generation run 2026-05-11
67 min completedmodel pipeline-v5plan not recordedrun/eebdcf01…Selection
Verification
- record
- seen / partial
- working
The model's own caveats
4 further caveats recorded as free text — readable on the working page
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
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- none — agent transcripts are persisted from 2026-09 onward
21 searches — query, source, results, what was kept and why
| # | source | query | seen | kept | rationale |
|---|---|---|---|---|---|
| 1 | PubChem | 3C-E | 1 | 1 | Confirmed chemical identity of 3C-E |
| 2 | PubMed · absence | 3C-E 1-(4-ethoxy-3,5-dimethoxyphenyl)propan-2-amine psychedelic phenethylamine | 0 | — | — |
| 3 | OpenAlex | 3C-E phenethylamine psychedelic Shulgin PiHKAL | 21 | 2 | Both papers directly relate to 3C-E pharmacology |
| 4 | PubMed | PMID 31849671 | 1 | — | — |
| 5 | PubMed | PMID 30789291 | 1 | — | — |
| 6 | WebSearch | PiHKAL Shulgin 3C-E mescaline analog | 10 | 1 | Confirms 3C-E is in PiHKAL and first synthesized by Shulgin |
| 7 | ClinicalTrials.gov · absence | 3C-E mescaline analog phenethylamine psychedelic | 0 | — | — |
| 8 | WebSearch | 3C-E 4-ethoxy-3,5-dimethoxyphenyl psychedelic legal status scheduling | 10 | 2 | Primary general information sources |
| 9 | PsychonautWiki | — | 1 | 2 | Secondary community source for dose/duration context |
| 10 | WebSearch | 3C-E 3C-escaline legal status UK analog act US federal scheduled | 10 | 2 | Legal status data for major jurisdictions |
| 11 | Erowid/PiHKAL | — | 1 | 4 | Primary source for 3C-E pharmacology and effects |
| 12 | PubMed | mescaline pharmacology receptor binding review | 1 | 1 | Comprehensive review of mescaline class pharmacology applicable to 3C-E |
| 13 | PubMed | psychedelic tolerance cross-tolerance LSD serotonin receptor | 2 | 1 | Directly relevant to 3C-E tolerance mechanism |
| 14 | PubChem | CID 44350137 | 1 | — | — |
| 15 | Multiple | 3C-E dose duration comparison | — | — | — |
| 16 | WebSearch | 3C-E alpha-methylescaline Germany NpSG scheduled | 10 | — | — |
| 17 | psychedelicsdaily.com | — | 1 | — | — |
| 18 | Multiple | 3C-E legal status cross-jurisdiction | — | — | — |
| 19 | Erowid PiHKAL | — | 1 | — | — |
| 20 | PubMed | PMID 16277614 | 1 | — | — |
| 21 | Multiple sources | 3C-E SMILES CAS verification | — | — | — |
53 claims by section — every cited sentence, checked against its source
safety12 · 8 ok
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Hallucinogen persisting perception disorder (HPPD): Reported across the serotonergic psychedelic class, with generally low prevalence and frequently self-resolving course. No HPPD cases have been specifically attributed to 3C-E.supported
Generally low prevalence. Spontaneously subsides in most cases within one year. 7854_2025_610
De la Fuente Revenga et al. (2022) demonstrated in the mouse HTR model that tolerance to 5-HT₂A-mediated behavioral effects develops within 24 hours of a single administration and that cross-tolerance occurs between different psychedelic 5-HT₂A agonists (DOI and LSD), but not with non-psychedelic 5-HT₂A agonists (lisuride)supported
Tolerance develops within 24h of single administration. Cross-tolerance between DOI and LSD. 5-HT2A receptor downregulation in frontal cortex mediates tolerance. acschemneuro.2c00170
The mechanism is 5-HT₂A receptor activation-dependent and independent of β-arrestin-2 signaling.supported
5-HT2A receptor downregulation in frontal cortex mediates tolerance. Mechanism independent of beta-arrestin-2. acschemneuro.2c00170
A notable caveat applies to the mescaline analog class: Buckholtz et al. (1990) found that repeated mescaline administration (10 mg/kg daily for 5–10 days in rats) did not produce 5-HT₂ receptor downregulation, unlike repeated LSDsupported
Mescaline (10 mg/kg × 5-10 days) did NOT affect 5-HT2 binding, contrasting with LSD and indole hallucinogens. pmid:1969270
Tramadol inhibits the serotonin transporter (SERT), and the addition of direct 5-HT₂A agonism from 3C-E creates a pharmacodynamic interaction that may precipitate serotonin syndromesupported
Tramadol inhibits SERT; FDA issued Drug Safety Communication in 2016 linking opioids to serotonin syndrome. s00204-018-2244-6
The FDA issued a Drug Safety Communication specifically linking tramadol to serotonin toxicity risk when combined with serotonergic agents.supported
FDA issued Drug Safety Communication in 2016 linking opioids to serotonin syndrome. s00204-018-2244-6
Although 3C-E does not itself release monoamines, MAOI co-administration could extend its duration and intensify effects by slowing metabolic clearance of endogenous serotonin during 5-HT₂A receptor activationsupported
TMA (3,4,5-trimethoxyamphetamine) causes no detectable changes in extracellular 5-HT or DA levels in rat brain. Three adjacent methoxy groups abolish monoamine-releasing activity. TMA scarcely affects MAO enzymes. j.euroneuro.2014.04.009
CYP2D6 inhibitors (fluoxetine, paroxetine, bupropion, quinidine): If CYP2D6 is the primary metabolic enzyme for 3C-E (inferred from TMA-2 data), potent CYP2D6 inhibitors could reduce clearance and prolong the already extended duration of effects .supported
CYP2D6 identified as the sole isoenzyme involved in O-demethylation of DOx class compounds including TMA-2. j.toxlet.2008.09.014
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
comparative-pharmacology10 · 9 ok
Within the 3,4,5-trisubstituted series specifically, Halberstadt et al. (2019) showed that TMA is approximately twice as potent as mescaline in the mouse HTR assay. 3C-E extends this pattern: the amphetamine chain combined with 4-ethoxy substitution produces greater HTR potency than TMA alone.supported
TMA induced HTR and was twice as potent as mescaline. Replacing 4-methoxy with ethoxy or propoxy increased potency in the HTR assay for both mescaline and TMA. 0269881119826610
Parrish et al. (2005) demonstrated that phenylisopropylamines produce higher phospholipase C activation at 5-HT₂A receptors than their phenethylamine counterpartssupported
Phenylisopropylamine analogs have higher 5-HT2A intrinsic activities than phenethylamine counterparts for phospholipase C. pmid:16277614
Replacing the 4-methoxy group with a 4-ethoxy group (TMA → 3C-E) increases potency in the HTR assay within the 3,4,5-substituted seriessupported
Replacing 4-methoxy with ethoxy or propoxy increased potency in the HTR assay for both mescaline and TMA. 0269881119826610
This contrasts with the 2,4,5-substituted series (TMA-2 and its alkoxy analogs MEM and MPM), where 4-alkoxy homologation did not produce consistent potency increasessupported
Provides evidence for distinct SAR between 2,4,5- and 3,4,5-substituted phenylalkylamine hallucinogens. 0269881119826610
Oberlender et al. (1995) explored the effects of chiral 4-alkyl substituents in hallucinogenic amphetamines, demonstrating that the size and branching of the 4-position substituent significantly modulates potency — though their work focused on alkyl rather than alkoxy groups.partially supported
Potency of hallucinogenic amphetamines drops when 4-alkyl chain exceeds propyl length. Chirality at 4-alkyl group showed slight but non-significant potency differences at 5-HT2A. pmid:7658446
Claim in comparative-pharmacology — inconclusiveinconclusiveworking →
Marcher-Rørsted et al. (2020) investigated the significance of the 2,5-dimethoxy motif for 5-HT₂A agonism and found it to be a critical structural determinant for high-affinity binding in that seriespartially supported
Removal of either 2- or 5-methoxy group reduces affinity modestly but significantly reduces in vivo HTR potency. The 2,5-dimethoxy motif important for in vivo potency. acschemneuro.0c00129
Kolaczynska et al. (2019) provided comprehensive receptor interaction profiles for 4-alkoxy-substituted 2,5-dimethoxyphenethylamines and their amphetamine analogs, including binding data at 5-HT₂A, 5-HT₂C, adrenergic, dopaminergic, and TAAR1 receptorssupported
Receptor binding affinities of 2C-O and DO-alkoxy derivatives at 5-HT1A, 5-HT2A, 5-HT2C, TAAR1, alpha-adrenergic, D2 and monoamine transporters. fphar.2019.01423
Matsumoto et al. (2014) demonstrated that TMA — the direct structural parent of 3C-E — produces no detectable monoamine release in rat brain, while MDMA and related empathogenic amphetamines produce robust serotonin and dopamine releasesupported
TMA (3,4,5-trimethoxyamphetamine) causes no detectable changes in extracellular 5-HT or DA levels in rat brain. Three adjacent methoxy groups abolish monoamine-releasing activity. j.euroneuro.2014.04.009
In drug discrimination paradigms, mescaline and its analogs generalize to LSD and DOM, supporting shared 5-HT₂A agonist pharmacology across the phenethylamine and indole hallucinogen classes. 3C-E has not been tested directly in drug discrimination studies, but its HTR activity predicts that it would substitute for other 5-HT₂A agonists in such assays.supported
Review of drug discrimination studies with LSD, phenethylamines and tryptamines as discriminative stimuli. Covers TMA and mescaline analogs. s00213-008-1356-8
receptor-pharmacology8 · 7 ok
5-HT₂A receptor: Primary target. Agonist activity confirmed by dose-dependent head-twitch response in mice. Halberstadt et al. (2013) demonstrated that 5-HT₂A receptor activation mediates the behavioral effects of the phenylalkylamine hallucinogen class, including locomotor hyperactivity.supported
HTR experiments conducted with mescaline, escaline, proscaline, TMA, 3C-E, 3C-P, TMA-2, MEM, and MPM in C57BL/6J mice. 0269881119826610
5-HT₂A receptor: Primary target. Agonist activity confirmed by dose-dependent head-twitch response in mice. Halberstadt et al. (2013) demonstrated that 5-HT₂A receptor activation mediates the behavioral effects of the phenylalkylamine hallucinogen class, including locomotor hyperactivity.supported
5-HT2A receptor mediates locomotor hyperactivity induced by phenylalkylamine hallucinogens including mescaline and TMA-2. M100907 (5-HT2A antagonist) blocks the effect. Not observed in 5-HT2A knockout mice. j.neuropharm.2013.01.014
5-HT₂C receptor: Likely co-target. Phenethylamine and amphetamine hallucinogens typically display some degree of 5-HT₂C agonism, though the exact contribution to subjective effects remains debated. Kolaczynska et al. (2019) characterized receptor profiles for the structurally related 4-alkoxy-substituted 2,5-dimethoxyphenethylamine series, documenting dual 5-HT₂A/5-HT₂C activity. Whether the 3,5-dimethoxy regiochemistry of 3C-E produces a comparable selectivity profile has not been determined.supported
Receptor binding affinities of 2C-O and DO-alkoxy derivatives at 5-HT1A, 5-HT2A, 5-HT2C, TAAR1, alpha-adrenergic, D2 and monoamine transporters. fphar.2019.01423
Monoamine transporters (DAT, SERT, NET): Negligible activity expected. TMA, the 4-methoxy parent of 3C-E, produces no detectable changes in extracellular serotonin or dopamine in rat brain via in vivo microdialysis.supported
TMA (3,4,5-trimethoxyamphetamine) causes no detectable changes in extracellular 5-HT or DA levels in rat brain. j.euroneuro.2014.04.009
MAO-A and MAO-B: No significant inhibition expected. TMA showed no meaningful MAO inhibitory activity.supported
TMA scarcely affects MAO enzymes. j.euroneuro.2014.04.009
Adrenergic, dopaminergic, and trace amine receptors: Kolaczynska et al. (2019) profiled α₂-adrenergic, D₂, and TAAR1 binding for the related 2,5-dimethoxy alkoxy series, but these receptors have not been tested for the 3,5-dimethoxy series that includes 3C-E.supported
Receptor binding affinities of 2C-O and DO-alkoxy derivatives at 5-HT1A, 5-HT2A, 5-HT2C, TAAR1, alpha-adrenergic, D2 and monoamine transporters. fphar.2019.01423
Parrish et al. (2005) measured phospholipase C (PLC) activation as the functional readout for a series of phenylalkylamine 5-HT₂A agonists and found that phenylisopropylamines (the amphetamine class including 3C-E) consistently produce greater PLC activation than their phenethylamine counterparts at equimolar concentrationssupported
Phenylisopropylamine analogs have higher 5-HT2A intrinsic activities than phenethylamine counterparts for phospholipase C. pmid:16277614
Claim in receptor-pharmacology — inconclusiveinconclusiveworking →
pharmacology7 · 7 ok
The most direct evidence comes from Halberstadt et al. (2019), who tested 3C-E in the mouse head-twitch response (HTR) assay — a well-validated behavioral readout of 5-HT₂A receptor activation. 3C-E induced dose-dependent HTR in C57BL/6J mice, with potency exceeding that of its 4-methoxy parent compound TMA (3,4,5-trimethoxyamphetamine)supported
HTR experiments conducted with mescaline, escaline, proscaline, TMA, 3C-E, 3C-P, TMA-2, MEM, and MPM in C57BL/6J mice... Replacing 4-methoxy with ethoxy or propoxy increased potency in the HTR assay for both mescaline and TMA. 0269881119826610
The HTR assay has been validated as a translational predictor of human psychedelic potency: Halberstadt et al. (2020) established a strong positive correlation (r = 0.9448) between HTR potency in mice and reported hallucinogenic potency in humans across 36 compounds.supported
Strong positive correlation (r=0.9448) between HTR potencies in mice and reported hallucinogenic potencies in humans (n=36 compounds including 3C-E). j.neuropharm.2019.107933
Matsumoto et al. (2014) demonstrated via in vivo microdialysis that TMA produces no detectable changes in extracellular serotonin or dopamine levels in rat brain, distinguishing the 3,4,5-trimethoxyamphetamine series mechanistically from MDMA and other empathogenic amphetaminessupported
TMA (3,4,5-trimethoxyamphetamine) causes no detectable changes in extracellular 5-HT or DA levels in rat brain. Three adjacent methoxy groups abolish monoamine-releasing activity. j.euroneuro.2014.04.009
TMA also showed no meaningful inhibition of monoamine oxidase A or B. 3C-E, as a close structural analog (differing only by one carbon at the 4-position alkoxy group), is expected to share this mechanistic profile .supported
TMA scarcely affects MAO enzymes. j.euroneuro.2014.04.009
Parrish et al. (2005) demonstrated that phenylisopropylamine analogs have significantly higher intrinsic activities for 5-HT₂A receptor-mediated phospholipase C activation compared to their phenethylamine counterpartssupported
Phenylisopropylamine analogs have higher 5-HT2A intrinsic activities than phenethylamine counterparts for phospholipase C. pmid:16277614
Ewald and Maurer (2008) identified CYP2D6 as the sole cytochrome P450 isoenzyme responsible for the main metabolic steps of TMA-2 (2,4,5-trimethoxyamphetamine) and related 2,5-dimethoxyamphetamine derivativessupported
CYP2D6 identified as the sole isoenzyme involved in O-demethylation of DOx class compounds including TMA-2. j.toxlet.2008.09.014
The related DOx/TMA-2 compounds act as non-mechanism-based competitive CYP2D6 inhibitors with Ki values of 2.7–19.9 µM in human liver microsomespartially supported
These drugs are competitive CYP2D6 inhibitors (Ki 7.1-296 µM). j.toxlet.2008.09.014
chemistry5 · 4 ok
This single-carbon homologation increases lipophilicity at the 4-position and enhances potency in the head-twitch response assay. 3C-E is thus the amphetamine analog of escaline and the 4-ethoxy analog of TMA.supported
Replacing 4-methoxy with ethoxy or propoxy increased potency in the HTR assay for both mescaline and TMA. 0269881119826610
The 3,4,5-substitution pattern distinguishes the mescaline/TMA/3C series from the 2,5-dimethoxy series (DOx, 2C-x compounds), which have different SAR profiles — notably, 4-alkoxy homologation increases potency in the 3,4,5 series but not in the 2,4,5-regioisomeric seriessupported
Provides evidence for distinct SAR between 2,4,5- and 3,4,5-substituted phenylalkylamine hallucinogens. 0269881119826610
Monte et al. (1997) demonstrated that the 3,5-methoxy groups in the mescaline pharmacophore must remain conformationally mobile for 5-HT₂A receptor activation, unlike the constrained 2,5-dimethoxy series.supported
Mescaline 3 and 5 methoxy groups must remain conformationally mobile for receptor activation. Constraining them reduces intrinsic efficacy at 5-HT2A. pmid:9301661
Parrish et al. (2005) demonstrated across a series of phenylalkylamine pairs that (R)-configured phenylisopropylamines produce greater phospholipase C activation at the 5-HT₂A receptor than their (S)-counterparts.supported
(R) isomers more active than (S) at human 5-HT2A. Alpha-methylation confers greater intrinsic efficacy. pmid:16277614
Claim in chemistry — inconclusiveinconclusiveworking →
summary4 · 4 ok
Its pharmacological profile is defined by 5-HT₂A receptor agonism without significant monoamine release.supported
TMA (3,4,5-trimethoxyamphetamine) causes no detectable changes in extracellular 5-HT or DA levels in rat brain. Three adjacent methoxy groups abolish monoamine-releasing activity. j.euroneuro.2014.04.009
The compound's primary research significance derives from a 2019 head-twitch response (HTR) study demonstrating dose-dependent 5-HT₂A-mediated activity and confirming that 4-alkoxy homologation in the 3,4,5-substitution pattern increases potency relative to the parent compound TMAsupported
Replacing 4-methoxy with ethoxy or propoxy increased potency in the HTR assay for both mescaline and TMA. Potency relationships closely parallel human hallucinogenic data. 0269881119826610
3C-E acts as a serotonin 5-HT₂A receptor agonist, confirmed by dose-dependent induction of the head-twitch response in micesupported
HTR experiments conducted with mescaline, escaline, proscaline, TMA, 3C-E, 3C-P, TMA-2, MEM, and MPM in C57BL/6J mice. 0269881119826610
The compound is not habit-forming; rapid tolerance develops via 5-HT₂A receptor downregulation, with cross-tolerance to other serotonergic psychedelicssupported
Tolerance develops within 24h of single administration. Cross-tolerance between DOI and LSD. 5-HT2A receptor downregulation in frontal cortex mediates tolerance. acschemneuro.2c00170
neuroscience2 · 2 ok
The absence of monoamine release by 3C-E's parent scaffold TMA implies that the compound's neural effects are mediated predominantly through postsynaptic 5-HT₂A receptor signaling rather than through the presynaptic monoamine flooding that characterizes empathogenic amphetamines.supported
TMA (3,4,5-trimethoxyamphetamine) causes no detectable changes in extracellular 5-HT or DA levels in rat brain. Three adjacent methoxy groups abolish monoamine-releasing activity. j.euroneuro.2014.04.009
Does the tolerance profile of 3C-E follow the indole psychedelic pattern (rapid 5-HT₂ downregulation) or the mescaline pattern (no detectable downregulation)? Buckholtz et al. (1990) found that repeated mescaline administration did not downregulate 5-HT₂ receptors, unlike LSD. Whether 3C-E, as a more potent mescaline analog, crosses the threshold for receptor downregulation is unknown.supported
Mescaline (10 mg/kg × 5-10 days) did NOT affect 5-HT2 binding, contrasting with LSD and indole hallucinogens. Mescaline may have distinct tolerance profile. pmid:1969270
pharmacokinetic-detail2 · 2 ok
Ewald and Maurer (2008) identified CYP2D6 as the sole CYP isoenzyme responsible for the main metabolic steps of TMA-2 in human liver microsomessupported
CYP2D6 identified as the sole isoenzyme involved in O-demethylation of DOx class compounds including TMA-2. j.toxlet.2008.09.014
The DOx/TMA-2 compounds inhibit CYP2D6 competitively with Ki values of 2.7–19.9 µMpartially supported
These drugs are competitive CYP2D6 inhibitors (Ki 7.1-296 µM). j.toxlet.2008.09.014
clinical-evidence1 · 1 ok
The broader mescaline pharmacophore has attracted renewed research interest — Vamvakopoulou et al. (2023) reviewed mescaline as a "forgotten psychedelic" with underexplored therapeutic potential — but this interest has centered on mescaline itself rather than its synthetic analogs.supported
Reviews pharmacology, historical use, and therapeutic potential of mescaline and its analogs. j.neuropharm.2022.109294
effects-overview1 · 1 ok
Compared to the DOx series (DOM, DOI), 3C-E shares the extended duration but arises from a distinct regiochemistry (3,5-dimethoxy versus 2,5-dimethoxy) with different SAR characteristics.supported
Provides evidence for distinct SAR between 2,4,5- and 3,4,5-substituted phenylalkylamine hallucinogens. 0269881119826610
history1 · 1 ok
Its primary research contribution came in 2019, when Halberstadt et al. included 3C-E in a systematic comparison of mescaline analog behavioral pharmacology using the mouse head-twitch response assay, confirming its 5-HT₂A agonist activity and demonstrating that 4-ethoxy substitution increases potency relative to the 4-methoxy parent compound TMA.supported
HTR experiments conducted with mescaline, escaline, proscaline, TMA, 3C-E, 3C-P, TMA-2, MEM, and MPM in C57BL/6J mice... Replacing 4-methoxy with ethoxy or propoxy increased potency in the HTR assay for both mescaline and TMA. 0269881119826610