generation run 2026-04-26
52 min completedmodel pipeline-v5plan not recordedrun/830b1ba1…Selection
Verification
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- seen / partial
- working
The model's own caveats
none raised on this run
Reproduce
- inputs
- 26 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
20 searches — query, source, results, what was kept and why
| # | source | query | seen | kept | rationale |
|---|---|---|---|---|---|
| 1 | OpenAlex | 4-hydroxy-N,N-diethyltryptamine 4-OH-DET receptor binding pharmacology | 7 | 3 | Kozell 2023 may contain specific 4-HO-DET binding data; Malaca toxicology review covers 4-HO analogs; Taschwer 2016 for chemical identity confirmation |
| 2 | PubMed | N,N-diethyltryptamine DET serotonin receptor binding 5-HT2A | 4 | 3 | Gatch 2021 is key primary source directly testing 4-OH-DET; Rabin 2002 shows DET 5-HT2A functional activity; Khazan 1965 historical DET data |
| 3 | ClinicalTrials.gov · absence | 4-HO-DET diethyltryptamine psychedelic | 0 | — | Confirms no registered clinical trials for this compound |
| 4 | PubMed | psychedelic tolerance cross-tolerance serotonin receptor downregulation tryptamine | 2 | 2 | Relevant for tolerance mechanism section applicable to 4-HO-DET as 5-HT2AR agonist |
| 5 | PubMed | serotonin toxicity serotonergic psychedelics MAOI interaction | 7 | 1 | Key reference for interaction safety warnings applicable to 4-HO-DET class |
| 6 | PubMed | tryptamine new psychoactive substances NPS serotonin 5-HT2A | 4 | 2 | NPS pharmacology studies potentially including tryptamine analogs |
| 7 | OpenAlex | 4-HO-DET 4-hydroxy diethyltryptamine psychedelic | 4 | 2 | Tittarelli review likely mentions 4-HO-DET; Glatfelter 2023 directly studies diethyl tryptamine variants |
| 8 | PubMed | 4-hydroxy-N,N-diethyltryptamine psychedelic | 1 | 1 | Covers DET as a parent compound and 4-hydroxy tryptamine analogs |
| 9 | PubChem | 4-HO-DET | 1 | 1 | Verified chemical identity; confirms all seed data values except SMILES not returned |
| 10 | PubMed | 4-HO-DET ethocin tryptamine | 10 | — | — |
| 11 | WebSearch | 4-HO-DET ethocin CZ-74 tryptamine Shulgin TIHKAL history synthesis | 10 | 3 | Key historical and dosage data from established sources |
| 12 | PubMed | tramadol serotonin syndrome mechanism serotonergic drug interaction monoamine | 2 | 1 | Mechanism for dangerous tramadol interaction with serotonergic psychedelics including 4-HO-DET |
| 13 | Erowid | TIHKAL entry 16 4-HO-DET | 1 | 1 | Primary Shulgin source for dosage, duration, synthesis, and clinical history |
| 14 | OpenAlex | Kozell Eshleman substituted tryptamines 5-HT2A 5-HT1A SERT pharmacology 2023 | 5 | 2 | Binding data confirmation and drug interaction reference |
| 15 | ClinicalTrials.gov · absence | 4-HO-DET diethyltryptamine psychedelic | 0 | — | Confirms no registered trials |
| 16 | CrossRef | DOI 10.1124/jpet.122.001454 verification | 1 | 1 | DOI verification for api_verified status |
| 17 | WebSearch | 4-HO-DET legal status UK US EU Canada Australia controlled | 10 | 2 | Legal status for major jurisdictions |
| 18 | PsychonautWiki | 4-HO-DET dose duration effects interactions legal | 1 | 3 | Confirms community-sourced dose/duration/interaction data in DB |
| 19 | WikiDoc | 4-HO-DET chemical data legal status history | 1 | 2 | CAS number verification and historical confirmation |
| 20 | PubMed | hallucinogen persisting perception disorder HPPD tryptamine | 2 | 2 | HPPD risk for 5-HT2A agonist class applicable to 4-HO-DET |
64 claims by section — every cited sentence, checked against its source
safety17 · 11 ok
Claim in safety — not_supportednot supportedworking →
Litjens et al. (2014) reviewed the condition and found the majority of cases attributed to drugs with 5-HT₂A agonist activitysupported
HPPD review: majority of cases attributed to drugs with agonistic effects on 5-HT2AR. j.euroneuro.2014.05.008
Espiard et al. (2005) documented a case of HPPD following psilocybin use, confirming the risk extends to 4-hydroxylated tryptamines specificallysupported
18-year-old patient developed HPPD after mixed intoxication with psilocybin and cannabis. Perceptual disturbances persisted >8 months. pmid:15963699
Classical psychedelics develop rapid tolerance (tachyphylaxis) through downregulation of 5-HT₂A receptors in the frontal cortexsupported
LSD (5-day dosing) selectively decreases 5-HT2 binding in cortex without affecting other receptors. Psilocybin also reduces 5-HT2 binding. Tolerance mechanism linked to receptor downregulation. pmid:1969270
Classical psychedelics develop rapid tolerance (tachyphylaxis) through downregulation of 5-HT₂A receptors in the frontal cortexsupported
Repeated DOI administration induces progressive HTR tolerance via 5-HT2AR downregulation. acschemneuro.2c00170
De la Fuente Revenga et al. (2022) demonstrated in mice that tolerance to 5-HT₂A-mediated head twitch response develops within 24 hours of a single dose, progresses over 4 days of repeated administration, and is dependent on 5-HT₂A receptor internalization but independent of β-arrestin-2partially supported
Repeated DOI administration induces progressive HTR tolerance via 5-HT2AR downregulation. Tolerance is 5-HT2AR-mediated and independent of beta-arrestin-2. acschemneuro.2c00170
Cross-tolerance is expected with all 5-HT₂A agonist psychedelics: LSD, psilocybin/psilocin, mescaline, DMT, and other 4-substituted tryptaminessupported
Cross-tolerance between DOI and LSD. Tolerance is 5-HT2AR-mediated. acschemneuro.2c00170
Cross-tolerance is expected with all 5-HT₂A agonist psychedelics: LSD, psilocybin/psilocin, mescaline, DMT, and other 4-substituted tryptaminessupported
LSD (5-day dosing) selectively decreases 5-HT2 binding in cortex. Psilocybin also reduces 5-HT2 binding. Tolerance mechanism linked to receptor downregulation. pmid:1969270
Claim in safety — inconclusiveinconclusiveworking →
Tramadol: Tramadol inhibits the serotonin transporter (SERT) in human SERT-transfected HEK293 cellssupported
Tramadol, tapentadol, meperidine, methadone, and dextromethorphan inhibit human SERT in HEK293 cells. s00204-018-2244-6
The FDA issued a Drug Safety Communication in 2016 linking opioid analgesics including tramadol to serotonin toxicity risksupported
FDA Drug Safety Communication 2016 covers entire opioid class. s00204-018-2244-6
Claim in safety — inconclusiveinconclusiveworking →
Eckernäs et al. (2023) demonstrated that harmine (a MAO-A inhibitor) inhibited DMT metabolism in vitro, confirming the pharmacokinetic basis for this potentiation.partially supported
CYP2D6 inhibitors (harmine, SKF-525A) reduce metabolism. Implications for slow CYP2D6 metabolizers. 00498254.2023.2278488
SSRIs and SNRIs: Halman et al. (2024) systematically reviewed drug-drug interactions involving classical psychedelics and found evidence that chronic SSRI use attenuates or blunts psychedelic effects, likely through 5-HT₂A receptor downregulation from sustained serotonin elevationsupported
52 studies on DDIs between classic psychedelics and other drugs. Interactions studied with antidepressants... Both attenuated and potentiated effects observed. 02698811231211219
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
pharmacology11 · 9 ok
The 4-hydroxyindole pharmacophore — shared with psilocin, 4-HO-MET, and other psychedelic tryptamines — is the structural determinant of 5-HT₂A binding and hallucinogenic activitysupported
Comprehensive SAR review for classic serotonergic hallucinogens: tryptamines, ergolines, phenethylamines. 5-HT2A as principal receptor target. 7854_2017_475
The 4-hydroxyindole pharmacophore — shared with psilocin, 4-HO-MET, and other psychedelic tryptamines — is the structural determinant of 5-HT₂A binding and hallucinogenic activitysupported
Radioligand competition at 5-HT2A using [125I]DOI and [3H]MDL100907. Rigid 4-hydroxyindole tryptamine analogs compared to psilocin. LSD-DOI discrimination used to assess hallucinogen-like activity. pmid:10514296
Claim in pharmacology — inconclusiveinconclusiveworking →
The most direct pharmacological evidence comes from Gatch, Hoch, and Carbonaro (2021), who demonstrated that 4-HO-DET fully substitutes for the selective 5-HT₂A agonist DOM in drug-discrimination assays in male Sprague-Dawley ratssupported
4-OH-DET and related tryptamines fully substituted for DOM discriminative stimulus in rats. acsptsci.0c00173
Halberstadt et al. (2011) established that psilocin acts as an agonist at 5-HT₁A, 5-HT₂A, and 5-HT₂C receptors in mice, with each receptor mediating distinct behavioral components: 5-HT₂A drives the head twitch response (the rodent marker of hallucinogenic activity), 5-HT₁A mediates locomotor suppression, and 5-HT₂C modulates locomotor path linearitysupported
Psilocin (4-HO-DMT) acts at 5-HT1A, 5-HT2A, and 5-HT2C receptors; HTR mediated by 5-HT2A; locomotor effects by 5-HT1A. 0269881110388326
Claim in pharmacology — inconclusiveinconclusiveworking →
The parent compound N,N-diethyltryptamine (DET, lacking the 4-hydroxyl) produces concentration-dependent stimulation of phosphoinositide hydrolysis via 5-HT₂A receptors in PC12-5-HT₂A cells, establishing the functional activity of the N,N-diethyl scaffold at this receptorsupported
DET causes concentration-dependent phosphoinositide hydrolysis via 5-HT2A in PC12 cells. pmid:11900766
The addition of the 4-hydroxyl group is expected to increase 5-HT₂A affinity and potency based on established structure-activity relationships for the tryptamine series.supported
Comprehensive SAR review for classic serotonergic hallucinogens: tryptamines, ergolines, phenethylamines. 5-HT2A as principal receptor target. 7854_2017_475
Psilocin pharmacokinetic data from Hasler et al. (1997) and Meshkat et al. (2025)supported
Oral psilocybin 10-20mg: peak psilocin 8.2±2.8 ng/mL at 105±37 min. Absolute bioavailability 52.7±20%. Major metabolite 4-HIAA. pmid:9204776
Psilocin pharmacokinetic data from Hasler et al. (1997) and Meshkat et al. (2025)supported
Systematic review of 14 studies. Psilocin Tmax 1.8-4h; bioavailability 52.7±20%; Vd 277-1016L; metabolism primarily CYP2D6 and CYP3A4 with secondary MAO-A; elimination half-life 1.5-4h. pharmaceutics17040411
CYP2D6 involvement in indole tryptamine metabolism is further supported by Eckernäs et al. (2023), who demonstrated CYP2D6-mediated formation of oxygenated metabolites from DMT.supported
DMT rapidly metabolized by CYP2D6 via hydroxylation on the indole core. 00498254.2023.2278488
neuroscience8 · 3 ok
The following neural mechanisms are extrapolated from the established neuroscience of 5-HT₂A agonist psychedelics, particularly psilocin and LSD, and are expected to apply to 4-HO-DET based on its confirmed 5-HT₂A-mediated hallucinogen-like activity.supported
4-OH-DET and related tryptamines fully substituted for DOM discriminative stimulus in rats. All show abuse liability similar to DOM. acsptsci.0c00173
Claim in neuroscience — inconclusiveinconclusiveworking →
Claim in neuroscience — inconclusiveinconclusiveworking →
Claim in neuroscience — inconclusiveinconclusiveworking →
Halberstadt et al. (2011) showed that 5-HT₁A agonism produces locomotor suppression distinct from 5-HT₂A-mediated head twitch, and Shahar et al. (2022) confirmed that 5-HT₁A activation functionally antagonizes the 5-HT₂A-mediated head twitch responsesupported
HTR mediated by 5-HT2A; locomotor effects by 5-HT1A. 0269881110388326
Halberstadt et al. (2011) showed that 5-HT₁A agonism produces locomotor suppression distinct from 5-HT₂A-mediated head twitch, and Shahar et al. (2022) confirmed that 5-HT₁A activation functionally antagonizes the 5-HT₂A-mediated head twitch responsesupported
5-HT2AR as key mediator of HTR in mice. Inhibitory effect of 5-HT1AR agonism on HTR. ijms232214148
Claim in neuroscience — inconclusiveinconclusiveworking →
Claim in neuroscience — inconclusiveinconclusiveworking →
receptor-pharmacology7 · 7 ok
DOM drug-discrimination (in vivo). Gatch, Hoch, and Carbonaro (2021) tested 4-HO-DET directly in male Sprague-Dawley rats trained to discriminate DOM (2,5-dimethoxy-4-methylamphetamine, a selective 5-HT₂A agonist) from saline. 4-HO-DET fully substituted for the DOM discriminative stimulus, indicating functional 5-HT₂A agonism sufficient to produce hallucinogen-like interoceptive effects in vivosupported
4-OH-DET and related tryptamines fully substituted for DOM discriminative stimulus in rats. acsptsci.0c00173
Multi-receptor binding screen. Glatfelter et al. (2023) examined receptor binding profiles across a matrix of 4-substituted tryptamines with varied N,N-dialkyl groups, explicitly including the N,N-diethyl (4-HO-DET) variantsupported
Examined 4-hydroxy, 4-acetoxy, 4-propionoxy variants with N,N-dialkyl (dimethyl, methyl-ethyl, diethyl, methyl-propyl, ethyl-propyl, diisopropyl, methyl-allyl, diallyl) substitutions in binding screen. Diethyl variant included. acsptsci.2c00222
DET functional activity. Rabin et al. (2002) demonstrated that the parent compound N,N-diethyltryptamine (DET) stimulates phosphoinositide hydrolysis through 5-HT₂A receptors in PC12-5-HT₂A cells in a concentration-dependent mannersupported
DET causes concentration-dependent phosphoinositide hydrolysis via 5-HT2A in PC12 cells. pmid:11900766
Psilocin multi-receptor pharmacology. Halberstadt et al. (2011) demonstrated that psilocin — differing from 4-HO-DET only in N,N-dimethyl versus N,N-diethyl substitution — produces receptor-specific behavioral effects in mice: 5-HT₂A mediates the head twitch response, 5-HT₁A mediates locomotor suppression, and 5-HT₂C modulates path linearitysupported
Psilocin (4-HO-DMT) acts at 5-HT1A, 5-HT2A, and 5-HT2C receptors; HTR mediated by 5-HT2A; locomotor effects by 5-HT1A. 0269881110388326
Shahar et al. (2022) further confirmed that 5-HT₁A agonism inhibits 5-HT₂A-mediated head twitch response, indicating functional antagonism between these receptor systems.supported
Inhibitory effect of 5-HT1AR agonism on HTR. ijms232214148
Gerasimov et al. (1999) established that conformationally constrained pyrrolidine analogs of psilocin bind 5-HT₂A with affinity comparable to psilocin itself and produce LSD-like discriminative stimulus effects, confirming that the 4-hydroxyindole scaffold is the primary determinant of hallucinogenic activity independent of amine side-chain flexibilitysupported
Radioligand competition at 5-HT2A using [125I]DOI and [3H]MDL100907. Rigid 4-hydroxyindole tryptamine analogs compared to psilocin. LSD-DOI discrimination used to assess hallucinogen-like activity. pmid:10514296
The 4-hydroxyl group increases potency relative to unsubstituted tryptamines — DET requires higher doses than 4-HO-DET to produce comparable effects — consistent with the enhanced 5-HT₂A affinity conferred by 4-position oxygenation in the indole series.supported
Comprehensive SAR review for classic serotonergic hallucinogens: tryptamines, ergolines, phenethylamines. 5-HT2A as principal receptor target. 7854_2017_475
summary6 · 3 ok
Claim in summary — inconclusiveinconclusiveworking →
4-HO-DET is presumed to act primarily through 5-HT₂A receptor agonism based on the shared 4-hydroxyindole pharmacophore with psilocinsupported
Comprehensive SAR review for classic serotonergic hallucinogens: tryptamines, ergolines, phenethylamines. 5-HT2A as principal receptor target. 7854_2017_475
In vivo, the compound fully substitutes for the selective 5-HT₂A agonist DOM in rat drug-discrimination assays, confirming hallucinogen-like activitysupported
4-OH-DET and related tryptamines fully substituted for DOM discriminative stimulus in rats. acsptsci.0c00173
Claim in summary — inconclusiveinconclusiveworking →
As a 5-HT₂A agonist, tolerance develops rapidly through receptor downregulation in the frontal cortex, with full reset occurring over approximately 7 dayspartially supported
Repeated DOI administration induces progressive HTR tolerance via 5-HT2AR downregulation. Cross-tolerance between DOI and LSD. Tolerance is 5-HT2AR-mediated and independent of beta-arrestin-2. acschemneuro.2c00170
Claim in summary — inconclusiveinconclusiveworking →
comparative-pharmacology4 · 3 ok
All 4-hydroxylated tryptamines in this comparison share the active 4-hydroxyindole pharmacophore and exhibit broadly similar potency ranges, though systematic head-to-head potency comparisons in controlled human studies have not been published for any pair.supported
Comprehensive SAR review for classic serotonergic hallucinogens: tryptamines, ergolines, phenethylamines. 5-HT2A as principal receptor target. 7854_2017_475
Gatch et al. (2021) tested both 4-HO-DMT and 4-HO-DET in the same DOM discrimination paradigm — both fully substituted for DOM, indicating equivalent functional 5-HT₂A agonism in vivosupported
4-OH-DET and related tryptamines fully substituted for DOM discriminative stimulus in rats. acsptsci.0c00173
Claim in comparative-pharmacology — inconclusiveinconclusiveworking →
Gatch et al. (2021) systematically compared 4-hydroxy and 4-acetoxy tryptamines in the DOM discrimination assay and found that 4-hydroxy compounds were uniformly more potent than their 4-acetoxy counterpartssupported
4-hydroxy compounds more potent than 4-acetoxy. acsptsci.0c00173
chemistry3 · 2 ok
It shares the 4-hydroxyindole pharmacophore — the structural motif responsible for 5-HT₂A agonism — with psilocin (4-HO-DMT), 4-HO-MET, and other members of the 4-HO-xT series. 4-HO-DET is the direct N,N-diethyl homolog of psilocin, differing only in the substitution of two ethyl groups for two methyl groups on the terminal amine nitrogen of the tryptamine side chain.supported
Comprehensive SAR review for classic serotonergic hallucinogens: tryptamines, ergolines, phenethylamines. 5-HT2A as principal receptor target. 7854_2017_475
Claim in chemistry — inconclusiveinconclusiveworking →
Conformationally constrained analogs — such as the pyrrolidine-containing 4-hydroxytryptamines studied by Gerasimov et al. — introduce chirality, but the flexible diethylamine side chain of 4-HO-DET does not.supported
Rigid 4-hydroxyindole tryptamine analogs compared to psilocin. LSD-DOI discrimination used to assess hallucinogen-like activity. pmid:10514296
history3 · 1 ok
Claim in history — inconclusiveinconclusiveworking →
Claim in history — inconclusiveinconclusiveworking →
Psycholytic therapy at that time was practiced across approximately 30 European clinical centers by more than 100 outpatient psychotherapistspartially supported
Used at 30 European clinical centers. fpsyt.2022.1020505
pharmacokinetic-detail3 · 3 ok
Meshkat et al. (2025) conducted a systematic review of psilocybin/psilocin pharmacokinetics across published clinical studies:supported
Systematic review of 14 studies. Psilocin Tmax 1.8-4h; bioavailability 52.7±20%; Vd 277-1016L; metabolism primarily CYP2D6 and CYP3A4 with secondary MAO-A; elimination half-life 1.5-4h. pharmaceutics17040411
Hasler et al. (1997) provided early confirmation of psilocin oral bioavailability and plasma kinetics using HPLC-ECD determination following oral and intravenous psilocybin in human subjects.supported
Oral psilocybin 10-20mg: peak psilocin 8.2±2.8 ng/mL at 105±37 min. Absolute bioavailability 52.7±20%. Major metabolite 4-HIAA. pmid:9204776
Eckernäs et al. (2023) demonstrated that DMT is rapidly metabolized by CYP2D6 in vitro, with formation of oxygenated indole metabolites; co-incubation with harmine (a MAO-A inhibitor) shifted the metabolic pathway toward CYP-mediated oxidationpartially supported
CYP2D6 inhibitors (harmine, SKF-525A) reduce metabolism. Implications for slow CYP2D6 metabolizers. 00498254.2023.2278488
clinical-evidence2 · 1 ok
Claim in clinical-evidence — inconclusiveinconclusiveworking →
Passie, Guss, and Krähenmann (2022) contextualized Leuner's work within the broader psycholytic therapy movement, which operated across approximately 30 clinical centers in Europesupported
Used at 30 European clinical centers. fpsyt.2022.1020505