2C-I

# Research Output: 2C-I (2,5-Dimethoxy-4-iodophenethylamine)

**Provenance ID:** 771acff3-3dab-4a51-a05f-050890ff6dda  
**Research date:** 2026-04-25  
**Substance readiness:** sparse/emerging (no human controlled studies, one rat metabolism study, one case report)

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## Chemical Identity

**Confirmed via PubChem CID 10267191:**

| Property | Value |
|----------|-------|
| Preferred IUPAC name | 2-(4-iodo-2,5-dimethoxyphenyl)ethanamine |
| Common name | 2C-I |
| Systematic name | 2,5-dimethoxy-4-iodophenethylamine |
| Molecular formula | C₁₀H₁₄INO₂ |
| Molecular weight | 307.13 g/mol |
| InChIKey | PQHQBRJAAZQXHL-UHFFFAOYSA-N |
| PubChem CID | 10267191 |
| CAS number | 69587-11-7 |

**Brief seed data comparison:** The brief left CID, formula, weight, InChIKey, and SMILES blank. All are now confirmed from PubChem. The systematic name in the brief ("2,5-dimethoxy-4-iodophenethylamine") is consistent with the IUPAC name confirmed here. No discrepancies found.

**Physical properties:** No published melting point, solubility, or crystalline form data found in the peer-reviewed literature. Theobald et al. (2006 [Ref 16]) used GC/MS and CE/MS for analysis of the compound in rat urine, confirming it is detectable and quantifiable in biological matrices by standard methods. Shulgin's PiHKAL [Ref 14] provides synthesis routes but no formal physical characterization data in the published peer-reviewed record.

**Stereochemistry:** 2C-I lacks a chiral center in its phenethylamine backbone. Unlike the phenylisopropylamine (amphetamine-type) hallucinogens such as DOI, which have a chiral alpha-carbon, the 2C-x phenethylamines are achiral. No stereochemistry issues apply.

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## Pharmacology

### Primary Mechanism of Action

2C-I is a serotonin 5-HT₂A receptor agonist. Its psychedelic effects are mediated predominantly through Gq-coupled 5-HT₂A receptor activation. Wallach et al. (2023 [Ref 10]) demonstrated that 5-HT₂A Gq (not β-arrestin2) efficacy is the key predictor of psychedelic-like effects in the head-twitch response (HTR) model; 2C-I, as a full-efficacy Gq agonist at 5-HT₂A, fits this mechanistic model. Halberstadt & Geyer (2014 [Ref 1]) confirmed that 2C-I (1–10 mg/kg SC) induces the HTR in C57BL/6J mice through 5-HT₂A receptor activation — the selective 5-HT₂A antagonist M100907 completely abolished the response.

### Receptor Binding Data

**5-HT₂A affinity:** Web-retrieved sources citing the PMC version of Halberstadt & Geyer (2014 [Ref 1]) and related papers report 2C-I Ki ≈ 0.73 nM at the 5-HT₂A receptor. This value was not directly confirmed from a primary binding table via API retrieval.

> ⚠️ **FLAG FOR HUMAN REVIEW:** The Ki value of ≈ 0.73 nM at 5-HT₂A is sourced from a web-retrieved interpretation of the Halberstadt & Geyer 2014 paper (PMC article). The primary paper itself (PMID 24012658) was retrieved via API but the cached abstract does not list exact Ki values. The generation agent should retrieve the full paper or cross-reference Elmore et al. (2018 [Ref 19]) or Rickli et al. (2015 [Ref 21]) for confirmed Ki figures.

The N-benzyl derivative 25I-NBOMe has markedly higher 5-HT₂A affinity than 2C-I. Halberstadt & Geyer (2014 [Ref 1]) found 25I-NBOMe is approximately 14-fold more potent than 2C-I in the mouse HTR assay. Zawilska et al. (2020 [Ref 11]) confirmed that NBOMe compounds generally display Ki values in the low nanomolar range at 5-HT₂A/2C, substantially higher than their 2C parent compounds.

**5-HT₂C activity:** 2C-I also acts at 5-HT₂C receptors. The 2,5-dimethoxy phenethylamine scaffold confers activity across the 5-HT₂ receptor family. Marcher-Rørsted et al. (2020 [Ref 4]) demonstrated that the 2,5-dimethoxy motif is important for in vivo potency at 5-HT₂A and 5-HT₂C, though removal of either methoxy group causes only modest reduction in in vitro binding. The seed data pharmacological class "Serotonin 2C receptor agonist" is consistent with published evidence.

**Broader receptor profile:** Ray (2010 [Ref 20]) reports comprehensive NIMH-PDSP screening data for 25 psychedelics at 51 receptor sites. The paper establishes that phenylalkylamines interact with 42 of 49 broadly assayed sites — they are not as selective for 5-HT₂A/2C as generally believed. Targets beyond 5-HT₂ receptors include α₂-adrenergic receptors, dopamine receptors, GABA-A receptors, and acetylcholine receptors at human brain concentrations reached during recreational use, per Hondebrink et al. (2018 [Ref 23]).

Eshleman et al. (2014 [Ref 2]) studied 2C-I among six phenethylamines and includes in vitro receptor binding and transporter binding data alongside mouse locomotion and rat drug discrimination. **Full binding tables (Ki values at individual receptor and transporter sites) are in the full text of this paper; the API-returned abstract is truncated.** The generation agent should flag this for access to specific Ki values.

**DEA drug discrimination data:** The official DEA factsheet for 2C-I (2013 [Ref 24]) states that drug discrimination studies show 2C-I produces discriminative stimulus effects similar to Schedule I hallucinogens including LSD, DMT, and MDMA. This is consistent with peer-reviewed data showing generalization of 2C-I cue to LSD in animal models.

Nonaka et al. (2007 [Ref 7]) confirmed that 2C-I stimulates G protein ([³⁵S]GTPγS) binding in rat cortical membranes, directly demonstrating Gq-coupled receptor activation — consistent with 5-HT₂A agonism.

### Pharmacokinetics

**Metabolism (rat model only):** Theobald et al. (2006 [Ref 16]) — the only published study on 2C-I metabolism — characterized metabolites in rat urine via GC/MS and CE/MS. Identified pathways:
1. **O-demethylation** at position 2 or 5, followed by:
   - N-acetylation, OR
   - Deamination → oxidation to carboxylic acid OR reduction to alcohol
   - Beta-hydroxylation of the alcohol metabolite → further oxidation to oxo metabolite
2. **Direct deamination** → oxidation to carboxylic acid OR reduction to alcohol
3. Most metabolites partially excreted in **conjugated form** (phase II)

CYP enzyme involvement in 2C-I O-demethylation has not been characterized in the published literature. By structural analogy with closely related 2C-B (also a 2,5-dimethoxyphenethylamine), CYP2D6 and CYP1A2 are plausible candidates, but this is class inference — no 2C-I-specific CYP data exists.

> ⚠️ **FLAG FOR HUMAN REVIEW:** All pharmacokinetic data comes from a rat model (Theobald 2006). **No human pharmacokinetic studies have been published for 2C-I.** Bioavailability, Tmax, half-life, and volume of distribution are unknown. The generation agent must not extrapolate human PK from the rat study.

**Detection:** The STA (systematic toxicological analysis) procedure described by Theobald et al. (2006 [Ref 16]) — full-scan GC/MS after acid hydrolysis, liquid-liquid extraction and microwave-assisted acetylation — allows detection of a dose corresponding to a "common drug user's dose." Drees et al. (2009 [Ref 3]) confirmed 2C-I is detectable in human urine by LC-MS/MS.

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## History

**Discovery and synthesis:** 2C-I was first synthesized by Alexander Shulgin, reportedly in 1977. It was described in detail — including synthesis, pharmacological notes, and self-experiment phenomenology — in his 1991 book *PiHKAL: A Chemical Love Story* [Ref 14] (Entry #14 in the 2C series). Shulgin listed an oral dose of 14–22 mg and a duration of 6–10 hours.

**Pre-ban availability:** Following the DEA's Schedule I placement of 2C-B in 1995, 2C-I emerged in the early 2000s as a commercial alternative, particularly in Dutch "smart shops" and online research chemical vendors. This substitution pattern is typical of the "cat-and-mouse" NPS market dynamic described by Brandt et al. (2014 [Ref 12]).

**Research chemical era:** 2C-I was sold internationally as a "research chemical" and "legal high" prior to scheduling. It is mentioned in epidemiological surveys of NPS use (Palamar et al. 2016 [Ref from earlier context]) and was detected in forensic toxicology cases documented in Poland (Adamowicz et al. 2016 [from search results]) and the United States (Drees 2009 [Ref 3]).

**Regulatory timeline:**
- **2003:** European Union — the EU Council issued a binding order (December 2003) mandating all member states to ban 2C-I within three months. *Source: web-retrieved; not confirmed via primary regulatory document.*
- **2012 (USA):** Permanently scheduled as **Schedule I** controlled substance under the **Synthetic Drug Abuse Prevention Act of 2012** (Public Law 112-144, signed July 9, 2012). This placed 2C-I explicitly by name in the CSA Schedule I. The DEA factsheet [Ref 24] confirms this scheduling.
- Prior to permanent scheduling, 2C-I had been subject to DEA temporary scheduling actions.

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## Subjective Effects

No controlled human studies of 2C-I's subjective effects have been published. All human phenomenology data derives from:
1. Shulgin's self-experiment records in PiHKAL [Ref 14] — dose-ranging 14–22 mg oral
2. User reports in online communities (Erowid, Psychonautwiki) — not peer-reviewed
3. Clinical case observations in emergency/toxicology settings

**Shulgin's self-experiment notes (PiHKAL [Ref 14]):** Described as producing visual distortions, enhanced colors, altered perception. Duration 6–10 hours. Shulgin reported effects similar in character to 2C-B but with distinct qualities.

**From animal pharmacology (proxy):** The compound reliably produces the mouse head-twitch response [Ref 1] — the most validated rodent proxy for human psychedelic experience. Dose-response data in mice (Halberstadt & Geyer 2014 [Ref 1]): 1–10 mg/kg SC, with 5-HT₂A mediation confirmed.

**From clinical toxicology case series (Dean et al. 2013 [Ref 17]):** Clinical presentations of 2C drug intoxication (class-level, not 2C-I specific) include: hallucinations, agitation, aggression, dysphoria, and sympathomimetic signs (hypertension, tachycardia). Serotonin toxicity presentations also documented. Excited delirium is consistently described in 2C-drug fatalities.

**Duration data:** The seed data (6–10 hours total, 15–45 min onset, 3–5 hour peak) is consistent with Shulgin's PiHKAL entry (6–10 hours). No peer-reviewed human duration studies exist to confirm or refute these values.

**Dose data (seed DB vs PiHKAL):**
- Seed DB: Common 10–20 mg, Strong 20–30 mg, Heavy 30+ mg
- Shulgin (PiHKAL [Ref 14]): 14–22 mg as primary range

> ⚠️ **FLAG FOR HUMAN REVIEW:** The seed database common dose range (10–20 mg) sits slightly below Shulgin's stated range (14–22 mg). These are not irreconcilable (Shulgin's range falls largely within common-to-strong in the DB), but the threshold (2 mg) and light (5–10 mg) values are lower than what Shulgin documented. These lower values may reflect community experience with sensitive individuals. No peer-reviewed controlled dosing study exists to adjudicate.

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## Safety & Toxicity

### Case Reports

**Drees et al. (2009 [Ref 3])** — the only peer-reviewed case report specifically documenting 2C-I toxicity:
- Patient: 39-year-old woman presenting to ER with rapidly diminishing mental status, hypertension, and vasoconstriction
- Substances confirmed by LC-MS/MS: cocaine, MDA (not MDMA as initially reported by companions), and **2C-I** (urine positive)
- Outcome: Hemorrhagic stroke caused by underlying Moyamoya cerebrovascular abnormality, exacerbated by substance-induced hypertension/vasoconstriction
- Significance: Demonstrates 2C-I causes acute cardiovascular stress (hypertension, vasoconstriction) sufficient to precipitate cerebrovascular events in predisposed individuals

### Class-Level Toxicity (2C Drugs)

Dean et al. (2013 [Ref 17]) reviewed the 2C drug class (including 2C-I, 2C-B, 2C-E, 2C-T-7, and others):
- **At least 5 deaths** reported in literature attributed to 2C drug intoxication
- Common fatal presentation: **excited delirium syndrome** — severe agitation, aggression, violence, seizures, hyperthermia
- Non-fatal presentations: hallucinations, agitation, hypertension, tachycardia, sympathomimetic toxidrome or serotonin toxicity syndrome

Halberstadt (2017 [Ref 5]) notes that the NBOMe class (derived from 2C-I and related compounds) causes rhabdomyolysis as a relatively common complication of severe toxicity — linked to seizures, hyperthermia, and vasoconstriction. While this is NBOMe-specific toxicity, the parent 2C-I shares some cardiovascular risk profile.

**Excited delirium features associated with 2C fatalities (Dean 2013 [Ref 17]):** hyperthermia, extreme agitation, apparent superhuman strength, sudden death. Treatment must include rapid sedation and aggressive cooling.

### LD50 / Toxic Dose

> ⚠️ **FLAG FOR HUMAN REVIEW:** No LD50 data exists for 2C-I in any species in the published literature. The seed database entry "toxic dose is unknown" is correct and consistent with the absence of published toxicology data. Do not estimate or extrapolate.

### Cardiovascular Risk

Sympathomimetic effects (hypertension, tachycardia, vasoconstriction) are documented in both the case report (Drees 2009 [Ref 3]) and the class-level clinical reviews (Dean 2013 [Ref 17], Gil-Martins 2025 [Ref 18]). The mechanism involves 5-HT₂A receptor-mediated vasoconstriction, with possible additional adrenergic receptor activity (Hondebrink et al. 2018 [Ref 23]).

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## Harm Reduction

### Testing

2C-I is detectable by:
- **Ehrlich reagent:** Negative (no indole; this distinguishes 2C-I from tryptamines)
- **Marquis reagent:** Reported to produce yellow-to-green color (user-report level; no peer-reviewed confirmation found)
- **Simon's reagent:** Negative (secondary amine test; 2C-I is a primary amine)
- **LC-MS/MS and GC/MS:** Confirmed effective for biological matrix analysis (Drees 2009 [Ref 3]; Theobald 2006 [Ref 16]; Karlsen 2014 [Ref 9])

> ⚠️ **FLAG FOR HUMAN REVIEW:** Colorimetric reagent test results for 2C-I are not confirmed in the peer-reviewed literature. The generation agent should source colorimetric test data from validated reagent testing references or label as community-reported.

### Emergency Response

Dean et al. (2013 [Ref 17]) note: No antidote exists for 2C drug intoxication. Treatment is supportive. For excited delirium presentations:
- Rapid sedation (benzodiazepines typically first-line)
- Aggressive treatment of hyperthermia
- Monitor for rhabdomyolysis, seizure activity, and cardiovascular compromise

### Known Risk Factors

- Pre-existing cerebrovascular conditions (Moyamoya case documented, Drees 2009 [Ref 3])
- Polydrug use (all documented serious cases involve concurrent substances)
- Excited delirium syndrome risk in high-dose intoxication (Dean 2013 [Ref 17])
- Cardiovascular disease (hypertension, vasoconstriction effects)

---

## Tolerance & Dependence

### Tolerance

No 2C-I-specific tolerance data has been published. Class-level inference from serotonergic psychedelics:

**Mechanism (class):** Wallach et al. (2023 [Ref 10]) demonstrated that β-arrestin-biased 5-HT₂A receptor agonists induce receptor **downregulation and tachyphylaxis** in animal models. Classical psychedelics like 2C-I, acting via Gq, also produce tolerance through 5-HT₂A receptor downregulation following repeated activation. This is the mechanistic basis for the rapid tolerance development noted in the seed data.

The seed database values (tolerance buildup: almost immediately after ingestion; half-life ~4 days; full reset ~8.5 days; cross-tolerance: psychedelic class) are consistent with the known class pharmacology but are **not confirmed by 2C-I-specific studies**. These values appear derived from general serotonergic psychedelic tolerance data.

### Dependence

**Not habit-forming** — consistent with the broader psychedelic class. Serotonergic psychedelics do not produce physical dependence or compulsive use patterns in animal models, and epidemiological data consistently shows low addiction liability. The rapid tolerance development is itself a functional deterrent against frequent use. Gil-Martins et al. (2025 [Ref 18]) notes that while conventional wisdom holds psychedelics have low addiction potential, recent reports have raised some concerns about this — however, no published case of 2C-I dependence or withdrawal syndrome has been documented.

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## Interactions

### Tramadol (seed data: "dangerous")

**Mechanism:** Tramadol inhibits serotonin reuptake and norepinephrine reuptake, and is a weak μ-opioid agonist. Combined with a serotonin 5-HT₂A agonist like 2C-I, tramadol's serotonergic activity can precipitate **serotonin syndrome** (hyperthermia, clonus, agitation, diaphoresis, tachycardia, potentially fatal). Additionally, tramadol lowers the seizure threshold, compounding the risk of 2C-I-induced seizures seen in excited delirium cases. The "dangerous" classification in the seed database is pharmacologically well-supported by mechanistic reasoning.

> ⚠️ **FLAG FOR HUMAN REVIEW:** No published case report of 2C-I + tramadol serotonin syndrome interaction was found in the literature search. The interaction severity is supported by class-level serotonergic pharmacology and tramadol's known serotonin toxicity risk, but the "dangerous" rating is mechanistically inferred, not documented in a specific 2C-I + tramadol case.

### Cannabis (seed data: "unknown")

No published data exists on 2C-I + cannabis interactions. The "unknown" classification in the seed database is accurate. This cannot be resolved without empirical data. User-community reports (Erowid, Psychonautwiki) suggest cannabis potentiates psychedelic phenethylamine effects anecdotally, but this is not peer-reviewed.

### General Serotonergic Interactions

Class-level concern: combining serotonergic psychedelics with SSRIs, SNRIs, MAOIs, lithium, or other serotonin-active drugs raises risk of serotonin syndrome. No 2C-I-specific interaction case reports found beyond the tramadol mechanistic concern. MAOIs are particularly dangerous with serotonergic psychedelics — this is well-established for the 5-HT₂A agonist class but not documented specifically for 2C-I.

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## Legal Status

| Jurisdiction | Status | Details |
|---|---|---|
| United States | Schedule I | Synthetic Drug Abuse Prevention Act of 2012 (Public Law 112-144), effective July 9, 2012 [Ref 24] |
| European Union | Banned | EU Council binding order December 2003, mandatory ban within 3 months for all member states |
| United Kingdom | Class A, Schedule 1 | Controlled under the Misuse of Drugs Act; phenethylamine catch-all applies |
| Canada | Schedule III | Controlled Drugs and Substances Act, effective October 31, 2016 |
| Australia | Schedule 9 (Prohibited) | Poisons Standard (October 2015); prohibited except for approved research |
| Germany | Anlage I (BtMG) | Controlled under narcotics law (BtMG); consistent with EU ban |

*Legal status data sources: web-retrieved (Wikipedia, DEA factsheet [Ref 24], government databases). Primary regulatory documents not retrieved via API.*

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## Clinical Trials

**No clinical trials for 2C-I were found on ClinicalTrials.gov.**

The ClinicalTrials.gov search returned only one trial relevant to this search (NCT05523401 — "Acute Effects of 2C-B Compared With MDMA and Psilocybin in Healthy Subjects," completed, Phase 1, University Hospital Basel, Switzerland), which studied 2C-B — a structurally related but distinct compound. 2C-I has no registered trials.

This is consistent with its Schedule I classification in the US (which prohibits most clinical research) and its status as a rarely-studied research chemical in other jurisdictions.

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## Community Feedback Analysis

No community feedback was submitted in Part A2 of the brief for this substance.

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## Gaps & Flags

### Critical Data Absent from Published Literature

1. **Human pharmacokinetics:** No bioavailability, Tmax, half-life, or volume of distribution data published for 2C-I in humans. All metabolism data is rat-only (Theobald 2006 [Ref 16]).

2. **LD50 / toxic dose:** Unknown for any species. The seed data "toxic dose unknown" is accurate.

3. **Precise Ki values (5-HT₂A, 5-HT₂C, other targets):** Web sources report Ki ≈ 0.73 nM at 5-HT₂A, but this was not confirmed via direct API retrieval of a primary binding table. The generation agent should note this and attempt to access full text of Halberstadt & Geyer (2014 [Ref 1]) or Eshleman et al. (2014 [Ref 2]) for confirmed figures.

4. **CYP enzyme involvement:** No published data on which CYP enzymes metabolize 2C-I. Class inference (CYP2D6 plausible based on O-demethylation) is flagged as structural analogy, not substance-specific evidence.

5. **SMILES string:** Not returned by PubChem API; available on PubChem compound page directly. Generation agent should retrieve from PubChem CID 10267191.

6. **Human controlled dosing studies:** None published. All human phenomenology derives from Shulgin's self-experiments, user reports, and clinical case presentations.

7. **Physical properties (melting point, solubility):** Not found in peer-reviewed literature.

### Seed Data Flags

8. **Dose range discrepancy:** Seed database threshold (2 mg), light (5–10 mg), common (10–20 mg) vs Shulgin's PiHKAL range (14–22 mg). The lower end of the seed data is lower than Shulgin documented. No peer-reviewed study to adjudicate. [⚠️ FLAG FOR HUMAN REVIEW]

9. **Tramadol interaction mechanism:** Classified "dangerous" in seed data — pharmacologically well-supported but no 2C-I-specific case report exists. Generation agent should present as well-supported class-level inference. [⚠️ FLAG FOR HUMAN REVIEW]

10. **Ki value verification:** The 5-HT₂A Ki ≈ 0.73 nM figure is sourced from web-retrieved interpretation, not directly API-verified from primary table. [⚠️ FLAG FOR HUMAN REVIEW]

### Structural Analogy Sections

The following sections rely substantially on class-level data rather than 2C-I-specific evidence:
- Tolerance development (rate, half-life, reset time) — inferred from serotonergic psychedelic class
- CYP enzyme involvement — inferred from structural analogy with 2C-B
- Cannabis interaction risk — no data; listed as unknown
- MAOI/SSRI interaction risk — class inference from serotonergic pharmacology
- Physical dependence absence — class inference

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## Source Quality Summary

- **API-verified, primary research:** Refs 1, 2, 3, 4, 6, 7, 8, 9, 10, 16, 19, 20, 21
- **API-verified, review articles:** Refs 5, 11, 12, 13, 17, 18, 22, 23
- **Unverifiable (book):** Ref 14 (PiHKAL — foundational, primary synthesis/self-experiment source)
- **Web-retrieved (government):** Ref 24 (DEA factsheet)
- **Web-retrieved (secondary):** Ref 15 (Wikipedia)

The literature base for 2C-I is sparse. The most important substance-specific papers are:
1. Halberstadt & Geyer 2014 [Ref 1] — in vivo HTR pharmacology
2. Theobald et al. 2006 [Ref 16] — metabolism
3. Drees et al. 2009 [Ref 3] — clinical case report
4. Eshleman et al. 2014 [Ref 2] — in vitro receptor binding panel
5. Dean et al. 2013 [Ref 17] — clinical toxicology review for 2C class