25I-NBOH

# Research Output: 25I-NBOH

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## Chemical Identity

**Verified from PubChem (CID 10001761):**

| Field | Value | Source |
|-------|-------|--------|
| PubChem CID | 10001761 | [Ref 14 + PubChem lookup] |
| IUPAC Name | 2-[[2-(4-iodo-2,5-dimethoxyphenyl)ethylamino]methyl]phenol | PubChem (matches brief) |
| Molecular Formula | C₁₇H₂₀INO₃ | PubChem |
| Molecular Weight | 413.25 g/mol | PubChem |
| InChIKey | FEUZHYRXGQTBRO-UHFFFAOYSA-N | PubChem (not in brief — confirmed new) |
| CAS | Not confirmed via API | — |

The brief's seed data listed no SMILES, molecular formula, molecular weight, or InChIKey. All four are now confirmed from PubChem and should be populated.

The brief's IUPAC name ("2-[[2-(4-iodo-2,5-dimethoxyphenyl)ethylamino]methyl]phenol") matches PubChem exactly.

**Structural context:** 25I-NBOH is the ortho-hydroxybenzyl (phenol) analog of 25I-NBOMe. The defining structural difference between the NBOH and NBOMe series is the benzyl substituent: NBOH bears a free 2-hydroxybenzyl group (phenol), while NBOMe bears a 2-methoxybenzyl group. This distinction has analytical consequences (thermal lability, see below) and may affect pharmacokinetics and metabolism.

**Thermal lability:** 25I-NBOH is thermolabile and degrades to its parent compound 2C-I under routine gas chromatography (GC) conditions, leading to misidentification as 2C-I in forensic screening (Arantes et al. 2017 [Ref 15]; Chia et al. 2019 [Ref 20]; Kupriyanova et al. 2024 [Ref 25]). Liquid chromatography (LC-MS/MS or HPLC-HRMS) or derivatization with trifluoroacetic anhydride prior to GC-MS is required for reliable identification (Kupriyanova et al. 2024 [Ref 25]; Chia et al. 2019 [Ref 20]).

**Physical properties:** No published melting point, solubility, or stability data for 25I-NBOH were found in the peer-reviewed literature. The compound is typically supplied as a hydrochloride salt for research purposes (inferred from NBOH class literature). Physical properties remain a gap.

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## Pharmacology

### Receptor Binding and Functional Potency

25I-NBOH is a potent, full agonist at the 5-HT₂A and 5-HT₂C receptors. Eshleman et al. (2018 [Ref 1]) is the most directly cited primary pharmacology study for 25I-NBOH specifically. Key findings:

- **5-HT₂A receptor:** Very high affinity; full efficacy (full agonist); functional potency in the **subnanomolar to low nanomolar range**, comparable to LSD, in inositol-phosphate accumulation assays (Eshleman et al. 2018 [Ref 1]).
- **5-HT₂C receptor:** Very high affinity; full efficacy; very high potency comparable to LSD and serotonin (Eshleman et al. 2018 [Ref 1]).
- **5-HT₂B receptor:** Lower affinity, potency, and efficacy compared to 5-HT₂A or 5-HT₂C (Eshleman et al. 2018 [Ref 1]).
- **5-HT₁A receptor:** Very low potency and low efficacy — de facto minimal agonist activity (Eshleman et al. 2018 [Ref 1]).
- **Monoamine transporters (DAT, SERT, NET):** Low to mid-micromolar affinity and potency; consistent with negligible psychostimulant activity (Eshleman et al. 2018 [Ref 1]).

**⚠️ FLAG:** Eshleman et al. (2018 [Ref 1]) describe 25I-NBOH's potency as "subnanomolar to low nanomolar" in the 5-HT₂A functional assay but the abstract does not report specific Ki or EC₅₀ values. The full paper contains tabulated values; specific Ki numbers (commonly cited as ~0.04–0.1 nM at 5-HT₂A in secondary sources) could not be confirmed via abstract-level verification alone. The generation agent should note this limitation and present range descriptors rather than specific numerical Ki values unless the full paper text is accessed.

**Comparative context within NBOH series:** The NBOH scaffold with the ortho-hydroxybenzyl group (phenol) confers similar ultra-high 5-HT₂A affinity to the NBOMe scaffold. Braden et al. (2006 [Ref 14]) demonstrated in the foundational N-benzyl phenethylamine SAR study that adding an N-arylmethyl (N-benzyl) group to 2C-class phenethylamines increases 5-HT₂A binding affinity by up to **300-fold** compared to N-alkyl homologs, primarily via interaction with receptor residue Phe339⁽⁶·⁵¹⁾. Subsequent SAR studies confirmed that ortho substitution on the benzyl ring (as in NBOH and NBOMe) further enhances affinity, while para substitution reduces it (Nichols et al. 2014 [Ref 35]).

### Mechanism of Action

25I-NBOH exerts its psychedelic effects primarily through **Gq-protein-coupled signaling** at 5-HT₂A receptors. Wallach et al. (2023 [Ref 6]) demonstrated across a large panel of 5-HT₂A agonists that Gq-efficacy (not β-arrestin2 recruitment) correlates with psychedelic potential as measured by the mouse head-twitch response (HTR). Beta-arrestin-biased agonists at 5-HT₂A block rather than produce psychedelic effects.

25I-NBOH also has measurable β-arrestin2 recruitment at 5-HT₂AR (Pottie et al. 2020 [Ref 7]; Pottie et al. 2023 [Ref 24]). The NBOH scaffold has been characterized in biased agonism studies comparing Gq vs β-arrestin2 pathways; 25CN-NBOH (the cyano analog) was used as a comparator in multiple studies (Jensen et al. 2020 [Ref 18]; Poulie et al. 2022 [Ref 23]).

The 2,5-dimethoxy substituents on the phenethylamine scaffold are essential for full in vivo psychedelic potency. Marcher-Rørsted et al. (2020 [Ref 31]) showed that removing either the 2- or 5-methoxy group markedly reduces in vivo HTR activity in mice, more than would be predicted from in vitro receptor binding data alone.

### Electrophysiological Effects

In prefrontal cortical neurons, the close NBOH analog 25CN-NBOH (the most selective tool compound in the series) acutely increases spontaneous excitatory postsynaptic current (sEPSC) frequency via 5-HT₂AR activation, while paradoxically suppressing neuronal firing rate via M-current channels — a 5-HT₂AR-independent mechanism (Wang et al. 2025 [Ref 32]). These dual excitatory/inhibitory cellular actions are relevant to understanding the complex cognitive effects of 25I-NBOH.

### Pharmacokinetics and Metabolism

Nielsen et al. (2017 [Ref 2]) is the definitive metabolism study for 25I-NBOH:

- **Primary CYP enzyme:** CYP2D6 (contrasts with 25I-NBOMe, whose primary enzyme is CYP3A4)
- **Intrinsic hepatic clearance (CLint):** 118.7 mL/min/kg (higher than 25I-NBOMe at 70.1 mL/min/kg)
- **Metabolic pathways:** hydroxylation, O-demethylation, N-dealkylation, dehydrogenation, and combinations thereof — plus direct glucuronidation (phase II)
- **Direct glucuronidation** may partly offset the impact of CYP2D6 genetic polymorphism on inter-individual variability
- **Drug-drug interaction risk:** Unlike 25I-NBOMe (CYP3A4), 25I-NBOH is primarily metabolized by CYP2D6; strong CYP2D6 inhibitors (e.g., fluoxetine, paroxetine, bupropion) could increase 25I-NBOH plasma levels

No published human pharmacokinetic studies (bioavailability, Tmax, t½, volume of distribution) exist for 25I-NBOH. All pharmacokinetic data are from in vitro microsomal studies.

### Microglial / Neuroimmune Effects

Wiens et al. (2024 [Ref 5]) used 25I-NBOH as a selective 5-HT₂R agonist control in a microglial study. At non-toxic concentrations, 25I-NBOH inhibited microglial phagocytic activity, reactive oxygen species (ROS) production, and nitric oxide (NO) production via 5-HT₂R activation — similar to psilocin. This result is relevant to potential anti-inflammatory activity of the NBOH class but was not studied therapeutically.

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## History

### Discovery and Synthesis

The N-benzyl phenethylamine class was first systematically characterized by **Braden, Parrish, Naylor, and Nichols** at Purdue University in **2006** (Braden et al. 2006 [Ref 14]). This study revealed that adding an N-arylmethyl group to 2C-class phenethylamines dramatically increased 5-HT₂A receptor affinity (up to 300-fold), with the N-benzyl moiety interacting specifically with Phe339⁽⁶·⁵¹⁾ in the receptor binding pocket.

The **NBOMe series** (N-2-methoxybenzyl) was subsequently developed as research tools and emerged on drug markets around 2010–2011. The **NBOH series** (N-2-hydroxybenzyl/phenol) likely emerged shortly after, but the precise date of first synthesis or market appearance for 25I-NBOH specifically is not documented in the peer-reviewed literature.

The first published **scientific identification of 25I-NBOH in actual drug seizures** was by Arantes et al. (2017 [Ref 15]), who found the compound in blotter papers seized by state-level forensic laboratories in **Brazil**. Individual dose loads on seized blotters ranged from **300 to 1,000 µg** — consistent with the upper end of the seed dose ranges. This study noted that 25I-NBOH was thermolabile and fragmented to 2C-I under routine GC-MS screening, making it likely to have been encountered in seizures earlier but misidentified.

**Timeline summary:**
- 2006: N-benzyl phenethylamines first characterized at Nichols lab (Braden et al.)
- ~2010–2015: NBOH/NBOMe series appear on research chemical markets (estimated)
- 2013 (June): Louisiana (US) schedules 25I-NBOH as Schedule I (Erowid [Ref 34])
- 2015 (August): Sweden schedules 25I-NBOH under Narcotic Drugs Punishments Act (Erowid [Ref 34])
- 2017: First peer-reviewed report of 25I-NBOH in seized materials (Arantes et al. [Ref 15])
- 2017: Metabolism study (Nielsen et al. [Ref 2]) and first pharmacological profiling (Eshleman et al. 2018 [Ref 1])

**Street names / market names:** 25I-NBOH has been found on blotter papers and is sometimes sold mislabelled. The Pelletier et al. (2024 [Ref 30]) case report describes a powder labelled as "25I-NBOH" that was actually 25E-NBOH plus MDPHP — illustrating the substitution/adulteration risk in the unregulated market.

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## Subjective Effects

No controlled human studies of 25I-NBOH's subjective effects exist. All human-facing characterization is inferred from:
1. Animal studies using 25I-NBOH as a selective 5-HT₂AR agonist tool compound
2. Case reports and surveillance data for NBOH/NBOMe class
3. Reports from seized material databases

**From animal data (25I-NBOH-specific):**
- **Head twitch response (HTR)** in mice — the canonical 5-HT₂AR-mediated behavior; 25I-NBOH is regularly used as a positive control in HTR experiments (Contreras et al. 2021 [Ref 3]; Halberstadt 2017 [Ref 16])
- **Behavioral arrest** preceding HTR by a precise temporal interval, associated with Phase 1 EEG waveform (3.5–4.5 Hz) (Contreras et al. 2021 [Ref 3])
- **Nicotine pretreatment** attenuates HTR and Phase 2 EEG waveforms, while increasing behavioral arrest duration (Contreras et al. 2021 [Ref 3])
- Prepulse inhibition disruption (per 25I-NBOMe analog data, Bilel et al. 2025 [Ref 19])

**Inferred from NBOMe class and structural analog data:**
The NBOMe/NBOH class produces effects qualitatively similar to classical serotonergic psychedelics (LSD, psilocybin, mescaline) but with a duration typically reported as **shorter** (5–8 hours total) and a reportedly intense onset. Adverse effects commonly reported in clinical intoxication cases include (Zawilska et al. 2020 [Ref 4]; Halberstadt 2017 [Ref 16]):
- Visual and auditory hallucinations
- Confusion, anxiety, panic, fear
- Agitation, uncontrollable behavior
- Seizures, excited delirium
- Sympathomimetic signs: mydriasis, tachycardia, hypertension, hyperthermia, diaphoresis

**⚠️ FLAG (user-report-only data):** The seed dose and duration data (Threshold 50 µg; Light 200–500 µg; Common 500–900 µg; Strong 900–1400 µg; total duration 5–8 hours; aftereffects 3–12 days) originates from community consensus, not controlled clinical studies. The seized blotter doses of 300–1,000 µg (Arantes et al. 2017 [Ref 15]) are consistent with the light-to-common range. The aftereffects duration (3–12 days) is notably long and appears to reflect community reports of lingering cognitive effects; no pharmacological mechanism is identified in published literature.

The mouse HTR translates well to human psychedelic potency: Halberstadt et al. (2020 [Ref 17]) demonstrated a strong correlation (r = 0.9448) between HTR potency in C57BL/6J mice and human hallucinogenic potency across 36 compounds. This validates using 25I-NBOH's robust HTR induction as evidence of high human psychedelic potency.

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## Safety & Toxicity

### Acute Toxicity

No LD₅₀ or therapeutic index data were found for 25I-NBOH specifically in the published literature. **FLAG:** The seed data states "potentially fatal at heavy dosages" — this is a reasonable inference from analog data but is not confirmed by published 25I-NBOH-specific case reports.

**25I-NBOH human case reports:** Only one case in the published literature involves a product labelled as "25I-NBOH." Pelletier et al. (2024 [Ref 30]) report a 23-year-old male who developed **serotonin syndrome and loss of consciousness** after consuming a powder labeled as 25I-NBOH. Toxicological analysis identified the actual substances as **25E-NBOH** (2.3 ng/mL plasma) **plus MDPHP** (a stimulant cathinone; 3.4 ng/mL plasma). 25I-NBOH was specifically searched for and not detected. This case demonstrates the adulteration/substitution risk in the market.

**25I-NBOMe (structural analog) fatal cases — directly informing 25I-NBOH risk:**
- Poklis et al. (2014 [Ref 12]): First postmortem 25I-NBOMe tissue distribution study; 19-year-old fatality; peripheral blood 405 pg/mL, brain 2.54 ng/g.
- Lowe et al. (2015 [Ref 10]): 15-year-old death from multi-system organ failure after 25I-NBOMe + psilocybin; antemortem blood 0.76 ng/mL.
- Shanks et al. (2015 [Ref 11]): Two teenage male deaths; 25I-NBOMe postmortem heart blood 19.8 ng/mL.
- Kaminska et al. (2021 [Ref 8]): Review reports 51 non-fatal intoxications and 21 deaths in Europe associated with 25I-NBOMe.

**Toxidrome features (from NBOMe/NBOH class literature):**
- Halberstadt (2017 [Ref 16]) reviewed 51 toxicity cases and identified **rhabdomyolysis** as a relatively common complication of severe NBOMe toxicity, linked mechanistically to NBOMe-induced seizures, hyperthermia, and vasoconstriction
- Additional complications documented: disseminated intravascular coagulation (DIC), hypoglycemia, metabolic acidosis, acute kidney injury, multiorgan failure (Zawilska et al. 2020 [Ref 4])
- Excited delirium with violent behavior reported (Zawilska et al. 2020 [Ref 4])

**Acute CNS toxicity (analog data):** Bilel et al. (2025 [Ref 19]) demonstrated that 25I-NBOMe in mice disrupts prepulse inhibition (PPI), increases dopamine release in the nucleus accumbens shell (at 1 mg/kg i.p.), and prevents long-term potentiation (LTP) in the medial prefrontal cortex — with the LTP prevention not reversible by the selective 5-HT₂AR antagonist MDL100907, suggesting off-target mechanisms contributing to neurotoxic potential.

### Psychological Risks

Based on NBOMe/NBOH class data:
- Acute psychological distress ("bad trips"), panic attacks (Hermanns-Clausen et al. 2017 [Ref 21])
- Seizures at high doses
- Potential for hallucinogen persisting perception disorder (HPPD) — documented for serotonergic psychedelics generally but not specifically for 25I-NBOH

### Misidentification Risk

25I-NBOH is occasionally substituted for 25I-NBOMe (or vice versa), or sold as LSD on blotter paper. The thermal lability under GC-MS means it can be misidentified as 2C-I in forensic labs (Arantes et al. 2017 [Ref 15]). From a user safety standpoint, misidentification on the drug market creates unquantifiable dose risk.

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## Harm Reduction

### Testing and Identification

- **GC-MS is unreliable** for NBOH identification due to thermal degradation to 2C-I. LC-MS/MS or derivatization (trifluoroacetyl) required for positive identification (Kupriyanova et al. 2024 [Ref 25]; Chia et al. 2019 [Ref 20]).
- Reagent testing (Ehrlich, Hofmann, etc.) will react positively for NBOH compounds, but cannot differentiate NBOH from NBOMe or other phenethylamines.
- **⚠️ FLAG:** No published studies specifically validate point-of-care reagent test sensitivity or specificity for 25I-NBOH.

### Dose Caution

Seized blotter doses (300–1,000 µg) overlap with the community-reported "common" dose range (500–900 µg), meaning full-dose blotters exist in the market. The potency is comparable to LSD but the dose per blotter may be substantially higher.

### Emergency Response

No 25I-NBOH-specific clinical management guidelines exist. Based on NBOMe/NBOH class data, management of severe intoxication should include:
- Benzodiazepines for seizure control and agitation (referenced in Zawilska et al. 2020 [Ref 4])
- Cooling for hyperthermia
- CK monitoring for rhabdomyolysis
- Renal function monitoring
- Antipsychotics (note: some may lower seizure threshold)
- Antidote: no specific antidote; ketanserin (5-HT₂A antagonist) has been proposed for NBOMe toxicity but controlled evidence is lacking

### Contraindications

Based on class pharmacology (inferred — no 25I-NBOH-specific contraindication studies):
- Severe cardiovascular disease (sympathomimetic effects; vasoconstriction)
- History of seizures
- CYP2D6 poor metabolic status (reduced clearance)
- Concurrent serotonergic medications (SSRIs, MAOIs, SNRIs, tramadol)
- Psychiatric history (psychosis, bipolar disorder)

---

## Tolerance & Dependence

### Tolerance

Serotonergic hallucinogens as a class produce rapid tolerance (tachyphylaxis) primarily via 5-HT₂A receptor downregulation and desensitization. This is a well-established property of the class and applies to 25I-NBOH by structural and mechanistic analogy. The seed data states "buildup almost immediately after ingestion" and "half-life [of tolerance reset]: 1 week; full reset: 2 weeks" — these values are consistent with published class-level data for classical serotonergic psychedelics but are not verified from 25I-NBOH-specific studies.

**⚠️ FLAG:** Wallach et al. (2023 [Ref 6]) found that beta-arrestin-biased 5-HT₂A agonists can induce receptor downregulation and tachyphylaxis more rapidly than Gq-biased agonists. The biased agonism profile of 25I-NBOH specifically (Gq vs β-arrestin2 balance) has not been quantitatively characterized in the manner of 25CN-NBOH, so the tolerance kinetics remain incompletely described.

### Cross-tolerance

Cross-tolerance with other serotonergic psychedelics (LSD, psilocybin, mescaline, other NBOH/NBOMe compounds) is expected based on shared 5-HT₂A receptor mechanism. This is consistent with the seed data.

### Dependence

25I-NBOH is not considered habit-forming (consistent with the class). Classical serotonergic psychedelics do not produce physical dependence. The rapid tolerance development itself limits compulsive use patterns.

---

## Interactions

### Tramadol — Dangerous (Seed Data Classification: Confirmed Mechanistically)

Tramadol is a **serotonin reuptake transporter (SERT) inhibitor** (in addition to weak mu-opioid agonism). It inhibits SERT in human HEK293 cells transfected with human SERT (Baldo 2018 [Ref 28]). Combined with a potent 5-HT₂A agonist such as 25I-NBOH, tramadol can produce dangerous elevation of intrasynaptic serotonin, with risk of **serotonin syndrome** — characterized by hyperthermia, clonus, hyperreflexia, agitation, and potentially life-threatening autonomic instability (Baldo 2018 [Ref 28]).

The FDA issued a Drug Safety Communication in March 2016 specifically warning about opioid-serotonin toxicity interactions (noted in Baldo 2018 [Ref 28]). The combination of a potent 5-HT₂A full agonist with a SERT inhibitor represents an additive or synergistic serotonergic load.

Additionally, tramadol lowers seizure threshold — compounding the seizure risk that exists with high-dose 25I-NBOH use alone (Zawilska et al. 2020 [Ref 4]).

**Assessment:** The "dangerous" classification in the seed data is mechanistically well-supported by the literature.

### Cannabis — Unknown (Seed Data)

No published studies characterize the 25I-NBOH + cannabis interaction. Cannabis (THC) acts via CB1 receptors, which modulate dopaminergic and glutamatergic neurotransmission. No direct pharmacodynamic or pharmacokinetic interaction mechanism is established. Empirically, cannabis is commonly combined with psychedelics in recreational settings, with reports of intensified or destabilized effects. This interaction remains unresolved in the literature.

### Other Serotonergic Drugs (Not in Seed Data — Flag for Review)

SSRIs, SNRIs, MAOIs: All may interact with 25I-NBOH via additive serotonergic mechanisms. MAOIs in particular pose high-risk combinations (Gillman 2005) and should be flagged as a contraindication/dangerous interaction even though not listed in seed data.

### CYP2D6 Inhibitors

25I-NBOH is primarily metabolized by CYP2D6 (Nielsen et al. 2017 [Ref 2]). Strong CYP2D6 inhibitors (fluoxetine, paroxetine, bupropion, quinidine) may substantially increase 25I-NBOH exposure. This is a pharmacokinetic interaction requiring flagging.

---

## Legal Status

Based on Arantes et al. (2017 [Ref 15]) and Erowid legal status data (web-retrieved [Ref 34]):

| Jurisdiction | Status | Notes |
|---|---|---|
| United States (federal) | Not explicitly scheduled by DEA | May be covered as structural analog under Federal Analog Act if intended for human consumption |
| United States (Louisiana) | Schedule I | As of June 2013 |
| United Kingdom | Effectively banned | UK Psychoactive Substances Act 2016 covers all novel psychoactive substances; no exemption for NBOH compounds |
| European Union | Variable by member state | Not EU-wide controlled; 25I-NBOMe was EU-banned in 2014 but 25I-NBOH has different legal status |
| Sweden | Controlled (Narcotic Drugs Punishments Act) | Added August 18, 2015 |
| Brazil | Controlled | Added to controlled substances list; noted in Arantes et al. 2017 |
| Canada | Not explicitly scheduled | Potentially analog act coverage |
| Australia | Likely covered by analog provisions | Not confirmed via published source |
| UNODC | Not under UN Convention control | As of Arantes et al. 2017 |

**⚠️ FLAG:** Legal status data is largely from Erowid (web-retrieved, 2023 snapshot) and the 2017 Arantes paper. Regulatory landscapes change rapidly for NPS; these should be verified against current government schedules before publication. The US federal status in particular is uncertain — the compound is not explicitly listed as a DEA Schedule I substance, but analog act coverage depends on prosecutorial application.

---

## Clinical Trials

A search of ClinicalTrials.gov returned **no registered clinical trials** for 25I-NBOH. 25I-NBOH has been used exclusively as a pharmacological tool compound in preclinical (animal and cell) research. No therapeutic development program was identified.

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## Community Feedback Analysis

No community feedback was submitted in Part A2 of the brief. No community feedback items to assess.

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## Gaps & Flags

### Critical Data Gaps

1. **No human pharmacokinetic data:** No published bioavailability, Tmax, t½, or volume of distribution data for 25I-NBOH in humans. All PK data are from in vitro microsomal studies (Nielsen et al. 2017 [Ref 2]).

2. **No confirmed specific Ki/EC₅₀ values for 25I-NBOH:** Eshleman et al. (2018 [Ref 1]) describe potency as "subnanomolar to low nanomolar" but abstract-level verification did not yield specific numerical Ki values. This gap should be noted by the generation agent; values commonly cited in secondary sources (~0.04–0.1 nM) cannot be confirmed from accessible abstracts.

3. **No 25I-NBOH-specific human fatality case reports:** All fatal case data applies to 25I-NBOMe (structural analog), not 25I-NBOH. The toxicological risk profile for 25I-NBOH is substantially inferred from analog data. The seed data statement "potentially fatal at heavy dosages" is reasonable but cannot be attributed to a 25I-NBOH-specific source.

4. **No published LD₅₀ data** for 25I-NBOH (no animal toxicology studies with mortality endpoints).

5. **Physical properties unknown:** No published melting point, aqueous solubility, LogP, or stability data for 25I-NBOH found in peer-reviewed literature.

6. **Subjective effect data is user-report only:** There are no controlled human studies. All dose ranges, durations, and effect descriptions are from community consensus. The seed data effect profile (57 effects, all at community_consensus provenance) cannot be cross-referenced against clinical trial or clinical pharmacology data.

7. **Aftereffects duration (3–12 days):** The seed data's aftereffects window is exceptionally long and appears to reflect user community reports of cognitive/perceptual disturbances. No pharmacological or clinical literature basis found for this specific duration with 25I-NBOH.

8. **CAS number:** Not confirmed through any API source.

9. **SMILES string:** Not in the brief; should be populated from PubChem (CID 10001761).

### Safety-Critical Flags for Human Review

- **Seed data "Acute toxicity: high; Chronic toxicity: high"** — These classifications are inferred from analog data (25I-NBOMe). They are reasonable but not confirmed by 25I-NBOH-specific published sources. Flag as class-inferred.

- **Interaction: Tramadol (dangerous)** — Mechanistically supported by Baldo 2018 [Ref 28] (SERT inhibition by tramadol + 5-HT₂A agonism → serotonin syndrome risk). Confirmed classification appropriate.

- **Missing interactions:** SSRIs, MAOIs, SNRIs should also be listed as high-risk interactions given the mechanism. These are absent from the seed data.

- **CYP2D6 drug interactions:** Strong CYP2D6 inhibitors (fluoxetine, paroxetine, bupropion) could significantly increase 25I-NBOH blood levels — this pharmacokinetic interaction is confirmed from Nielsen et al. 2017 [Ref 2] and should be added.

- **Legal status volatility:** The legal status table is based on snapshot data (2017–2023). Several jurisdictions may have updated schedules since the most recent published sources.

### Contradictions with Seed Data

- **Seed IUPAC:** Matches PubChem exactly — no contradiction.
- **Seed dose data (light: 200–500 µg):** Lower bound slightly below the 300–1,000 µg range found in seized blotters (Arantes 2017 [Ref 15]). The "threshold: 50 µg" and "light" floor cannot be verified from seizure data alone. These values are consistent with community consensus.
- **Seed description of 25I-NBOH as "emerging":** Accurate given its limited scheduling status compared to 25I-NBOMe.
- **No PubChem CID in seed data:** PubChem CID 10001761 confirmed — should be populated.