generation run 2026-05-03
47 min completedmodel pipeline-v5plan not recordedrun/7fbd4166…Selection
Verification
- record
- seen / partial
- working
The model's own caveats
none raised on this run
Reproduce
- inputs
- 30 source keys (listed under Sources)
- plan
- not recorded — template version, prompt hash and git SHA are written from 2026-09 onward
- model
- pipeline-v5
- streams
- 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 | DOI 2,5-dimethoxy-4-iodoamphetamine serotonin receptor psychedelic | 10 | 3 | Highest-cited papers directly relevant to DOI pharmacology |
| 2 | ClinicalTrials.gov · absence | DOI 2,5-dimethoxy-4-iodoamphetamine | 0 | 0 | No trials exist; absence is informative |
| 3 | PubMed | DOI 2,5-dimethoxy-4-iodoamphetamine head twitch response animal model hallucinogen | 10 | 4 | DOI-specific behavioral pharmacology data |
| 4 | PubMed | DOI 2,5-dimethoxy-4-iodoamphetamine pharmacology receptor binding | 15 | 5 | — |
| 5 | PubChem | DOI 2,5-dimethoxy-4-iodoamphetamine | 1 | 1 | Correct non-radioactive DOI compound confirmed |
| 6 | OpenAlex | DOI 2,5-dimethoxy-4-iodoamphetamine hallucinogen head-twitch animal model | 10 | 3 | Core DOI-focused papers with high citation counts |
| 7 | PsychonautWiki | DOI dose duration effects tolerance combinations | 1 | 1 | Confirms seed data dose/duration |
| 8 | PubChem | 1-(4-iodo-2,5-dimethoxyphenyl)propan-2-amine | 1 | 1 | Confirms chemical identity data for brief |
| 9 | Wikidoc | DOI pharmacology history dose duration | 1 | 3 | Notes conflict between Shulgin/Wikidoc dose (1.5-3 mg) vs seed data (0.5-3 mg) |
| 10 | Psychedelic Science Review | DOI pharmacology Ki binding affinity | 1 | 2 | Provides specific receptor binding affinity data not found in PubMed |
| 11 | Federal Register/Web | DOI scheduling DEA legal status | 5 | 2 | Legal status data critical for article |
| 12 | Crossref/DOI verification | Coutts Malicky 1973 synthesis DOI DOx | 1 | 1 | Primary historical source for first DOI synthesis |
| 13 | Multiple · absence | Monoamine releasing agent classification verification | 0 | 0 | Identifies likely error in seed data pharmacological classification |
| 14 | PubMed | hallucinogen tolerance 5-HT2A receptor downregulation repeated administration | 1 | 1 | Direct DOI tolerance mechanism paper |
| 15 | PubMed | DOI 2,5-dimethoxy-4-iodoamphetamine cognitive flexibility lasting effects molecular psychiatry | 1 | 1 | Critical recent paper on DOI lasting neuroplasticity effects |
| 16 | WebSearch | DOI DOx class UK legal status Europe scheduled | 10 | 2 | Legal status context for UK |
| 17 | Psychedelic Science Review | DOI Ki values receptor binding | 1 | 1 | Only source with tabulated human Ki values for DOI |
57 claims by section — every cited sentence, checked against its source
neuroscience9 · 9 ok
Šabanović et al. (2024) provided direct evidence that a single dose of DOI (2 mg/kg) increases brain volumes across multiple sensory and association cortical areas, measured by ex vivo MRI at 24 hours post-administrationsupported
Single dose 2 mg/kg (±)-DOI: increased brain volumes in sensory/association areas 1 day post-dose (MRI). s41380-024-02439-2
Activation triggers CREB-dependent transcription of plasticity-associated immediate early genes: Arc, Bdnf1, Cebpb, Egr1, Egr2, and cFospartially supported
DOI enhances pCREB via MAP kinase and CaMKII pathways, upregulates Arc, Bdnf1, Cebpb, Egr2, cFos in rat neocortex. fnmol.2021.790213
Notably, Egr-2 induction is hallucinogen-specific — it is not produced by non-hallucinogenic 5-HT₂A agonists and requires the 5-HT₂A–mGluR2 heteromeric complex.supported
egr-2 induction by DOI eliminated in mGluR2-KO. Suggests 5-HT2AR-mGluR2 complex required for hallucinogenic effects. j.neulet.2011.01.046
Anderson et al. (2024) found that DOI's excitatory postsynaptic effects in the claustrum–ACC circuit are mediated by 5-HT₂C receptors, not 5-HT₂A, and that serotonin and DOI produce opposing effects in this pathwaysupported
DOI stimulates EPSCs in claustrum neurons projecting to anterior cingulate cortex; effect reversed by 5-HT2C (not 5-HT2A) inhibition. j.pneurobio.2024.102660
DOI enhances D2 receptor signalling through D2–5-HT₂A heteroreceptor complexes in striatal circuitssupported
DOI enhances D2R-mediated inhibition of CRE-luciferase via D2-5-HT2A heteroreceptor complex. j.bbrc.2013.11.104
The documented BDNF/Arc/CREB upregulation and volumetric brain changes support this classificationsupported
DOI enhances pCREB via MAP kinase and CaMKII pathways, upregulates Arc, Bdnf1, Cebpb, Egr2, cFos in rat neocortex. fnmol.2021.790213
The documented BDNF/Arc/CREB upregulation and volumetric brain changes support this classificationsupported
Single dose 2 mg/kg (±)-DOI: increased brain volumes in sensory/association areas 1 day post-dose (MRI). s41380-024-02439-2
The Xu et al. (2026) finding that hallucinogenic effects require Gᵢ signalling establishes a new framework: hallucinogenesis is not simply a consequence of 5-HT₂A activation magnitude but depends on which intracellular signalling cascade is engagedsupported
5-HT2A-mediated non-canonical Gi signalling is essential for hallucinogenic effect. Identified DOI-NBOMe as Gq-biased derivative with therapeutic effects without hallucinogenic activity. s41586-025-10061-7
Does the Gᵢ-hallucinogenesis model hold across all dose ranges? The inverted-U locomotor response (5-HT₂A at low doses, 5-HT₂C at high doses) suggests dose-dependent receptor balance shifts that may complicate a simple Gᵢ-signalling narrative.supported
DOI produces inverted U-shaped dose-response on locomotion. Lower doses (0.625-5 mg/kg) increase locomotion via 5-HT2A; higher doses (>=10 mg/kg) decrease via 5-HT2C. npp.2009.29
pharmacology9 · 8 ok
The NIMH-PDSP receptorome screen revealed interactions with 42 of 49 broadly assayed targets, though 5-HT₂A and 5-HT₂C remain the primary high-affinity sitessupported
DOI and other phenylalkylamines interact with 42 of 49 sites tested. journal.pone.0009019
Claim in pharmacology — inconclusiveinconclusiveworking →
The hallucinogenic activity of DOI requires non-canonical Gᵢ signalling at 5-HT₂A rather than classical Gq/phospholipase C (PLC) activationsupported
5-HT2A-mediated non-canonical Gi signalling is essential for hallucinogenic effect. Identified DOI-NBOMe as Gq-biased derivative with therapeutic effects without hallucinogenic activity. s41586-025-10061-7
DOI simultaneously activates the canonical Gq pathway, engaging PLC, IP3/DAG, and downstream MAP kinase and CaMKII cascadessupported
DOI enhances pCREB via MAP kinase and CaMKII pathways... Effect blocked by 5-HT2A antagonist MDL100,907. fnmol.2021.790213
In mGluR2 knockout mice, the head-twitch response is abolished, high-affinity DOI binding sites are undetectable, and the hallucinogen-specific gene egr-2 is not induced — while c-fos (shared with non-hallucinogens) remains intact.supported
mGluR2 KO abolishes DOI head-twitch response. DOI high-affinity binding site undetected in mGluR2-KO. egr-2 induction by DOI eliminated in mGluR2-KO. j.neulet.2011.01.046
DOI enhances dopamine D2 receptor signalling through D2–5-HT₂A heteroreceptor complexes in ventral and dorsal striatum, increasing D2 receptor density and high-affinity agonist binding — an effect shared with lsd but absent for non-hallucinogenic 5-HT₂A agonists.partially supported
DOI and LSD increase D2R binding density and reduce high-affinity D2R agonist binding in ventral/dorsal striatum. j.bbrc.2013.11.104
At the neuroendocrine level, DOI stimulates release of ACTH, corticosterone, oxytocin, prolactin, and renin via activation of hypothalamic CRF and oxytocin neurons.supported
DOI at 2.5 mg/kg i.p. stimulates ACTH, corticosterone, oxytocin, renin, and prolactin via 5-HT2A. pmid:11331386
In the claustrum–anterior cingulate cortex circuit, DOI's effects on excitatory postsynaptic currents are mediated by 5-HT₂C (not 5-HT₂A) receptors, and serotonin and DOI exert opposing effects on synaptic transmission in this pathwaysupported
DOI stimulates EPSCs in claustrum neurons projecting to anterior cingulate cortex; effect reversed by 5-HT2C (not 5-HT2A) inhibition. j.pneurobio.2024.102660
DOI produces an inverted-U locomotor dose-response in mice: lower doses (0.625–5 mg/kg) increase locomotor activity via 5-HT₂A, while higher doses (≥10 mg/kg) decrease activity via 5-HT₂Csupported
DOI produces inverted U-shaped dose-response on locomotion. Lower doses (0.625-5 mg/kg) increase locomotion via 5-HT2A; higher doses (>=10 mg/kg) decrease via 5-HT2C. npp.2009.29
safety8 · 5 ok
Claim in safety — inconclusiveinconclusiveworking →
DOI produces vasoconstriction via 5-HT₂A receptor activation in vascular smooth musclesupported
DOI contracts rat aorta via 5-HT2A receptor, blocked by ketanserin. pmid:9435197
DOx compounds have been distributed on blotter paper as lsd, leading to unintentional consumption at doses appropriate for LSD (100–200 µg) but dramatically below DOI's active rangesupported
DOx compounds misrepresented as LSD at Boom Festival 2014. Drug checking service intercepted unintentional DOx consumption. hup.2608
Claim in safety — inconclusiveinconclusiveworking →
Tolerance to DOI's behavioral effects (head-twitch response) develops within 24 hours of a single dose, mediated by 5-HT₂A receptor downregulation in frontal cortex confirmed by [³H]ketanserin bindingpartially supported
Repeated DOI induces progressive HTR decrease. Tolerance involves 5-HT2AR downregulation in frontal cortex, independent of beta-arrestin-2. acschemneuro.2c00170
Daily administration (5 mg/kg) produces progressive tolerance; every-other-day dosing (48-hour intervals) does not — indicating receptor recovery occurs within approximately 48 hours in mice.supported
Daily DOI 5 mg/kg causes tolerance; every-other-day does not. j.neuropharm.2014.03.003
The non-hallucinogenic 5-HT₂A agonist lisuride does not produce cross-tolerance with DOI, suggesting tolerance is specific to the hallucinogenic signalling pathway.supported
No cross-tolerance with non-psychedelic lisuride. acschemneuro.2c00170
Claim in safety — inconclusiveinconclusiveworking →
summary8 · 7 ok
Claim in summary — inconclusiveinconclusiveworking →
The radioiodinated form [¹²⁵I]-R-(−)-DOI became the prototypical 5-HT₂A radioligand in the late 1980s, and DOI remains the reference agonist for the head-twitch response model of hallucinogenesissupported
[125I]DOI labels 5-HT2A sites in rat cortex with high affinity (KD = 0.63 nM). pmid:2795135
The radioiodinated form [¹²⁵I]-R-(−)-DOI became the prototypical 5-HT₂A radioligand in the late 1980s, and DOI remains the reference agonist for the head-twitch response model of hallucinogenesissupported
DOI is the most popular pharmacological tool for HTR studies of hallucinogens. dta.1333
No clinical trials have been registered; current investigational interest centers on its anti-inflammatory properties and non-hallucinogenic derivative development.supported
Identified DOI-NBOMe as Gq-biased derivative with therapeutic effects without hallucinogenic activity. s41586-025-10061-7
DOI acts as a full agonist at 5-HT₂A (Ki = 0.65 nM) and 5-HT₂C (Ki = 2.36 nM) receptors, with hallucinogenic activity now attributed to non-canonical Gᵢ signalling rather than Gq/PLC activationsupported
5-HT2A-mediated non-canonical Gi signalling is essential for hallucinogenic effect. s41586-025-10061-7
The 5-HT₂A–mGluR2 heteromeric complex is required for full behavioral response.supported
mGluR2 KO abolishes DOI head-twitch response... Suggests 5-HT2AR-mGluR2 complex required for hallucinogenic effects. j.neulet.2011.01.046
Tolerance develops within 24 hours of a single dose via 5-HT₂A receptor downregulation in frontal cortex, with full cross-tolerance to lsdpartially supported
Repeated DOI induces progressive HTR decrease. Cross-tolerance between DOI and LSD. Tolerance involves 5-HT2AR downregulation in frontal cortex. acschemneuro.2c00170
The primary safety risks are cardiovascular stress from sustained vasoconstriction, psychological distress during the prolonged 16–30 hour experience, and adulteration when DOx compounds are sold as LSD on blottersupported
DOx compounds misrepresented as LSD at Boom Festival 2014. Drug checking service intercepted unintentional DOx consumption. hup.2608
comparative-pharmacology6 · 5 ok
The 2,5-dimethoxy motif is the shared pharmacophore; potency differences arise from the 4-substituent's electronic and steric properties.supported
2,5-dimethoxyphenethylamine scaffold confers potent 5-HT2A agonist activity. Removal of either methoxy group reduces in vitro potency modestly but significantly reduces in vivo HTR potency. acschemneuro.0c00129
Both DOI and lsd are high-affinity 5-HT₂A agonists that produce hallucinogenic effects via Gᵢ signalling and enhance D2 signalling through D2–5-HT₂A heteroreceptor complexessupported
5-HT2A-mediated non-canonical Gi signalling is essential for hallucinogenic effect. s41586-025-10061-7
Cross-tolerance: Full bidirectional cross-tolerance confirmed.supported
Cross-tolerance between DOI and LSD. acschemneuro.2c00170
Claim in comparative-pharmacology — inconclusiveinconclusiveworking →
DOI activates Gᵢ signalling; non-hallucinogenic agonists are Gq-biasedsupported
5-HT2A-mediated non-canonical Gi signalling is essential for hallucinogenic effect. Identified DOI-NBOMe as Gq-biased derivative with therapeutic effects without hallucinogenic activity. s41586-025-10061-7
DOI enhances D2 heteroreceptor signalling; non-hallucinogenic agonists do notsupported
DOI enhances D2R-mediated inhibition of CRE-luciferase via D2-5-HT2A heteroreceptor complex. j.bbrc.2013.11.104
history5 · 3 ok
Claim in history — inconclusiveinconclusiveworking →
The radioiodinated form, [¹²⁵I]-R-(−)-DOI, was developed and characterized by McKenna and Peroutka in 1989, demonstrating KD = 0.63 nM and Bmax = 2.5 pmol/g tissue at 5-HT₂A sites in rat cortexpartially supported
[125I]DOI labels 5-HT2A sites in rat cortex with high affinity (KD = 0.63 nM). pmid:2795135
Nau et al. (2013) demonstrated that (R)-DOI potently blocks TNF-α-mediated inflammation via 5-HT₂A activation, and Flanagan et al. (2019) showed reversal of established airway inflammation in chronic asthma modelssupported
(R)-DOI produces super-potent blockade of TNF-α-induced proinflammatory markers in rat aortic smooth muscle cells and in whole animal. Mechanism confirmed via 5-HT2A receptor selective antagonists. journal.pone.0075426
Nau et al. (2013) demonstrated that (R)-DOI potently blocks TNF-α-mediated inflammation via 5-HT₂A activation, and Flanagan et al. (2019) showed reversal of established airway inflammation in chronic asthma modelssupported
(R)-DOI reverses inflammation and symptoms in chronic asthma mouse model via 5-HT2A receptor activation. j.lfs.2019.116790
Claim in history — inconclusiveinconclusiveworking →
receptor-pharmacology5 · 5 ok
Radioligand characterization of [¹²⁵I]-R-(−)-DOI at rat cortical 5-HT₂A sites: KD = 0.63 nM, Bmax = 2.5 pmol/g tissue.partially supported
[125I]DOI labels 5-HT2A sites in rat cortex with high affinity (KD = 0.63 nM). pmid:2795135
The NIMH Psychoactive Drug Screening Program (PDSP) receptorome study found DOI interacts with 42 of 49 broadly assayed receptor targetssupported
DOI and other phenylalkylamines interact with 42 of 49 sites tested. journal.pone.0009019
Gq/PLC pathway (canonical): Activates IP3/DAG → MAP kinase → CREB-dependent gene expressionsupported
DOI enhances pCREB via MAP kinase and CaMKII pathways... Effect blocked by 5-HT2A antagonist MDL100,907. fnmol.2021.790213
β-arrestin-2 recruitment: DOI recruits β-arrestin-2 at 5-HT₂A, though tolerance development is independent of this pathwaypartially supported
Tolerance involves 5-HT2AR downregulation in frontal cortex, independent of beta-arrestin-2. acschemneuro.2c00170
The 2,5-dimethoxy motif is the pharmacophore essential for high-affinity 5-HT₂A binding across the DOx seriessupported
2,5-dimethoxyphenethylamine scaffold confers potent 5-HT2A agonist activity. Removal of either methoxy group reduces in vitro potency modestly but significantly reduces in vivo HTR potency. acschemneuro.0c00129
clinical-evidence4 · 3 ok
Šabanović et al. (2024) demonstrated that a single 2 mg/kg dose of (±)-DOI in mice improved cognitive flexibility in a probabilistic reversal learning task one week after treatment and induced a novel strategy of learning from reward omissionssupported
Single dose 2 mg/kg (±)-DOI: Lasting improvement in cognitive flexibility in reversal learning task one week post-treatment. s41380-024-02439-2
Nau et al. (2013) demonstrated that systemic (R)-DOI potently blocks TNF-α-induced proinflammatory gene expression (ICAM-1, VCAM-1, IL-6, IL-1β, MCP-1, CX3CL1) in rat aortic arch and intestine at sub-hallucinogenic doses, mediated exclusively by 5-HT₂Asupported
(R)-DOI produces super-potent blockade of TNF-α-induced proinflammatory markers in rat aortic smooth muscle cells and in whole animal. Mechanism confirmed via 5-HT2A receptor selective antagonists. journal.pone.0075426
Flanagan et al. (2019) extended this to a chronic mouse asthma model, demonstrating reversal of established airway inflammation and structural remodelingsupported
(R)-DOI reverses inflammation and symptoms in chronic asthma mouse model via 5-HT2A receptor activation. j.lfs.2019.116790
Claim in clinical-evidence — inconclusiveinconclusiveworking →
chemistry3 · 3 ok
The 2,5-dimethoxy motif on the phenyl ring is the pharmacophore essential for high-affinity 5-HT₂A agonism in this seriessupported
2,5-dimethoxyphenethylamine scaffold confers potent 5-HT2A agonist activity. Removal of either methoxy group reduces in vitro potency modestly but significantly reduces in vivo HTR potency. acschemneuro.0c00129
The R-(−) enantiomer is the pharmacologically active form, as demonstrated by its exclusive use in radioligand studies ([¹²⁵I]-R-(−)-DOI) and anti-inflammatory researchsupported
[125I]DOI labels 5-HT2A sites in rat cortex with high affinity (KD = 0.63 nM). pmid:2795135
The R-(−) enantiomer is the pharmacologically active form, as demonstrated by its exclusive use in radioligand studies ([¹²⁵I]-R-(−)-DOI) and anti-inflammatory researchsupported
(R)-DOI produces super-potent blockade of TNF-α-induced proinflammatory markers in rat aortic smooth muscle cells and in whole animal. journal.pone.0075426