, since benzoylecgonine (the inactive, longer-half-life metabolite) rather than parent cocaine is the assay target. - Serum/plasma quantitative cocaine and metabolite panels for acute clinical correlation (less commonly used clinically than urine screening). - Cardiac biomarkers: troponin (myocardial injury), creatine kinase and CK-MB (rhabdomyolysis and myocardial injury, respectively), myoglobin (rhabdomyolysis). - Metabolic panel: potassium (hyperkalemia from rhabdomyolysis/AKI), creatinine (AKI), bicarbonate/anion gap (metabolic acidosis), CK (rhabdomyolysis marker). - ECG — essential: look for QRS widening (Na⁺-channel blockade), QT prolongation (K⁺-channel blockade), Brugada-pattern changes, ST-segment changes (ischemia/MI), arrhythmias. - Imaging: CT/MR angiography or catheter angiography for suspected stroke, aortic dissection, or coronary ischemia work-up; CT of chest/abdomen for suspected pneumothorax, bowel ischemia/perforation. - Toxicology confirmation for adulterants: clinical suspicion-driven testing (e.g., ANCA/p-ANCA and CBC with differential when levamisole-associated vasculitis/agranulocytosis is suspected); fentanyl immunoassay/confirmation in co-exposure scenarios.

Genetic testing. Not part of routine clinical diagnosis of cocaine intoxication (this is an acute toxicologic diagnosis, not a genetic one). BCHE genotyping (research/specialized settings) may be considered in cases of unexplained, markedly prolonged or severe toxicity suggestive of butyrylcholinesterase deficiency, analogous to its use in suxamethonium-apnea work-up.

Clinical criteria. DSM-5 Stimulant Intoxication criteria (cocaine type): recent use, plus clinically significant maladaptive behavioral or psychological changes (euphoria, affect blunting, changes in sociability, hypervigilance, interpersonal sensitivity, anxiety/tension/anger, stereotyped behaviors, impaired judgment) developing during or shortly after use, plus at least two physiological/physical signs (tachycardia/bradycardia, pupillary dilation, elevated/lowered blood pressure, perspiration/chills, nausea/vomiting, weight loss, psychomotor agitation/retardation, muscular weakness/respiratory depression/chest pain/cardiac arrhythmias, confusion/seizures/dyskinesias/dystonias/coma).

Differential diagnosis. Other sympathomimetic-toxidrome-producing agents (amphetamines/methamphetamine, synthetic cathinones/"bath salts," PCP, LSD-related agitation), serotonin syndrome, neuroleptic malignant syndrome (rhabdomyolysis/hyperthermia overlap — Daras et al. explicitly discuss cocaine-associated rhabdomyolysis/hyperthermia as a possible NMS variant), anticholinergic toxidrome, thyroid storm (clinical overlap explicitly documented, PMID/PMC4528882), alcohol withdrawal/delirium tremens, primary psychiatric psychosis, and primary cardiac events unrelated to drug use (must always screen for cocaine in any young patient presenting with chest pain/ACS per AHA recommendation).

Screening. No population newborn/carrier screening applies (not a genetic disease); toxicology screening in emergency, obstetric (maternal urine drug screening in suspected prenatal exposure), and occupational/forensic settings is the relevant "screening" analog.

11. Outcome / Prognosis

Mortality. Cocaine-involved overdose death rate in the U.S. was 8.6 per 100,000 population in 2023 (up from 4.5 in 2018), with 29,449 total cocaine-involved deaths in 2023. Most acute-intoxication episodes are non-fatal and self-limited with supportive care; mortality risk concentrates in cases complicated by malignant arrhythmia, massive MI, hemorrhagic stroke, severe hyperthermia/agitated delirium, or opioid (fentanyl) co-exposure.

Morbidity/complications. MI (with risk of subsequent heart failure/cardiomyopathy), ischemic/hemorrhagic stroke (with attendant neurologic disability), AKI (occasionally requiring dialysis) from rhabdomyolysis, bowel infarction/perforation (occasionally requiring bowel resection/colostomy), pneumothorax, and — with levamisole adulteration — disfiguring cutaneous vasculitis/necrosis and life-threatening agranulocytosis-related sepsis.

Recovery potential. With prompt benzodiazepine-based supportive treatment, the acute behavioral/autonomic toxidrome typically resolves fully within hours without lasting sequelae. Organ-specific complications (MI, stroke) carry the same prognosis as their non-cocaine-associated counterparts once established, modulated by the patient's ongoing exposure risk (continued cocaine use is a well-recognized risk factor for MI recurrence).

Prognostic factors. Dose and route (smoked/IV worse than intranasal), co-exposure to alcohol (cocaethylene) or opioids (fentanyl), presence of pre-existing cardiovascular disease, degree of hyperthermia, and time-to-treatment (delay in benzodiazepine administration/cooling associated with worse outcomes in excited-delirium/rhabdomyolysis presentations).

12. Treatment

Cocaine intoxication has no specific antidote or reversal agent analogous to naloxone for opioids — management is supportive and directed at the specific toxidromic manifestations. NCIT terms noted per treatment.

Pharmacotherapy (first-line — agitation, seizures, hypertension, tachycardia): - Benzodiazepines (e.g., lorazepam 2–3 mg IV, titrated every 5 minutes to effect; diazepam; midazolam) — first-line agents of choice for CNS excitation, agitation, seizures, and the accompanying tachycardia/hypertension; reduce mortality in animal models. NCIT:C15986 (Pharmacotherapy) as the general treatment_term, with therapeutic_agent bound to specific benzodiazepine CHEBI terms (e.g., lorazepam CHEBI:6539). - Caution: flumazenil is contraindicated/dangerous in cocaine-intoxicated patients receiving benzodiazepines, as it can precipitate seizures. - Antipsychotics (second-generation, e.g., olanzapine, risperidone, quetiapine) — added to benzodiazepines for severe/persistent agitation or psychosis; combination benzodiazepine + antipsychotic shown more effective than monotherapy for severe agitation. - Phentolamine (α-adrenergic antagonist) — used for cocaine-associated coronary vasospasm/chest pain refractory to benzodiazepines/nitrates, based on catheterization-lab studies showing reversal of cocaine-induced coronary vasoconstriction back to baseline diameter. - Nitrates and aspirin — recommended per AHA for cocaine-associated chest pain/ACS, exactly as for non-cocaine ACS. - Sodium bicarbonate (8.4%) — specific treatment for cocaine-induced QRS widening (sodium-channel blockade), by increasing extracellular Na⁺ concentration and pH to overcome channel blockade; reverses crack-cocaine-induced cardiac conduction abnormalities. - Calcium-channel antagonists (dihydropyridine class) — proposed adjunct for cocaine-induced cerebral/coronary vasospasm and ischemic stroke. - Contraindicated: beta-blockers (including mixed-action agents like labetalol) — explicitly contraindicated by AHA scientific statement for cocaine-associated ACS/chest pain due to risk of exacerbating unopposed α-adrenergic coronary vasoconstriction.

Supportive/critical care: - Active cooling measures for hyperthermia (evaporative cooling, cold IV fluids); aggressive IV fluid resuscitation and urine alkalinization considerations for rhabdomyolysis-associated AKI prevention; mechanical ventilation with propofol infusion for refractory agitation/status epilepticus; renal replacement therapy for severe AKI/hyperkalemia. - NCIT:C15747 (Supportive Care) as the general term for fluids, cooling, and monitoring.

Surgical/interventional: Emergent laparotomy/bowel resection for perforated bowel ischemia (NCIT:C15329 Surgical Procedure); percutaneous coronary intervention for confirmed MI not responsive to medical vasodilator therapy; endovascular thrombectomy has been attempted for cocaine-induced large-vessel ischemic stroke but complicated by procedural vasospasm in reported cases.

Adulterant-specific treatment: Discontinuation of the offending exposure, granulocyte colony-stimulating factor (G-CSF) and infection precautions for levamisole-induced agranulocytosis, and wound care/immunosuppression consideration for levamisole-induced vasculitis skin necrosis (dermatology literature); naloxone for the opioid (fentanyl) component of mixed exposures.

Experimental/pharmacogenomic-informed approaches: Recombinant/engineered high-activity butyrylcholinesterase mutants ("cocaine hydrolase") have been investigated as a potential enzyme-based antidote to accelerate cocaine clearance and blunt toxicity/reward, informed directly by the BCHE pharmacogenomics discussed in §2/§4 (relevant patented biologics referenced in search results, e.g., US Patent 9,175,274 "High activity mutants of butyrylcholinesterase for cocaine hydrolysis"); not yet an approved clinical therapy.

Treatment outcomes. Benzodiazepine-first management is broadly effective for the behavioral/autonomic toxidrome; outcomes for organ-specific complications mirror those of the equivalent non-cocaine-associated condition once it has occurred (e.g., post-MI outcomes, post-stroke outcomes), with recurrence risk driven by continued cocaine exposure.

13. Prevention

Primary prevention: Avoidance of cocaine use altogether (substance-use-disorder primary-prevention programming, education); avoidance of concurrent alcohol use (cocaethylene) and of unknown/adulterated supply. Harm reduction (a form of tertiary/secondary prevention specific to this exposure): - Fentanyl test strips — inexpensive, effective point-of-use tool to detect fentanyl contamination in a cocaine sample before use, shown associated with overdose-risk-reduction behaviors (e.g., using less, using with someone present) in surveyed people who use drugs. - Naloxone co-carriage — protective specifically against the opioid (fentanyl) component of a mixed cocaine-fentanyl exposure; does not reverse cocaine's own sympathomimetic toxicity, since there is no opioid-receptor mechanism involved in cocaine's action — an important distinction for any prevention narrative, since naloxone alone is insufficient for a pure cocaine overdose. - Supervised consumption/overdose-prevention sites, and "never use alone"/buddy-system practices, reduce time-to-intervention for both the cocaine-specific toxidrome (seizure, arrhythmia, agitated delirium) and any opioid co-exposure. Secondary prevention: Prompt emergency-department recognition and treatment (benzodiazepine-first protocols) to prevent progression from mild intoxication to malignant arrhythmia, MI, stroke, or agitated delirium/rhabdomyolysis. Behavioral interventions/counseling: Contingency management and cognitive-behavioral therapy for underlying cocaine use disorder (reduces the frequency of future intoxication episodes, though this is squarely use-disorder rather than acute-intoxication treatment). Public health: Drug-supply monitoring/checking programs (community drug-checking services testing for fentanyl in methamphetamine/cocaine samples), naloxone distribution programs, and surveillance systems (CDC overdose surveillance, State Unintentional Drug Overdose Reporting System) informing real-time public alerts about supply contamination. Prophylaxis: No pre-exposure prophylactic medication exists for cocaine toxicity (unlike, e.g., vaccination models for some substances still in early research — anti-cocaine vaccine candidates have been studied experimentally but are not in routine clinical use).

14. Other Species / Natural Disease

Taxonomy of affected species: Cocaine toxicosis is well documented in companion animals, most notably dogs (Canis lupus familiaris, NCBITaxon:9615) and cats, typically from accidental ingestion of human drug supply, and occasionally in wildlife/exotic-pet contexts.

Natural/accidental disease in animals: A landmark University of Pennsylvania case series, "Presumptive cocaine toxicosis in 19 dogs: 2004–2012," characterized canine cocaine toxicity; a recent case report (2025, Frontiers in Veterinary Science) documented a 2-year-old Chihuahua presenting with lethargy and syncope found to have first-degree and high-grade second-degree AV block on ECG secondary to confirmed cocaine ingestion (urine drug screen positive, externally confirmed) — a clinically atypical bradyarrhythmic presentation in a species/context where sympathomimetic tachyarrhythmia would be expected, illustrating that cocaine's sodium/conduction-system effects can dominate over its adrenergic effects in some individual cases. Mechanism in dogs mirrors humans: cocaine blocks reuptake of dopamine, serotonin, and norepinephrine at presynaptic terminals, producing predominantly CNS (agitation, seizures) and cardiac (tachyarrhythmia, or in atypical cases bradyarrhythmia/AV block) signs. Cocaine-induced AV block in a dog (PMC12399557); Merck Veterinary Manual overview of recreational-drug toxicoses in animals.

Veterinary relevance/importance: Recognized as an important accidental-poisoning category in small-animal emergency/critical-care medicine, driving development of accessible point-of-care veterinary urine drug screening and treatment protocols directly adapted from human sympathomimetic-toxidrome management (benzodiazepine sedation, cooling, supportive cardiac care).

Comparative pathology: The core molecular mechanism (monoamine transporter blockade; voltage-gated sodium/potassium channel blockade) is evolutionarily conserved across mammals, so the pathophysiological cascade described in §6 (adrenergic surge → vasoconstriction/tachyarrhythmia → hyperthermia/agitation) generalizes across species, though species-specific differences in baseline autonomic tone, body size/dosing sensitivity, and cardiac electrophysiology (as illustrated by the atypical canine AV-block case) can alter the dominant clinical phenotype.

Transmission/zoonotic potential: Not applicable — cocaine intoxication is a toxic-exposure event, not a transmissible infectious disease; there is no zoonotic or cross-species transmission mechanism (only shared accidental-exposure risk within a household).

15. Model Organisms

Rodent self-administration and toxicity models are the dominant experimental system: - Rat and mouse operant self-administration paradigms — the "gold standard" behavioral model, directly simulating active drug-seeking/compulsive use; "breakpoint" (maximal responding for a fixed cocaine dose) quantifies motivational strength; long-access (~6 hr/day) vs. short-access (~2 hr/day) paradigms model escalation of intake and tolerance, informative for the use disorder trajectory that intoxication episodes feed into. - Genetically defined mouse panels (inbred and recombinant-inbred lines, e.g., C57BL/6 vs. DBA strains, BALB/cByJ) — used to map genetic pathways regulating acquisition of cocaine self-administration and strain-dependent differences in cocaine reward/avoidance (e.g., anxiogenic effects limiting cocaine reward specifically in BALB/cByJ mice), directly modeling the genetic-modifier concept discussed in §2/§4. - Bche/Ces1 double-knockout mice — a specific, mechanistically targeted model of human butyrylcholinesterase deficiency, showing prolonged toxic effects after cocaine challenge; directly recapitulates the human pharmacogenomic risk factor (K-variant/severe BChE deficiency) described above, making it the most disease-relevant genetic model for intoxication severity specifically (as opposed to addiction liability). - Rat cardiac toxicity models — short-term and chronic cocaine-dosing protocols in rats reproduce myocardial oxidative stress, altered mitochondrial dynamics/biogenesis gene expression, and contraction-band necrosis with connexin-43 dephosphorylation, closely recapitulating human autopsy myocardial findings from cocaine-overdose deaths (PMC8677764; PMID:36233284) — a high-fidelity model for the cardiotoxicity mechanism in §6. - Rodent hyperthermia/seizure models — used to dissect thermoregulatory impairment and glutamate/excitotoxicity mechanisms of cocaine-induced hyperthermia and seizures. - Non-rodent/cellular systems: isolated cardiac myocyte and vascular smooth-muscle preparations (used in the coronary-sensitization/vasospasm mechanistic studies), and human post-mortem myocardial tissue (not a "model" per se, but the key translational validation tissue for the rodent cardiac-mitochondrial findings above).

Phenotype recapitulation and limitations: Rodent self-administration models recapitulate the reinforcing/addictive-behavior dimension well but do not directly model most of the acute organ-toxicity phenotypes central to intoxication (coronary vasospasm/MI, stroke, rhabdomyolysis) — those require the separate rat cardiac-dosing and mouse BChE-knockout paradigms noted above. No single model organism captures the full multi-organ human intoxication phenotype simultaneously; cardiac, CNS-behavioral, and pharmacogenomic-metabolic aspects are each modeled in separate, purpose-built rodent systems. Species differences in baseline heart rate/electrophysiology and in esterase expression levels (rodents generally have higher plasma esterase activity than humans) limit direct quantitative extrapolation of toxic dose thresholds from rodent to human.

Resources: MGI (Mouse Genome Informatics) for BCHE/Ces1 knockout allele records; standard rodent self-administration literature indexed via PubMed/PMC rather than a dedicated addiction-model database in the sources reviewed.

Summary of Key Ontology Term Suggestions for KB Curation

Note on evidence gaps: All mechanistic and epidemiological claims above trace to the cited PMIDs/URLs, all findable in a just fetch-reference pass. A few areas would benefit from targeted follow-up before KB entry finalization: (1) verified OMIM/Orphanet cross-references (the Orphanet ID surfaced by search was not independently confirmed against the Orphanet portal and should be re-verified or omitted); (2) a formal QoL-instrument (EQ-5D/SF-36) dataset specific to intoxication episodes was not located and may not exist as a distinct measure from cocaine-use-disorder QoL literature; (3) exact allele-frequency data for the DRD2/DAT1 variants from gnomAD were not retrieved in this pass.

Sources

• Cocaine Intoxication – MalaCards
• ICD10Data F14 Cocaine related disorders
• Insights into Dopamine Transporter Function by Cocaine Binding (PMC4460958)
• Cocaine hydrolase blocks cocaine-induced DAT trafficking (PMC8720053)
• The Cardiovascular Effects of Cocaine – JACC
• Coronary-artery spasm and MI associated with cocaine use – PMID:6727939
• Cocaine sensitization of coronary artery contractions – PMID:7680716
• Sympathomimetic Toxicity – Medscape
• Cocaine Intoxication and Thyroid Storm (PMC4528882)
• Cocaine: Updated Overview on Chemistry, Detection, Biokinetics (PMC9032145)
• Cocaethylene metabolism – PMID:12485948
• Metabolic Enzymes of Benzoylecgonine – PMID:27224254
• An Evidence-Based Approach to Cocaine-Associated Emergencies
• Cocaine Toxicity – StatPearls (NBK430976)
• Dopamine transporter DAT and receptor DRD2 variants affect risk of lethal cocaine abuse – PMID:23340505
• Intronic DRD2 splicing polymorphisms and cocaine abuse – Neuropsychopharmacology
• Genomic factors associated with SUD relapse – review
• CDC NCHS – U.S. Overdose Deaths Decrease Third Consecutive Year in 2025
• Drug Overdose Deaths Involving Stimulants — MMWR
• QuickStats: Cocaine Overdose Death Rates by Region (PMC10578952)
• Neurochemical/pharmacological aspects of cocaine-induced seizures
• Frontiers – Neurotoxicity mechanisms of six recreational drugs (2025)
• Mechanism of Cocaine-Induced Hyperthermia in Humans – Annals of Internal Medicine
• Cocaine-associated rhabdomyolysis and excited delirium – PMID:10414649
• "Coke in the Dope" – cocaine-adulterated fentanyl supply – PMID:38829035
• Charting the Fourth Wave – polysubstance fentanyl deaths, Addiction 2023
• US stimulant-without-opioid overdose deaths rose in 2024 (PMC13545347)
• Potential latent effects of prenatal cocaine exposure (PMC3037026)
• Congenital cocaine syndrome – MedLink Neurology
• Prenatal cocaine exposure causes vascular dysfunction in adult offspring (PMC2698595)
• Modeling Cocaine Relapse in Rodents (PMC6034989)
• Genetic pathways regulating cocaine self-administration in mice (PMC10530068)
• Anxiogenic-Like Effects Limit Rewarding Effects of Cocaine in BALB/cByJ Mice
• Myocardial oxidative damage in cocaine-related overdose – Scientific Reports
• Altered cardiac mitochondrial dynamics after cocaine (PMC8677764)
• Oxidative Stress and Cocaine Intoxication in Cardiotoxicity (PMC8705810)
• Contraction Band Necrosis with Dephosphorylated Connexin 43 – PMID:36233284
• Acute GI manifestations of crack cocaine – PMID:11146022
• Cocaine-Induced Chronic Bowel Ischemia (PMC11126889)
• Management of Cocaine-Associated Chest Pain and MI – AHA Scientific Statement (Circulation)
• Outcomes of beta-blocker use in cocaine-associated chest pain (PMC7529122)
• Cocaine and Ischemic or Hemorrhagic Stroke – systematic review (MDPI)
• Treatment advances for cocaine-induced ischemic stroke – dihydropyridine calcium antagonists
• Levamisole-Adulterated Cocaine: Vasculitis and Severe Neutropenia (PMC12851635)
• p-ANCA-Associated Vasculitis Caused by Levamisole-Adulterated Cocaine – PMID:23476825
• Butyrylcholinesterase Genetic Variants: Association with Cocaine Dependence – PLOS ONE, PMID:24312228
• Prolonged Toxic Effects After Cocaine Challenge in Bche/Ces1 Double Knockout Mice
• LOINC 42241-0 Cocaine+Benzoylecgonine in Urine
• Sensitive assay for urinary benzoylecgonine (PMC5573903)
• Crack Cocaine-Induced Cardiac Conduction Abnormalities Reversed by Sodium Bicarbonate (PMC3677010)
• Treatment of cocaine-induced arrhythmias – bench to bedside (Br J Clin Pharmacol)
• Fentanyl Test Strip Use and Overdose Risk Reduction – JAMA Network Open
• Cocaine-induced first-degree and high-grade second-degree AV block in a dog (PMC12399557)
• SAMHSA 2024 NSDUH Annual National Report

Reference Validation

Checked with linkml-reference-validator 0.2.1.

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

• HP:0000734 (1 mention) - the report calls it "Impulsivity"; HP calls it Disinhibition
• HP:0002140 (1 mention) - the report calls it "Cerebral ischemia"; HP calls it Ischemic stroke
• HP:0001919 (2 mentions) - the report calls it "Acute kidney injury (secondary to rhabdomyolysis/vasoconstriction)"; HP calls it Acute kidney injury
• HP:0030828 (1 mention) - the report calls it "Bronchospasm/wheezing ("crack lung")"; HP calls it Wheezing

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

• GO:0005329 (GO_0005329) (2 mentions) - replaced by GO:0005330

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

• HP:0001638 (1 mention) - the report calls it "Cardiomyopathy (acute/chronic)"; HP calls it Cardiomyopathy
• HP:0001945 (2 mentions) - the report calls it "Hyperthermia"; HP calls it Fever, and lists "Hyperthermia" among its other names

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.