generation run 2026-05-14
68 min completedmodel pipeline-v5plan not recordedrun/69b40f17…Selection
Verification
- record
- seen / partial
- working
The model's own caveats
- sparse_evidence
- context
Reproduce
- inputs
- 37 source keys (listed under Sources)
- plan
- not recorded — template version, prompt hash and git SHA are written from 2026-09 onward
- model
- pipeline-v5
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- none — agent transcripts are persisted from 2026-09 onward
36 searches — query, source, results, what was kept and why
| # | source | query | seen | kept | rationale |
|---|---|---|---|---|---|
| 1 | PubChem | cocaine | 1 | — | — |
| 2 | OpenAlex | Erythroxylum coca alkaloids cocaine taxonomy ethnobotany | 10 | 3 | Top three are directly relevant to Erythroxylum taxonomy, phylogeny, and coca vs cocaine review |
| 3 | PubMed | cocaethylene alcohol cocaine interaction formation toxicity | 8 | 3 | Important herb-drug interaction: alcohol + cocaine produces toxic cocaethylene |
| 4 | PubMed · absence | Erythroxylum coca botanical taxonomy alkaloids review | 0 | — | — |
| 5 | PubChem | norcocaine | 1 | — | — |
| 6 | PubMed | coca leaf altitude sickness acute mountain sickness traditional medicine | 2 | 1 | Direct adverse event case report for coca tea |
| 7 | ClinicalTrials.gov | cocaine use disorder treatment | 8 | 2 | Relevant to cocaine treatment trials |
| 8 | PubMed | cocaine cardiotoxicity adverse events cardiovascular fatality case report | 8 | 4 | Comprehensive reviews of cardiovascular adverse effects and fatalities |
| 9 | PubMed | cocaine pharmacokinetics bioavailability routes of administration | 10 | 4 | Directly relevant to cocaine pharmacokinetics by route |
| 10 | PubMed · absence | coca leaf cocaine alkaloid quantification HPLC | 0 | — | — |
| 11 | PubChem | benzoylecgonine | 1 | — | — |
| 12 | PubMed | cocaine drug testing urine benzoylecgonine detection window | 8 | 2 | Directly address detection windows for cocaine metabolites |
| 13 | PubChem | ecgonine | 1 | — | — |
| 14 | Web | coca leaf cocaine percentage alkaloid content | — | — | — |
| 15 | PubMed | cocaine induced psychosis paranoia hallucinations | 4 | 1 | — |
| 16 | PubMed | cocaine pharmacokinetics saliva intravenous intranasal smoked | 1 | 1 | — |
| 17 | POWO | — | — | — | — |
| 18 | PubMed | cocaine cocaine cardiotoxicity adverse events cardiovascular fatality case report | 8 | 7 | — |
| 19 | WHO | — | — | — | — |
| 20 | Web | cocaine Schedule II DEA medical use topical anesthetic ENT | — | — | — |
| 21 | PubMed | levamisole cocaine adulteration agranulocytosis | 2 | 2 | — |
| 22 | PubChem | cocaine | — | — | — |
| 23 | PubMed | cocaine pharmacokinetics humans plasma IV | 1 | 1 | — |
| 24 | PubMed | cocaine stroke cerebrovascular | 8 | 1 | — |
| 25 | PubMed | cocaine nasal septum perforation rhinitis sinusitis intranasal use | 1 | 1 | — |
| 26 | PubMed | oral cocaine bioavailability pharmacokinetics | 1 | 1 | — |
| 27 | Web | Bolivia Peru coca leaf legal status traditional use | — | — | — |
| 28 | Web | UNODC 2024 coca cultivation hectares | — | — | — |
| 29 | Web | cocaine Class A UK EU Australia legal status 2024 | — | — | — |
| 30 | PubMed | crack cocaine pulmonary complications | 7 | 1 | — |
| 31 | PubMed | cocaine withdrawal sleep insomnia dysphoria | 1 | 1 | — |
| 32 | PubMed | cocaine hepatotoxicity liver injury rhabdomyolysis | 5 | 3 | — |
| 33 | WHO | — | — | — | — |
| 34 | Multiple | Coca alkaloid concentrations verification | — | — | — |
| 35 | PubChem | cocaine ecgonine benzoylecgonine norcocaine structures | — | — | — |
| 36 | PubMed | cocaine induced psychosis paranoia hallucinations | 8 | 2 | — |
72 claims by section — every cited sentence, checked against its source
safety25 · 16 ok
Cardiovascular complications represent the most clinically significant toxicity of cocaine across all preparations:supported
Cocaine users frequently present to the emergency department, with chest pain being the most common presenting complaint. j.cjca.2022.05.003
Cocaine intoxication is the most frequent cause of drug-related death reported by medical examiners in the United Statessupported
Cocaine intoxication is the most frequent cause of drug-related death reported by medical examiners in the US; events most often related to cardiovascular manifestations. pmid:20857618
Cardiovascular complications represent the most clinically significant toxicity of cocaine across all preparations:supported
cocaine has the ability to cause irreversible structural damage to the heart, greatly accelerate cardiovascular disease, and initiate sudden cardiac death. 00129784-200909030-00005
Cardiovascular complications represent the most clinically significant toxicity of cocaine across all preparations:supported
Chest pain is the most common cocaine-related medical problem, leading to the evaluation of approximately 64,000 patients annually for possible myocardial infarction. clc.20746
Documented pathology includes perivenular and midzonal coagulative necrosis and periportal microvesicular fatty changesupported
Coagulative-type perivenular and midzonal necrosis and periportal microvesicular fatty change. pmid:2328957
Cocaine induces its own hepatic CYP metabolism with chronic dosing, potentially increasing norcocaine production over timesupported
Cocaine enhances its own cytochrome P450-dependent metabolism; increased production of norcocaine in microsomes is catalyzed mainly by CYP3A enzyme(s). pmid:8617431
Multi-organ failure involving rhabdomyolysis (CPK >100,000 U/L), acute kidney injury, and hepatic ischemia has been documented as cocaine-induced C-KLM syndrome.supported
Cocaine-associated multi-organ failure including rhabdomyolysis (CPK >100,000 U/L), acute kidney injury, liver ischemia. cureus.50745
Smoked cocaine carries preparation-specific pulmonary risk. "Crack lung" syndrome presents as acute respiratory distress with fever, hemoptysis, and dyspnea within 48 hours of inhalation, featuring diffuse alveolar hemorrhage, interstitial pneumonia, pulmonary edema, and eosinophilic infiltration.supported
acute respiratory syndromes called 'crack-lung' with fever, hemoptysis, dyspnea, and pulmonary infiltration on chest X-rays have been reported up to 48h after free-base cocaine inhalation, with features of pulmonary edema, interstitial pneumonia, diffuse alveolar hemorrhage, and eosinophil infiltration. j.cbi.2013.10.011
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Prevalence reaches as high as 86.5% in some clinical populationssupported
In some settings, cocaine-induced psychosis has been as high as 86.5%. 08897077.2014.933726
Risk factors include high cumulative dose, lifetime duration of use, smoked or intravenous route, cannabis co-use, ADHD comorbidity, and male sexpartially supported
Risk factors include quantity consumed, lifetime use, onset of dependence, route of administration, other substance use disorder comorbidity. 08897077.2014.933726
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
{{Recovery}}No FDA-approved pharmacotherapy for cocaine use disorder exists as of 2026supported
No FDA-approved pharmacotherapies for cocaine use disorder currently available. 02698811251399593
Hepatic CES1 and CYP3A4 catalyze transesterification of cocaine with ethanol to form cocaethylene, a metabolite that is more toxic than cocaine, has a longer duration of action, and amplifies cardiovascular riskpartially supported
About 24% of intravenous cocaine was converted to cocaethylene. Within each route, the cocaine-ethanol combination produced greater increases in heart rate than cocaine alone. a0022950
Hepatic CES1 and CYP3A4 catalyze transesterification of cocaine with ethanol to form cocaethylene, a metabolite that is more toxic than cocaine, has a longer duration of action, and amplifies cardiovascular risksupported
products of chemical reactions of cocaine with alcohol catalyzed by CES-1 and CYP3A4, that are more toxic than cocaine itself. j.toxrep.2022.08.001
Hepatic CES1 and CYP3A4 catalyze transesterification of cocaine with ethanol to form cocaethylene, a metabolite that is more toxic than cocaine, has a longer duration of action, and amplifies cardiovascular riskpartially supported
Norcocaine and cocaethylene exhibit greater toxicity than cocaine itself. j.cbi.2026.112088
Cocaethylene yield varies by cocaine route: oral (34%) > intravenous (24%) > smoked (18%).supported
About 24% of intravenous cocaine was converted to cocaethylene. The oral route (34%) was significantly greater than from the smoked route (18%). a0022950
Claim in safety — inconclusiveinconclusiveworking →
Cocaine use in pregnancy is associated with increased placental abruption risk, adverse neonatal outcomes, and fetal CNS development effects.partially supported
Increased risk of adverse maternal and neonatal outcomes with prenatal exposure to cocaine and opioids observed. s12884-024-07062-1
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
preparations11 · 6 ok
Claim in preparations — inconclusiveinconclusiveworking →
Claim in preparations — inconclusiveinconclusiveworking →
Claim in preparations — inconclusiveinconclusiveworking →
Claim in preparations — inconclusiveinconclusiveworking →
Coca leaf chewing at traditional use amounts does not produce the euphoria characteristic of refined cocaine.supported
This article contrasts coca with cocaine in an attempt to explain the differences but also the reasons for this widespread misconception. s40794-019-0095-7
Blood cocaine concentrations from leaf chewing are unlikely to produce drug accumulation.supported
Drug accumulation unlikely from coca leaf chewing. pmid:7242115
Oral bioavailability of cocaine is 32–45%, with significant first-pass hepatic metabolism producing norcocaine and benzoylecgonine.partially supported
Mean oral cocaine bioavailability 0.32 after 100 mg and 0.45 after 200 mg. bky007
Rapidly administered cocaine preferentially engages mesocorticolimbic circuits, promoting psychomotor sensitization and accelerating addiction progressionsupported
It is widely accepted that the more rapidly drugs of abuse reach the brain the greater their potential for addiction. This might be one reason why cocaine and nicotine are more addictive when they are smoked than when they are administered by other routes. pmid:15681025
Claim in preparations — inconclusiveinconclusiveworking →
Preparation-specific risks: "Crack lung" — acute respiratory distress with fever, hemoptysis, and dyspnea within 48 hours of inhalation, involving diffuse alveolar hemorrhage, interstitial pneumonia, and eosinophilic infiltrationsupported
acute respiratory syndromes called 'crack-lung' with fever, hemoptysis, dyspnea, and pulmonary infiltration on chest X-rays have been reported up to 48h after free-base cocaine inhalation, with features of pulmonary edema, interstitial pneumonia, diffuse alveolar hemorrhage, and eosinophil infiltration. j.cbi.2013.10.011
Pyrolysis produces anhydroecgonine methyl ester (AEME), a specific biomarker of the smoked route.supported
Anhydroecgonine methyl ester detectable in saliva following smoked administration. pmid:9323527
summary10 · 5 ok
Claim in summary — inconclusiveinconclusiveworking →
Claim in summary — inconclusiveinconclusiveworking →
Cocaine blocks the dopamine, norepinephrine, and serotonin transporters, with DAT inhibition in mesolimbic circuits mediating the primary reinforcing and euphoriant effectspartially supported
The long held view is cocaine's pharmacological effects are mediated by monoamine reuptake inhibition. This article proposes that cocaine serves as a negative allosteric modulator to alter the function of the dopamine reuptake transporter (DAT) and reverse its direction of transport. j.neuropharm.2014.06.012
Claim in summary — inconclusiveinconclusiveworking →
Plasma half-life is dose-dependent, ranging from approximately 38 to 87 minutes, and oral bioavailability is 32–45% — explaining why coca leaf preparations produce qualitatively milder effects than refined cocaine administered by faster routes.partially supported
terminal plasma half-life: t1/2(beta) = 13.5 + 24.5 dose (min), range ~38-87 min for 1-3 mg/kg. Intranasal bioavailability ~60%. pmid:7242115
Plasma half-life is dose-dependent, ranging from approximately 38 to 87 minutes, and oral bioavailability is 32–45% — explaining why coca leaf preparations produce qualitatively milder effects than refined cocaine administered by faster routes.supported
Mean oral cocaine bioavailability 0.32 after 100 mg and 0.45 after 200 mg. bky007
Cocaine carries significant cardiovascular toxicity risk across all preparations, including myocardial infarction, arrhythmias, and sudden cardiac deathsupported
Cocaine users frequently present to the emergency department, with chest pain being the most common presenting complaint. The incidence of acute myocardial infarction in patients with cocaine-associated chest pain is often quoted as 6%. j.cjca.2022.05.003
Claim in summary — inconclusiveinconclusiveworking →
Claim in summary — inconclusiveinconclusiveworking →
No approved pharmacotherapy for cocaine use disorder exists as of 2026supported
No FDA-approved pharmacotherapies for cocaine use disorder currently available. 02698811251399593
neuroscience8 · 7 ok
Terminal plasma half-life is dose-dependent: t₁/₂(β) = 13.5 + 24.5 × dose (mg/kg) minutes, yielding approximately 38–87 minutes for typical doses of 1–3 mg/kgsupported
terminal plasma half-life: t1/2(beta) = 13.5 + 24.5 dose (min), range ~38-87 min for 1-3 mg/kg. pmid:7242115
CYP3A4 is the primary enzyme responsible for N-demethylation of cocaine to norcocaine, an active metabolite with greater toxicity than the parent compoundpartially supported
human P-450 3A4 is a cocaine demethylase, and P-450 isoforms of the 3A family are responsible for the majority of norcocaine production by human hepatic microsomes. pmid:8488174
Cocaine binding to DAT increases synaptic dopamine in the nucleus accumbens and other mesolimbic regionssupported
cocaine serves as a negative allosteric modulator to alter the function of the dopamine reuptake transporter (DAT) and reverse its direction of transport, resulting in a firing-dependent, retro-transport of dopamine into the synaptic cleft. j.neuropharm.2014.06.012
A proposed mechanistic refinement suggests cocaine may function as a negative allosteric modulator of DAT, reversing transporter direction to induce firing-dependent retro-transport of dopamine into the synaptic cleft — potentially explaining why cocaine produces greater euphoria than other DAT inhibitors of equivalent binding potency.supported
This article proposes that cocaine serves as a negative allosteric modulator to alter the function of the dopamine reuptake transporter (DAT) and reverse its direction of transport, resulting in a firing-dependent, retro-transport of dopamine into the synaptic cleft. j.neuropharm.2014.06.012
Claim in neuroscience — inconclusiveinconclusiveworking →
Drug accumulation from coca leaf chewing is unlikely given the slow absorption rate (~8 min absorption half-life for mucosal routes at low doses).supported
Absorption half-life ~8 min for GI and nasal inhalation. Drug accumulation unlikely from coca leaf chewing. pmid:7242115
Cocaine induces its own hepatic CYP metabolism with chronic dosing, potentially increasing norcocaine production over time.supported
Cocaine enhances its own cytochrome P450-dependent metabolism; increased production of norcocaine in microsomes is catalyzed mainly by CYP3A enzyme(s). pmid:8617431
Concurrent ethanol consumption leads to transesterification of cocaine to cocaethylene, catalyzed by hepatic carboxylesterase-1 (CES1) and CYP3A4supported
products of chemical reactions of cocaine with alcohol catalyzed by CES-1 and CYP3A4. j.toxrep.2022.08.001
alkaloid-profile7 · 5 ok
Norcocaine (C₁₆H₁₉NO₄; MW 289.33 g/mol) is an active N-demethylated metabolite formed via CYP3A4 in human liver; norcocaine is more toxic than the parent compound.partially supported
Cocaine was metabolized to norcocaine by microsomes prepared from lymphoblastoid cells expressing transfected human P-450 3A4. Thus, human P-450 3A4 is a cocaine demethylase, and P-450 isoforms of the 3A family are responsible for the majority of norcocaine production by human hepatic microsomes. pmid:8488174
Claim in alkaloid-profile — inconclusiveinconclusiveworking →
Geographic origin, altitude, and soil conditions modulate alkaloid expression within varieties. E. coca var. ipadu shows significantly lower genetic diversity than other cultivated taxa, consistent with a genetic bottleneck during Amazonian dispersal.partially supported
E. coca var. coca likely ancestral to E. coca var. ipadu. pmid:15650009
Cocaine biosynthesis occurs in the aerial portions of the plant — specifically in the palisade parenchyma and spongy mesophyll of young developing leavessupported
The enzyme (cocaine synthase, a BAHD acyltransferase) is highest in young developing leaves in the palisade parenchyma and spongy mesophyll. pp.114.248187
The final biosynthetic step is catalyzed by a BAHD acyltransferase (cocaine synthase), which esterifies methylecgonine with benzoyl-CoA to yield cocaine.supported
The esterification of methylecgonine with benzoic acid is the final step in cocaine biosynthesis in Erythroxylum coca. The enzyme (cocaine synthase, a BAHD acyltransferase). pp.114.248187
Comprehensive phytochemical review documents 383 compounds across 53 Erythroxylum speciessupported
383 compounds from Erythroxylum reported, including diterpenes, triterpenes, alkaloids, flavonoids. Comprehensive overview of phytoconstituents from 53 Erythroxylum species 1960-2021. s13659-022-00338-z
Claim in alkaloid-profile — inconclusiveinconclusiveworking →
history6 · 2 ok
Claim in history — inconclusiveinconclusiveworking →
The two primary cultivated species, E. coca and E. novogranatense, were utilized specifically for their tropane alkaloid content before formal domestication of either species.supported
The genus Erythroxylum contains species used by indigenous people of South America long before the domestication of plants. Two species, E. coca and E. novogranatense, have been utilized for thousands of years specifically for their tropane alkaloid content. molecules24203788
Documented traditional applications include stamina enhancement during physical labor, hunger and fatigue suppression, altitude sickness mitigation, mild analgesia, and ritual and ceremonial usesupported
Few travel health measures are as controversial as the use of coca leaves at high altitude... This article contrasts coca with cocaine in an attempt to explain the differences. s40794-019-0095-7
Claim in history — inconclusiveinconclusiveworking →
Claim in history — inconclusiveinconclusiveworking →
Claim in history — inconclusiveinconclusiveworking →
botanical-overview4 · 4 ok
The family Erythroxylaceae contains approximately 240 species in four genera; Erythroxylum is the largest, comprising approximately 230 species distributed primarily across tropical and subtropical regionspartially supported
Erythroxylum contains approximately 230 species. s13659-022-00338-z
Two species bear pharmacologically significant tropane alkaloid concentrations: E. coca and the closely related E. novogranatense (Morris) Hieron.supported
Two species, E. coca and E. novogranatense, have been utilized for thousands of years specifically for their tropane alkaloid content. molecules24203788
Four cultivated taxa account for all commercially alkaloid-bearing coca:supported
Four cultivated Erythroxylum taxa (E. coca var. coca, E. novogranatense var. novogranatense, E. coca var. ipadu, E. novogranatense var. truxillense) are indigenous to the Andean region of South America. pmid:15650009
AFLP fingerprinting reveals clear genetic differentiation between E. coca and E. novogranatense, and between var. coca and var. ipadusupported
Clear distinction revealed between E. coca and E. novogranatense. E. coca var. coca likely ancestral to E. coca var. ipadu. pmid:15650009
legal-status1 · 1 ok
In chronic cocaine users, mean time to first negative specimen (benzoylecgonine equivalents <300 ng/mL) is 43.6 ± 17.1 hours after cessationsupported
Mean time to first negative specimen (BE equivalents < 300 ng/mL) was 43.6 ± 17.1 hours (16-66 h). pmid:12422991