generation run 2026-05-11
59 min completedmodel pipeline-v5plan not recordedrun/53ffbe24…Selection
Verification
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- seen / partial
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The model's own caveats
8 further caveats recorded as free text — readable on the working page
Reproduce
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- 20 source keys (listed under Sources)
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- not recorded — template version, prompt hash and git SHA are written from 2026-09 onward
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15 searches — query, source, results, what was kept and why
| # | source | query | seen | kept | rationale |
|---|---|---|---|---|---|
| 1 | Erowid/PiHKAL | PiHKAL #54 2,5-DMA | 1 | 1 | Primary source for dose, duration, and human effects data; foundational psychedelic pharmacology reference |
| 2 | WebSearch/DEA | 2,5-dimethoxyamphetamine legal status scheduling DEA | 10 | 2 | Legal status data for all major jurisdictions |
| 3 | WebSearch | 2,5-DMA 2,5-dimethoxyamphetamine PiHKAL Shulgin DOH street name history | 10 | 2 | Primary sources for historical context and effects data |
| 4 | PubMed | 2,5-dimethoxyamphetamine pharmacology | 10 | 4 | Selected papers directly relevant to 2,5-dimethoxyamphetamine pharmacology, receptor binding, and metabolism |
| 5 | PubMed | 2,5-DMA 2,5-dimethoxyamphetamine serotonin receptor binding | 1 | 1 | Direct binding study of 2,5-DMA and its derivatives at 5-HT1 and 5-HT2 sites |
| 6 | ClinicalTrials.gov · absence | 2,5-dimethoxyamphetamine | 0 | 0 | No active or completed trials exist |
| 7 | ECDD Repository | — | 1 | 1 | WHO/ECDD scheduling history and pharmacological characterization |
| 8 | OpenAlex | 2,5-dimethoxyamphetamine | 172 | 2 | Ray 2010 includes multi-receptor binding panel for phenylalkylamines; Nieddu 2022 is analytical review covering DOx class |
| 9 | PubChem | 2,5-dimethoxyamphetamine | 1 | 1 | Primary database confirmation of chemical identity |
| 10 | WebSearch | 2,5-dimethoxyamphetamine DEA Schedule I year | 10 | 0 | Legal history research - scheduling date unconfirmed |
| 11 | WebSearch | 2,5-dimethoxyamphetamine CAS number SMILES DEA Schedule I controlled substance | 10 | 3 | Chemical identifier verification |
| 12 | WebSearch | 2,5-DMA Australia scheduled drug | 10 | 1 | Confirms Australian scheduling status |
| 13 | PMC | Receptor Interaction Profiles 4-Alkoxy 2,5-Dimethoxyphenethylamines | 1 | 1 | Key pharmacological profiling challenging monoamine releasing agent classification |
| 14 | Frontiers in Pharmacology | Binding functional SAR 4-substituted 2,5-dimethoxyphenyl isopropylamine 5-HT2A 5-HT2B | 1 | 1 | Most specific quantitative data available for 2,5-DMA at target receptors |
| 15 | PubMed | Halberstadt head twitch response mescaline analogs serotonin | 1 | 1 | Head twitch response data for mescaline analogs contextualizes 2,5-DMA's low activity |
39 claims by section — every cited sentence, checked against its source
pharmacology10 · 9 ok
2,5-DMA acts primarily as a weak partial agonist at serotonin 5-HT₂A receptorssupported
h5-HT2A pKi=6.68 (Ki~209 nM). Agonist activity confirmed. fphar.2023.1101290
2,5-DMA acts primarily as a weak partial agonist at serotonin 5-HT₂A receptorssupported
Affinities of 2,5-DMA derivatives at rat cortical 5-HT1 and 5-HT2 sites... 2,5-DMA itself included as parent compound baseline. pmid:6479216
At the human 5-HT₂A receptor, the compound exhibits a pKi of 6.68 (Ki ≈ 209 nM) in radioligand binding and a functional pEC₅₀ of 5.47 (EC₅₀ ≈ 3,386 nM) in calcium mobilization assayssupported
h5-HT2A pKi=6.68 (Ki~209 nM), h5-HT2B pKi=5.98. Functional EC50 at 5-HT2A = 3,386 nM (pEC50 5.47). fphar.2023.1101290
This affinity is approximately 300-fold weaker than that of its 4-iodo derivative DOI (pKi = 9.15, Ki ≈ 0.7 nM), directly explaining 2,5-DMA's minimal hallucinogenic potency.supported
DOI by comparison: pKi 9.15 (Ki~0.7 nM). 4-position substituent markedly increases 5-HT2A affinity. fphar.2023.1101290
Shannon et al. (1984) confirmed that 2,5-DMA and its derivatives interact preferentially with 5-HT₂ over 5-HT₁ sites, and that R(−)-isomers of 4-substituted derivatives show enhanced potency with high 5-HT₂ selectivity. 2,5-DMA itself shows weak, non-selective binding across serotonin receptor subtypes.supported
R(-) isomers of DOI, DOM, DON more potent than racemates with 5-HT2 selectivity. 2,5-DMA itself included as parent compound baseline. pmid:6479216
Kolaczynska et al. (2019) tested 2,5-dimethoxyphenethylamines and related amphetamines at monoamine transporters and found no significant inhibition at any monoamine uptake transporter (IC₅₀ > 10 µM) for compounds in this structural seriessupported
No significant monoamine transporter inhibition (IC50 >10 µM for all compounds). fphar.2019.01423
Kolaczynska et al. (2019) identified TAAR1 binding (21–3,300 nM) for 4-alkoxy phenethylamine analogs in the same structural series, but 2,5-DMA itself was not specifically assayed for TAAR1 activitysupported
TAAR1 binding for phenethylamines 21-3300 nM. fphar.2019.01423
Claim in pharmacology — inconclusiveinconclusiveworking →
By structural analogy with the DOx class, CYP2D6 is the primary enzyme responsible for O-demethylation of 2,5-dimethoxyamphetamine derivativessupported
CYP2D6 is the sole isoenzyme involved in O-demethylation of DOM, DOI, DOC, DOB, MDOB, and TMA-2 (all 2,5-dimethoxyamphetamine derivatives). j.toxlet.2008.09.014
All tested 2,5-dimethoxyamphetamine derivatives act as competitive CYP2D6 inhibitors, with Ki values of 7.1–296 µM (recombinant CYP2D6) and 2.7–19.9 µM (human liver microsomes)supported
Ki values 7.1-296 µM (recombinant CYP2D6) and 2.7-19.9 µM (human liver microsomes) as competitive inhibitors. j.toxlet.2008.09.014
safety5 · 4 ok
Severe poisoning with the structurally related compound 25I-NBOMe has produced tachycardia (90% of cases), hypertension (70%), agitation (60%), and seizuressupported
Sympathomimetic toxicity pattern: tachycardia (90%), hypertension (70%), agitation (60%), hallucinations (50%). Seizures, ICU admissions. j.ajem.2015.04.065
De la Fuente Revenga et al. (2022) demonstrated that repeated administration of DOI produces rapid, progressive tolerance to head-twitch responses via 5-HT₂A receptor downregulation in the frontal cortex — a mechanism independent of β-arrestin-2partially supported
Repeated DOI induces progressive HTR decrease; tolerance after single dose. Mechanism involves 5-HT2AR downregulation independent of beta-arrestin-2. acschemneuro.2c00170
Smith et al. (2014) confirmed cross-tolerance between phenethylamine hallucinogens (DOI, 2C-T-7) and found this tolerance to be insurmountable through dose escalation, indicating receptor-level desensitization.supported
Tolerance developed to HTR elicited by DOI and 2C-T-7, not tryptamines. Cross-tolerance insurmountable between phenethylamine-derived hallucinogens. jpet.114.219337
Claim in safety — inconclusiveinconclusiveworking →
CYP2D6-mediated drug interactions are theoretically possible: DOx class compounds competitively inhibit CYP2D6 with Ki values of 7.1–296 µMsupported
Ki values 7.1-296 µM (recombinant CYP2D6)... Drug-drug interactions via CYP2D6 possible but unlikely at therapeutic concentrations. j.toxlet.2008.09.014
summary5 · 4 ok
A weak partial agonist at the serotonin 5-HT₂A receptor (Ki ≈ 209 nM), 2,5-DMA produces predominantly stimulant and sympathomimetic effects rather than perceptual alterations at active oral doses of 80–160 mg, with a duration of 6–8 hours.partially supported
2,5-DMA (no 4-substituent): h5-HT2A pKi=6.68 (Ki~209 nM). Agonist activity confirmed. fphar.2023.1101290
2,5-DMA binds human 5-HT₂A receptors with approximately 300-fold lower affinity than its 4-iodo derivative DOI (Ki ≈ 0.7 nM vs. ≈ 209 nM), and demonstrates no significant monoamine transporter inhibition (IC₅₀ > 10 µM)partially supported
h5-HT2A pKi=6.68 (Ki~209 nM)... DOI by comparison: pKi 9.15 (Ki~0.7 nM). fphar.2023.1101290
2,5-DMA binds human 5-HT₂A receptors with approximately 300-fold lower affinity than its 4-iodo derivative DOI (Ki ≈ 0.7 nM vs. ≈ 209 nM), and demonstrates no significant monoamine transporter inhibition (IC₅₀ > 10 µM)partially supported
No significant monoamine transporter inhibition (IC50 >10 µM for all compounds). fphar.2019.01423
Claim in summary — not_supportednot supportedworking →
Cross-tolerance with serotonergic psychedelics develops through 5-HT₂A receptor downregulation in the frontal cortex, though the degree to which tolerance develops to the compound's predominant stimulant effects has not been studiedpartially supported
Mechanism involves 5-HT2AR downregulation independent of beta-arrestin-2. acschemneuro.2c00170
comparative-pharmacology4 · 4 ok
DOI data from Hemanth et al. (2023)supported
DOI by comparison: pKi 9.15 (Ki~0.7 nM). fphar.2023.1101290
The 4-alkyl chain length series data from Luethi et al. (2026) confirmed that 4-substituted compounds achieve 5-HT₂A Ki values of 2–56 nM, compared to effectively inactive binding for the unsubstituted parent.supported
5-HT2A affinities 2-56 nM; 4-propyl most potent in vitro (1-9 nM). s41380-025-03325-1
Halberstadt et al. (2019) demonstrated that the head-twitch response potency hierarchy for mescaline analogs parallels human hallucinogenic potency rankings; the absence of a 4-position substituent in 2,5-DMA correlates with minimal psychedelic-like activity in animal models.supported
HTR potency relationships parallel human hallucinogenic data. Alpha-methylation of mescaline increases hallucinogenic potency. 0269881119826610
Unlike unsubstituted amphetamine, which is a potent monoamine releaser, 2,5-DMA and its DOx derivatives show no significant monoamine transporter inhibition (IC₅₀ > 10 µM at DAT, NET, and SERT)supported
No significant monoamine transporter inhibition (IC50 >10 µM for all compounds). fphar.2019.01423
pharmacokinetic-detail4 · 4 ok
The CYP2D6 pathway assignment is based on Ewald and Maurer (2008), who characterized metabolism of DOM, DOI, DOC, DOB, and MDOB — all sharing the 2,5-dimethoxy-substituted amphetamine coresupported
CYP2D6 is the sole isoenzyme involved in O-demethylation of DOM, DOI, DOC, DOB, MDOB, and TMA-2 (all 2,5-dimethoxyamphetamine derivatives). j.toxlet.2008.09.014
CYP2D6 inhibition potential for the DOx class is weak: Ki values range from 7.1–296 µM (recombinant CYP2D6) and 2.7–19.9 µM (human liver microsomes)supported
Ki values 7.1-296 µM (recombinant CYP2D6) and 2.7-19.9 µM (human liver microsomes) as competitive inhibitors. j.toxlet.2008.09.014
Analytical detection of 2,5-DMA and related DOx compounds in biological matrices is feasible via LC-MS/MS screening methods.supported
Validated LC-MS/MS screening method covering 35 designer drugs including DOx class compounds. LOD 1.0-5.0 ng/mL in serum. s00216-009-3394-4
Analytical detection of 2,5-DMA and related DOx compounds in biological matrices is feasible via LC-MS/MS screening methods.supported
Review of analytical methods for quantification of 2,5-dimethoxy-amphetamines (DOx class) and 2,5-dimethoxy-phenethylamines (2C-x class) in traditional and alternative biological matrices. s11419-022-00638-6
receptor-pharmacology4 · 3 ok
The most comprehensive binding data for 2,5-DMA at serotonin receptor subtypes come from Hemanth et al. (2023), who measured affinity and functional activity at human 5-HT₂A and 5-HT₂B receptors.supported
h5-HT2A pKi=6.68 (Ki~209 nM), h5-HT2B pKi=5.98. Functional EC50 at 5-HT2A = 3,386 nM (pEC50 5.47). Agonist activity confirmed. fphar.2023.1101290
Claim in receptor-pharmacology — inconclusiveinconclusiveworking →
Monoamine transporter interaction has been excluded for the 2,5-dimethoxyamphetamine series: Kolaczynska et al. (2019) reported IC₅₀ > 10 µM at all monoamine uptake transporters (DAT, NET, SERT) for structurally related compoundssupported
No significant monoamine transporter inhibition (IC50 >10 µM for all compounds). fphar.2019.01423
Activity at TAAR1 (21–3,300 nM) has been demonstrated for 4-alkoxy analogs in the same structural series, but 2,5-DMA-specific TAAR1 data are absent.supported
TAAR1 binding for phenethylamines 21-3300 nM. fphar.2019.01423
chemistry3 · 3 ok
Addition of lipophilic substituents at the 4-position (methyl, bromo, iodo, chloro) dramatically increases 5-HT₂A receptor affinity and hallucinogenic potency: Luethi et al. (2026) demonstrated that 4-alkyl-substituted compounds achieve Ki values of 2–56 nM at h5-HT₂A, compared to effectively absent activity for the unsubstituted parentsupported
5-HT2A affinities 2-56 nM; 4-propyl most potent in vitro (1-9 nM). s41380-025-03325-1
Oberlender et al. (1995) further showed that the stereochemistry of 4-alkyl substituents modulates hallucinogenic potency within the series.partially supported
SAR for chirality and 4-alkyl substituent in DOx-class hallucinogenic amphetamines. Equal diastereomeric affinity at [125I]DOI-labelled 5-HT2A/C sites. pmid:7658446
Shannon et al. (1984) demonstrated that R(−)-enantiomers of DOx derivatives exhibit significantly greater potency at 5-HT₂ binding sites than racematessupported
R(-) isomers of DOI, DOM, DON more potent than racemates with 5-HT2 selectivity. pmid:6479216
neuroscience3 · 2 ok
Claim in neuroscience — inconclusiveinconclusiveworking →
Tolerance to DOI-induced head-twitch responses develops rapidly via 5-HT₂A receptor downregulation in the frontal cortex, a mechanism independent of β-arrestin-2partially supported
Repeated DOI induces progressive HTR decrease; tolerance after single dose. Mechanism involves 5-HT2AR downregulation independent of beta-arrestin-2. acschemneuro.2c00170
Cross-tolerance between phenethylamine hallucinogens (DOI, 2C-T-7) is insurmountable through dose escalation, indicating receptor-level desensitization rather than downstream adaptation.supported
Cross-tolerance insurmountable between phenethylamine-derived hallucinogens. Implications for therapeutic use of 5-HT2A agonists. jpet.114.219337
history1 · 1 ok
The 4-substituted derivatives DOI, DOC, and DOB were first synthesized in 1973, while DOM (4-methyl-2,5-dimethoxyamphetamine) had been synthesized earlier and became the prototypical DOx psychedelic.supported
DOI first synthesized 1973 alongside DOC and DOB. DOx compounds are potent 5-HT2 receptor agonists. acsptsci.4c00157