generation run 2026-04-24
29,966 min completedmodel pipeline-v5plan not recordedrun/16783ebd…Selection
Verification
- record
- seen / partial
- working
The model's own caveats
none raised on this run
Reproduce
- inputs
- 22 source keys (listed under Sources)
- plan
- not recorded — template version, prompt hash and git SHA are written from 2026-09 onward
- model
- pipeline-v5
- streams
- none — agent transcripts are persisted from 2026-09 onward
20 searches — query, source, results, what was kept and why
| # | source | query | seen | kept | rationale |
|---|---|---|---|---|---|
| 1 | OpenAlex | DOC 4-chloro-2,5-dimethoxyamphetamine psychedelic serotonin receptor | 3 | 3 | WHO report is authoritative summary; analytical review covers detection methods; molecular review covers pharmacology context |
| 2 | PubChem | 4-chloro-2,5-dimethoxyamphetamine | 1 | 1 | Confirmed chemical identity data for DOC |
| 3 | PubMed | DOC 2,5-dimethoxy-4-chloroamphetamine pharmacology serotonin | 3 | 3 | All directly relevant to DOC pharmacology, toxicology, and metabolism |
| 4 | OpenAlex | DOB DOI DOM DOC serotonin 5-HT2A receptor binding hallucinogen pharmacology | 7 | 4 | Ray provides broad receptor profile; Nelson provides DOC-specific binding affinities; Luethi contextualizes DOC as designer drug; Halberstadt covers animal pharmacology models |
| 5 | ClinicalTrials.gov · absence | DOC 4-chloro-2,5-dimethoxyamphetamine | 0 | — | Confirms no registered clinical trials involving DOC |
| 6 | PubMed | DOI head twitch response 5-HT2A agonist behavioral pharmacology mouse rat | 2 | 1 | HTR model directly relevant to DOx class animal pharmacology |
| 7 | PubMed | 4-chloro-2,5-dimethoxyamphetamine toxicity case report adverse | 1 | 1 | Direct clinical case of DOC intoxication with toxicological confirmation |
| 8 | WebSearch/Erowid | DOC 4-chloro-2,5-dimethoxyamphetamine synthesis 1973 Shulgin PIHKAL history discovery | 10 | 2 | Historical context and primary dose/duration data |
| 9 | CrossRef/DOI verification | 10.1139/v73-210 Coutts Malicky 1973 DOC synthesis | 1 | 1 | Verified original synthesis paper |
| 10 | NCATS Inxight Drugs | DOC binding affinity Ki 5-HT2A 5-HT2C | 1 | 1 | Specific binding affinity data not found in structured APIs |
| 11 | DEA Federal Register | DEA DOC DOI Schedule I final rule 2023 2024 | 5 | 3 | US regulatory history for DOC scheduling |
| 12 | ECDD Repository | DOC ECDD WHO recommendation legal status pharmacology | 1 | 2 | Official WHO scheduling recommendation and adverse effects summary |
| 13 | PiHKAL/Erowid | DOC PiHKAL entry #64 Shulgin dose duration effects | 1 | 1 | Primary historical self-experimental source for DOC effects and dosing |
| 14 | PubMed | 1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane DOX family serotonergic review 2024 Glennon Dukat | 1 | 1 | Authoritative review of DOx class from leading expert group; covers DOC history and SAR |
| 15 | PubMed | tramadol serotonin toxicity mechanism | 1 | 1 | Mechanistic basis for dangerous DOC+tramadol interaction |
| 16 | WebSearch | DOC 2,5-dimethoxy-4-chloroamphetamine legal status DEA schedule USA UK Germany | 10 | 3 | Primary legal status data for major jurisdictions |
| 17 | WebSearch | DOC 2,5-dimethoxy-4-chloroamphetamine SMILES synthesis Coutts Malicky 1973 original paper | 10 | 1 | Primary historical source for DOC synthesis history |
| 18 | WebFetch/NCATS Inxight | DOC Ki binding affinity receptor pharmacology | 1 | 2 | Only source with specific Ki values for DOC at primary targets |
| 19 | PubMed | 5-HT2B cardiac valvulopathy psychedelic hallucinogen | 2 | 2 | 5-HT2B cardiac valvulopathy risk context for DOC |
| 20 | WebSearch | DOC 2,5-dimethoxy-4-chloroamphetamine not releasing agent SERT monoamine transport pharmacology | 10 | 1 | Confirms critical seed data error: monoamine releasing agent classification is incorrect for DOC |
53 claims by section — every cited sentence, checked against its source
safety12 · 11 ok
Barnett et al. (2014) reported a 37-year-old male found deceased with DOC in iliac blood at 377 ng/mL and no other psychoactive drugs except caffeinesupported
37-year-old male. DOC concentrations: 377 ng/mL iliac blood, 3193 ng/mL urine, 3143 ng/g liver, 683 ng/g brain. Only caffeine co-detected. bku087
Lelievre et al. (2022) reported a young woman presenting with vomiting, convulsions, and cardiorespiratory arrestsupported
Case of young woman admitted to hospital with vomiting, convulsions and cardiorespiratory arrest following DOC use. s11419-022-00628-8
Interpretation of postmortem DOC concentrations is limited by redistribution artifacts.supported
Discusses challenges interpreting postmortem DOC concentrations. s11419-022-00628-8
DOC has high affinity at serotonin₂B receptors, inferred from a strong positive correlation (r > 0.9) between 5-HT₂A and 5-HT₂B binding affinities across the chemical/dox class. 5-HT₂B receptor agonism is the established mechanism of drug-induced cardiac valvulopathy, demonstrated with fenfluramine and mdmasupported
Binding affinities of 17 phenylisopropylamine hallucinogens at cloned human 5-HT2A, 5-HT2B, and 5-HT2C receptors. Correlation r>0.9 between all three subtypes. DOC included. pmid:9933142
DOC has high affinity at serotonin₂B receptors, inferred from a strong positive correlation (r > 0.9) between 5-HT₂A and 5-HT₂B binding affinities across the chemical/dox class. 5-HT₂B receptor agonism is the established mechanism of drug-induced cardiac valvulopathy, demonstrated with fenfluramine and mdmasupported
MDMA and MDA activate 5-HT2B receptors and induce mitogenic responses in valvular interstitial cells. pmid:12761331
DOC has high affinity at serotonin₂B receptors, inferred from a strong positive correlation (r > 0.9) between 5-HT₂A and 5-HT₂B binding affinities across the chemical/dox class. 5-HT₂B receptor agonism is the established mechanism of drug-induced cardiac valvulopathy, demonstrated with fenfluramine and mdmasupported
Systematic review: LSD and MDMA activate 5-HT2B receptors with fibrotic signaling in valvular interstitial cells. DOx compounds have high 5-HT2B affinity per Nelson 1999. a-2794-6487
Prolonged psychedelic states carry elevated risk of acute psychological distress, anxiety, and panic reactions, particularly in unprepared users or those who have unwittingly consumed DOC believing it to be lsdsupported
Patients believed they had ingested LSD. Severe symptoms documented. j.toxac.2017.01.002
Claim in safety — inconclusiveinconclusiveworking →
Rapid tachyphylaxis develops with repeated dosing of 5-HT₂A agonists, mechanistically linked to downregulation via beta-arrestin2 pathway activation. Cross-tolerance to other serotonergic psychedelics (LSD, psilocybin, mescaline, and other DOx compounds) is expected based on shared 5-HT₂A agonismsupported
Beta-arrestin-biased ligands block psychedelic effects and induce receptor downregulation and tachyphylaxis. s41467-023-44016-1
Tramadol: tramadol inhibits serotonin-transporter and acts as a weak µ-opioid agonist and SNRIpartially supported
Reviews tramadol as SERT inhibitor. Tramadol inhibits human SERT in HEK293 cells. s00204-018-2244-6
Bonson et al. (1996) demonstrated this attenuation with LSD in humanssupported
Chronic SSRI administration attenuates subjective LSD effects, likely via 5-HT2A receptor downregulation. 0893-133x(95)00145-4
CYP2D6 substrates: DOC competitively inhibits cyp2d6 (Ki = 2.7–19.9 µM in human liver microsomes)supported
DOC is a competitive CYP2D6 inhibitor (Ki 7.1-296 µM recombinant, 2.7-19.9 µM HLM). j.toxlet.2008.09.014
clinical-evidence8 · 8 ok
This represents the first published fatality attributed solely to DOC.supported
First reported fatal case attributed to DOC alone. bku087
Plasma DOC concentrations were < 18 µg/L; urine concentrations ranged from 300 to 1,300 µg/L.supported
Plasma concentrations below 18 μg/L; urine 300-1300 μg/L. j.toxac.2017.01.002
This case highlighted the challenges of interpreting postmortem DOC concentrations due to redistribution artifacts.supported
Discusses challenges interpreting postmortem DOC concentrations. s11419-022-00628-8
The patient had believed they were consuming doi and MDMA.supported
Patient reported to have ingested DOI + MDMA but actually ingested DOC + MDMA. mej.0b013e3282fc765b
All human data for DOC derive from self-experimental reports (Shulgin, N = 1), clinical intoxication cases, and postmortem analysessupported
First case report of recreational use of 2,5-dimethoxy-4-chloroamphetamine confirmed by toxicological screening. mej.0b013e3282fc765b
All human data for DOC derive from self-experimental reports (Shulgin, N = 1), clinical intoxication cases, and postmortem analysessupported
Five non-fatal DOC exposures (ages 18-23) in France. j.toxac.2017.01.002
All human data for DOC derive from self-experimental reports (Shulgin, N = 1), clinical intoxication cases, and postmortem analysessupported
First reported fatal case attributed to DOC alone. 37-year-old male. DOC concentrations: 377 ng/mL iliac blood, 3193 ng/mL urine, 3143 ng/g liver, 683 ng/g brain. bku087
All human data for DOC derive from self-experimental reports (Shulgin, N = 1), clinical intoxication cases, and postmortem analysessupported
Case of young woman admitted to hospital with vomiting, convulsions and cardiorespiratory arrest following DOC use. Second fatal case in published literature. s11419-022-00628-8
pharmacokinetic-detail7 · 6 ok
Abbara et al. (2017) reported plasma DOC concentrations of < 18 µg/L and urine concentrations of 300–1,300 µg/L in a five-patient non-fatal case seriessupported
Five non-fatal DOC exposures (ages 18-23) in France. Plasma concentrations below 18 μg/L; urine 300-1300 μg/L. j.toxac.2017.01.002
cyp2d6 is the primary metabolizing enzyme for DOC, catalyzing O-demethylation at both the 2- and 5-methoxy positions to yield the two main metabolitessupported
CYP2D6 identified as the sole isoenzyme involved in O-demethylation of DOC and related DOx compounds. j.toxlet.2008.09.014
DOC competitively inhibits CYP2D6 with Ki values of 2.7–19.9 µM in human liver microsomes and 7.1–296 µM using recombinant CYP2D6supported
DOC is a competitive CYP2D6 inhibitor (Ki 7.1-296 µM recombinant, 2.7-19.9 µM HLM). j.toxlet.2008.09.014
Interpretation of these values is limited by postmortem redistribution.supported
Discusses challenges interpreting postmortem DOC concentrations. s11419-022-00628-8
Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →
Identification requires specific GC-MS or LC-MS/MS screening panelssupported
Identified via LC/UV, GC/MS, quantified via LC/MS/MS. j.toxac.2017.01.002
Nieddu et al. (2023) highlighted the need for updated validated analytical methods for chemical/dox and chemical/2c-x compounds in biological matrices.supported
Review of analytical methods for quantification of 2,5-dimethoxy-amphetamines (DOx) and -phenethylamines (2C-x) in traditional and alternative biological matrices. s11419-022-00638-6
pharmacology7 · 6 ok
The psychedelic mechanism is mediated primarily through 5-HT₂A receptor Gq/11 signaling, which activates phospholipase C-β (PLC-β) and downstream inositol trisphosphate (IP₃) and diacylglycerol (DAG) cascadessupported
5-HT2A-Gq (not beta-arrestin2) efficacy predicts psychedelic potential via head-twitch response magnitude in mice. s41467-023-44016-1
Wallach et al. (2023) demonstrated that 5-HT₂A-Gq efficacy — not beta-arrestin2 recruitment — is the key predictor of psychedelic potential as measured by head-twitch response (HTR) magnitude in micesupported
5-HT2A-Gq (not beta-arrestin2) efficacy predicts psychedelic potential via head-twitch response magnitude in mice. s41467-023-44016-1
DOC produces the head-twitch response in rats and mice, consistent with its 5-HT₂A pharmacologysupported
Review of head twitch response (HTR), prepulse inhibition, and exploratory behavior models for hallucinogens. Behavioral effects mediated primarily by 5-HT2A receptor activation. 7854_2016_466
Eshleman et al. (2014) directly assayed DOC at the serotonin-transporter (SERT), dopamine-transporter (DAT), and norepinephrine-transporter (NET), finding minimal to no activitysupported
In vitro receptor binding and function data for 2C-C, 2C-D, 2C-E, 2C-I, 2C-T-2, and DOC. Includes transporter binding, mouse locomotion, and rat drug discrimination data. s00213-013-3303-6
Ewald and Maurer (2008) identified cyp2d6 as the primary — and potentially sole — cytochrome P450 isoenzyme responsible for DOC's O-demethylation at the 2- and 5-methoxy positionssupported
CYP2D6 identified as the sole isoenzyme involved in O-demethylation of DOC and related DOx compounds. j.toxlet.2008.09.014
DOC also functions as a competitive, non-mechanism-based inhibitor of CYP2D6, with Ki values of 7.1–296 µM (recombinant CYP2D6) and 2.7–19.9 µM (human liver microsomes)supported
DOC is a competitive CYP2D6 inhibitor (Ki 7.1-296 µM recombinant, 2.7-19.9 µM HLM). j.toxlet.2008.09.014
Claim in pharmacology — inconclusiveinconclusiveworking →
summary6 · 5 ok
Claim in summary — inconclusiveinconclusiveworking →
DOC binds 5-ht2a (Ki = 4.0 nM) and 5-ht2c (Ki = 3.54 nM) receptors with low-nanomolar affinity, acting as a partial-agonist that signals primarily through the Gq/11-phospholipase C pathwaypartially supported
5-HT2A-Gq (not beta-arrestin2) efficacy predicts psychedelic potential via head-twitch response magnitude in mice. s41467-023-44016-1
It does not function as a monoamine releasing agentsupported
In vitro receptor binding and function data for 2C-C, 2C-D, 2C-E, 2C-I, 2C-T-2, and DOC. Includes transporter binding, mouse locomotion, and rat drug discrimination data. s00213-013-3303-6
Two published fatalities exist in the literature, with severe intoxication presenting as a sympathomimetic toxidrome including seizures, hyperthermia, and rhabdomyolysispartially supported
First reported fatal case attributed to DOC alone. 37-year-old male. DOC concentrations: 377 ng/mL iliac blood, 3193 ng/mL urine, 3143 ng/g liver, 683 ng/g brain. Only caffeine co-detected. bku087
Two published fatalities exist in the literature, with severe intoxication presenting as a sympathomimetic toxidrome including seizures, hyperthermia, and rhabdomyolysispartially supported
Case of young woman admitted to hospital with vomiting, convulsions and cardiorespiratory arrest following DOC use. Second fatal case in published literature. s11419-022-00628-8
No dependence potential has been demonstrated. tolerance develops rapidly via 5-HT₂A downregulation mediated by beta-arrestin2 recruitment, with cross-tolerance expected across serotonergic psychedelicssupported
Beta-arrestin-biased ligands block psychedelic effects and induce receptor downregulation and tachyphylaxis. s41467-023-44016-1
history5 · 4 ok
The first fatal case attributed solely to DOC was reported by Barnett et al. in 2014 in the United States.supported
First reported fatal case attributed to DOC alone. bku087
Claim in history — inconclusiveinconclusiveworking →
The compound has been encountered in powdered, liquid, and blotter paper forms, and is frequently misrepresented as lsd when distributed on blotterssupported
Five non-fatal DOC exposures (ages 18-23) in France. Patients believed they had ingested LSD. j.toxac.2017.01.002
The first published clinical case of recreational DOC use was reported by Ovaska et al. in 2008 in the United Kingdomsupported
DOC covered under UK Misuse of Drugs Act 1971 as substituted amphetamine. mej.0b013e3282fc765b
Glennon and Dukat (2024) provided the most comprehensive recent review of the DOx class, situating DOC within the broader development of doi and other DOx agents as pharmacological probes for serotonergic receptor functionsupported
Comprehensive historical and pharmacological review of the DOx class. DOI, DOC, DOB all first synthesized 1973. DOx compounds are 5-HT2 receptor agonists. SAR, receptor binding, behavioral pharmacology, and development as research tools reviewed. acsptsci.4c00157
receptor-pharmacology3 · 3 ok
Nelson et al. (1999) demonstrated a positive correlation (r > 0.9) between 5-HT₂A and serotonin₂B binding affinities across 17 phenylisopropylamine hallucinogenssupported
Binding affinities of 17 phenylisopropylamine hallucinogens at cloned human 5-HT2A, 5-HT2B and 5-HT2C receptors. Correlation r>0.9 between all three subtypes. pmid:9933142
Ray (2010) reported NIMH Psychoactive Drug Screening Program (PDSP) data for DOC across 51 receptor and transporter sitessupported
Receptor affinity pharmacology of 25 psychedelic drugs at 51 receptors, transporters, and ion channels (NIMH-PDSP). Phenylalkylamines interact with 42 of 49 sites tested. journal.pone.0009019
Wallach et al. (2023) established that 5-HT₂A-Gq efficacy, rather than beta-arrestin2 recruitment, predicts psychedelic potential as assessed by HTR magnitudesupported
5-HT2A-Gq (not beta-arrestin2) efficacy predicts psychedelic potential via head-twitch response magnitude in mice. s41467-023-44016-1
chemistry2 · 1 ok
The 2,5-dimethoxy pattern on the phenyl ring is the defining structural feature shared across the DOx series (including dom, doi, and dob) and is critical for high-affinity 5-ht2a bindingsupported
Comprehensive historical and pharmacological review of the DOx class. DOI, DOC, DOB all first synthesized 1973. SAR, receptor binding, behavioral pharmacology, and development as research tools reviewed. acsptsci.4c00157
Claim in chemistry — inconclusiveinconclusiveworking →
comparative-pharmacology2 · 2 ok
The 4-position substituent modulates potency, selectivity, and metabolic stability across the series.supported
Comprehensive historical and pharmacological review of the DOx class. DOI, DOC, DOB all first synthesized 1973. SAR, receptor binding, behavioral pharmacology, and development as research tools reviewed. acsptsci.4c00157
The misrepresentation of DOC as LSD on blotter paper is clinically significant because DOC's longer duration (12–24 h vs LSD's 8–12 h), different dose sensitivity, and more pronounced sympathomimetic effects create unexpected risk for users anticipating an LSD experience.partially supported
Five non-fatal DOC exposures (ages 18-23) in France. Patients believed they had ingested LSD. Severe symptoms documented. j.toxac.2017.01.002
neuroscience1 · 1 ok
DOC's low-nanomolar 5-HT₂A affinity and robust head-twitch response production in rodents confirm engagement of the 5-HT₂A pathway that, in other psychedelics, drives default-mode-network (DMN) dissolution, increased global functional connectivity, and elevated neural entropysupported
Review of head twitch response (HTR), prepulse inhibition, and exploratory behavior models for hallucinogens. Behavioral effects mediated primarily by 5-HT2A receptor activation. 7854_2016_466