generation run 2026-05-11
63 min completedmodel pipeline-v5plan not recordedrun/5cc929cf…Selection
Verification
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- seen / partial
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The model's own caveats
5 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
17 searches — query, source, results, what was kept and why
| # | source | query | seen | kept | rationale |
|---|---|---|---|---|---|
| 1 | OpenAlex | 3,4-dimethoxyphenethylamine pink spot schizophrenia DMPEA urine | 3 | 1 | Historical context for DMPEA naming; important to flag that 3,4-DMPEA != 2C-H |
| 2 | PubMed | phenethylamine receptor binding affinity 5-HT2A structure activity relationship psychedelic | 15 | 3 | Marcher-Rørsted 2020 directly investigates the 2,5-DMPEA scaffold (which is 2C-H), making it the most relevant receptor pharmacology paper |
| 3 | PubMed · absence | DMPEA dimethoxyphenethylamine psychedelic schizophrenia | 0 | — | — |
| 4 | PubMed · absence | 2C-H 2,5-dimethoxyphenethylamine pharmacology | 0 | — | — |
| 5 | OpenAlex | phenethylamine psychedelics 2C series serotonin receptor binding affinity | 10 | 4 | Landmark papers covering 2C phenethylamine pharmacology and class effects |
| 6 | PubChem | 2,5-dimethoxyphenethylamine | 1 | 1 | Primary chemical identity data for 2C-H |
| 7 | OpenAlex | 2,5-dimethoxyphenethylamine DMPEA pharmacology psychedelic | 2 | 1 | NMR data for 2C series compounds including potentially 2C-H |
| 8 | ClinicalTrials.gov | 2C-H 2,5-dimethoxyphenethylamine | 1 | 0 | — |
| 9 | PubMed | PMID 30188017 | 1 | 1 | KEY PAPER: directly tested 2C-H for MAO-B inhibition, providing mechanistic explanation for Shulgin's observation that 2C-H is probably orally inactive |
| 10 | WebSearch | Buck 1932 first synthesis 2,5-dimethoxyphenethylamine | 10 | 1 | Historical synthesis reference |
| 11 | Psychedelic Review / WebFetch | 2C-H compound information | 1 | 3 | Key pharmacological data including receptor binding affinities |
| 12 | WebSearch | 2C-H PiHKAL Shulgin 'probably inactive' MAO dose unknown synthesis | 10 | 1 | Primary source for Shulgin's historical notes on 2C-H |
| 13 | WebSearch | 2C-H phenethylamine legal status UK USA Australia scheduling controlled substance | 10 | 3 | Legal status data |
| 14 | PubMed | tramadol serotonin toxicity syndrome serotonergic drugs combination risk | 10 | 2 | Evidence base for dangerous tramadol interaction listed in brief |
| 15 | PubMed | PMID 33860179 | 1 | 1 | Primary paper establishing 2C-H as anti-inflammatory pharmacophore - most pharmacologically significant finding for this substance |
| 16 | WebSearch | 2C-H legal status Wikipedia | 10 | 1 | Legal status research for all major jurisdictions |
| 17 | NIST WebBook WebFetch | 2,5-dimethoxyphenethylamine physical properties | 1 | 2 | Government-grade verified chemical identifiers |
60 claims by section — every cited sentence, checked against its source
pharmacology16 · 8 ok
Claim in pharmacology — inconclusiveinconclusiveworking →
Claim in pharmacology — not_supportednot supportedworking →
Claim in pharmacology — inconclusiveinconclusiveworking →
For the 2C series as a class, psychedelic effects are mediated primarily through 5-HT₂A receptor partial agonismsupported
5-HT2A/2C receptors mediate alterations of perception and cognition induced by serotonergic psychedelics. s00204-020-02693-7
For the 2C series as a class, psychedelic effects are mediated primarily through 5-HT₂A receptor partial agonismsupported
2,5-Dimethoxyphenethylamines (2C compounds) are 5-HT2A/2C receptor agonists that induce hallucinogenic effects. j.neuropharm.2018.02.033
Marcher-Rørsted et al. (2020) demonstrated that removing either methoxy group produces modest in vitro affinity reductions but significant attenuation of in vivo head-twitch response in mice, confirming that both methoxy groups contribute to receptor binding geometry while the 4-substituent drives functional potency.partially supported
Elimination of either the 2- or 5-methoxy group leads to modest drop in binding affinity... Trend not mirrored in vivo — removal of either methoxy group resulted in significant reduction in head-twitch response in mice. acschemneuro.0c00129
Wagmann et al. (2019) screened 12 2C-series compounds and 5 FLY analogues against human MAO-A and MAO-B using in vitro heterologously expressed enzyme assays with HILIC-HR-MS/MS analysis. 2C-H was identified as the most potent MAO-B inhibitor in the 2C series, with an IC₅₀ of 1.7 µM (range across nine active compounds: 1.7–180 µM)supported
17 drugs tested: 12 2Cs... and five FLY analogs. 2C-H had the lowest MAO-B IC50 (most potent MAO-B inhibitor in the series) at 1.7 µM. dta.2494
Claim in pharmacology — inconclusiveinconclusiveworking →
Claim in pharmacology — inconclusiveinconclusiveworking →
Second, the MAO-B inhibitory activity itself is pharmacologically relevant — at systemic concentrations achievable via non-oral routes, 2C-H could elevate dopamine and phenethylamine levels through MAO-B inhibition.supported
2C-H had the lowest MAO-B IC50 (most potent MAO-B inhibitor in the series) at 1.7 µM. MAO inhibition may contribute pharmacologically. dta.2494
Flanagan et al. (2021) investigated 21 5-HT₂A receptor agonists — spanning phenylalkylamine, ergoline, and tryptamine chemotypes — using a rat-based allergic asthma screening platform and identified 2C-H (2,5-dimethoxyphenethylamine) as the minimal structural unit necessary for anti-inflammatory activity in the 5-HT₂A agonist classsupported
Investigated 21 agonists at 5-HT2A from three chemotypes (phenylalkylamine, ergoline, tryptamine)... 2C-H identified as the minimal structural unit required for anti-inflammatory effects. acsptsci.0c00063
Anti-inflammatory effects showed no correlation with intracellular calcium mobilization (the canonical 5-HT₂A signaling pathway) or with behavioral psychedelic potency, demonstrating that the anti-inflammatory and psychoactive effects of 5-HT₂A agonists are mediated by dissociable signaling pathways.supported
Anti-inflammatory effects do not correlate with behavioral activity or calcium mobilization via 5-HT2A, suggesting functional selectivity. acsptsci.0c00063
This finding was extended by Flanagan et al. (2024), who showed that (R)-DOI and (R)-DOTFM produce comparable in vitro 5-HT₂A activity but divergent anti-inflammatory outcomes in a murine ovalbumin asthma model, confirming functionally selective receptor signaling underlying the anti-inflammatory versus psychedelic effects.supported
(R)-DOTFM lacks anti-inflammatory activity despite comparable in vitro 5-HT2A binding. Functionally selective anti-inflammatory mechanisms in peripheral tissues. acsptsci.3c00297
Claim in pharmacology — inconclusiveinconclusiveworking →
Claim in pharmacology — inconclusiveinconclusiveworking →
Claim in pharmacology — inconclusiveinconclusiveworking →
safety13 · 11 ok
Claim in safety — inconclusiveinconclusiveworking →
For the 2C series as a class, reported toxic effects include hallucinations, agitation, aggression, dysphoria, hypertension, tachycardia, seizures, hyperthermia, serotonin toxicity, and sympathomimetic toxidromesupported
Hallucinations, agitation, aggression, hypertension, tachycardia, seizures, hyperthermia common... Both serotonin toxicity and sympathomimetic presentations seen. s13181-013-0295-x
At least five deaths have been attributed to 2C-series compounds in the published literature, all involving pharmacologically active members (2c-e, 2c-i, 2c-b) — none involving 2C-H specifically.partially supported
At least 5 deaths reported; excited delirium consistent among fatalities. s13181-013-0295-x
The potent MAO-B inhibition of 2C-H (IC₅₀ = 1.7 µM) introduces a distinct toxicological consideration independent of serotonergic activitysupported
2C-H had the lowest MAO-B IC50 (most potent MAO-B inhibitor in the series) at 1.7 µM. MAO inhibition may contribute pharmacologically. dta.2494
Gil-Martins et al. (2024) observed mitochondrial dysfunction and oxidative stress in vitro for 2C-T subclass compounds within the broader 2,5-dimethoxyphenethylamine familysupported
In vitro neurotoxicity of 2C-T-2, 2C-T-4, 2C-T-7... mitochondrial dysfunction, ATP depletion, GSH reduction observed. jox14020044
De la Fuente Revenga et al. (2022) demonstrated that repeated 5-HT₂A agonist administration causes receptor downregulation in the frontal cortex, with tolerance observable within 24 hours of a single dosepartially supported
Repeated DOI induces progressive decrease in head-twitch response (HTR)... 5-HT2AR downregulation in frontal cortex. acschemneuro.2c00170
The tolerance mechanism is independent of β-arrestin-2.supported
Tolerance independent of beta-arrestin-2. acschemneuro.2c00170
Claim in safety — inconclusiveinconclusiveworking →
Tramadol exerts serotonergic effects through serotonin reuptake inhibition and stimulation of serotonin release. 2C-H compounds this risk through dual mechanisms: weak 5-HT₂A partial agonism and potent MAO-B inhibition (IC₅₀ = 1.7 µM)supported
Tramadol has serotonergic effects. Higher risk combinations (MAOI + tramadol) must be avoided. s00482-015-1512-0
Tramadol exerts serotonergic effects through serotonin reuptake inhibition and stimulation of serotonin release. 2C-H compounds this risk through dual mechanisms: weak 5-HT₂A partial agonism and potent MAO-B inhibition (IC₅₀ = 1.7 µM)supported
Warning associated with all serotonergic antidepressants combined with tramadol due to serotonin syndrome risk. 0897190013504957
Tramadol exerts serotonergic effects through serotonin reuptake inhibition and stimulation of serotonin release. 2C-H compounds this risk through dual mechanisms: weak 5-HT₂A partial agonism and potent MAO-B inhibition (IC₅₀ = 1.7 µM)supported
2C-H had the lowest MAO-B IC50 (most potent MAO-B inhibitor in the series) at 1.7 µM. dta.2494
The MAOI-tramadol combination is specifically identified as a contraindicated pairing in the pain management literature due to serotonin syndrome risk.supported
Tramadol has serotonergic effects. Higher risk combinations (MAOI + tramadol) must be avoided. s00482-015-1512-0
2C-H's own MAO-B inhibitory activity (IC₅₀ = 1.7 µM) creates a pharmacologically significant interaction with exogenous MAOIssupported
2C-H had the lowest MAO-B IC50 (most potent MAO-B inhibitor in the series) at 1.7 µM. MAO inhibition may contribute pharmacologically. dta.2494
neuroscience7 · 4 ok
Claim in neuroscience — inconclusiveinconclusiveworking →
Claim in neuroscience — inconclusiveinconclusiveworking →
The identification of 2C-H as an anti-inflammatory pharmacophore implicates a distinct 5-HT₂A signaling pathway dissociated from both calcium mobilization and psychedelic behavioral responsessupported
Anti-inflammatory effects do not correlate with behavioral activity or calcium mobilization via 5-HT2A, suggesting functional selectivity. acsptsci.0c00063
Claim in neuroscience — inconclusiveinconclusiveworking →
The anti-inflammatory activity of the 2C-H scaffold may represent a third functionally selective pathway, potentially involving suppression of disease-induced arginase 1 expression as described by Flanagan et al. (2024).supported
Anti-inflammatory effects of certain psychedelics mediated by suppression of arginase 1 expression... Functionally selective anti-inflammatory mechanisms in peripheral tissues. acsptsci.3c00297
Different agonists stabilize distinct receptor conformations that preferentially activate different downstream signaling cascades. 2C-H may preferentially engage the anti-inflammatory signaling conformation while inadequately stabilizing the conformation associated with Gq-mediated calcium mobilization and psychedelic behavioral outputsupported
Anti-inflammatory effects do not correlate with behavioral activity or calcium mobilization via 5-HT2A, suggesting functional selectivity. acsptsci.0c00063
Different agonists stabilize distinct receptor conformations that preferentially activate different downstream signaling cascades. 2C-H may preferentially engage the anti-inflammatory signaling conformation while inadequately stabilizing the conformation associated with Gq-mediated calcium mobilization and psychedelic behavioral outputsupported
5-HT2A receptor Gq-signaling can be fine-tuned to generate ligands distinct from classical psychedelics. s41467-023-44016-1
receptor-pharmacology6 · 4 ok
Receptor binding data for 2C-H derive from NIMH Psychoactive Drug Screening Program (PDSP) profiling, as reported by Psychedelic Science Review and consistent with the receptor profiling methodology described by Ray (2010).supported
Receptor affinity pharmacology of 25 psychedelic drugs at 51 receptors, transporters, and ion channels (NIMH-PDSP). journal.pone.0009019
Data from Wagmann et al. (2019), who tested all compounds using human heterologously expressed MAO-A and MAO-B enzymes with HILIC-HR-MS/MS analysissupported
17 drugs tested: 12 2Cs... and five FLY analogs. 13 showed MAO-A inhibition, 11 showed MAO-B inhibition. dta.2494
Claim in receptor-pharmacology — inconclusiveinconclusiveworking →
The anti-inflammatory pharmacophore identification by Flanagan et al. (2021) implies that 2C-H engages a functionally selective signaling pathway at the 5-HT₂A receptor — one that produces anti-inflammatory effects without activating the calcium mobilization cascade associated with psychedelic behavioral outputsupported
Anti-inflammatory effects do not correlate with behavioral activity or calcium mobilization via 5-HT2A, suggesting functional selectivity. acsptsci.0c00063
Claim in receptor-pharmacology — inconclusiveinconclusiveworking →
The anti-inflammatory pathway engaged by the 2C-H scaffold may represent a third functionally selective mode, potentially involving suppression of disease-induced arginase 1 expression.supported
Anti-inflammatory effects of certain psychedelics mediated by suppression of arginase 1 expression... Functionally selective anti-inflammatory mechanisms in peripheral tissues. acsptsci.3c00297
clinical-evidence4 · 4 ok
Nau et al. (2015) demonstrated that 5-HT₂A receptor activation prevents allergic asthma in a mouse model, establishing the receptor target as a therapeutic pathway for inflammatory airway disease.supported
5-HT2A receptor agonist (R)-DOI prevents allergic asthma in ovalbumin mouse model... Suggests 5-HT2 receptor agonists as novel asthma therapy. pmid:25416380
Flanagan et al. (2019) showed that 5-HT₂A agonism alleviates airway inflammation and structural remodeling in a chronic mouse asthma model.supported
(R)-DOI reverses inflammation and symptoms in chronic asthma mouse model via 5-HT2A receptor activation. j.lfs.2019.116790
Flanagan et al. (2021) identified 2C-H as the anti-inflammatory pharmacophore for the 5-HT₂A agonist class using a rat-based allergic asthma screening platform — the first study to establish a specific pharmacological significance for 2C-H itself.supported
2,5-dimethoxyphenethylamine (2C-H) represents the pharmacophore for anti-inflammatory activity... 2C-H identified as the minimal structural unit required for anti-inflammatory effects. acsptsci.0c00063
Flanagan et al. (2024) further demonstrated functionally selective anti-inflammatory signaling at 5-HT₂A, with dissociation from psychedelic behavioral output, using (R)-DOI and (R)-DOTFM as comparator compounds in a murine ovalbumin asthma model.supported
(R)-DOTFM lacks anti-inflammatory activity despite comparable in vitro 5-HT2A binding. Functionally selective anti-inflammatory mechanisms in peripheral tissues. acsptsci.3c00297
comparative-pharmacology4 · 3 ok
Claim in comparative-pharmacology — not_supportednot supportedworking →
Flanagan et al. (2021) screened 21 5-HT₂A agonists spanning three chemotypes and identified that anti-inflammatory activity tracks with the 2,5-dimethoxyphenethylamine scaffold (2C-H) rather than with psychedelic potencysupported
Anti-inflammatory effects do not correlate with behavioral activity or calcium mobilization via 5-HT2A... 2C-H identified as the minimal structural unit required for anti-inflammatory effects. acsptsci.0c00063
Among 12 2C-series compounds tested by Wagmann et al. (2019), 2C-H showed the lowest IC₅₀ for MAO-B inhibition (1.7 µM), meaning it is both the most susceptible to MAO-B degradation as a substrate and the most potent MAO-B inhibitorsupported
2C-H had the lowest MAO-B IC50 (most potent MAO-B inhibitor in the series) at 1.7 µM. dta.2494
Gil-Martins et al. (2024) characterized neurotoxicity mechanisms for the 2C-T subclass of 2,5-dimethoxyphenethylamines, observing mitochondrial dysfunction and oxidative stress in vitrosupported
In vitro neurotoxicity of 2C-T-2, 2C-T-4, 2C-T-7... mitochondrial dysfunction, ATP depletion, GSH reduction observed. jox14020044
history3 · 2 ok
Claim in history — inconclusiveinconclusiveworking →
In 2015, Chapman and Avanes published NMR spectral data confirming the chemical identity of 2C-series grey-market samples, contributing analytical reference standards for forensic identification.supported
1H NMR spectra of 28 alleged psychedelic phenylethanamines from 15 grey-market internet vendors. Members from each principal phenylethanamine family analyzed: eleven para-substituted 2,5-dimethoxyphenylethanamines (2C and 2C-T series). isomerdesign-1
The compound's pharmacological significance gained independent recognition in 2021, when Flanagan et al. identified 2C-H as the anti-inflammatory pharmacophore for 5-HT₂A receptor agonists in a rat model of allergic asthmasupported
2,5-dimethoxyphenethylamine (2C-H) represents the pharmacophore for anti-inflammatory activity... 2C-H identified as the minimal structural unit required for anti-inflammatory effects. acsptsci.0c00063
pharmacokinetic-detail3 · 0 ok
summary3 · 2 ok
Its primary research significance emerged in 2021, when Flanagan et al. identified the 2,5-dimethoxyphenethylamine scaffold as the anti-inflammatory pharmacophore for 5-HT₂A receptor agonists, establishing a pharmacological role for 2C-H independent of psychoactivity.supported
2,5-dimethoxyphenethylamine (2C-H) represents the pharmacophore for anti-inflammatory activity... 2C-H identified as the minimal structural unit required for anti-inflammatory effects. acsptsci.0c00063
It is the most potent MAO-B inhibitor among tested 2C compounds (IC₅₀ = 1.7 µM), a property that both explains its oral inactivity through rapid first-pass deamination and introduces pharmacologically relevant monoamine oxidase interactionssupported
2C-H had the lowest MAO-B IC50 (most potent MAO-B inhibitor in the series) at 1.7 µM. MAO inhibition may contribute pharmacologically. dta.2494
Claim in summary — inconclusiveinconclusiveworking →
chemistry1 · 1 ok
Marcher-Rørsted et al. (2020) demonstrated that removal of either methoxy group produces modest reductions in in vitro receptor affinity but significant loss of in vivo psychedelic activity (measured by head-twitch response in mice), confirming that both methoxy groups contribute to the compound's receptor engagement geometrysupported
Elimination of either the 2- or 5-methoxy group leads to modest drop in binding affinity... Trend not mirrored in vivo — removal of either methoxy group resulted in significant reduction in head-twitch response in mice. acschemneuro.0c00129