generation run 2026-05-09
85 min completedmodel pipeline-v5plan not recordedrun/9d87f82f…Selection
Verification
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- seen / partial
- working
The model's own caveats
15 further caveats recorded as free text — readable on the working page
Reproduce
- inputs
- 28 source keys (listed under Sources)
- plan
- not recorded — template version, prompt hash and git SHA are written from 2026-09 onward
- model
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- 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 | DOET 2,5-dimethoxy-4-ethylamphetamine | 10 | 3 | Selected highest-relevance papers with DOET-specific or DOx-class data |
| 2 | WebSearch | DOET 2,5-dimethoxy-4-ethylamphetamine DEA scheduling legal status controlled substance | 10 | 2 | Confirmed US and Australian scheduling; UK and Canada need additional searches |
| 3 | WebSearch | Snyder 1971 DOET psychotropic drug Archives General Psychiatry Dow Chemical clinical study | 10 | 3 | Confirms details of the key human clinical study |
| 4 | ClinicalTrials.gov · absence | DOET 2,5-dimethoxy-4-ethylamphetamine | 0 | 0 | No results |
| 5 | PubChem | DOET | 1 | 1 | Only compound returned; confirmed as DOET identity |
| 6 | PubMed | DOET 2,5-dimethoxy-4-ethylamphetamine psychedelic pharmacology | 8 | 8 | All 8 articles directly relevant to DOET pharmacology, clinical effects, or structure-activity relationships |
| 7 | Erowid PiHKAL | DOET PiHKAL entry #66 | 1 | 5 | Primary source for DOET synthesis, dosing, and Shulgin's observations |
| 8 | WebSearch | DOET UK Misuse of Drugs Act Class A scheduled | 10 | 1 | Confirmed UK scheduling status |
| 9 | WebSearch | DOET Canada controlled drug substance schedule analogue | 10 | 1 | Established likely Canadian scheduling status |
| 10 | Wikidoc | DOET pharmacological data | 1 | 3 | Confirmed key data points but limited detail |
| 11 | WebSearch | DOx amphetamine metabolism CYP2D6 pharmacokinetics | 10 | 1 | Key metabolic pathway paper for DOx class |
| 12 | PubMed | serotonin hallucinogen tolerance repeated administration 5-HT2A downregulation | 1 | 1 | Only result; directly relevant to DOx class tolerance mechanism |
| 13 | DOI verification | Verify DOIs for Snyder 1968 and Weingartner 1970 | 2 | 2 | All three DOIs verified as valid via Crossref |
| 14 | PubMed | Multiple targeted searches for Glennon, Halberstadt, Barfknecht, DOM LD50, DOx stereochemistry, metabolism | 3 | 5 | Selected all relevant papers found; many queries returned no results from PubMed API |
| 15 | WebSearch | DOET receptor binding Ki 5-HT2A 12 nM values | 8 | 2 | Key binding affinity data - needs FLAG for source verification |
| 16 | Frontiers in Pharmacology 2023 paper | DOET binding affinity 5-HT2A 5-HT2B | 1 | 3 | Important safety and SAR data for DOx class |
| 17 | WebSearch | Dow Chemical DOET DOM STP psychedelic research 1960s clinical trial | 10 | 3 | Key historical context for DOET development |
| 18 | Web search aggregate | DOET receptor binding Ki values 5-HT2A 5-HT2C | 3 | 2 | Flagged as needing primary source verification |
| 19 | Erowid PiHKAL #66 | DOET dose duration synthesis effects PiHKAL | 1 | 5 | Primary source for all dosing and subjective data |
| 20 | Web search | DOET UN Convention Psychotropic Substances DEA Schedule I US February 1973 | 5 | 4 | Established legal status across major jurisdictions |
74 claims by section — every cited sentence, checked against its source
safety16 · 10 ok
Wohlfarth and colleagues included DOET in a forensic LC-MS/MS screening panel for 35 designer drugs, confirming it is recognized as a substance of concern by forensic toxicologists, though no detected cases appear in the accessible literaturepartially supported
LC-MS/MS method covering 31 designer drugs including DOET, DOB, DOM, DOC and 2C-series. LOD 1-5 ng/mL. s00216-009-3394-4
Huang and Ho documented that DOET produces pressor (blood pressure-raising) action in rats, an effect blocked by the serotonin antagonist cinanserin, confirming a serotonin-mediated cardiovascular mechanismsupported
DOET exhibits pressor action in rats (blocked by cinanserin). pmid:235610
DOET also increases rectal temperature in rats, with this hyperthermic action suppressed by cinanserin or methysergidesupported
DOET increases rectal temperature in rats (blocked by cinanserin or methysergide). pmid:235610
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Cross-tolerance occurs between DOET and other serotonergic hallucinogens (LSD, mescaline, DOM) due to shared 5-HT₂A mechanismpartially supported
Cross-tolerance between DOI and LSD; tolerance via 5-HT2A receptor downregulation, not beta-arrestin-2 dependent. acschemneuro.2c00170
CYP2D6 inhibitors: Fluoxetine, paroxetine, and other potent CYP2D6 inhibitors could inhibit DOET's O-demethylation (the presumed primary metabolic pathway), potentially prolonging and intensifying effectssupported
CYP2D6 identified as the sole isoenzyme involved in O-demethylation of DOC and related DOx compounds. j.toxlet.2008.09.014
Claim in safety — inconclusiveinconclusiveworking →
Stimulants: Concurrent use of amphetamines, cocaine, or other sympathomimetics with DOET is expected to produce additive cardiovascular effects (hypertension, hyperthermia), given DOET's documented pressor and hyperthermic actions in rodents.supported
DOET exhibits pressor action in rats (blocked by cinanserin). DOET increases rectal temperature in rats (blocked by cinanserin or methysergide). pmid:235610
5-HT₂A antagonists: Ketanserin, risperidone, and other 5-HT₂A antagonists block the hallucinogenic effects of DOx compounds, as confirmed in animal modelssupported
M100907 (5-HT2A antagonist) blocked locomotor hyperactivity. j.neuropharm.2013.01.014
5-HT₂A antagonists: Ketanserin, risperidone, and other 5-HT₂A antagonists block the hallucinogenic effects of DOx compounds, as confirmed in animal modelssupported
DOET among 5HT-2 agonists producing inhibition of locomotor and investigatory behavior in novel environment; blocked by ketanserin/ritanserin. bf02244617
Pre-existing cardiovascular conditions: DOET's documented pressor and hyperthermic effects in animal models and the theoretical 5-HT₂B-mediated valvulopathy risk make the compound inadvisable for individuals with hypertension, arrhythmia, or pre-existing cardiac valve diseasesupported
DOET exhibits pressor action in rats (blocked by cinanserin). DOET increases rectal temperature in rats (blocked by cinanserin or methysergide). pmid:235610
Claim in safety — inconclusiveinconclusiveworking →
Hepatic impairment: Given the presumed CYP2D6-dependent metabolism of DOET, significant hepatic impairment could alter drug clearance and prolong effectssupported
CYP2D6 identified as the sole isoenzyme involved in O-demethylation of DOC and related DOx compounds. j.toxlet.2008.09.014
summary12 · 7 ok
Claim in summary — inconclusiveinconclusiveworking →
Synthesized by Alexander Shulgin at Dow Chemical Company in the early 1960s, DOET entered clinical evaluation under Solomon Snyder at Johns Hopkins University as a potential "psychic energizer" before the DOM (STP) crisis of 1967 terminated all DOx pharmaceutical developmentsupported
Historical account of DOM development; Shulgin's role at Dow Chemical; Owsley Stanley 1967 distribution; corrects inaccuracies in popular accounts; Dow Chemical commissioned Snyder at Johns Hopkins to study DOET as potential pharmaceutical. dta.3667
Claim in summary — inconclusiveinconclusiveworking →
Claim in summary — inconclusiveinconclusiveworking →
DOET binds to cloned human 5-HT₂A receptors with Ki ≈ 12 nM and to 5-HT₂C with Ki ≈ 108 nM, functioning as a partial agonist at 5-HT₂A with greater relative efficacy at 5-HT₂Cpartially supported
DOx phenylisopropylamines are partial agonists at 5-HT2A (Imax 22-58% relative to 5-HT); more efficacious at 5-HT2C; alpha-methyl group determines efficacy. pmid:12055129
The 5-HT₂A dependence of its behavioral effects is confirmed by selective antagonist blockade with M100907 in mice and ketanserin in ratssupported
Confirms DOET increases locomotor activity in C57BL/6J mice via 5-HT2A receptor activation; M100907 (5-HT2A antagonist) blocked locomotor hyperactivity. j.neuropharm.2013.01.014
The 5-HT₂A dependence of its behavioral effects is confirmed by selective antagonist blockade with M100907 in mice and ketanserin in ratssupported
DOET among 5HT-2 agonists producing inhibition of locomotor and investigatory behavior in novel environment; blocked by ketanserin/ritanserin. bf02244617
CYP2D6-mediated O-demethylation is the presumed primary metabolic pathway, inferred from structurally related DOx compounds.supported
CYP2D6 identified as the sole isoenzyme involved in O-demethylation of DOC and related DOx compounds. j.toxlet.2008.09.014
Claim in summary — inconclusiveinconclusiveworking →
Cardiovascular concern arises from documented pressor and hyperthermic effects in rodents, compounded by theoretical cardiac valvulopathy risk via 5-HT₂B agonism shared across the DOx classsupported
DOET exhibits pressor action in rats (blocked by cinanserin). DOET increases rectal temperature in rats (blocked by cinanserin or methysergide). pmid:235610
Claim in summary — inconclusiveinconclusiveworking →
Tolerance develops rapidly through 5-HT₂A receptor downregulation, with cross-tolerance to other serotonergic hallucinogens; no physical dependence or withdrawal syndrome has been documentedsupported
Repeated DOI administration induces progressive decrease in head-twitch response (HTR); cross-tolerance between DOI and LSD; tolerance via 5-HT2A receptor downregulation, not beta-arrestin-2 dependent. acschemneuro.2c00170
pharmacology10 · 5 ok
Its psychedelic effects are mediated primarily through 5-HT₂A activation, a mechanism established for the DOx class by the strong correlation (r = 0.938) between 5-HT₂ binding affinities and hallucinogenic potency in humanspartially supported
correlation r=0.938 between 5-HT2 binding affinities and DOM drug discrimination ED50; correlation r=0.924 with human hallucinogenic potency. pmid:6513725
Titeler, Lyon, and Glennon extended this finding with radioligand binding studies showing phenylisopropylamines display 10–100-fold higher affinities for 5-HT₂ relative to 5-HT₁C and 100–1000-fold higher affinities relative to 5-HT₁A or 5-HT₁B, with binding-potency correlation of r = 0.90.supported
10-100 fold higher affinities for 5-HT2 vs 5-HT1C; 100-1000 fold higher vs 5-HT1A/1B; strong correlation between hallucinogenic potencies and 5-HT2 affinity (r=0.90) for phenylisopropylamines. pmid:3127847
Claim in pharmacology — inconclusiveinconclusiveworking →
Claim in pharmacology — inconclusiveinconclusiveworking →
DOx phenylisopropylamines function as partial agonists at 5-HT₂A (Imax 22–58% relative to serotonin), with substantially greater relative efficacy at 5-HT₂C; the related compound DOI has been demonstrated as a full 5-HT₂C agonistpartially supported
DOx phenylisopropylamines are partial agonists at 5-HT2A (Imax 22-58% relative to 5-HT); more efficacious at 5-HT2C. pmid:12055129
Claim in pharmacology — inconclusiveinconclusiveworking →
Claim in pharmacology — inconclusiveinconclusiveworking →
Claim in pharmacology — inconclusiveinconclusiveworking →
Broad-spectrum receptor profiling reveals that phenylalkylamine psychedelics interact with 42 of 49 assayed binding sites, indicating a multi-receptor interaction profile considerably wider than the canonical 5-HT₂A/5-HT₂C selectivity model suggests.supported
Phenylalkylamines interact with 42 of 49 sites tested; not as selective as generally believed. journal.pone.0009019
Ewald and Maurer identified CYP2D6 as the sole isoenzyme involved in O-demethylation of DOC (a closely related DOx compound), with Ki values of 7.1–296 µM using recombinant CYP2D6 and 2.7–19.9 µM with human liver microsomessupported
CYP2D6 identified as the sole isoenzyme involved in O-demethylation of DOC and related DOx compounds. DOC is a competitive CYP2D6 inhibitor (Ki 7.1-296 µM recombinant, 2.7-19.9 µM HLM). j.toxlet.2008.09.014
receptor-pharmacology9 · 8 ok
DOET fully substitutes for mescaline in drug discrimination paradigms at 0.3 mg/kg in rats, confirming shared discriminative stimulus properties with serotonergic hallucinogens. Stimulants (d-amphetamine, cocaine) did not substitute for mescaline in these paradigms.supported
DOM and DOET (0.3 mg/kg) fully substituted for mescaline as discriminative stimulus in rats; d-amphetamine and cocaine did not. pmid:1197576
DOET fully substitutes for mescaline in drug discrimination paradigms at 0.3 mg/kg in rats, confirming shared discriminative stimulus properties with serotonergic hallucinogens. Stimulants (d-amphetamine, cocaine) did not substitute for mescaline in these paradigms.supported
Rats trained to discriminate DOM generalized with mescaline and DOET but not amphetamine. pmid:6771804
Nelson et al. examined 17 phenylisopropylamine hallucinogens at cloned human 5-HT₂A, 5-HT₂B, and 5-HT₂C receptors, finding high positive correlations (r > 0.9) between affinities at all three subtypessupported
Binding affinities of 17 phenylisopropylamine hallucinogens at cloned human 5-HT2A, 5-HT2B, and 5-HT2C receptors; high positive correlation (r>0.9) between affinities at all three receptor subtypes. pmid:9933142
Claim in receptor-pharmacology — inconclusiveinconclusiveworking →
Canal and colleagues demonstrated that 5-HT₂C potently modulates the head-twitch response induced by phenethylamine hallucinogens in mice, suggesting a regulatory role in the overall hallucinogenic response.supported
5-HT2C potently modulates hallucinogen response. s00213-010-1784-0
Broad receptorome profiling by Ray revealed that phenylalkylamine psychedelics interact with 42 of 49 broadly assayed receptor sites, challenging the assumption of narrow 5-HT₂A/5-HT₂C selectivitysupported
Phenylalkylamines interact with 42 of 49 sites tested; not as selective as generally believed. journal.pone.0009019
Halberstadt, Powell, and Geyer demonstrated that DOET increases locomotor activity in C57BL/6J mice, an effect blocked by the selective 5-HT₂A antagonist M100907.supported
Confirms DOET increases locomotor activity in C57BL/6J mice via 5-HT2A receptor activation; M100907 (5-HT2A antagonist) blocked locomotor hyperactivity. j.neuropharm.2013.01.014
Wing, Tapson, and Geyer showed that DOET inhibits locomotor and investigatory behavior in rats tested in a Behavioral Pattern Monitor in novel environments, with this effect blocked by the 5-HT₂ antagonist ketanserin.supported
DOET among 5HT-2 agonists producing inhibition of locomotor and investigatory behavior in novel environment; blocked by ketanserin/ritanserin. bf02244617
González-Maeso and colleagues showed that hallucinogenic 5-HT₂A agonists (including DOI) induce distinct transcriptome fingerprints in mouse somatosensory cortex that differ from those produced by non-hallucinogenic 5-HT₂A agonists such as lisuridesupported
DOI and LSD show similar transcriptome fingerprints in somatosensory cortex; lisuride (non-hallucinogenic 5-HT2A agonist) shows different fingerprint. pmid:14523084
history8 · 2 ok
Claim in history — inconclusiveinconclusiveworking →
Alexander Shulgin synthesized DOET while employed as a research chemist at Dow Chemical Company in the early 1960s, as the direct ethyl homologue of his earlier compound DOM (2,5-dimethoxy-4-methylamphetamine), which he had first prepared in 1963supported
Historical account of DOM development; Shulgin's role at Dow Chemical; Dow Chemical commissioned Snyder at Johns Hopkins to study DOET as potential pharmaceutical. dta.3667
Claim in history — inconclusiveinconclusiveworking →
Claim in history — inconclusiveinconclusiveworking →
DOM had been distributed widely as "STP" at the Human Be-In, causing numerous adverse reactions attributable partly to the drug's long duration and partly to misinformation that chlorpromazine treatment worsened rather than helped the responsesupported
Historical account of DOM development; Owsley Stanley 1967 distribution; corrects inaccuracies in popular accounts. dta.3667
Claim in history — inconclusiveinconclusiveworking →
Claim in history — inconclusiveinconclusiveworking →
Claim in history — inconclusiveinconclusiveworking →
clinical-evidence5 · 1 ok
Claim in clinical-evidence — inconclusiveinconclusiveworking →
Claim in clinical-evidence — inconclusiveinconclusiveworking →
Claim in clinical-evidence — inconclusiveinconclusiveworking →
Claim in clinical-evidence — inconclusiveinconclusiveworking →
Jacob and Shulgin (1983) evaluated sulfur analogues of DOM and DOET in human subjectssupported
Thio analogues of DOM and DOET synthesized and evaluated in man. pmid:6842515
comparative-pharmacology5 · 2 ok
In drug discrimination paradigms, DOET fully substitutes for mescaline and DOM at 0.3 mg/kg in rats, confirming shared serotonergic discriminative stimulus propertiespartially supported
DOM and DOET (0.3 mg/kg) fully substituted for mescaline as discriminative stimulus in rats. pmid:1197576
In drug discrimination paradigms, DOET fully substitutes for mescaline and DOM at 0.3 mg/kg in rats, confirming shared serotonergic discriminative stimulus propertiessupported
Rats trained to discriminate DOM generalized with mescaline and DOET but not amphetamine. DOM stimulus blocked by serotonin antagonists cinanserin/methysergide, not by dopamine antagonist haloperidol. pmid:6771804
Claim in comparative-pharmacology — inconclusiveinconclusiveworking →
Claim in comparative-pharmacology — inconclusiveinconclusiveworking →
Claim in comparative-pharmacology — inconclusiveinconclusiveworking →
chemistry4 · 2 ok
Claim in chemistry — inconclusiveinconclusiveworking →
Extension of the alpha-methyl group to an alpha-ethyl moiety abolishes hallucinogenic activity in phenylalkylamines, confirming that the alpha-methyl is essential for psychedelic effects and that the 4-position ethyl group — not the side chain — is the structure-activity variable determining potency within the DOx series.supported
Structural distinctions between hallucinogenic amphetamines and MDMA: alpha-methyl extension to alpha-ethyl abolishes hallucinogenic activity. fpsyt.2022.863088
Claim in chemistry — inconclusiveinconclusiveworking →
This stereochemical preference is the opposite of the amphetamine stimulant pattern, where the S-(+)-enantiomer (dextroamphetamine) is typically more active, and is consistent with the general rule for phenylalkylamine hallucinogens.supported
levo-isomer more active for hallucinogens. fpsyt.2022.863088
neuroscience3 · 2 ok
DOx compounds including DOI (the most studied member of the class) induce distinct transcriptome fingerprints in somatosensory cortex that differ from those of non-hallucinogenic 5-HT₂A agonists, suggesting pathway-specific downstream signaling.supported
DOI and LSD show similar transcriptome fingerprints in somatosensory cortex; lisuride (non-hallucinogenic 5-HT2A agonist) shows different fingerprint; all absent in 5-HT2AR knockout mice. pmid:14523084
The DOx class has served as a translational model in schizophrenia research, where DOx-induced behavioral disruptions — prepulse inhibition deficits, locomotor changes, head-twitch responses — in rodents model aspects of psychotic symptomatologysupported
Review of behavioral models for serotonergic hallucinogens including DOx compounds; head-twitch response, locomotor changes, pre-pulse inhibition; 5-HT2A as primary target. s1461145713000722
Claim in neuroscience — inconclusiveinconclusiveworking →
pharmacokinetic-detail2 · 2 ok
Ewald and Maurer characterized this pathway for DOC using recombinant CYP2D6 isoenzymes, finding Ki values of 7.1–296 µM with recombinant enzyme and 2.7–19.9 µM with human liver microsomessupported
DOC is a competitive CYP2D6 inhibitor (Ki 7.1-296 µM recombinant, 2.7-19.9 µM HLM). j.toxlet.2008.09.014
DOx compounds also demonstrate the capacity to inhibit CYP2D6 competitively, raising the possibility of auto-inhibition of metabolism at higher doses and pharmacokinetic drug-drug interactions with other CYP2D6 substrates.supported
DOC is a competitive CYP2D6 inhibitor (Ki 7.1-296 µM recombinant, 2.7-19.9 µM HLM). Interactions with other CYP2D6 substrates possible but unlikely. j.toxlet.2008.09.014