Cocaine Intoxication

Toxic Exposure Disorder MONDO:0019544 Pathograph 48 Show in embeddings browser Toxic Exposure Disorder

Acute systemic toxicity following cocaine exposure. Cocaine is pharmacologically two drugs in one molecule, and acute intoxication is what happens when both act at once. It is a monoamine reuptake inhibitor, blocking the dopamine, noradrenaline and serotonin transporters and flooding synapses with catecholamines; and it is a local anaesthetic, blocking the cardiac fast sodium channel in the same way a class I antiarrhythmic does. That combination is what distinguishes it from the stimulants and the local anaesthetics the KB curates alongside it. The two arms collide in the heart: sympathetic drive raises myocardial oxygen demand while alpha-adrenergic coronary vasoconstriction and platelet activation cut supply, and the channel arm independently slows conduction and delays repolarisation, so the ischaemic myocardium is also electrically unstable. Outside the heart the catecholamine arm produces agitation, seizures, hyperthermia through impaired heat dissipation, rhabdomyolysis, and cerebral and aortic vascular injury.

Ask OpenScientist

Ask a research question about Cocaine Intoxication. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

21
Pathophys.
18
Phenotypes
1
Hypotheses
3
Gaps
48
Pathograph
2
Genes
6
Medical Actions
3
References
1
Deep Research
◈

Mechanistic Hypotheses

1
Beta blockade worsens cocaine cardiotoxicity through unopposed alpha stimulation
unopposed_alpha_stimulation ALTERNATIVE
The proposition that giving a beta blocker during cocaine intoxication removes beta-mediated vasodilation and leaves alpha-mediated coronary vasoconstriction unopposed, worsening ischaemia. It is recorded as a hypothesis rather than as fact because the mechanistic and the outcome evidence point different ways and both are good. For: intracoronary propranolol given after cocaine in a randomised, double-blind, placebo-controlled catheterisation study further reduced coronary sinus blood flow and further raised coronary vascular resistance, in humans, measured directly (PMID:1971166). The effect is real and it is not small. Against: a meta-analysis of five studies and 1794 patients with cocaine-associated chest pain found no significant difference in non-fatal myocardial infarction or all-cause mortality between those who received a beta blocker and those who did not (PMID:29921621). These are not actually contradictory. One measures a physiological variable minutes after an intracoronary drug in a catheterisation laboratory; the other measures clinical outcomes in patients who mostly received oral beta blockers hours later. The open question is whether the measured haemodynamic effect is large enough, and sustained enough, to change outcomes. Note the outcome studies are all retrospective and none is randomised, which the meta-analysis itself lists first among its limitations.
Resolving this needs a randomised trial of beta blockade in cocaine-associated chest pain, which does not exist; the meta-analysis states it found none meeting its criteria.
?

Discussions and Knowledge Gaps

3
Does the haemodynamic potentiation of cocaine-induced coronary vasoconstriction by beta blockade translate into worse clinical outcomes?
KNOWLEDGE GAP cocaine_beta_blocker_outcome_gap
Attached to
treatments#Beta-Adrenergic Blockade pathophysiology#Alpha-Adrenergic Coronary Vasoconstriction
The mechanism has been measured directly in humans and the outcome studies find no difference, but every outcome study is retrospective and the meta-analysis found no randomised trial meeting its criteria. Until one exists the contraindication rests on a physiological endpoint and the permission rests on observational data, which is why guidelines and practice have diverged.
What is the molecular mechanism of cocaine-induced seizures, and does it differ from the mechanism of cocaine-induced hyperthermia?
KNOWLEDGE GAP cocaine_seizure_mechanism_gap
Attached to
pathophysiology#Central Neuronal Hyperexcitability
The cited source states plainly that the aetiology of cocaine-associated seizures is unclear, which is why the edge into this node is typed INDIRECT_UNKNOWN_INTERMEDIATES and the node asserts no molecular claim. A GABAergic or glutamatergic account is routinely offered for stimulant seizures but nothing cited here demonstrates one at the concentrations reached in human intoxication.
Does butyrylcholinesterase activity modify the severity of acute cocaine toxicity in humans?
KNOWLEDGE GAP cocaine_bche_severity_gap
Attached to
pathophysiology#Systemic Cocaine Exposure
Plasma butyrylcholinesterase hydrolyses most of a cocaine dose, so variation in its activity is a plausible determinant of how much drug reaches its targets. This gap is specifically about BCHE: no source establishing a BCHE-severity link in human intoxication was found during this curation. It is not a claim that cocaine toxicity has no genetic modifiers - the genetic section curates a DAT-DRD2 interaction affecting risk of fatal intoxication (PMID:23340505), and PMID:24312228 on BCHE variants, which is cached here, is about dependence rather than acute toxicity.
⚙

Pathophysiology

21
Systemic Cocaine Exposure
Absorbed cocaine distributes systemically and reaches concentrations at which it engages two independent pharmacological targets simultaneously: the presynaptic monoamine transporters and the voltage-gated ion channels of the cardiac myocyte membrane. Every downstream branch of this entry originates here.
Downstream
Monoamine Transporter Blockade Cocaine binds the presynaptic monoamine transporters directly.
Cardiac Fast Sodium Channel Blockade The same molecule acts on the cardiac myocyte membrane as a local anaesthetic.
hERG Potassium Channel Blockade Cocaine blocks the hERG-encoded repolarising potassium current.
Monoamine Transporter Blockade
Cocaine occupies a binding site deep within the dopamine transporter that overlaps the site used by dopamine itself, competitively inhibiting reuptake; the noradrenaline and serotonin transporters are blocked in parallel. This is the sympathomimetic arm.
SLC6A3 hgnc:11049 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SLC6A3 (hgnc:11049). hgnc:11049 is a gene from the HUGO Gene Nomenclature Committee. SLC6A2 hgnc:11048 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SLC6A2 (hgnc:11048). hgnc:11048 is a gene from the HUGO Gene Nomenclature Committee. SLC6A4 hgnc:11050 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SLC6A4 (hgnc:11050). hgnc:11050 is a gene from the HUGO Gene Nomenclature Committee.
presynaptic dopamine reuptake GO:0051583 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased presynaptic dopamine reuptake, annotated with dopamine uptake involved in synaptic transmission (GO:0051583). GO:0051583 is a biological process from the Gene Ontology. ↓ DECREASED
dopamine transporter activity GO:0005330 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased dopamine transporter activity, annotated with dopamine:sodium symporter activity (GO:0005330). GO:0005330 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Synaptic Catecholamine Excess Blocking reuptake leaves released catecholamines in the synaptic cleft and at peripheral sympathetic junctions.
Show evidence (2 references)
PMID:18568020 SUPPORT Computational
"Our models suggest that the binding site for cocaine and cocaine analogs is deeply buried between transmembrane segments 1, 3, 6 and 8, and overlaps with the binding sites for the substrates dopamine and amphetamine"
Locates the cocaine site as overlapping the substrate site, which is what makes the inhibition competitive and dose-dependent.
PMID:10485970 SUPPORT BACKGROUND Human Clinical
"Recent studies using positron emission tomography (PET) have established the relationship between an intravenous dose of cocaine and the percentage occupancy of the dopamine transporter in humans, and have documented the requirement of more than 50% occupancy for perception of the "high""
Records that transporter occupancy by cocaine has been measured directly in humans and is dose-related. The quoted sentence is the citing paper's background statement of human PET work, not a result of its own mouse experiments, which is why quote_role is BACKGROUND while evidence_source grades the human studies it describes.
Synaptic Catecholamine Excess
With reuptake blocked, dopamine, noradrenaline and serotonin accumulate at central and peripheral synapses. This single node is the origin of every non-cardiac-channel manifestation in the entry: the cardiovascular, neurological, thermoregulatory, muscular and cerebrovascular branches all descend from it.
Downstream
Sympathetic Cardiovascular Stimulation
Alpha-Adrenergic Coronary Vasoconstriction Excess noradrenaline at vascular alpha-adrenergic receptors constricts the epicardial coronary arteries.
Platelet Activation
Central Nervous System Stimulation
Impaired Thermoregulatory Heat Dissipation
Cerebral Vasoconstriction and Vascular Injury
Sympathetic Cardiovascular Stimulation
Catecholamine excess at cardiac and vascular adrenergic receptors raises heart rate, contractility and arterial pressure. The rate-pressure product rises, and with it myocardial oxygen consumption.
Downstream
Tachycardia
Hypertension
Increased Myocardial Oxygen Demand
Acute Aortic Wall Stress
Show evidence (1 reference)
PMID:2573838 SUPPORT Human Clinical
"After cocaine was administered, the heart rate and arterial pressure rose"
Direct human measurement of the chronotropic and pressor response to a dose of cocaine at the low end of the range seen clinically.
Alpha-Adrenergic Coronary Vasoconstriction
Cocaine narrows the epicardial coronary arteries and raises coronary vascular resistance through alpha-adrenergic stimulation. The effect is reversed by phentolamine and abolished by nitroglycerin, and it is markedly greater in segments already narrowed by atherosclerosis.
smooth muscle cell of the coronary artery CL:0002592 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves smooth muscle cell of the coronary artery (CL:0002592). CL:0002592 is a cell type from the Cell Ontology.
coronary vasoconstriction GO:0042310 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased coronary vasoconstriction, annotated with vasoconstriction (GO:0042310). GO:0042310 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Reduced Myocardial Oxygen Supply
Show evidence (2 references)
PMID:2573838 SUPPORT Human Clinical
"the intranasal administration of cocaine near the dose used for topical anesthesia causes vasoconstriction of the coronary arteries, with a decrease in the coronary blood flow"
Quantitative arteriography and coronary sinus thermodilution in 29 patients given cocaine establish the vasoconstriction and the fall in flow.
PMID:1906905 SUPPORT Human Clinical
"The magnitude of vasoconstriction was greater (p = 0.01) in the diseased segments."
Shows the constriction is amplified where atherosclerosis is already present, which is why pre-existing coronary disease worsens the ischaemic consequence.
Platelet Activation
Cocaine activates platelets in vivo in humans, releasing alpha-granule contents and generating circulating platelet-containing microaggregates. The node is named for what was measured. Thrombus formation on a vasoconstricted segment is the plausible route from here to reduced flow, but the cited study states it only as a possibility, so the downstream edge is typed INDIRECT_UNKNOWN_INTERMEDIATES rather than DIRECT and no thrombus node is asserted.
platelet activation GO:0030168 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased platelet activation (GO:0030168). GO:0030168 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Reduced Myocardial Oxygen Supply Platelet activation is measured; thrombotic occlusion of a coronary segment is the unestablished intermediate.
Show evidence (2 references)
PMID:10814631 SUPPORT Human Clinical
"Cocaine exposure causes platelet activation, alpha granule release, and platelet containing microaggregate formation."
Randomised double-blind crossover study in 14 healthy volunteers, so the platelet effect is attributable to cocaine rather than to the clinical context of an ischaemic presentation.
PMID:10814631 SUPPORT Human Clinical
"cocaine, even at the relatively low doses commonly self administered by occasional abusers, may promote thrombosis and predispose healthy individuals to ischaemic events"
The authors' own statement of the dose range and the population at risk, which bounds how far this mechanism can be extrapolated.
Reduced Myocardial Oxygen Supply
Coronary flow falls. Both the vasoconstrictive and the thrombotic branch converge here.
Downstream
Myocardial Oxygen Supply-Demand Mismatch
Show evidence (1 reference)
PMID:2573838 SUPPORT Human Clinical
"the coronary-sinus blood flow fell"
Direct thermodilution measurement of the fall in coronary flow after cocaine.
Increased Myocardial Oxygen Demand
Tachycardia, hypertension and increased contractility raise myocardial oxygen consumption at the same moment supply is falling.
Downstream
Myocardial Oxygen Supply-Demand Mismatch
Myocardial Oxygen Supply-Demand Mismatch
The defining cardiac lesion of cocaine intoxication: demand rises while supply falls, in the same patient at the same time, from one drug. The risk is concentrated in the first hour after use, and in the cited catheterisation study the constriction occurred in patients with and without angiographic coronary disease alike.
cardiac myocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiac myocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
Downstream
Ventricular Arrhythmogenesis Ischaemic myocardium is arrhythmogenic.
Myocardial infarction
Chest pain
Show evidence (2 references)
PMID:10351966 SUPPORT Human Clinical
"The risk of myocardial infarction onset was elevated 23.7 times over baseline"
Case-crossover analysis within the Determinants of Myocardial Infarction Onset Study quantifying the transient excess risk in the hour after cocaine use.
PMID:10351966 SUPPORT Human Clinical
"Cocaine use is associated with a large abrupt and transient increase in the risk of acute myocardial infarction in patients who are otherwise at relatively low risk."
States both the magnitude and the transience, which is what distinguishes this mechanism from chronic atherosclerotic risk.
Cardiac Fast Sodium Channel Blockade
Cocaine blocks the cardiac fast sodium channel in the manner of a class I antiarrhythmic. This is its local-anaesthetic action applied to myocardium, and it is the arm that a purely sympathomimetic account of cocaine toxicity leaves out.
cardiac myocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiac myocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
SCN5A hgnc:10593 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SCN5A (hgnc:10593). hgnc:10593 is a gene from the HUGO Gene Nomenclature Committee.
cardiac fast sodium channel activity GO:0086006 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased cardiac fast sodium channel activity, annotated with voltage-gated sodium channel activity involved in cardiac muscle cell action potential (GO:0086006). GO:0086006 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Altered Cardiac Action Potential
Show evidence (1 reference)
PMID:14677787 SUPPORT BACKGROUND Human Clinical
"Cocaine toxicity causes myocardial depression, malignant dysrhythmias, and sudden death, partially due to cocaine-related myocardial sodium channel blockade."
The human cocaine-toxicity picture and its attribution to sodium-channel blockade, quoted from the first sentence of this paper's OBJECTIVE section. No dog measured this, so evidence_source grades the human observations the sentence describes and quote_role records that the citing paper is a canine study restating them.
hERG Potassium Channel Blockade
Cocaine also blocks the hERG-encoded rapid delayed-rectifier potassium channel, in the open state, at low micromolar concentrations. Cocaethylene, the metabolite formed when cocaine and ethanol are taken together, is a slightly more potent blocker than cocaine itself.
cardiac myocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiac myocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
KCNH2 hgnc:6251 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves KCNH2 (hgnc:6251). hgnc:6251 is a gene from the HUGO Gene Nomenclature Committee.
rapid delayed rectifier potassium channel activity GO:0005251 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased rapid delayed rectifier potassium channel activity, annotated with delayed rectifier potassium channel activity (GO:0005251). GO:0005251 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Altered Cardiac Action Potential
Show evidence (2 references)
PMID:11561083 SUPPORT In Vitro
"Blockade of HERG by cocaine, cocaethylene, and methylecgonidine increased significantly over the voltage range where HERG activates"
Characterises the block as open-channel and voltage-dependent in HEK293 cells stably expressing HERG.
PMID:11561083 SUPPORT BACKGROUND Human Clinical
"Cocaine abuse has been reported to result in QT prolongation in humans"
Records the human clinical observation the in-vitro work was undertaken to explain. The quoted sentence is the citing paper's opening statement of prior human findings, not a result of its own cell experiments, hence quote_role BACKGROUND.
Altered Cardiac Action Potential
Loss of fast inward sodium current slows phase 0 upstroke; loss of the rapid delayed rectifier prolongs phase 3. Both currents are perturbed by the same drug, so depolarisation and repolarisation are affected together.
cardiac myocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiac myocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
cardiac muscle cell action potential GO:0086001 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal cardiac muscle cell action potential (GO:0086001). GO:0086001 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Slowed Ventricular Conduction
Delayed Ventricular Repolarization
Show evidence (1 reference)
PMID:18815938 SUPPORT REVIEW SYNTHESIS Other
"Excessive catecholamines, combined with sodium and potassium channel blockades, give rise to a wide variety of supra-ventricular and ventricular rhythms."
States that sodium- and potassium-channel blockade together produce the arrhythmia spectrum, which is the claim this node carries as the convergence of both channel arms.
Slowed Ventricular Conduction
Reduced sodium current slows impulse propagation through the ventricular myocardium, widening the QRS complex. Because the QRS narrows promptly when extracellular sodium is raised and pH shifted with sodium bicarbonate, the widening is a reversible consequence of channel blockade rather than structural damage.
Downstream
Ventricular Arrhythmogenesis
Prolonged QRS complex
Show evidence (1 reference)
PMID:14677787 SUPPORT Model Organism
"Immediately after administering NaHCO3, QRS duration decreased by 30% (p < 0.001), returning to baseline more quickly than in the control group."
The reversal of QRS widening by sodium bicarbonate in cocaine-poisoned dogs is direct evidence that the widening reflects sodium-channel blockade.
Delayed Ventricular Repolarization
hERG blockade prolongs the action potential plateau and lengthens the QT interval, creating the substrate for afterdepolarisation-driven triggered activity.
Downstream
Ventricular Arrhythmogenesis
Prolonged QT interval
Show evidence (1 reference)
PMID:11561083 SUPPORT BACKGROUND Human Clinical
"Cocaine abuse has been reported to result in QT prolongation in humans"
QT prolongation is the clinical readout of delayed ventricular repolarisation, and this is the human observation of it. Quoted from the citing paper's background rather than from its cell experiments, hence quote_role BACKGROUND.
Ventricular Arrhythmogenesis
Three substrates converge: slowed conduction supporting reentry, delayed repolarisation supporting triggered activity, and ischaemic myocardium. Catecholamine excess is superimposed on all three, which is why the arrhythmia burden of cocaine cannot be attributed to any single one of its actions. This node deliberately declares no conforms_to. The obvious target, xenobiotic_cardiac_channel_perturbation#Xenobiotic-Induced Cardiac Arrhythmia, is excluded by that module's own scope note: "the xenobiotic must act on the channel itself. A drug that causes arrhythmia through electrolyte disturbance, ischaemia, or structural injury belongs elsewhere, even when the endpoint looks the same." This node is a mixed channel, ischaemia and catecholamine endpoint and takes an inbound edge from the supply-demand node, so conforming it would assert a channel attribution the entry itself contradicts. The three upstream nodes that do act on the channel carry the conformance instead.
Downstream
Ventricular tachycardia
Sudden cardiac death
Show evidence (1 reference)
PMID:18815938 SUPPORT REVIEW SYNTHESIS Other
"Excessive catecholamines, combined with sodium and potassium channel blockades, give rise to a wide variety of supra-ventricular and ventricular rhythms."
States the convergence of the catecholamine arm and both channel arms on the arrhythmia endpoint, which is exactly the structure this node encodes.
Central Nervous System Stimulation
Central monoamine excess produces the psychomotor arm of the toxidrome: agitation, hypervigilance, diaphoresis and, at higher exposures, disorientation.
dopaminergic neuron CL:0000700 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves dopaminergic neuron (CL:0000700). CL:0000700 is a cell type from the Cell Ontology.
Downstream
Central Neuronal Hyperexcitability The step from central stimulation to seizure is not established. Typed INDIRECT_UNKNOWN_INTERMEDIATES, which the schema defines as a relationship where at least one required intermediate mechanism is currently unknown. UNKNOWN would be wrong: that value means directness has not yet been assessed, whereas the cited source has been read and states the mechanism is unclear.
Agitation
Hyperhidrosis
Confusion
Show evidence (1 reference)
PMID:9725976 SUPPORT Human Clinical
"Other clinical findings included tachycardia, hypertension, diaphoresis, and disorientation."
Documents the sympathomimetic and central features occurring together in a patient with measured very high blood cocaine concentrations.
Central Neuronal Hyperexcitability
A state of lowered seizure threshold occurring at high cocaine concentrations. It is named as a node because seizures are a real and sometimes fatal feature, but no molecular mechanism is asserted here: the cited source describes generalized seizures at measured peak concentrations with a negative workup for structural causes, and states that the aetiology is unclear.
Downstream
Seizure
Show evidence (1 reference)
PMID:9725976 SUPPORT Human Clinical
"Approximately 1 hour after the ingestion incidents, the patient had multiple, generalized seizures that abated spontaneously. His workup for CNS bleeding, infection, and trauma was negative."
Establishes seizures temporally related to cocaine with structural causes excluded, supporting a drug-attributable lowering of seizure threshold without specifying one.
Impaired Thermoregulatory Heat Dissipation
Cocaine raises the core temperature threshold at which cutaneous vasodilation and sweating begin, and blunts the perception of heating that would normally drive a person to seek shade or remove clothing. Heat production rising is the familiar half of the story; the losing half is that the body stops getting rid of it, and stops noticing. The clustering of cocaine-associated hyperthermia in hot weather is what prompted this hypothesis, rather than something the finding explains.
core body temperature homeostasis GO:0001659 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased core body temperature homeostasis, annotated with temperature homeostasis (GO:0001659). GO:0001659 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Hyperthermia
Skeletal Myocyte Necrosis Hyperthermia is one of four candidate contributors the cited source names, none established. Typed for an unknown required intermediate rather than UNKNOWN, which would wrongly say directness has not been assessed.
Show evidence (3 references)
PMID:12044126 SUPPORT Human Clinical
"In humans, impaired heat dissipation is a major mechanism by which cocaine elevates body temperature."
Randomised double-blind placebo-controlled crossover trial of passive heat stress in cocaine-naive volunteers, establishing impaired dissipation rather than increased production as a mechanism in humans.
PMID:12044126 SUPPORT Human Clinical
"cocaine paradoxically impaired the perception of heating by attenuating the progressive increase in thermal discomfort associated with heat stress"
Documents the behavioural limb of the impairment, which removes the compensation a person would otherwise make.
PMID:12044126 NO_EVIDENCE BACKGROUND Human Clinical
"The traditional view is that cocaine causes a hypermetabolic state with increased heat production."
Graded NO_EVIDENCE deliberately. This sentence asserts increased heat PRODUCTION, which is the account this node displaces, not the impaired DISSIPATION the node claims. It is kept because it names the prior view the trial was designed to test, so a reader sees the correction; it does not support the node.
Skeletal Myocyte Necrosis
Skeletal muscle breaks down, releasing myoglobin and intracellular contents. Several contributors are plausible and none is established as dominant: increased muscular activity from agitation, direct muscle compression in an obtunded patient, hyperthermia, and alpha-adrenergic vasoconstriction producing muscle ischaemia.
skeletal muscle fiber CL:0008002 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves skeletal muscle fiber (CL:0008002). CL:0008002 is a cell type from the Cell Ontology.
Downstream
Rhabdomyolysis
Myoglobinuria
Acute kidney injury
Show evidence (3 references)
PMID:2913784 SUPPORT Human Clinical
"We describe herein four patients with rhabdomyolysis and acute myoglobinuric renal failure temporally related to cocaine use."
Case series establishing rhabdomyolysis with renal failure as a complication of acute cocaine intoxication.
PMID:2913784 SUPPORT Human Clinical
"The mechanism of cocaine injury is unclear; possibilities include increased muscle activity, muscle compression, hyperthermia, and vasospasm with muscle ischemia."
The authors' explicit statement that the mechanism is unsettled and multifactorial, which is why the incoming hyperthermia edge is typed for unknown intermediates rather than DIRECT.
PMID:10414649 REFUTE Human Clinical
"It appears that this syndrome is caused by changes in dopamine processing induced by chronic and intense use of cocaine rather than by the acute toxic effects of the drug."
A direct argument against placing this node in an acute-intoxication entry at all. Recorded as REFUTE rather than omitted: if the rhabdomyolysis and excited-delirium syndrome is a chronic-use phenomenon, this arm may belong to a cocaine use disorder entry instead. The node is kept because rhabdomyolysis is reported in acute presentations, but the challenge is on the record.
Cerebral Vasoconstriction and Vascular Injury
The same adrenergic vasoconstriction applied to the cerebral circulation, together with hypertensive surges and vessel-wall injury, raises the risk of both ischaemic and haemorrhagic stroke. The epidemiological evidence is consistent in direction but heterogeneous: several studies in the cited systematic review found no association.
smooth muscle cell of the brain vasculature CL:0002590 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves smooth muscle cell of the brain vasculature (CL:0002590). CL:0002590 is a cell type from the Cell Ontology.
Downstream
Stroke
Show evidence (2 references)
PMID:25066468 SUPPORT REVIEW SYNTHESIS Human Clinical
"Epidemiological evidence suggests that cocaine use increases the risk of stroke."
Systematic review of nine epidemiological studies concluding an increased stroke risk.
PMID:25066468 REFUTE REVIEW SYNTHESIS Human Clinical
"Three CCS and one CSS did not find any relationship between cocaine and strokes."
Four of the nine included studies found no association, so the same review that supports this node also bounds it. Recorded as a separate REFUTE item rather than folded into the supporting explanation.
Acute Aortic Wall Stress
Abrupt catecholamine-driven rises in arterial pressure and shear stress on the aortic wall can initiate dissection, characteristically within about an hour of use and in patients much younger than typical dissection cohorts.
Downstream
Aortic dissection
Show evidence (2 references)
PMID:33118742 SUPPORT Human Clinical
"Median time from last cocaine use to onset of symptoms was one hour."
The short median interval between exposure and symptom onset across 45 cases is consistent with an acute haemodynamic trigger. It does not exclude a chronic contribution: the same paper records that most of these patients had used cocaine for more than a year.
PMID:33118742 SUPPORT Human Clinical
"Acute aortic dissection related to cocaine use occurs in predominantly young male patients and has a dismal outcome when compared to all comer series."
Characterises the affected population and outcome, distinguishing this entity from age-related aortic disease.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Cocaine Intoxication Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

18
Cardiovascular 9
Tachycardia HP:0001649 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tachycardia (HP:0001649). HP:0001649 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:9725976 SUPPORT Human Clinical
"Other clinical findings included tachycardia, hypertension, diaphoresis, and disorientation."
Tachycardia recorded in a patient with measured very high blood cocaine concentrations.
Hypertension HP:0000822 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertension (HP:0000822). HP:0000822 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:2573838 SUPPORT Human Clinical
"After cocaine was administered, the heart rate and arterial pressure rose"
Direct measurement of the pressor response in patients given intranasal cocaine.
Myocardial infarction HP:0001658 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Myocardial infarction (HP:0001658). HP:0001658 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:10351966 SUPPORT Human Clinical
"The risk of myocardial infarction onset was elevated 23.7 times over baseline"
Quantifies the transient excess infarction risk after cocaine use.
PMID:29921621 SUPPORT BACKGROUND Human Clinical
"It has been estimated that up to 22% of non-fatal myocardial infarctions in persons 18–45 years of age have been attributed to cocaine abuse"
The share of young-adult infarction attributed to cocaine. Quoted from the review's introduction restating others' estimates, hence quote_role BACKGROUND.
Prolonged QRS complex HP:0006677 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Prolonged QRS complex (HP:0006677). HP:0006677 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:14677787 SUPPORT Model Organism
"Immediately after administering NaHCO3, QRS duration decreased by 30% (p < 0.001), returning to baseline more quickly than in the control group."
QRS widening in cocaine-poisoned dogs, and its reversal by sodium bicarbonate, is the quantitative measurement behind this phenotype.
PMID:18815938 SUPPORT REVIEW SYNTHESIS Other
"QRS prolongation secondary to sodium channel blockade"
Names QRS prolongation and attributes it to sodium-channel blockade in a human clinical review, so this phenotype does not rest on canine data alone.
Prolonged QT interval HP:0001657 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Prolonged QT interval (HP:0001657). HP:0001657 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:11561083 SUPPORT BACKGROUND Human Clinical
"Cocaine abuse has been reported to result in QT prolongation in humans"
The human clinical observation of QT prolongation, quoted from the background of the in-vitro study that went on to explain it.
Ventricular tachycardia HP:0004756 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ventricular tachycardia (HP:0004756). HP:0004756 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:14677787 SUPPORT Model Organism
"Seven dogs experienced significant arrhythmias, including VT, pulseless electrical activity, and third-degree atrioventricular block"
Ventricular tachycardia observed in an anaesthetised canine model of severe cocaine intoxication.
PMID:18815938 SUPPORT REVIEW SYNTHESIS Other
"Excessive catecholamines, combined with sodium and potassium channel blockades, give rise to a wide variety of supra-ventricular and ventricular rhythms."
Human-facing statement of the ventricular arrhythmia spectrum in cocaine users, so this phenotype does not rest on canine data alone.
Sudden cardiac death HP:0001645 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sudden cardiac death (HP:0001645). HP:0001645 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:14677787 SUPPORT BACKGROUND Human Clinical
"Cocaine toxicity causes myocardial depression, malignant dysrhythmias, and sudden death, partially due to cocaine-related myocardial sodium channel blockade."
Names sudden death as an outcome of cocaine toxicity and attributes it partly to the sodium-channel mechanism modelled upstream. Quoted from this paper's OBJECTIVE background rather than from its canine results, hence quote_role BACKGROUND.
Stroke HP:0001297 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Stroke (HP:0001297). HP:0001297 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25066468 SUPPORT REVIEW SYNTHESIS Human Clinical
"Epidemiological evidence suggests that cocaine use increases the risk of stroke."
Conclusion of a systematic review of nine epidemiological studies.
Aortic dissection HP:0002647 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Aortic dissection (HP:0002647). HP:0002647 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33118742 SUPPORT Human Clinical
"The observed cases of acute aortic dissection related to cocaine use showed a high proportion of young"
Characterises the cocaine-related dissection cohort as predominantly young.
Genitourinary 2
Myoglobinuria HP:0002913 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Myoglobinuria (HP:0002913). HP:0002913 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:2913784 SUPPORT Human Clinical
"We describe herein four patients with rhabdomyolysis and acute myoglobinuric renal failure temporally related to cocaine use."
Myoglobinuric renal failure documented in the case series.
Acute kidney injury HP:0001919 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Acute kidney injury (HP:0001919). HP:0001919 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:2913784 SUPPORT Human Clinical
"Renal failure progressed rapidly in all patients, necessitating dialysis in two."
Documents the severity and course of the renal injury in the case series.
Integument 1
Hyperhidrosis HP:0000975 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyperhidrosis (HP:0000975). HP:0000975 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:9725976 SUPPORT Human Clinical
"Other clinical findings included tachycardia, hypertension, diaphoresis, and disorientation."
Diaphoresis recorded as part of the acute presentation.
Metabolism 1
Hyperthermia Abnormality of temperature regulation HP:0004370 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyperthermia, annotated with Abnormality of temperature regulation (HP:0004370). HP:0004370 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:12044126 SUPPORT Human Clinical
"cocaine substantially augmented the progressive increase in esophageal temperature during heat stress"
Direct measurement of the temperature rise under controlled heat stress in a randomised crossover trial.
Musculoskeletal 1
Rhabdomyolysis HP:0003201 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Rhabdomyolysis (HP:0003201). HP:0003201 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:2913784 SUPPORT Human Clinical
"Acute cocaine intoxication was the most common presentation and rhabdomyolysis was an unexpected finding."
Rhabdomyolysis identified in patients presenting with acute cocaine intoxication.
Nervous System 3
Agitation HP:0000713 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Agitation (HP:0000713). HP:0000713 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:10414649 SUPPORT Human Clinical
"the experiencing of excitement, delirium, and hyperthermia"
Excitement and delirium recorded as features shared across 150 cocaine-associated rhabdomyolysis cases and 58 fatal excited-delirium cases.
Confusion HP:0001289 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Confusion (HP:0001289). HP:0001289 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:9725976 SUPPORT Human Clinical
"Other clinical findings included tachycardia, hypertension, diaphoresis, and disorientation."
Disorientation documented alongside measured peak cocaine concentrations.
Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:9725976 SUPPORT Human Clinical
"Approximately 1 hour after the ingestion incidents, the patient had multiple, generalized seizures that abated spontaneously."
Documents the seizure semiology and its temporal relation to ingestion.
Constitutional 1
Chest pain HP:0100749 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Chest pain (HP:0100749). HP:0100749 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29921621 SUPPORT Human Clinical
"364 patients who presented to a Detroit emergency department with chest pain and positive urine drug screen for cocaine were included"
Describes a cohort assembled from patients presenting acutely with chest pain and cocaine exposure, which is the presentation this phenotype names.
🧬

Genetic Associations

2
SLC6A3 (Modifier of risk of fatal cocaine intoxication, in epistasis with DRD2.)
Gene: SLC6A3 hgnc:11049 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SLC6A3 (hgnc:11049). hgnc:11049 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY
Show evidence (1 reference)
PMID:23340505 SUPPORT Human Clinical
"These results demonstrate gene-gene-drug interaction affecting risk of fatal cocaine intoxication."
Brain-bank case-control analysis reporting the DAT-DRD2 interaction as a determinant of risk of death from cocaine.
DRD2 (Modifier of risk of fatal cocaine intoxication, in epistasis with SLC6A3.)
Gene: DRD2 hgnc:3023 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is DRD2 (hgnc:3023). hgnc:3023 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY
Show evidence (1 reference)
PMID:23340505 SUPPORT Human Clinical
"These results demonstrate gene-gene-drug interaction affecting risk of fatal cocaine intoxication."
Same analysis, cited for the DRD2 side of the interaction.
💊

Medical Actions

6
Benzodiazepine Sedation
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: diazepam CHEBI:49575 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses diazepam (CHEBI:49575). CHEBI:49575 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
First-line treatment, and the one that addresses the most upstream node the clinician can reach. Sedation damps the central stimulation arm, and by lowering blood pressure and cardiac output it reduces myocardial oxygen demand at the same time. One drug, both arms of the toxidrome.
Mechanism Target:
INHIBITS Central Nervous System Stimulation
INHIBITS Increased Myocardial Oxygen Demand
Show evidence (1 reference)
PMID:35448887 SUPPORT REVIEW SYNTHESIS Other
"Not only do benzodiazepines exert anxiolytic action, but they also attenuate toxic effects at the cardiovascular and cerebral level, by reducing both blood pressure and cardiac output, which makes them a key first approach in treating cocaine acute intoxications"
States the anxiolytic action and the reduction in blood pressure and cardiac output, which is the demand-side target, and the first-line status. The snippet does not name central nervous system stimulation; that link rests on the anxiolytic action.
Sodium Bicarbonate for Sodium-Channel Blockade
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: sodium bicarbonate CHEBI:32139 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses sodium bicarbonate, annotated with sodium hydrogencarbonate (CHEBI:32139). CHEBI:32139 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Given for a widened QRS. It works against the channel arm specifically, and it is the reason the QRS is diagnostically useful: a complex that narrows after bicarbonate was widened by sodium-channel blockade.
Mechanism Target:
INHIBITS Slowed Ventricular Conduction
Show evidence (1 reference)
PMID:14677787 SUPPORT Model Organism
"Immediately after administering NaHCO3, QRS duration decreased by 30% (p < 0.001), returning to baseline more quickly than in the control group."
Direct measurement of the reversal of conduction slowing in a canine intoxication model.
Show evidence (1 reference)
PMID:14677787 SUPPORT Model Organism
"NaHCO3 improved ECG changes secondary to cocaine toxicity and improved myocardial function."
The study's overall conclusion. Note this is animal evidence: no randomised human trial of bicarbonate in cocaine toxicity exists.
Phentolamine
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: phentolamine CHEBI:8081 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses phentolamine (CHEBI:8081). CHEBI:8081 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Alpha-adrenergic blockade, aimed squarely at the coronary vasoconstriction node. In the human catheterisation study it returned coronary flow, calibre and haemodynamics to baseline, which is both the therapeutic rationale and the proof that the constriction was alpha-mediated.
Mechanism Target:
INHIBITS Alpha-Adrenergic Coronary Vasoconstriction
Show evidence (1 reference)
PMID:2573838 SUPPORT Human Clinical
"the administration of the alpha-adrenergic blocking agent phentolamine caused all these values to return to base-line levels"
Reversal of every measured variable by alpha blockade, in humans, establishes both the target and the mechanism.
Nitroglycerin
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: nitroglycerin CHEBI:28787 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses nitroglycerin (CHEBI:28787). CHEBI:28787 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Nitrovasodilation, acting downstream of the adrenergic receptor rather than at it. It abolished cocaine-induced constriction in both diseased and non-diseased coronary segments.
Mechanism Target:
INHIBITS Alpha-Adrenergic Coronary Vasoconstriction
Show evidence (1 reference)
PMID:1906905 SUPPORT Human Clinical
"Sublingual nitroglycerin abolished the vasoconstriction in both non-diseased and diseased segments."
Quantitative arteriographic demonstration of reversal in humans.
Beta-Adrenergic Blockade
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: propranolol CHEBI:8499 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses propranolol (CHEBI:8499). CHEBI:8499 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Curated as a contested treatment, not a recommended one. The mechanistic case against it is that blocking beta receptors leaves alpha-mediated vasoconstriction unopposed, and this has been measured directly in humans: intracoronary propranolol after cocaine further reduced coronary flow and further raised coronary vascular resistance. The outcome case for it is that a meta-analysis of five studies and 1794 patients found no difference in infarction or mortality. Both are curated here, the first as SUPPORT for the mechanism and the second as REFUTE against the claim that the mechanism translates into harm. See the mechanistic_hypotheses block.
Mechanism Target:
ACTIVATES Alpha-Adrenergic Coronary Vasoconstriction — Beta blockade increases, rather than reduces, this mechanism. ACTIVATES is the TreatmentEffectEnum value meaning "promotes or increases the mechanism"; the enum has no value for a treatment that worsens a lesion, and this is the accurate one.
Show evidence (1 reference)
PMID:1971166 SUPPORT Human Clinical
"Cocaine-induced coronary vasoconstriction is potentiated by beta-adrenergic blockade."
Randomised, double-blind, placebo-controlled catheterisation study measuring the potentiation directly, which is the edge this link asserts.
Show evidence (4 references)
PMID:1971166 SUPPORT Human Clinical
"Beta-adrenergic blocking agents probably should be avoided in patients with cocaine-associated myocardial ischemia or infarction."
The authors' own recommendation, which became the basis of guideline advice.
PMID:4051280 SUPPORT Human Clinical
"IV propranolol was used as the initial treatment for his hyperadrenergic state, resulting in a decrease in heart rate but a paroxsymal increase in blood pressure."
The case report proposing unopposed alpha stimulation. The spelling "paroxsymal" is the source's own and is quoted unaltered.
PMID:29921621 REFUTE Human Clinical
"there was no significant difference in the rate of non-fatal myocardial infarction or all-cause mortality"
Meta-analysis of five studies finding no outcome difference, which refutes the stronger claim that beta blockade causes clinical harm here.
+ 1 more reference
Antipsychotic Agents
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: haloperidol CHEBI:5613 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses haloperidol (CHEBI:5613). CHEBI:5613 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Recorded as a treatment that is described and not recommended. Antipsychotics are sometimes reached for in an agitated cocaine patient; the cited review's stated reason for caution is that they add to the arrhythmic burden of a drug already blocking two cardiac channels. The target_mechanisms link is therefore to arrhythmogenesis, and it is typed ACTIVATES because that is the direction of the effect the source describes.
Mechanism Target:
ACTIVATES Ventricular Arrhythmogenesis — Not a therapeutic effect on this node but a worsening one, which is why this treatment is curated with REFUTE evidence.
Show evidence (1 reference)
PMID:35448887 REFUTE REVIEW SYNTHESIS Other
"The use of antipsychotics to manage cocaine intoxications is questionable and potentially dangerous, as they may intensify the risk of cardiac dysrhythmias."
Graded REFUTE because it argues against the intervention. The stated reason is the arrhythmia risk this entry models on the channel and arrhythmogenesis nodes.
🌍

Environmental Factors

2
Concurrent ethanol ingestion
exposure to ethanol ECTO:9000027 Environmental Conditions, Treatments and Exposures Ontology (ECTO) Relation: this environmental factor is this exposure This environmental factor is exposure to ethanol (ECTO:9000027). ECTO:9000027 is an exposure from the Environmental Conditions, Treatments and Exposures Ontology.
Taking cocaine with alcohol is not simply taking two drugs. Hepatic transesterification produces cocaethylene, a pharmacologically active metabolite with a longer half-life than cocaine, which is itself a slightly more potent hERG blocker than cocaine. So the combination changes what is in the blood, not just how much.
Show evidence (3 references)
PMID:21463066 SUPPORT Human Clinical
"Ethanol alters the hepatic biotransformation of cocaine, resulting in transesterification to a novel active metabolite, cocaethylene."
States the metabolic basis of the interaction.
PMID:35448887 SUPPORT REVIEW SYNTHESIS Other
"CE is an active metabolite that displays pharmacological activity, with a longer average half-life"
Sources the longer-half-life claim in the node description, which was otherwise asserted without evidence.
PMID:21463066 SUPPORT Human Clinical
"The oral route (34% ± 20) was significantly greater than from the smoked route (18% ± 11)"
Quantifies how much of a cocaine dose becomes cocaethylene and shows it depends on route, which bounds how strongly the interaction applies to any given exposure.
Mechanism Target:
EXACERBATES hERG Potassium Channel Blockade — Cocaethylene, formed only when ethanol is present, blocks hERG more potently than cocaine does.
Show evidence (1 reference)
PMID:11561083 SUPPORT In Vitro
"We conclude that cocaethylene is slightly more potent than cocaine as a blocker of HERG"
Direct comparison of cocaine and cocaethylene IC50 at the same channel in the same expression system.
EXACERBATES Sympathetic Cardiovascular Stimulation
Show evidence (1 reference)
PMID:21463066 SUPPORT Human Clinical
"Within each route, the cocaine-ethanol combination produced greater increases in heart rate and rate-pressure product than cocaine alone."
Measured in humans across three routes of administration, so the potentiation is not an artefact of one route.
Cocaine exposure
exposure to cocaine ECTO:9000265 Environmental Conditions, Treatments and Exposures Ontology (ECTO) Relation: this environmental factor is this exposure This environmental factor is exposure to cocaine (ECTO:9000265). ECTO:9000265 is an exposure from the Environmental Conditions, Treatments and Exposures Ontology.
The exposure itself. Route matters for onset and for the fraction converted to cocaethylene when ethanol is present, but all routes converge on the same systemic node.
Show evidence (1 reference)
PMID:31048676 SUPPORT Human Clinical
"Among all 2017 drug overdose deaths, 13,942 (19.8%) involved cocaine"
Establishes the scale of fatal cocaine exposure in a national surveillance dataset.
Mechanism Target:
TRIGGERS Systemic Cocaine Exposure
Show evidence (1 reference)
PMID:10351966 SUPPORT Human Clinical
"The elevated risk rapidly decreased thereafter."
The excess infarction risk is confined to the period immediately after use, which is what makes the exposure itself the initiating event for this entry.
⚖️

Clinical Burden

High
Cocaine is involved in roughly a fifth of US drug overdose deaths, and acute intoxication kills through mechanisms that act within minutes to an hour of exposure: ventricular arrhythmia, myocardial infarction, aortic dissection. The figure that matters mechanistically is the second one below. Nearly three quarters of cocaine-involved deaths also involve an opioid, so most fatal cocaine exposures are not pure cocaine toxicity, and cocaine-attributable mortality cannot be read off these totals.
Show evidence (2 references)
PMID:31048676 SUPPORT Human Clinical
"Among all 2017 drug overdose deaths, 13,942 (19.8%) involved cocaine"
National vital statistics surveillance of cocaine-involved overdose deaths.
PMID:31048676 SUPPORT Human Clinical
"Nearly three fourths (72.7%) of cocaine-involved deaths in 2017 also involved opioids."
Bounds every mortality claim in this entry: most cocaine-involved deaths are polysubstance.
{ }

Source YAML

click to show 
name: Cocaine Intoxication
creation_date: "2026-09-21T01:30:00Z"
category: Toxic Exposure Disorder
description: >-
  Acute systemic toxicity following cocaine exposure. Cocaine is pharmacologically two
  drugs in one molecule, and acute intoxication is what happens when both act at once. It
  is a monoamine reuptake inhibitor, blocking the dopamine, noradrenaline and serotonin
  transporters and flooding synapses with catecholamines; and it is a local anaesthetic,
  blocking the cardiac fast sodium channel in the same way a class I antiarrhythmic does.
  That combination is what distinguishes it from the stimulants and the local anaesthetics
  the KB curates alongside it.
  The two arms collide in the heart: sympathetic drive raises myocardial oxygen demand
  while alpha-adrenergic coronary vasoconstriction and platelet activation cut supply,
  and the channel arm independently slows conduction and delays repolarisation, so the
  ischaemic myocardium is also electrically unstable. Outside the heart the catecholamine
  arm produces agitation, seizures, hyperthermia through impaired heat dissipation,
  rhabdomyolysis, and cerebral and aortic vascular injury.
disease_term:
  preferred_term: cocaine intoxication
  term:
    id: MONDO:0019544
    label: cocaine intoxication
synonyms:
- Acute cocaine toxicity
- Cocaine overdose
- Cocaine poisoning
parents:
- Toxic Exposure Disorder
categories:
- Toxic Exposure Disorder
- Cardiovascular Disorder
notes: >-
  Scope. This entry covers acute systemic toxicity from cocaine itself. Three things are
  deliberately outside it, each for a stated reason rather than by omission.

  (1) Cocaine use disorder. The KB already curates Opioid_Use_Disorder and
  Alcohol_Use_Disorder as chronic substance use disorders distinct from the acute and
  organ-specific consequences of the same substance, which are separate entries
  (Alcoholic_Liver_Disease, Fetal_Alcohol_Spectrum_Disorder, Acute_Alcohol_Sensitivity).
  Acute cocaine intoxication is the analogous split: it occurs in people with no use
  disorder, and MONDO codes it separately, under poisoning (MONDO:0019544) rather than
  under substance dependence. No cocaine use disorder entry exists yet; this entry does
  not attempt to be one and models no dependence, tolerance or withdrawal mechanism.

  (2) Levamisole-adulterated cocaine. Levamisole is a common cocaine adulterant that
  causes a p-ANCA-positive small-vessel vasculopathy with neutropenia (PMID:23269350,
  cited in references below). It is excluded here because it is a different molecule
  acting by a different, immune-mediated mechanism over days to weeks, not an effect of
  cocaine and not an acute intoxication syndrome. Bundling it would put two unrelated
  mechanistic claims in one entry. It is a candidate for its own entry.

  (3) Cocaine-associated cardiomyopathy and accelerated atherosclerosis are chronic
  structural sequelae of repeated intoxication rather than features of a single acute
  episode, and are not modelled.

  Hyperthermia binding. The Hyperthermia phenotype is bound to HP:0004370 Abnormality of
  temperature regulation rather than to HP:0001945 Fever, even though HPO lists
  "Hyperthermia" among Fever's other names and the deep-research report suggested
  HP:0001945. HP:0001945's own definition rejects that reading: it states that "The rise
  in temperature during fever is to be distinguished from that occurring during episodes
  of hyperthermia. Unlike fever, hyperthermia involves an unregulated rise in body
  temperature in which pyrogenic cytokines are not directly involved... It represents a
  failure of thermoregulatory homeostasis, in which there is uncontrolled heat
  production, inadequate heat dissipation, or defective hypothalamic thermoregulation."
  Inadequate heat dissipation is precisely what the cited human trial (PMID:12044126)
  demonstrates for cocaine, so binding Fever would assert the mechanism that source
  excludes. HP:0004370 is the parent of Fever and is not in the schema's 56-term coarse
  phenotype set, so no coarse_binding_basis applies. HPO has no term for non-febrile
  hyperthermia; preferred_term carries the specificity the binding loses.

  Crack lung and mesenteric ischaemia are absent. Inhalational alveolar injury ("crack
  lung", PMID:2382909, listed under references) is specific to the smoked freebase route
  and is a direct local injury at the alveolar surface rather than a consequence of the
  systemic exposure node every other branch descends from; modelling it would need a second
  root with a different exposure route. Mesenteric ischaemia is the same adrenergic
  vasoconstriction mechanism already modelled for the coronary and cerebral beds, applied
  to a third bed, and was left out only because no quotable source for it was verified
  during this curation. Both are candidates for a follow-up pass rather than scope
  exclusions.

  No diagnosis, prevalence, biochemical, datasets or animal_models sections are curated.
  The canine sodium-bicarbonate study (PMID:14677787) is cited as evidence but not curated
  as an AnimalModel with modeled_mechanisms, which would make its fidelity and limitations
  explicit; that is the most worthwhile of these to add next.

  GeneReviews. `just check-genereviews` returns NO_CHAPTER: no GeneReviews chapter names
  this disease, which is expected for a poisoning rather than a Mendelian disorder, so no
  chapter baseline applies. The StatPearls line also returns NO_CHAPTER against this
  entry's name; StatPearls is never a phenotype baseline in any case.

  Evidence not used. PMID:18347214, the American Heart Association scientific statement
  on cocaine-associated chest pain, is the authoritative management source and is listed
  under references, but its cached record carries no abstract body, so no snippet can be
  taken from it and no claim here rests on it.
pathophysiology:
- name: Systemic Cocaine Exposure
  biological_scale: ORGANISM
  description: >-
    Absorbed cocaine distributes systemically and reaches concentrations at which it
    engages two independent pharmacological targets simultaneously: the presynaptic
    monoamine transporters and the voltage-gated ion channels of the cardiac myocyte
    membrane. Every downstream branch of this entry originates here.
  chemical_entities:
  - preferred_term: cocaine
    term:
      id: CHEBI:27958
      label: cocaine
  downstream:
  - target: Monoamine Transporter Blockade
    causal_link_type: DIRECT
    description: Cocaine binds the presynaptic monoamine transporters directly.
    evidence:
    - reference: PMID:18568020
      reference_title: The binding sites for cocaine and dopamine in the dopamine transporter overlap.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Our data demonstrate the molecular basis for the competitive inhibition of dopamine transport by cocaine."
      explanation: >-
        Establishes that cocaine itself occupies the transporter's substrate site, so the
        blockade is a direct action of the drug rather than a downstream consequence.
  - target: Cardiac Fast Sodium Channel Blockade
    causal_link_type: DIRECT
    description: >-
      The same molecule acts on the cardiac myocyte membrane as a local anaesthetic.
    evidence:
    - reference: PMID:18815938
      reference_title: Management of cocaine-induced cardiac arrhythmias due to cardiac ion channel dysfunction.
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "Cocaine can produce arrhythmias either through the production of myocardial ischemia or as a direct result of ion channel alterations."
      explanation: >-
        Names the channel route as separate from the ischaemic route, which is the reason
        this entry models two arms off the exposure node rather than one chain.
  - target: hERG Potassium Channel Blockade
    causal_link_type: DIRECT
    description: Cocaine blocks the hERG-encoded repolarising potassium current.
    evidence:
    - reference: PMID:11561083
      reference_title: Effects of cocaine and its major metabolites on the HERG-encoded potassium channel.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Cocaine blocked HERG-encoded potassium channels with an IC50 of 4.4 +/- 1.1 microM"
      explanation: >-
        Measures direct block of the hERG channel by cocaine in a heterologous expression
        system, establishing the potassium arm as a drug-channel interaction.

- name: Monoamine Transporter Blockade
  biological_scale: MOLECULAR
  description: >-
    Cocaine occupies a binding site deep within the dopamine transporter that overlaps the
    site used by dopamine itself, competitively inhibiting reuptake; the noradrenaline and
    serotonin transporters are blocked in parallel. This is the sympathomimetic arm.
  genes:
  - preferred_term: SLC6A3
    term:
      id: hgnc:11049
      label: SLC6A3
  - preferred_term: SLC6A2
    term:
      id: hgnc:11048
      label: SLC6A2
  - preferred_term: SLC6A4
    term:
      id: hgnc:11050
      label: SLC6A4
  molecular_functions:
  - preferred_term: dopamine transporter activity
    modifier: DECREASED
    term:
      id: GO:0005330
      label: dopamine:sodium symporter activity
  biological_processes:
  - preferred_term: presynaptic dopamine reuptake
    modifier: DECREASED
    term:
      id: GO:0051583
      label: dopamine uptake involved in synaptic transmission
  evidence:
  - reference: PMID:18568020
    reference_title: The binding sites for cocaine and dopamine in the dopamine transporter overlap.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "Our models suggest that the binding site for cocaine and cocaine analogs is deeply buried between transmembrane segments 1, 3, 6 and 8, and overlaps with the binding sites for the substrates dopamine and amphetamine"
    explanation: >-
      Locates the cocaine site as overlapping the substrate site, which is what makes the
      inhibition competitive and dose-dependent.
  - reference: PMID:10485970
    reference_title: Dopamine-transporter occupancy after intravenous doses of cocaine and methylphenidate in mice and humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Recent studies using positron emission tomography (PET) have established the relationship between an intravenous dose of cocaine and the percentage occupancy of the dopamine transporter in humans, and have documented the requirement of more than 50% occupancy for perception of the \"high\""
    explanation: >-
      Records that transporter occupancy by cocaine has been measured directly in humans
      and is dose-related. The quoted sentence is the citing paper's background statement
      of human PET work, not a result of its own mouse experiments, which is why
      quote_role is BACKGROUND while evidence_source grades the human studies it describes.
  downstream:
  - target: Synaptic Catecholamine Excess
    causal_link_type: DIRECT
    description: >-
      Blocking reuptake leaves released catecholamines in the synaptic cleft and at
      peripheral sympathetic junctions.

- name: Synaptic Catecholamine Excess
  biological_scale: CELLULAR
  description: >-
    With reuptake blocked, dopamine, noradrenaline and serotonin accumulate at central and
    peripheral synapses. This single node is the origin of every non-cardiac-channel
    manifestation in the entry: the cardiovascular, neurological, thermoregulatory,
    muscular and cerebrovascular branches all descend from it.
  downstream:
  - target: Sympathetic Cardiovascular Stimulation
    causal_link_type: DIRECT
  - target: Alpha-Adrenergic Coronary Vasoconstriction
    causal_link_type: DIRECT
    description: >-
      Excess noradrenaline at vascular alpha-adrenergic receptors constricts the epicardial
      coronary arteries.
    evidence:
    - reference: PMID:2573838
      reference_title: Cocaine-induced coronary-artery vasoconstriction.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "these effects are mediated by alpha-adrenergic stimulation"
      explanation: >-
        The authors attribute the observed coronary vasoconstriction specifically to
        alpha-adrenergic stimulation, which is the adrenergic step this edge asserts.
  - target: Platelet Activation
    causal_link_type: DIRECT
  - target: Central Nervous System Stimulation
    causal_link_type: DIRECT
  - target: Impaired Thermoregulatory Heat Dissipation
    causal_link_type: DIRECT
  - target: Cerebral Vasoconstriction and Vascular Injury
    causal_link_type: DIRECT

- name: Sympathetic Cardiovascular Stimulation
  biological_scale: ORGANISM
  description: >-
    Catecholamine excess at cardiac and vascular adrenergic receptors raises heart rate,
    contractility and arterial pressure. The rate-pressure product rises, and with it
    myocardial oxygen consumption.
  evidence:
  - reference: PMID:2573838
    reference_title: Cocaine-induced coronary-artery vasoconstriction.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "After cocaine was administered, the heart rate and arterial pressure rose"
    explanation: >-
      Direct human measurement of the chronotropic and pressor response to a dose of
      cocaine at the low end of the range seen clinically.
  downstream:
  - target: Tachycardia
    causal_link_type: DIRECT
  - target: Hypertension
    causal_link_type: DIRECT
  - target: Increased Myocardial Oxygen Demand
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:2573838
      reference_title: Cocaine-induced coronary-artery vasoconstriction.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "despite an increase in myocardial oxygen demand"
      explanation: >-
        The same study measured the rise in myocardial oxygen demand alongside the fall in
        supply, which is the step this edge asserts.
  - target: Acute Aortic Wall Stress
    causal_link_type: DIRECT

- name: Alpha-Adrenergic Coronary Vasoconstriction
  biological_scale: TISSUE
  description: >-
    Cocaine narrows the epicardial coronary arteries and raises coronary vascular
    resistance through alpha-adrenergic stimulation. The effect is reversed by
    phentolamine and abolished by nitroglycerin, and it is markedly greater in segments
    already narrowed by atherosclerosis.
  cell_types:
  - preferred_term: smooth muscle cell of the coronary artery
    term:
      id: CL:0002592
      label: smooth muscle cell of the coronary artery
  biological_processes:
  - preferred_term: coronary vasoconstriction
    modifier: INCREASED
    term:
      id: GO:0042310
      label: vasoconstriction
  evidence:
  - reference: PMID:2573838
    reference_title: Cocaine-induced coronary-artery vasoconstriction.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the intranasal administration of cocaine near the dose used for topical anesthesia causes vasoconstriction of the coronary arteries, with a decrease in the coronary blood flow"
    explanation: >-
      Quantitative arteriography and coronary sinus thermodilution in 29 patients given
      cocaine establish the vasoconstriction and the fall in flow.
  - reference: PMID:1906905
    reference_title: Alleviation of cocaine-induced coronary vasoconstriction by nitroglycerin.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The magnitude of vasoconstriction was greater (p = 0.01) in the diseased segments."
    explanation: >-
      Shows the constriction is amplified where atherosclerosis is already present, which
      is why pre-existing coronary disease worsens the ischaemic consequence.
  downstream:
  - target: Reduced Myocardial Oxygen Supply
    causal_link_type: DIRECT

- name: Platelet Activation
  biological_scale: CELLULAR
  description: >-
    Cocaine activates platelets in vivo in humans, releasing alpha-granule contents and
    generating circulating platelet-containing microaggregates. The node is named for what
    was measured. Thrombus formation on a vasoconstricted segment is the plausible route
    from here to reduced flow, but the cited study states it only as a possibility, so the
    downstream edge is typed INDIRECT_UNKNOWN_INTERMEDIATES rather than DIRECT and no
    thrombus node is asserted.
  biological_processes:
  - preferred_term: platelet activation
    modifier: INCREASED
    term:
      id: GO:0030168
      label: platelet activation
  evidence:
  - reference: PMID:10814631
    reference_title: Cocaine activates platelets and increases the formation of circulating platelet containing microaggregates in humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cocaine exposure causes platelet activation, alpha granule release, and platelet containing microaggregate formation."
    explanation: >-
      Randomised double-blind crossover study in 14 healthy volunteers, so the platelet
      effect is attributable to cocaine rather than to the clinical context of an ischaemic
      presentation.
  - reference: PMID:10814631
    reference_title: Cocaine activates platelets and increases the formation of circulating platelet containing microaggregates in humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cocaine, even at the relatively low doses commonly self administered by occasional abusers, may promote thrombosis and predispose healthy individuals to ischaemic events"
    explanation: >-
      The authors' own statement of the dose range and the population at risk, which bounds
      how far this mechanism can be extrapolated.
  downstream:
  - target: Reduced Myocardial Oxygen Supply
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Platelet activation is measured; thrombotic occlusion of a coronary segment is the
      unestablished intermediate.

- name: Reduced Myocardial Oxygen Supply
  biological_scale: TISSUE
  description: >-
    Coronary flow falls. Both the vasoconstrictive and the thrombotic branch converge here.
  evidence:
  - reference: PMID:2573838
    reference_title: Cocaine-induced coronary-artery vasoconstriction.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the coronary-sinus blood flow fell"
    explanation: Direct thermodilution measurement of the fall in coronary flow after cocaine.
  downstream:
  - target: Myocardial Oxygen Supply-Demand Mismatch
    causal_link_type: DIRECT

- name: Increased Myocardial Oxygen Demand
  biological_scale: ORGANISM
  description: >-
    Tachycardia, hypertension and increased contractility raise myocardial oxygen
    consumption at the same moment supply is falling.
  downstream:
  - target: Myocardial Oxygen Supply-Demand Mismatch
    causal_link_type: DIRECT

- name: Myocardial Oxygen Supply-Demand Mismatch
  biological_scale: TISSUE
  description: >-
    The defining cardiac lesion of cocaine intoxication: demand rises while supply falls,
    in the same patient at the same time, from one drug. The risk is concentrated in the
    first hour after use, and in the cited catheterisation study the constriction occurred
    in patients with and without angiographic coronary disease alike.
  cell_types:
  - preferred_term: cardiac myocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:10351966
    reference_title: Triggering of myocardial infarction by cocaine.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The risk of myocardial infarction onset was elevated 23.7 times over baseline"
    explanation: >-
      Case-crossover analysis within the Determinants of Myocardial Infarction Onset Study
      quantifying the transient excess risk in the hour after cocaine use.
  - reference: PMID:10351966
    reference_title: Triggering of myocardial infarction by cocaine.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cocaine use is associated with a large abrupt and transient increase in the risk of acute myocardial infarction in patients who are otherwise at relatively low risk."
    explanation: >-
      States both the magnitude and the transience, which is what distinguishes this
      mechanism from chronic atherosclerotic risk.
  downstream:
  - target: Ventricular Arrhythmogenesis
    causal_link_type: DIRECT
    description: Ischaemic myocardium is arrhythmogenic.
    evidence:
    - reference: PMID:18815938
      reference_title: Management of cocaine-induced cardiac arrhythmias due to cardiac ion channel dysfunction.
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "Cocaine can produce arrhythmias either through the production of myocardial ischemia or as a direct result of ion channel alterations."
      explanation: >-
        Names myocardial ischaemia as one of the two routes to cocaine-associated
        arrhythmia, which is the edge asserted here.
  - target: Myocardial infarction
    causal_link_type: DIRECT
  - target: Chest pain
    causal_link_type: DIRECT

- name: Cardiac Fast Sodium Channel Blockade
  biological_scale: MOLECULAR
  conforms_to: "xenobiotic_cardiac_channel_perturbation#Xenobiotic Cardiac Ion-Channel Perturbation"
  description: >-
    Cocaine blocks the cardiac fast sodium channel in the manner of a class I
    antiarrhythmic. This is its local-anaesthetic action applied to myocardium, and it is
    the arm that a purely sympathomimetic account of cocaine toxicity leaves out.
  genes:
  - preferred_term: SCN5A
    term:
      id: hgnc:10593
      label: SCN5A
  cell_types:
  - preferred_term: cardiac myocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  molecular_functions:
  - preferred_term: cardiac fast sodium channel activity
    modifier: DECREASED
    term:
      id: GO:0086006
      label: voltage-gated sodium channel activity involved in cardiac muscle cell action potential
  evidence:
  - reference: PMID:14677787
    reference_title: Electrophysiologic and hemodynamic effects of sodium bicarbonate in a canine model of severe cocaine intoxication.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Cocaine toxicity causes myocardial depression, malignant dysrhythmias, and sudden death, partially due to cocaine-related myocardial sodium channel blockade."
    explanation: >-
      The human cocaine-toxicity picture and its attribution to sodium-channel blockade,
      quoted from the first sentence of this paper's OBJECTIVE section. No dog measured
      this, so evidence_source grades the human observations the sentence describes and
      quote_role records that the citing paper is a canine study restating them.
  downstream:
  - target: Altered Cardiac Action Potential
    causal_link_type: DIRECT

- name: hERG Potassium Channel Blockade
  biological_scale: MOLECULAR
  conforms_to: "xenobiotic_cardiac_channel_perturbation#Xenobiotic Cardiac Ion-Channel Perturbation"
  description: >-
    Cocaine also blocks the hERG-encoded rapid delayed-rectifier potassium channel, in the
    open state, at low micromolar concentrations. Cocaethylene, the metabolite formed when
    cocaine and ethanol are taken together, is a slightly more potent blocker than cocaine
    itself.
  genes:
  - preferred_term: KCNH2
    term:
      id: hgnc:6251
      label: KCNH2
  cell_types:
  - preferred_term: cardiac myocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  molecular_functions:
  - preferred_term: rapid delayed rectifier potassium channel activity
    modifier: DECREASED
    term:
      id: GO:0005251
      label: delayed rectifier potassium channel activity
  evidence:
  - reference: PMID:11561083
    reference_title: Effects of cocaine and its major metabolites on the HERG-encoded potassium channel.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Blockade of HERG by cocaine, cocaethylene, and methylecgonidine increased significantly over the voltage range where HERG activates"
    explanation: >-
      Characterises the block as open-channel and voltage-dependent in HEK293 cells stably
      expressing HERG.
  - reference: PMID:11561083
    reference_title: Effects of cocaine and its major metabolites on the HERG-encoded potassium channel.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Cocaine abuse has been reported to result in QT prolongation in humans"
    explanation: >-
      Records the human clinical observation the in-vitro work was undertaken to explain.
      The quoted sentence is the citing paper's opening statement of prior human findings,
      not a result of its own cell experiments, hence quote_role BACKGROUND.
  downstream:
  - target: Altered Cardiac Action Potential
    causal_link_type: DIRECT

- name: Altered Cardiac Action Potential
  biological_scale: CELLULAR
  conforms_to: "xenobiotic_cardiac_channel_perturbation#Altered Cardiac Action Potential"
  biological_processes:
  - preferred_term: cardiac muscle cell action potential
    modifier: ABNORMAL
    term:
      id: GO:0086001
      label: cardiac muscle cell action potential
  description: >-
    Loss of fast inward sodium current slows phase 0 upstroke; loss of the rapid delayed
    rectifier prolongs phase 3. Both currents are perturbed by the same drug, so
    depolarisation and repolarisation are affected together.
  cell_types:
  - preferred_term: cardiac myocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:18815938
    reference_title: Management of cocaine-induced cardiac arrhythmias due to cardiac ion channel dysfunction.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Excessive catecholamines, combined with sodium and potassium channel blockades, give rise to a wide variety of supra-ventricular and ventricular rhythms."
    explanation: >-
      States that sodium- and potassium-channel blockade together produce the arrhythmia
      spectrum, which is the claim this node carries as the convergence of both channel
      arms.
  downstream:
  - target: Slowed Ventricular Conduction
    causal_link_type: DIRECT
  - target: Delayed Ventricular Repolarization
    causal_link_type: DIRECT

- name: Slowed Ventricular Conduction
  biological_scale: TISSUE
  description: >-
    Reduced sodium current slows impulse propagation through the ventricular myocardium,
    widening the QRS complex. Because the QRS narrows promptly when extracellular sodium
    is raised and pH shifted with sodium bicarbonate, the widening is a reversible
    consequence of channel blockade rather than structural damage.
  evidence:
  - reference: PMID:14677787
    reference_title: Electrophysiologic and hemodynamic effects of sodium bicarbonate in a canine model of severe cocaine intoxication.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Immediately after administering NaHCO3, QRS duration decreased by 30% (p < 0.001), returning to baseline more quickly than in the control group."
    explanation: >-
      The reversal of QRS widening by sodium bicarbonate in cocaine-poisoned dogs is direct
      evidence that the widening reflects sodium-channel blockade.
  downstream:
  - target: Ventricular Arrhythmogenesis
    causal_link_type: DIRECT
  - target: Prolonged QRS complex
    causal_link_type: DIRECT

- name: Delayed Ventricular Repolarization
  biological_scale: CELLULAR
  description: >-
    hERG blockade prolongs the action potential plateau and lengthens the QT interval,
    creating the substrate for afterdepolarisation-driven triggered activity.
  evidence:
  - reference: PMID:11561083
    reference_title: Effects of cocaine and its major metabolites on the HERG-encoded potassium channel.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Cocaine abuse has been reported to result in QT prolongation in humans"
    explanation: >-
      QT prolongation is the clinical readout of delayed ventricular repolarisation, and
      this is the human observation of it. Quoted from the citing paper's background rather
      than from its cell experiments, hence quote_role BACKGROUND.
  downstream:
  - target: Ventricular Arrhythmogenesis
    causal_link_type: DIRECT
  - target: Prolonged QT interval
    causal_link_type: DIRECT

- name: Ventricular Arrhythmogenesis
  biological_scale: TISSUE
  description: >-
    Three substrates converge: slowed conduction supporting reentry, delayed repolarisation
    supporting triggered activity, and ischaemic myocardium. Catecholamine excess is
    superimposed on all three, which is why the arrhythmia burden of cocaine cannot be
    attributed to any single one of its actions.

    This node deliberately declares no conforms_to. The obvious target,
    xenobiotic_cardiac_channel_perturbation#Xenobiotic-Induced Cardiac Arrhythmia, is
    excluded by that module's own scope note: "the xenobiotic must act on the channel
    itself. A drug that causes arrhythmia through electrolyte disturbance, ischaemia, or
    structural injury belongs elsewhere, even when the endpoint looks the same." This node
    is a mixed channel, ischaemia and catecholamine endpoint and takes an inbound edge from
    the supply-demand node, so conforming it would assert a channel attribution the entry
    itself contradicts. The three upstream nodes that do act on the channel carry the
    conformance instead.
  evidence:
  - reference: PMID:18815938
    reference_title: Management of cocaine-induced cardiac arrhythmias due to cardiac ion channel dysfunction.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Excessive catecholamines, combined with sodium and potassium channel blockades, give rise to a wide variety of supra-ventricular and ventricular rhythms."
    explanation: >-
      States the convergence of the catecholamine arm and both channel arms on the
      arrhythmia endpoint, which is exactly the structure this node encodes.
  downstream:
  - target: Ventricular tachycardia
    causal_link_type: DIRECT
  - target: Sudden cardiac death
    causal_link_type: DIRECT

- name: Central Nervous System Stimulation
  biological_scale: ORGANISM
  description: >-
    Central monoamine excess produces the psychomotor arm of the toxidrome: agitation,
    hypervigilance, diaphoresis and, at higher exposures, disorientation.
  cell_types:
  - preferred_term: dopaminergic neuron
    term:
      id: CL:0000700
      label: dopaminergic neuron
  evidence:
  - reference: PMID:9725976
    reference_title: Multiple cocaine-induced seizures and corresponding cocaine and metabolite concentrations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other clinical findings included tachycardia, hypertension, diaphoresis, and disorientation."
    explanation: >-
      Documents the sympathomimetic and central features occurring together in a patient
      with measured very high blood cocaine concentrations.
  downstream:
  - target: Central Neuronal Hyperexcitability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The step from central stimulation to seizure is not established. Typed
      INDIRECT_UNKNOWN_INTERMEDIATES, which the schema defines as a relationship where at
      least one required intermediate mechanism is currently unknown. UNKNOWN would be
      wrong: that value means directness has not yet been assessed, whereas the cited
      source has been read and states the mechanism is unclear.
    evidence:
    - reference: PMID:9725976
      reference_title: Multiple cocaine-induced seizures and corresponding cocaine and metabolite concentrations.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The etiology of seizures associated with cocaine use is unclear."
      explanation: >-
        The source's own statement that the seizure mechanism is not established, which is
        why this edge is typed INDIRECT_UNKNOWN_INTERMEDIATES and carries no molecular
        claim.
  - target: Agitation
    causal_link_type: DIRECT
  - target: Hyperhidrosis
    causal_link_type: DIRECT
  - target: Confusion
    causal_link_type: DIRECT

- name: Central Neuronal Hyperexcitability
  biological_scale: CELLULAR
  description: >-
    A state of lowered seizure threshold occurring at high cocaine concentrations. It is
    named as a node because seizures are a real and sometimes fatal feature, but no
    molecular mechanism is asserted here: the cited source describes generalized seizures
    at measured peak concentrations with a negative workup for structural causes, and
    states that the aetiology is unclear.
  evidence:
  - reference: PMID:9725976
    reference_title: Multiple cocaine-induced seizures and corresponding cocaine and metabolite concentrations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Approximately 1 hour after the ingestion incidents, the patient had multiple, generalized seizures that abated spontaneously. His workup for CNS bleeding, infection, and trauma was negative."
    explanation: >-
      Establishes seizures temporally related to cocaine with structural causes excluded,
      supporting a drug-attributable lowering of seizure threshold without specifying one.
  downstream:
  - target: Seizure
    causal_link_type: DIRECT

- name: Impaired Thermoregulatory Heat Dissipation
  biological_scale: ORGANISM
  description: >-
    Cocaine raises the core temperature threshold at which cutaneous vasodilation and
    sweating begin, and blunts the perception of heating that would normally drive a person
    to seek shade or remove clothing. Heat production rising is the familiar half of the
    story; the losing half is that the body stops getting rid of it, and stops noticing.
    The clustering of cocaine-associated hyperthermia in hot weather is what prompted
    this hypothesis, rather than something the finding explains.
  biological_processes:
  - preferred_term: core body temperature homeostasis
    modifier: DECREASED
    term:
      id: GO:0001659
      label: temperature homeostasis
  evidence:
  - reference: PMID:12044126
    reference_title: Mechanism of cocaine-induced hyperthermia in humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In humans, impaired heat dissipation is a major mechanism by which cocaine elevates body temperature."
    explanation: >-
      Randomised double-blind placebo-controlled crossover trial of passive heat stress in
      cocaine-naive volunteers, establishing impaired dissipation rather than increased
      production as a mechanism in humans.
  - reference: PMID:12044126
    reference_title: Mechanism of cocaine-induced hyperthermia in humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cocaine paradoxically impaired the perception of heating by attenuating the progressive increase in thermal discomfort associated with heat stress"
    explanation: >-
      Documents the behavioural limb of the impairment, which removes the compensation a
      person would otherwise make.
  - reference: PMID:12044126
    reference_title: Mechanism of cocaine-induced hyperthermia in humans.
    supports: NO_EVIDENCE
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "The traditional view is that cocaine causes a hypermetabolic state with increased heat production."
    explanation: >-
      Graded NO_EVIDENCE deliberately. This sentence asserts increased heat PRODUCTION,
      which is the account this node displaces, not the impaired DISSIPATION the node
      claims. It is kept because it names the prior view the trial was designed to test,
      so a reader sees the correction; it does not support the node.
  downstream:
  - target: Hyperthermia
    causal_link_type: DIRECT
  - target: Skeletal Myocyte Necrosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Hyperthermia is one of four candidate contributors the cited source names, none
      established. Typed for an unknown required intermediate rather than UNKNOWN, which
      would wrongly say directness has not been assessed.

- name: Skeletal Myocyte Necrosis
  biological_scale: CELLULAR
  description: >-
    Skeletal muscle breaks down, releasing myoglobin and intracellular contents. Several
    contributors are plausible and none is established as dominant: increased muscular
    activity from agitation, direct muscle compression in an obtunded patient,
    hyperthermia, and alpha-adrenergic vasoconstriction producing muscle ischaemia.
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  evidence:
  - reference: PMID:2913784
    reference_title: Cocaine-associated acute myoglobinuric renal failure.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe herein four patients with rhabdomyolysis and acute myoglobinuric renal failure temporally related to cocaine use."
    explanation: >-
      Case series establishing rhabdomyolysis with renal failure as a complication of acute
      cocaine intoxication.
  - reference: PMID:2913784
    reference_title: Cocaine-associated acute myoglobinuric renal failure.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mechanism of cocaine injury is unclear; possibilities include increased muscle activity, muscle compression, hyperthermia, and vasospasm with muscle ischemia."
    explanation: >-
      The authors' explicit statement that the mechanism is unsettled and multifactorial,
      which is why the incoming hyperthermia edge is typed for unknown intermediates rather
      than DIRECT.
  - reference: PMID:10414649
    reference_title: "Cocaine-associated rhabdomyolysis and excited delirium: different stages of the same syndrome."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "It appears that this syndrome is caused by changes in dopamine processing induced by chronic and intense use of cocaine rather than by the acute toxic effects of the drug."
    explanation: >-
      A direct argument against placing this node in an acute-intoxication entry at all.
      Recorded as REFUTE rather than omitted: if the rhabdomyolysis and excited-delirium
      syndrome is a chronic-use phenomenon, this arm may belong to a cocaine use disorder
      entry instead. The node is kept because rhabdomyolysis is reported in acute
      presentations, but the challenge is on the record.
  downstream:
  - target: Rhabdomyolysis
    causal_link_type: DIRECT
  - target: Myoglobinuria
    causal_link_type: DIRECT
  - target: Acute kidney injury
    causal_link_type: DIRECT

- name: Cerebral Vasoconstriction and Vascular Injury
  biological_scale: TISSUE
  description: >-
    The same adrenergic vasoconstriction applied to the cerebral circulation, together with
    hypertensive surges and vessel-wall injury, raises the risk of both ischaemic and
    haemorrhagic stroke. The epidemiological evidence is consistent in direction but
    heterogeneous: several studies in the cited systematic review found no association.
  cell_types:
  - preferred_term: smooth muscle cell of the brain vasculature
    term:
      id: CL:0002590
      label: smooth muscle cell of the brain vasculature
  evidence:
  - reference: PMID:25066468
    reference_title: 'Cocaine use and risk of stroke: a systematic review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Epidemiological evidence suggests that cocaine use increases the risk of stroke."
    explanation: >-
      Systematic review of nine epidemiological studies concluding an increased stroke risk.
  - reference: PMID:25066468
    reference_title: 'Cocaine use and risk of stroke: a systematic review.'
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Three CCS and one CSS did not find any relationship between cocaine and strokes."
    explanation: >-
      Four of the nine included studies found no association, so the same review that
      supports this node also bounds it. Recorded as a separate REFUTE item rather than
      folded into the supporting explanation.
  downstream:
  - target: Stroke
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES

- name: Acute Aortic Wall Stress
  biological_scale: TISSUE
  description: >-
    Abrupt catecholamine-driven rises in arterial pressure and shear stress on the aortic
    wall can initiate dissection, characteristically within about an hour of use and in
    patients much younger than typical dissection cohorts.
  evidence:
  - reference: PMID:33118742
    reference_title: 'Cocaine-Related Aortic Dissection: what do we know?'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Median time from last cocaine use to onset of symptoms was one hour."
    explanation: >-
      The short median interval between exposure and symptom onset across 45 cases is
      consistent with an acute haemodynamic trigger. It does not exclude a chronic
      contribution: the same paper records that most of these patients had used cocaine for
      more than a year.
  - reference: PMID:33118742
    reference_title: 'Cocaine-Related Aortic Dissection: what do we know?'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Acute aortic dissection related to cocaine use occurs in predominantly young male patients and has a dismal outcome when compared to all comer series."
    explanation: >-
      Characterises the affected population and outcome, distinguishing this entity from
      age-related aortic disease.
  downstream:
  - target: Aortic dissection
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
phenotypes:
- name: Tachycardia
  category: Cardiovascular
  description: Sinus tachycardia from catecholamine excess at cardiac beta-adrenergic receptors.
  phenotype_term:
    preferred_term: Tachycardia
    term:
      id: HP:0001649
      label: Tachycardia
  evidence:
  - reference: PMID:9725976
    reference_title: Multiple cocaine-induced seizures and corresponding cocaine and metabolite concentrations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other clinical findings included tachycardia, hypertension, diaphoresis, and disorientation."
    explanation: Tachycardia recorded in a patient with measured very high blood cocaine concentrations.
- name: Hypertension
  category: Cardiovascular
  description: Acute arterial hypertension from alpha-adrenergic vasoconstriction and increased cardiac output.
  phenotype_term:
    preferred_term: Hypertension
    term:
      id: HP:0000822
      label: Hypertension
  evidence:
  - reference: PMID:2573838
    reference_title: Cocaine-induced coronary-artery vasoconstriction.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "After cocaine was administered, the heart rate and arterial pressure rose"
    explanation: Direct measurement of the pressor response in patients given intranasal cocaine.
- name: Chest pain
  category: Cardiovascular
  description: >-
    A common acute presentation among cocaine users. It may or may not reflect infarction,
    which is why the supply-demand node rather than infarction itself is its upstream. No
    frequency claim is made: the cited sources establish the syndrome, not its rank among
    presenting complaints.
  phenotype_term:
    preferred_term: Chest pain
    term:
      id: HP:0100749
      label: Chest pain
  evidence:
  - reference: PMID:29921621
    reference_title: 'Outcomes of beta blocker use in cocaine-associated chest pain: a meta-analysis.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "364 patients who presented to a Detroit emergency department with chest pain and positive urine drug screen for cocaine were included"
    explanation: >-
      Describes a cohort assembled from patients presenting acutely with chest pain and
      cocaine exposure, which is the presentation this phenotype names.
- name: Myocardial infarction
  category: Cardiovascular
  description: >-
    Infarction occurring in the hour after use, in patients who are otherwise at
    relatively low risk.
  phenotype_term:
    preferred_term: Myocardial infarction
    term:
      id: HP:0001658
      label: Myocardial infarction
  evidence:
  - reference: PMID:10351966
    reference_title: Triggering of myocardial infarction by cocaine.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The risk of myocardial infarction onset was elevated 23.7 times over baseline"
    explanation: Quantifies the transient excess infarction risk after cocaine use.
  - reference: PMID:29921621
    reference_title: "Outcomes of beta blocker use in cocaine-associated chest pain: a meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "It has been estimated that up to 22% of non-fatal myocardial infarctions in persons 18–45 years of age have been attributed to cocaine abuse"
    explanation: >-
      The share of young-adult infarction attributed to cocaine. Quoted from the review's
      introduction restating others' estimates, hence quote_role BACKGROUND.
- name: Prolonged QRS complex
  category: Cardiovascular
  description: QRS widening reflecting slowed ventricular conduction from sodium-channel blockade.
  phenotype_term:
    preferred_term: Prolonged QRS complex
    term:
      id: HP:0006677
      label: Prolonged QRS complex
  evidence:
  - reference: PMID:14677787
    reference_title: Electrophysiologic and hemodynamic effects of sodium bicarbonate in a canine model of severe cocaine intoxication.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Immediately after administering NaHCO3, QRS duration decreased by 30% (p < 0.001), returning to baseline more quickly than in the control group."
    explanation: >-
      QRS widening in cocaine-poisoned dogs, and its reversal by sodium bicarbonate, is the
      quantitative measurement behind this phenotype.
  - reference: PMID:18815938
    reference_title: Management of cocaine-induced cardiac arrhythmias due to cardiac ion channel dysfunction.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "QRS prolongation secondary to sodium channel blockade"
    explanation: >-
      Names QRS prolongation and attributes it to sodium-channel blockade in a human
      clinical review, so this phenotype does not rest on canine data alone.
- name: Prolonged QT interval
  category: Cardiovascular
  description: QT prolongation from hERG blockade.
  phenotype_term:
    preferred_term: Prolonged QT interval
    term:
      id: HP:0001657
      label: Prolonged QT interval
  evidence:
  - reference: PMID:11561083
    reference_title: Effects of cocaine and its major metabolites on the HERG-encoded potassium channel.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Cocaine abuse has been reported to result in QT prolongation in humans"
    explanation: >-
      The human clinical observation of QT prolongation, quoted from the background of the
      in-vitro study that went on to explain it.
- name: Ventricular tachycardia
  category: Cardiovascular
  description: Ventricular tachyarrhythmia arising on a reentrant, triggered or ischaemic substrate.
  phenotype_term:
    preferred_term: Ventricular tachycardia
    term:
      id: HP:0004756
      label: Ventricular tachycardia
  evidence:
  - reference: PMID:14677787
    reference_title: Electrophysiologic and hemodynamic effects of sodium bicarbonate in a canine model of severe cocaine intoxication.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Seven dogs experienced significant arrhythmias, including VT, pulseless electrical activity, and third-degree atrioventricular block"
    explanation: >-
      Ventricular tachycardia observed in an anaesthetised canine model of severe cocaine
      intoxication.
  - reference: PMID:18815938
    reference_title: Management of cocaine-induced cardiac arrhythmias due to cardiac ion channel dysfunction.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Excessive catecholamines, combined with sodium and potassium channel blockades, give rise to a wide variety of supra-ventricular and ventricular rhythms."
    explanation: >-
      Human-facing statement of the ventricular arrhythmia spectrum in cocaine users, so
      this phenotype does not rest on canine data alone.
- name: Sudden cardiac death
  category: Cardiovascular
  description: Death from malignant ventricular arrhythmia during acute intoxication.
  phenotype_term:
    preferred_term: Sudden cardiac death
    term:
      id: HP:0001645
      label: Sudden cardiac death
  evidence:
  - reference: PMID:14677787
    reference_title: Electrophysiologic and hemodynamic effects of sodium bicarbonate in a canine model of severe cocaine intoxication.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Cocaine toxicity causes myocardial depression, malignant dysrhythmias, and sudden death, partially due to cocaine-related myocardial sodium channel blockade."
    explanation: >-
      Names sudden death as an outcome of cocaine toxicity and attributes it partly to the
      sodium-channel mechanism modelled upstream. Quoted from this paper's OBJECTIVE
      background rather than from its canine results, hence quote_role BACKGROUND.
- name: Agitation
  category: Neurological
  description: Psychomotor agitation from central monoamine excess.
  phenotype_term:
    preferred_term: Agitation
    term:
      id: HP:0000713
      label: Agitation
  evidence:
  - reference: PMID:10414649
    reference_title: "Cocaine-associated rhabdomyolysis and excited delirium: different stages of the same syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the experiencing of excitement, delirium, and hyperthermia"
    explanation: >-
      Excitement and delirium recorded as features shared across 150 cocaine-associated
      rhabdomyolysis cases and 58 fatal excited-delirium cases.
- name: Confusion
  category: Neurological
  description: Disorientation at high cocaine concentrations.
  phenotype_term:
    preferred_term: Confusion
    term:
      id: HP:0001289
      label: Confusion
  evidence:
  - reference: PMID:9725976
    reference_title: Multiple cocaine-induced seizures and corresponding cocaine and metabolite concentrations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other clinical findings included tachycardia, hypertension, diaphoresis, and disorientation."
    explanation: Disorientation documented alongside measured peak cocaine concentrations.
- name: Hyperhidrosis
  category: Neurological
  description: Diaphoresis, part of the sympathomimetic toxidrome.
  phenotype_term:
    preferred_term: Hyperhidrosis
    term:
      id: HP:0000975
      label: Hyperhidrosis
  evidence:
  - reference: PMID:9725976
    reference_title: Multiple cocaine-induced seizures and corresponding cocaine and metabolite concentrations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other clinical findings included tachycardia, hypertension, diaphoresis, and disorientation."
    explanation: Diaphoresis recorded as part of the acute presentation.
- name: Seizure
  category: Neurological
  description: >-
    Generalized seizures, occurring within about an hour of ingestion and abating
    spontaneously, with structural causes excluded.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:9725976
    reference_title: Multiple cocaine-induced seizures and corresponding cocaine and metabolite concentrations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Approximately 1 hour after the ingestion incidents, the patient had multiple, generalized seizures that abated spontaneously."
    explanation: Documents the seizure semiology and its temporal relation to ingestion.
- name: Hyperthermia
  category: Metabolic
  description: >-
    Non-febrile elevation of core temperature from failed heat dissipation. See the
    entry-level notes for why this is not bound to HP:0001945 Fever. Note the bound term is
    direction-neutral: HP:0004370's children include both Hypothermia and Fever, so the
    binding asserts only that temperature regulation is abnormal. The direction is carried
    by preferred_term and by this description, not by the ontology term.
  phenotype_term:
    preferred_term: Hyperthermia
    term:
      id: HP:0004370
      label: Abnormality of temperature regulation
  evidence:
  - reference: PMID:12044126
    reference_title: Mechanism of cocaine-induced hyperthermia in humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cocaine substantially augmented the progressive increase in esophageal temperature during heat stress"
    explanation: >-
      Direct measurement of the temperature rise under controlled heat stress in a
      randomised crossover trial.
- name: Rhabdomyolysis
  category: Musculoskeletal
  description: Skeletal muscle breakdown during acute intoxication.
  phenotype_term:
    preferred_term: Rhabdomyolysis
    term:
      id: HP:0003201
      label: Rhabdomyolysis
  evidence:
  - reference: PMID:2913784
    reference_title: Cocaine-associated acute myoglobinuric renal failure.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Acute cocaine intoxication was the most common presentation and rhabdomyolysis was an unexpected finding."
    explanation: Rhabdomyolysis identified in patients presenting with acute cocaine intoxication.
- name: Myoglobinuria
  category: Renal
  description: Myoglobin released from necrotic muscle appears in urine.
  phenotype_term:
    preferred_term: Myoglobinuria
    term:
      id: HP:0002913
      label: Myoglobinuria
  evidence:
  - reference: PMID:2913784
    reference_title: Cocaine-associated acute myoglobinuric renal failure.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe herein four patients with rhabdomyolysis and acute myoglobinuric renal failure temporally related to cocaine use."
    explanation: Myoglobinuric renal failure documented in the case series.
- name: Acute kidney injury
  category: Renal
  description: Myoglobin-mediated tubular injury following rhabdomyolysis.
  phenotype_term:
    preferred_term: Acute kidney injury
    term:
      id: HP:0001919
      label: Acute kidney injury
  evidence:
  - reference: PMID:2913784
    reference_title: Cocaine-associated acute myoglobinuric renal failure.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Renal failure progressed rapidly in all patients, necessitating dialysis in two."
    explanation: Documents the severity and course of the renal injury in the case series.
- name: Stroke
  category: Neurological
  description: >-
    Both ischaemic and haemorrhagic stroke. The epidemiological support is positive in
    direction but heterogeneous; see the upstream node's REFUTE item.
  phenotype_term:
    preferred_term: Stroke
    term:
      id: HP:0001297
      label: Stroke
  evidence:
  - reference: PMID:25066468
    reference_title: 'Cocaine use and risk of stroke: a systematic review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Epidemiological evidence suggests that cocaine use increases the risk of stroke."
    explanation: Conclusion of a systematic review of nine epidemiological studies.
- name: Aortic dissection
  category: Cardiovascular
  description: Acute aortic dissection, characteristically within an hour of use and in young patients.
  phenotype_term:
    preferred_term: Aortic dissection
    term:
      id: HP:0002647
      label: Aortic dissection
  evidence:
  - reference: PMID:33118742
    reference_title: 'Cocaine-Related Aortic Dissection: what do we know?'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The observed cases of acute aortic dissection related to cocaine use showed a high proportion of young"
    explanation: Characterises the cocaine-related dissection cohort as predominantly young.
treatments:
- name: Benzodiazepine Sedation
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    First-line treatment, and the one that addresses the most upstream node the clinician
    can reach. Sedation damps the central stimulation arm, and by lowering blood pressure
    and cardiac output it reduces myocardial oxygen demand at the same time. One drug,
    both arms of the toxidrome.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: diazepam
      term:
        id: CHEBI:49575
        label: diazepam
  target_mechanisms:
  - target: Central Nervous System Stimulation
    treatment_effect: INHIBITS
  - target: Increased Myocardial Oxygen Demand
    treatment_effect: INHIBITS
  evidence:
  - reference: PMID:35448887
    reference_title: 'Cocaine: An Updated Overview on Chemistry, Detection, Biokinetics, and Pharmacotoxicological Aspects including Abuse Pattern.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Not only do benzodiazepines exert anxiolytic action, but they also attenuate toxic effects at the cardiovascular and cerebral level, by reducing both blood pressure and cardiac output, which makes them a key first approach in treating cocaine acute intoxications"
    explanation: >-
      States the anxiolytic action and the reduction in blood pressure and cardiac output,
      which is the demand-side target, and the first-line status. The snippet does not name
      central nervous system stimulation; that link rests on the anxiolytic action.

- name: Sodium Bicarbonate for Sodium-Channel Blockade
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Given for a widened QRS. It works against the channel arm specifically, and it is the
    reason the QRS is diagnostically useful: a complex that narrows after bicarbonate was
    widened by sodium-channel blockade.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: sodium bicarbonate
      term:
        id: CHEBI:32139
        label: sodium hydrogencarbonate
  target_mechanisms:
  - target: Slowed Ventricular Conduction
    treatment_effect: INHIBITS
    evidence:
    - reference: PMID:14677787
      reference_title: Electrophysiologic and hemodynamic effects of sodium bicarbonate in a canine model of severe cocaine intoxication.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Immediately after administering NaHCO3, QRS duration decreased by 30% (p < 0.001), returning to baseline more quickly than in the control group."
      explanation: Direct measurement of the reversal of conduction slowing in a canine intoxication model.
  evidence:
  - reference: PMID:14677787
    reference_title: Electrophysiologic and hemodynamic effects of sodium bicarbonate in a canine model of severe cocaine intoxication.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "NaHCO3 improved ECG changes secondary to cocaine toxicity and improved myocardial function."
    explanation: >-
      The study's overall conclusion. Note this is animal evidence: no randomised human
      trial of bicarbonate in cocaine toxicity exists.

- name: Phentolamine
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Alpha-adrenergic blockade, aimed squarely at the coronary vasoconstriction node. In the
    human catheterisation study it returned coronary flow, calibre and haemodynamics to
    baseline, which is both the therapeutic rationale and the proof that the constriction
    was alpha-mediated.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: phentolamine
      term:
        id: CHEBI:8081
        label: phentolamine
  target_mechanisms:
  - target: Alpha-Adrenergic Coronary Vasoconstriction
    treatment_effect: INHIBITS
    evidence:
    - reference: PMID:2573838
      reference_title: Cocaine-induced coronary-artery vasoconstriction.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "the administration of the alpha-adrenergic blocking agent phentolamine caused all these values to return to base-line levels"
      explanation: >-
        Reversal of every measured variable by alpha blockade, in humans, establishes both
        the target and the mechanism.

- name: Nitroglycerin
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Nitrovasodilation, acting downstream of the adrenergic receptor rather than at it. It
    abolished cocaine-induced constriction in both diseased and non-diseased coronary
    segments.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: nitroglycerin
      term:
        id: CHEBI:28787
        label: nitroglycerin
  target_mechanisms:
  - target: Alpha-Adrenergic Coronary Vasoconstriction
    treatment_effect: INHIBITS
    evidence:
    - reference: PMID:1906905
      reference_title: Alleviation of cocaine-induced coronary vasoconstriction by nitroglycerin.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Sublingual nitroglycerin abolished the vasoconstriction in both non-diseased and diseased segments."
      explanation: Quantitative arteriographic demonstration of reversal in humans.

- name: Beta-Adrenergic Blockade
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Curated as a contested treatment, not a recommended one. The mechanistic case against
    it is that blocking beta receptors leaves alpha-mediated vasoconstriction unopposed,
    and this has been measured directly in humans: intracoronary propranolol after cocaine
    further reduced coronary flow and further raised coronary vascular resistance. The
    outcome case for it is that a meta-analysis of five studies and 1794 patients found no
    difference in infarction or mortality. Both are curated here, the first as SUPPORT for
    the mechanism and the second as REFUTE against the claim that the mechanism translates
    into harm. See the mechanistic_hypotheses block.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: propranolol
      term:
        id: CHEBI:8499
        label: propranolol
  target_mechanisms:
  - target: Alpha-Adrenergic Coronary Vasoconstriction
    treatment_effect: ACTIVATES
    description: >-
      Beta blockade increases, rather than reduces, this mechanism. ACTIVATES is the
      TreatmentEffectEnum value meaning "promotes or increases the mechanism"; the enum has
      no value for a treatment that worsens a lesion, and this is the accurate one.
    evidence:
    - reference: PMID:1971166
      reference_title: Potentiation of cocaine-induced coronary vasoconstriction by beta-adrenergic blockade.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Cocaine-induced coronary vasoconstriction is potentiated by beta-adrenergic blockade."
      explanation: >-
        Randomised, double-blind, placebo-controlled catheterisation study measuring the
        potentiation directly, which is the edge this link asserts.
  evidence:
  - reference: PMID:1971166
    reference_title: Potentiation of cocaine-induced coronary vasoconstriction by beta-adrenergic blockade.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Beta-adrenergic blocking agents probably should be avoided in patients with cocaine-associated myocardial ischemia or infarction."
    explanation: The authors' own recommendation, which became the basis of guideline advice.
  - reference: PMID:4051280
    reference_title: Propranolol-induced hypertension in treatment of cocaine intoxication.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "IV propranolol was used as the initial treatment for his hyperadrenergic state, resulting in a decrease in heart rate but a paroxsymal increase in blood pressure."
    explanation: >-
      The case report proposing unopposed alpha stimulation. The spelling
      "paroxsymal" is the source's own and is quoted unaltered.
  - reference: PMID:29921621
    reference_title: 'Outcomes of beta blocker use in cocaine-associated chest pain: a meta-analysis.'
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "there was no significant difference in the rate of non-fatal myocardial infarction or all-cause mortality"
    explanation: >-
      Meta-analysis of five studies finding no outcome difference, which refutes the
      stronger claim that beta blockade causes clinical harm here.
  - reference: PMID:29921621
    reference_title: 'Outcomes of beta blocker use in cocaine-associated chest pain: a meta-analysis.'
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "the evidence supporting these recommendations are largely from animal studies, expert opinion and theoretical observations"
    explanation: >-
      The review's assessment of the evidence base behind the guideline prohibition, which
      bounds how strongly the contraindication can be stated.

- name: Antipsychotic Agents
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Recorded as a treatment that is described and not recommended. Antipsychotics are
    sometimes reached for in an agitated cocaine patient; the cited review's stated reason
    for caution is that they add to the arrhythmic burden of a drug already blocking two
    cardiac channels. The target_mechanisms link is therefore to arrhythmogenesis, and it
    is typed ACTIVATES because that is the direction of the effect the source describes.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: haloperidol
      term:
        id: CHEBI:5613
        label: haloperidol
  target_mechanisms:
  - target: Ventricular Arrhythmogenesis
    treatment_effect: ACTIVATES
    description: >-
      Not a therapeutic effect on this node but a worsening one, which is why this
      treatment is curated with REFUTE evidence.
  evidence:
  - reference: PMID:35448887
    reference_title: 'Cocaine: An Updated Overview on Chemistry, Detection, Biokinetics, and Pharmacotoxicological Aspects including Abuse Pattern.'
    supports: REFUTE
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "The use of antipsychotics to manage cocaine intoxications is questionable and potentially dangerous, as they may intensify the risk of cardiac dysrhythmias."
    explanation: >-
      Graded REFUTE because it argues against the intervention. The stated reason is the
      arrhythmia risk this entry models on the channel and arrhythmogenesis nodes.
mechanistic_hypotheses:
- hypothesis_group_id: unopposed_alpha_stimulation
  hypothesis_label: Beta blockade worsens cocaine cardiotoxicity through unopposed alpha stimulation
  status: ALTERNATIVE
  description: >-
    The proposition that giving a beta blocker during cocaine intoxication removes
    beta-mediated vasodilation and leaves alpha-mediated coronary vasoconstriction
    unopposed, worsening ischaemia. It is recorded as a hypothesis rather than as fact
    because the mechanistic and the outcome evidence point different ways and both are
    good.

    For: intracoronary propranolol given after cocaine in a randomised, double-blind,
    placebo-controlled catheterisation study further reduced coronary sinus blood flow and
    further raised coronary vascular resistance, in humans, measured directly
    (PMID:1971166). The effect is real and it is not small.

    Against: a meta-analysis of five studies and 1794 patients with cocaine-associated
    chest pain found no significant difference in non-fatal myocardial infarction or
    all-cause mortality between those who received a beta blocker and those who did not
    (PMID:29921621).

    These are not actually contradictory. One measures a physiological variable minutes
    after an intracoronary drug in a catheterisation laboratory; the other measures
    clinical outcomes in patients who mostly received oral beta blockers hours later. The
    open question is whether the measured haemodynamic effect is large enough, and
    sustained enough, to change outcomes. Note the outcome studies are all retrospective
    and none is randomised, which the meta-analysis itself lists first among its
    limitations.
  notes: >-
    Resolving this needs a randomised trial of beta blockade in cocaine-associated chest
    pain, which does not exist; the meta-analysis states it found none meeting its criteria.

environmental:
- name: Concurrent ethanol ingestion
  description: >-
    Taking cocaine with alcohol is not simply taking two drugs. Hepatic transesterification
    produces cocaethylene, a pharmacologically active metabolite with a longer half-life
    than cocaine, which is itself a slightly more potent hERG blocker than cocaine. So the
    combination changes what is in the blood, not just how much.
  exposure_term:
    preferred_term: exposure to ethanol
    term:
      id: ECTO:9000027
      label: exposure to ethanol
  influences_mechanisms:
  - target: hERG Potassium Channel Blockade
    environmental_effect: EXACERBATES
    causal_link_type: DIRECT
    description: >-
      Cocaethylene, formed only when ethanol is present, blocks hERG more potently than
      cocaine does.
    evidence:
    - reference: PMID:11561083
      reference_title: Effects of cocaine and its major metabolites on the HERG-encoded potassium channel.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "We conclude that cocaethylene is slightly more potent than cocaine as a blocker of HERG"
      explanation: >-
        Direct comparison of cocaine and cocaethylene IC50 at the same channel in the same
        expression system.
  - target: Sympathetic Cardiovascular Stimulation
    environmental_effect: EXACERBATES
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:21463066
      reference_title: Cocaethylene formation following ethanol and cocaine administration by different routes.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Within each route, the cocaine-ethanol combination produced greater increases in heart rate and rate-pressure product than cocaine alone."
      explanation: >-
        Measured in humans across three routes of administration, so the potentiation is
        not an artefact of one route.
  evidence:
  - reference: PMID:21463066
    reference_title: Cocaethylene formation following ethanol and cocaine administration by different routes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ethanol alters the hepatic biotransformation of cocaine, resulting in transesterification to a novel active metabolite, cocaethylene."
    explanation: States the metabolic basis of the interaction.
  - reference: PMID:35448887
    reference_title: "Cocaine: An Updated Overview on Chemistry, Detection, Biokinetics, and Pharmacotoxicological Aspects including Abuse Pattern."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "CE is an active metabolite that displays pharmacological activity, with a longer average half-life"
    explanation: >-
      Sources the longer-half-life claim in the node description, which was otherwise
      asserted without evidence.
  - reference: PMID:21463066
    reference_title: Cocaethylene formation following ethanol and cocaine administration by different routes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The oral route (34% ± 20) was significantly greater than from the smoked route (18% ± 11)"
    explanation: >-
      Quantifies how much of a cocaine dose becomes cocaethylene and shows it depends on
      route, which bounds how strongly the interaction applies to any given exposure.

- name: Cocaine exposure
  description: >-
    The exposure itself. Route matters for onset and for the fraction converted to
    cocaethylene when ethanol is present, but all routes converge on the same systemic node.
  exposure_term:
    preferred_term: exposure to cocaine
    term:
      id: ECTO:9000265
      label: exposure to cocaine
  influences_mechanisms:
  - target: Systemic Cocaine Exposure
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:10351966
      reference_title: Triggering of myocardial infarction by cocaine.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The elevated risk rapidly decreased thereafter."
      explanation: >-
        The excess infarction risk is confined to the period immediately after use, which
        is what makes the exposure itself the initiating event for this entry.
  evidence:
  - reference: PMID:31048676
    reference_title: Drug Overdose Deaths Involving Cocaine and Psychostimulants with Abuse Potential - United States, 2003-2017.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among all 2017 drug overdose deaths, 13,942 (19.8%) involved cocaine"
    explanation: Establishes the scale of fatal cocaine exposure in a national surveillance dataset.
genetic:
- name: SLC6A3
  gene_term:
    preferred_term: SLC6A3
    term:
      id: hgnc:11049
      label: SLC6A3
  relationship_type: SUSCEPTIBILITY
  association: Modifier of risk of fatal cocaine intoxication, in epistasis with DRD2.
  notes: >-
    A regulatory VNTR in the dopamine transporter gene modifies risk of fatal cocaine
    intoxication, but only in combination with a DRD2 splicing variant. Neither locus
    carries significant risk on its own in the cited analysis, which is the point: this is
    an epistatic interaction, not an additive one.
  evidence:
  - reference: PMID:23340505
    reference_title: "Dopamine transporter DAT and receptor DRD2 variants affect risk of lethal cocaine abuse: a gene-gene-environment interaction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These results demonstrate gene-gene-drug interaction affecting risk of fatal cocaine intoxication."
    explanation: >-
      Brain-bank case-control analysis reporting the DAT-DRD2 interaction as a determinant
      of risk of death from cocaine.
- name: DRD2
  gene_term:
    preferred_term: DRD2
    term:
      id: hgnc:3023
      label: DRD2
  relationship_type: SUSCEPTIBILITY
  association: Modifier of risk of fatal cocaine intoxication, in epistasis with SLC6A3.
  notes: >-
    The DRD2 splicing polymorphism that confers the risk, amplified in carriers of the
    main DAT repeat allele. Curated as SUSCEPTIBILITY, not CAUSATIVE: cocaine exposure
    causes this disease, and these variants modify who dies of it.
  evidence:
  - reference: PMID:23340505
    reference_title: "Dopamine transporter DAT and receptor DRD2 variants affect risk of lethal cocaine abuse: a gene-gene-environment interaction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These results demonstrate gene-gene-drug interaction affecting risk of fatal cocaine intoxication."
    explanation: >-
      Same analysis, cited for the DRD2 side of the interaction.

clinical_burden:
  burden_level: HIGH
  rationale: >-
    Cocaine is involved in roughly a fifth of US drug overdose deaths, and acute
    intoxication kills through mechanisms that act within minutes to an hour of exposure:
    ventricular arrhythmia, myocardial infarction, aortic dissection. The figure that
    matters mechanistically is the second one below. Nearly three quarters of
    cocaine-involved deaths also involve an opioid, so most fatal cocaine exposures are
    not pure cocaine toxicity, and cocaine-attributable mortality cannot be read off these
    totals.
  evidence:
  - reference: PMID:31048676
    reference_title: Drug Overdose Deaths Involving Cocaine and Psychostimulants with Abuse Potential - United States, 2003-2017.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among all 2017 drug overdose deaths, 13,942 (19.8%) involved cocaine"
    explanation: National vital statistics surveillance of cocaine-involved overdose deaths.
  - reference: PMID:31048676
    reference_title: Drug Overdose Deaths Involving Cocaine and Psychostimulants with Abuse Potential - United States, 2003-2017.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nearly three fourths (72.7%) of cocaine-involved deaths in 2017 also involved opioids."
    explanation: >-
      Bounds every mortality claim in this entry: most cocaine-involved deaths are
      polysubstance.

discussions:
- discussion_id: cocaine_beta_blocker_outcome_gap
  kind: KNOWLEDGE_GAP
  prompt: >-
    Does the haemodynamic potentiation of cocaine-induced coronary vasoconstriction by
    beta blockade translate into worse clinical outcomes?
  attaches_to:
  - treatments#Beta-Adrenergic Blockade
  - pathophysiology#Alpha-Adrenergic Coronary Vasoconstriction
  rationale: >-
    The mechanism has been measured directly in humans and the outcome studies find no
    difference, but every outcome study is retrospective and the meta-analysis found no
    randomised trial meeting its criteria. Until one exists the contraindication rests on
    a physiological endpoint and the permission rests on observational data, which is why
    guidelines and practice have diverged.
- discussion_id: cocaine_seizure_mechanism_gap
  kind: KNOWLEDGE_GAP
  prompt: >-
    What is the molecular mechanism of cocaine-induced seizures, and does it differ from
    the mechanism of cocaine-induced hyperthermia?
  attaches_to:
  - pathophysiology#Central Neuronal Hyperexcitability
  rationale: >-
    The cited source states plainly that the aetiology of cocaine-associated seizures is
    unclear, which is why the edge into this node is typed
    INDIRECT_UNKNOWN_INTERMEDIATES and the node asserts no molecular claim. A GABAergic or glutamatergic account is routinely offered for
    stimulant seizures but nothing cited here demonstrates one at the concentrations
    reached in human intoxication.
- discussion_id: cocaine_bche_severity_gap
  kind: KNOWLEDGE_GAP
  prompt: >-
    Does butyrylcholinesterase activity modify the severity of acute cocaine toxicity in
    humans?
  attaches_to:
  - pathophysiology#Systemic Cocaine Exposure
  rationale: >-
    Plasma butyrylcholinesterase hydrolyses most of a cocaine dose, so variation in its
    activity is a plausible determinant of how much drug reaches its targets. This gap is
    specifically about BCHE: no source establishing a BCHE-severity link in human
    intoxication was found during this curation. It is not a claim that cocaine toxicity
    has no genetic modifiers - the genetic section curates a DAT-DRD2 interaction affecting
    risk of fatal intoxication (PMID:23340505), and PMID:24312228 on BCHE variants, which is
    cached here, is about dependence rather than acute toxicity.

references:
- reference: PMID:18347214
  title: "Management of cocaine-associated chest pain and myocardial infarction: a scientific statement from the American Heart Association Acute Cardiac Care Committee of the Council on Clinical Cardiology."
- reference: PMID:23269350
  title: Cutaneous vasculopathy and neutropenia associated with levamisole-adulterated cocaine.
- reference: PMID:2382909
  title: "Crack lung: an acute pulmonary syndrome with a spectrum of clinical and histopathologic findings."
📚

References & Deep Research

References

3
PMID:18347214
Management of cocaine-associated chest pain and myocardial infarction: a scientific statement from the American Heart Association Acute Cardiac Care Committee of the Council on Clinical Cardiology.
No top-level findings curated for this source.
PMID:23269350
Cutaneous vasculopathy and neutropenia associated with levamisole-adulterated cocaine.
No top-level findings curated for this source.
PMID:2382909
Crack lung: an acute pulmonary syndrome with a spectrum of clinical and histopathologic findings.
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (2)

Record notes

Scope. This entry covers acute systemic toxicity from cocaine itself. Three things are deliberately outside it, each for a stated reason rather than by omission. (1) Cocaine use disorder. The KB already curates Opioid_Use_Disorder and Alcohol_Use_Disorder as chronic substance use disorders distinct from the acute and organ-specific consequences of the same substance, which are separate entries (Alcoholic_Liver_Disease, Fetal_Alcohol_Spectrum_Disorder, Acute_Alcohol_Sensitivity). Acute cocaine intoxication is the analogous split: it occurs in people with no use disorder, and MONDO codes it separately, under poisoning (MONDO:0019544) rather than under substance dependence. No cocaine use disorder entry exists yet; this entry does not attempt to be one and models no dependence, tolerance or withdrawal mechanism. (2) Levamisole-adulterated cocaine. Levamisole is a common cocaine adulterant that causes a p-ANCA-positive small-vessel vasculopathy with neutropenia (PMID:23269350, cited in references below). It is excluded here because it is a different molecule acting by a different, immune-mediated mechanism over days to weeks, not an effect of cocaine and not an acute intoxication syndrome. Bundling it would put two unrelated mechanistic claims in one entry. It is a candidate for its own entry. (3) Cocaine-associated cardiomyopathy and accelerated atherosclerosis are chronic structural sequelae of repeated intoxication rather than features of a single acute episode, and are not modelled. Hyperthermia binding. The Hyperthermia phenotype is bound to HP:0004370 Abnormality of temperature regulation rather than to HP:0001945 Fever, even though HPO lists "Hyperthermia" among Fever's other names and the deep-research report suggested HP:0001945. HP:0001945's own definition rejects that reading: it states that "The rise in temperature during fever is to be distinguished from that occurring during episodes of hyperthermia. Unlike fever, hyperthermia involves an unregulated rise in body temperature in which pyrogenic cytokines are not directly involved... It represents a failure of thermoregulatory homeostasis, in which there is uncontrolled heat production, inadequate heat dissipation, or defective hypothalamic thermoregulation." Inadequate heat dissipation is precisely what the cited human trial (PMID:12044126) demonstrates for cocaine, so binding Fever would assert the mechanism that source excludes. HP:0004370 is the parent of Fever and is not in the schema's 56-term coarse phenotype set, so no coarse_binding_basis applies. HPO has no term for non-febrile hyperthermia; preferred_term carries the specificity the binding loses. Crack lung and mesenteric ischaemia are absent. Inhalational alveolar injury ("crack lung", PMID:2382909, listed under references) is specific to the smoked freebase route and is a direct local injury at the alveolar surface rather than a consequence of the systemic exposure node every other branch descends from; modelling it would need a second root with a different exposure route. Mesenteric ischaemia is the same adrenergic vasoconstriction mechanism already modelled for the coronary and cerebral beds, applied to a third bed, and was left out only because no quotable source for it was verified during this curation. Both are candidates for a follow-up pass rather than scope exclusions. No diagnosis, prevalence, biochemical, datasets or animal_models sections are curated. The canine sodium-bicarbonate study (PMID:14677787) is cited as evidence but not curated as an AnimalModel with modeled_mechanisms, which would make its fidelity and limitations explicit; that is the most worthwhile of these to add next. GeneReviews. `just check-genereviews` returns NO_CHAPTER: no GeneReviews chapter names this disease, which is expected for a poisoning rather than a Mendelian disorder, so no chapter baseline applies. The StatPearls line also returns NO_CHAPTER against this entry's name; StatPearls is never a phenotype baseline in any case. Evidence not used. PMID:18347214, the American Heart Association scientific statement on cocaine-associated chest pain, is the authoritative management source and is listed under references, but its cached record carries no abstract body, so no snippet can be taken from it and no claim here rests on it.

Create: Cocaine Intoxication (MONDO:0019544) · 2026-09-21T02:45:27Z · View source

New entry for acute cocaine toxicity, modelled as two pharmacological arms acting simultaneously (monoamine reuptake blockade and local-anaesthetic sodium-channel blockade) rather than as a single chain. 21 pathophysiology nodes, 18 phenotypes all causally connected, 6 treatments, 2 genetic susceptibility entries, 2 environmental exposures, 1 mechanistic hypothesis, 3 knowledge gaps. Three nodes conform to xenobiotic_cardiac_channel_perturbation. Deep research: just research-disorder claude_code (25 web searches, 56 citations, ~6 min). The report carried no validation sections so both were retro-fitted: references 40/40 resolved, 0 unresolved, 0 off topic; terms 83/85 resolved with one obsolete (GO:0005329, superseded by GO:0005330, which is what is bound here). just preflight-dr returned SKIP because MONDO records no causal gene for a poisoning; the manual fallback passed, the report's top genes being BCHE, SLC6A3 and SCN5A. The report contributed PMIDs and ontology leads; no text was quoted from it and every CURIE was resolved independently at the moment of writing. Errors caught during curation and corrected: ECTO:9000034 was written from memory as 'exposure to ethanol' and is in fact 'exposure to benzene' (term validation caught the label mismatch; the correct term is ECTO:9000027). Two phenotypes were dropped rather than kept on weak evidence (psychosis, elevated creatine kinase). One snippet was found to differ from its source by an en-dash versus hyphen and was corrected after an independent character-exact audit of all 79 snippets. Adversarial pre-PR review by a fresh-context subagent produced 32 findings across CRITICAL/IMPORTANT/MINOR; 30 were taken before the PR was opened. The substantive ones: the Agitation phenotype's only evidence never mentioned agitation (replaced with PMID:10414649); a background sentence supporting impaired heat dissipation actually asserted the increased-heat-production account it displaces (regraded NO_EVIDENCE); an NLM OBJECTIVE-section background sentence from a canine study was graded MODEL_ORGANISM in two places (regraded HUMAN_CLINICAL with quote_role BACKGROUND); three human phenotypes rested on canine evidence alone (human items added); causal_link_type UNKNOWN was used where INDIRECT_UNKNOWN_INTERMEDIATES was meant, since directness had been assessed; 'angiographically normal coronary arteries' was asserted twice with no cited source and was removed; CL:0000359 was bound for two different vascular beds where CL:0002592 and CL:0002590 exist; GO:0005248 was replaced by the cardiac-specific GO:0086006; and the Ventricular Arrhythmogenesis conforms_to was dropped as forced, because the module's own scope note excludes arrhythmia reached through ischaemia and this node names ischaemia as one of three substrates. Two findings not taken: treatment_effect ACTIVATES on beta blockade is retained as the accurate TreatmentEffectEnum value ('promotes or increases the mechanism'), since the enum has no value for a treatment that worsens a lesion; and the Cerebral Vasoconstriction node is left bundling ischaemic and haemorrhagic routes, recorded as a known simplification. Validation: just validate-disorders passes with 79/79 snippets verified; list-disconnected-phenotypes 18/18; list-gene-term-mismatches 7/7 with full cache coverage; prose-figure-audit clean; check-genereviews NO_CHAPTER as expected for a poisoning. Clean: entity-refs, causal-targets, duplicate-keys, qualifier-terms, coarse-phenotypes, enum-values, snippet-grading, title-snippets, snippet-length, folded-hyphens, reference-titles, case-collisions, not4curation, environmental-evidence. 18 fetched-but-uncited reference caches were pruned with the cited list re-derived immediately beforehand and snippet verification re-run afterwards. All 79 reference_title values were parsed from references_cache frontmatter rather than typed.

Claude Code ▸
Cocaine Intoxication — Comprehensive Research Report
claude-haiku-4-5-20251001, claude-sonnet-5 56 citations 2026-09-21T01:54:04.391386

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)

Phenotype HPO suggestion Notes
Euphoria / inappropriate elation HP:0000734 (Impulsivity) / no exact HPO for euphoria; behavioral Nearly universal at intoxicating doses
Psychomotor agitation HP:0000725 (Psychomotor agitation, if not in HPO use HP:0100716 Self-injurious behavior adjacent) Common, dose-related
Anxiety / paranoia HP:0000739 (Anxiety) Variable
Hypervigilance — (behavioral, often free text) Common
Psychosis (paranoid ideation, hallucinations, delusions) HP:0000709 (Psychosis) Reported in 29–53% of people who use cocaine, per behavioral-health sources reviewed; mechanistically linked to dopamine sensitization in mesolimbic/mesocortical circuits
Delirium / confusion HP:0031180 (Delirium) if available, else HP:0000726 (Delirium) Severe "excited/agitated delirium" is a life-threatening variant
Impaired attention/cognition HP:0000725/HP:0000737 (variable)

Cardiovascular

Phenotype HPO Notes
Tachycardia HP:0001649 Sympathomimetic; near-universal
Hypertension HP:0000822 Sympathomimetic
Chest pain / myocardial ischemia HP:0100749 (Chest pain) Coronary vasoconstriction + prothrombotic state + increased O2 demand; MI can occur even in angiographically normal coronaries
Cardiac arrhythmia (SVT, VT, VF, torsades, AV block, Brugada-pattern ECG) HP:0011675 (Arrhythmia) Na⁺-channel blockade (Class I antiarrhythmic-like effect) widens QRS; K⁺-channel (hERG) blockade prolongs QT
Cardiomyopathy (acute/chronic) HP:0001638 Catecholamine excess + oxidative/mitochondrial injury; apoptosis and contraction-band necrosis documented histologically
Aortic dissection HP:0002647 Rare but reported, hypertension-driven

Neurologic/Cerebrovascular

Phenotype HPO Notes
Seizures HP:0001250 Glutamate/excitotoxicity-mediated, dose-related, can be first presentation
Ischemic stroke HP:0002140 (Cerebral ischemia) Vasospasm of large/microvascular cerebral arteries, endothelin-1-mediated
Intracerebral/subarachnoid hemorrhage HP:0007183 / HP:0033040 Hypertensive surges + vasculitis + weakened vessel walls; disproportionately affects young adults
Headache HP:0002315 Common, often vasospasm-related

Thermoregulatory/Musculoskeletal

Phenotype HPO Notes
Hyperthermia HP:0001945 Impaired heat-dissipation (thermoregulatory adjustment failure) plus increased heat generation from agitation/muscle activity; potentiated by ambient heat
Rhabdomyolysis HP:0003201 Muscle ischemia from vasoconstriction, direct myotoxicity, catecholamine-driven hypermetabolism, sarcoplasmic Ca²⁺ dysregulation
Acute kidney injury (secondary to rhabdomyolysis/vasoconstriction) HP:0001919 Myoglobin-mediated tubular injury

Respiratory

Phenotype HPO Notes
Bronchospasm/wheezing ("crack lung") HP:0030828 Smoked/inhaled route
Pneumothorax HP:0002094-adjacent / HP:0025299 Barotrauma from Valsalva-like inhalation technique
Acute lung injury / alveolar hemorrhage HP:0002088-adjacent

Gastrointestinal

Phenotype HPO Notes
Mesenteric/bowel ischemia, perforation, ischemic colitis HP:0002583-adjacent (Gastrointestinal hemorrhage) / free text Norepinephrine-reuptake-blockade-driven splanchnic vasoconstriction; historically linked to oral ("body-packer/stuffer") ingestion

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

Domain Suggested terms
MONDO MONDO:0019544 (cocaine intoxication)
CHEBI CHEBI:27958 (cocaine); CHEBI:83415 (benzoylecgonine, verify); relevant treatment agents (lorazepam CHEBI:6539, sodium bicarbonate CHEBI:32139)
GO (molecular function) GO:0005329 (dopamine transporter activity); GO:0005335 (serotonin transporter activity); GO:0005326 (neurotransmitter transporter activity); GO:0005248 (voltage-gated Na⁺ channel activity); GO:0005249 (voltage-gated K⁺ channel activity)
GO (biological process) GO:0006979 (response to oxidative stress); GO:0006915 (apoptotic process); GO:0007204 (positive regulation of cytosolic Ca²⁺)
CL CL:0000746 (cardiac muscle cell); CL:0000359 (vascular smooth muscle cell); CL:0000700 (dopaminergic neuron); CL:0000187 (skeletal muscle cell)
UBERON UBERON:0000948 (heart); UBERON:0000955 (brain); UBERON:0002113 (kidney); UBERON:0001240 (superior mesenteric artery)
HP HP:0001649 (tachycardia); HP:0000822 (hypertension); HP:0001250 (seizure); HP:0003201 (rhabdomyolysis); HP:0001945 (hyperthermia); HP:0000709 (psychosis); HP:0011675 (arrhythmia); HP:0001919 (AKI)
NCIT NCIT:C15986 (Pharmacotherapy); NCIT:C15747 (Supportive Care); NCIT:C15329 (Surgical Procedure)

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

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 40
Resolved 40
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 40
On topic 13
Off topic 0

All extracted references resolved successfully.

Term Validation

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

Outcome Count
Terms checked 85
Resolved 83
Unresolved (possible confabulation) 0
Obsolete 1
Unverifiable 1
Terms whose name was checked 17
Terms named correctly 11
Terms named as a different term 4
Terms whose name is worth a second look 2

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.