2C-C

# Research Output: 2C-C

## Chemical Identity

**Verified against PubChem CID 29979100 [Ref 11 — PiHKAL; also PubChem API]:**

| Property | Value |
|---|---|
| Preferred IUPAC Name | 2-(4-chloro-2,5-dimethoxyphenyl)ethanamine |
| Common/systematic name | 2,5-Dimethoxy-4-chlorophenethylamine |
| Molecular formula | C₁₀H₁₄ClNO₂ |
| Molecular weight | 215.67 g/mol |
| PubChem CID | 29979100 |
| InChIKey | CGKQFIWIPSIVAS-UHFFFAOYSA-N |
| SMILES | COc1cc(CCN)c(OC)cc1Cl |
| CAS (free base) | 88441-14-9 |
| CAS (HCl salt) | 88441-15-0 |
| HCl salt melting point | 220–222 °C (from PiHKAL synthesis) [Ref 14] |

**Discrepancies with brief seed data:**  
- Brief lists no SMILES, CAS, molecular formula, or PubChem CID — all now confirmed via PubChem API and cross-referenced via web sources.
- No discrepancy in formula or MW between brief and published data; brief was simply incomplete.

**Structure notes:** 2C-C is a member of the 2C-family: 2,5-dimethoxyphenethylamines with a 4-position substituent. In 2C-C, the 4-position substituent is chlorine. This places it structurally between the unsubstituted 2C-H and the more potent bromo (2C-B) and iodo (2C-I) analogs. The chlorine atom is a smaller halogen than bromine or iodine, which is relevant to receptor binding affinity (see Pharmacology).

---

## Pharmacology

### Primary Mechanism of Action

2C-C is a **5-HT₂A and 5-HT₂C receptor agonist**, the primary mechanism shared by all 2C-class phenethylamine hallucinogens. The 5-HT₂A receptor in the prefrontal cortex is the key mediator of psychedelic effects. Activation of 5-HT₂A receptors in layer V pyramidal cells of the neocortex induces enhanced asynchronous glutamatergic EPSP release, which is proposed to underlie perceptual distortions and hallucinogenic effects (Aghajanian and Marek 1997 [Ref 26]; Aghajanian and Marek 1999 [Ref 19]).

The Gq-coupled (phospholipase C/IP₃) signaling arm of 5-HT₂A — rather than β-arrestin2 recruitment — is associated with psychedelic potential as measured by head-twitch response in mice (Wallach et al. 2023 [Ref 20]). Phenethylamine-type hallucinogens like 2C-C are generally full or partial agonists preferentially activating the Gq pathway.

### Receptor Binding Data

Eshleman et al. (2014) [Ref 3] is the only published study directly reporting in vitro receptor binding data for 2C-C specifically, in a comparative panel with 2C-D, 2C-E, 2C-I, 2C-T-2, and DOC. The paper establishes Ki/EC₅₀ values at monoamine transporters (DAT, NET, SERT) and receptor types. Full numerical Ki values are not available in the abstract; the complete data table appears only in the full text. Key findings from the abstract: 2C-C is among the six phenethylamines characterized for behavioral pharmacology (mouse locomotion, rat drug discrimination) and in vitro transporter/receptor binding, confirming activity at 5-HT₂A/₂C targets.

**⚠️ FLAG for human review:** Full-text Ki values (numerical nM affinities) at 5-HT₂A and 5-HT₂C for 2C-C from Eshleman et al. 2014 [Ref 3] were not accessible via the API abstracts. The generation agent should note these values exist in the primary literature but cannot be cited with specific numbers without full-text access.

**Comparative receptor data from related compounds (class-level context):**
- Rickli et al. (2015) [Ref 4] characterized 2C-B and other 2C analogs alongside NBOMe derivatives at 5-HT₂A, adrenergic, dopaminergic, and monoamine transporter sites. NBOMe compounds showed higher 5-HT₂A binding affinity than corresponding 2C analogs, but 2C analogs were stronger in functional (calcium mobilization) assays.
- Elmore et al. (2018) [Ref 2] confirmed that 2C-C at 0.1–3.0 mg/kg (sc, rats) induced 5-HT₂A-mediated behaviors (wet dog shakes, back muscle contractions), fully blocked by the selective 5-HT₂A antagonist M100907. 25C-NBOMe (the N-benzyl analog of 2C-C) was substantially more potent than 2C-C in vivo, consistent with higher 5-HT₂A binding affinity.
- Ray (2010) [Ref 15] profiled 25 psychedelics at 51 receptors using NIMH-PDSP; 2C-C was **not** among the 25 compounds studied. Related 2C compounds (2C-B, 2C-E) were studied, showing 5-HT₂A/₂C as primary targets with secondary activity at adrenergic and dopaminergic sites.

**Structure-activity context for chloro vs. bromo/iodo:**  
Among 2C halogenated analogs, halogen size at the 4-position is correlated with 5-HT₂A affinity and potency: iodo > bromo > chloro. 2C-C (chloro) is therefore expected to have lower 5-HT₂A binding affinity and in vivo potency than 2C-B or 2C-I (Nichols 2018 [Ref 17]). This is consistent with Shulgin's observation that 2C-C requires a higher dose range (20–40 mg) than 2C-B (~15–25 mg) for equivalent effects (PiHKAL entry #22 [Ref 14]).

### Dopaminergic Involvement

Kim et al. (2021) [Ref 1] demonstrated that high-dose 2C-C in rodents affected D1 receptor, D2 receptor, and dopamine transporter (DAT/phospho-DAT) expression in the nucleus accumbens and medial prefrontal cortex. c-Fos immunopositive cells were increased in the nucleus accumbens. This suggests dopaminergic signaling involvement beyond primary serotonergic action, potentially contributing to abuse potential and stimulant properties.

### Pharmacokinetics

**No published human pharmacokinetic study exists for 2C-C specifically.** The following is inferred from class pharmacology:

- **Route:** Oral (primary). IV administration documented in PiHKAL (20 mg IV, "overwhelming" effects with peak at ~5 min) [Ref 14]. Oral onset 20–45 min.
- **Metabolism:** No published CYP enzyme data specific to 2C-C. Based on structural analogy with 2C-B (the most studied 2C analog), primary metabolic routes likely include O-demethylation at 2- and/or 5-methoxy positions and oxidative deamination via MAO. The methoxy groups are susceptible to O-demethylation by CYP2D6 and CYP3A4 (class inference).
- **As metabolite:** 2C-C appears as a metabolite of 25C-NBOMe via N-dealkylation (N-debenzylation) in human liver microsomes (Temporal et al. 2017 [Ref 25]). 2C-C was detected in blood (0.12 ng/mL) and urine (0.38 ng/mL) in a 25C-NBOMe fatality case (Kristofic et al. 2016 [Ref 7]).
- **Duration:** Total duration 4–8 hours (oral); peak 2–3 hours (community consensus/PsychonautWiki [Ref 28], consistent with PiHKAL [Ref 14]).
- **Half-life:** No published data.

⚠️ **FLAG:** No published human pharmacokinetic data (Tmax, Cmax, half-life, bioavailability, CYP involvement) for 2C-C exists. All PK statements are based on structural analogy with 2C-B or class inference.

---

## History

### Discovery and Synthesis

2C-C was first synthesized and characterized by **Alexander Shulgin**, an American pharmacologist and chemist. It is described as **entry #22** in *PiHKAL: A Chemical Love Story* (Shulgin and Shulgin, 1991) [Ref 11, Ref 14], under the chemical name 4-chloro-2,5-dimethoxy-PEA. The book documents Shulgin's synthesis of over 179 phenethylamine derivatives and constitutes the primary historical record for 2C-C.

**Synthesis routes** described in PiHKAL entry #22:
1. **Primary route:** Direct chlorination of 2,5-dimethoxyphenethylamine using liquid chlorine in glacial acetic acid at 0°C; crystallized as the HCl salt (mp 220–222°C).
2. **Alternative route:** Starting from 2C-B via phthalimide protection, cuprous chloride substitution, and hydrazine deprotection.

The synthesis of the 2C-family began in the 1970s–1980s. Shulgin first reported on related compounds in the literature earlier, but the comprehensive PiHKAL monograph published in 1991 is the canonical primary source. 2C-C has "only a short history of human use" and "is uncommon" compared to more popular 2C analogs (2C-B, 2C-I, 2C-E) [Erowid, based on PiHKAL].

### Market History

2C-C appeared in research chemical markets in the late 1990s–2000s alongside other 2C analogs. It has circulated as a research chemical but has never achieved the popularity of 2C-B or 2C-I. Its relative obscurity may relate to the inconvenience of liquid chlorine in synthesis compared to bromine/iodine (Shulgin's own observation [Ref 14]) and to lower potency compared to larger halogen analogs.

### Clinical/Institutional History

No clinical trials, therapeutic research, or institutional human studies have been conducted with 2C-C. No investigational new drug (IND) status identified.

---

## Subjective Effects

### Published Descriptions

**PiHKAL entry #22 (Shulgin and Shulgin 1991 [Ref 14])** is the primary source for subjective effects. Key findings:

- **Onset:** Longer latency than 2C-B — approximately **1.5–2 hours**. The seed data lists 20–45 min onset, but the come-up phase (45–90 min) accounts for this; Shulgin's "slower to come on" observation is consistent with the combined onset + come-up data.
- **Duration:** 4–8 hours.
- **Character:** Visual phenomena at higher doses; **less stimulating than 2C-B**. One subject described the experience as "a very intense form of relaxation," in contrast to the stimulatory profile of 2C-B.
- **At 20 mg IV:** "Overwhelming" effects with peak at ~5 minutes, consistent with rapid CNS entry via parenteral route.
- **General character:** Described as quieter, less intense, and more sedating relative to other 2C analogs at equivalent doses.

### Effect Domains from Literature and Community Consensus

Published data (primarily rodent studies and the PiHKAL account) supports the following effect domains, which are broadly consistent with the 5-HT₂A agonist mechanism:

**Perceptual:** Visual phenomena including distortions, color enhancement, patterning; auditory enhancement (class-level, by 5-HT₂A mechanism).

**Cognitive:** Enhanced introspection and pattern recognition (class-level); Shulgin reports note cognitive effects.

**Somatic:** Less stimulation than 2C-B suggests a relatively lower sympathomimetic burden; however, class-level effects include pupil dilation, elevated heart rate, and elevated blood pressure (consistent with 5-HT₂A and adrenergic activity).

**Entactogenic:** Shulgin's notes and community reports suggest mild empathy and emotional warmth enhancement, though 2C-C is considered less entactogenic than MDMA or 2C-B.

### Duration Data Verification

The seed data duration is confirmed by both Shulgin (PiHKAL [Ref 14]) and community consensus (PsychonautWiki [Ref 28]):
- Onset: 20–45 min (oral) — consistent
- Come up: 45–90 min (oral) — consistent with Shulgin's "1.5–2 h before effects fully manifest"
- Peak: 2–3 hours
- Offset: 1–3 hours  
- Total: 4–8 hours

These values appear reliable. No published controlled study contradicts them.

---

## Safety & Toxicity

### Human Toxicity

**LD₅₀ is unknown** — no published data for humans or animals. The brief correctly notes "toxic dose is unknown." [Ref 1, Ref 6]

**No published case reports describe 2C-C as the sole causative agent in a serious adverse event or death.** The only case identifying 2C-C in a human fatality (Kristofic et al. 2016 [Ref 7]) was a 25C-NBOMe death in which 2C-C was detected at low concentrations (0.12 ng/mL blood) as a likely metabolite of 25C-NBOMe, not as the primary toxic agent.

### Rodent Toxicity and Neurotoxicity

Kim et al. (2021) [Ref 1] documented high-dose neurotoxicity in rodents:
- Decreased locomotor activity and motor coordination (rota-rod)
- Impaired memory (Y-maze, novel object recognition, passive avoidance)
- Microglial activation (neuroinflammation) in striatum
- Dopamine receptor and DAT expression changes in nucleus accumbens and mPFC

The doses used in Kim et al. to produce neurotoxicity are described as "high doses" — the specific mg/kg values are not stated in the available abstract. The generation agent should flag that rodent neurotoxicity threshold doses are not extracted and that extrapolation to human doses requires caution.

### Class-Level Clinical Toxicology

Dean et al. (2013) [Ref 6] reviewed 2C drug intoxication reports (not 2C-C specific) and identified:
- Common adverse effects: hallucinations, agitation, aggression, dysphoria, hypertension, tachycardia, seizures, hyperthermia
- At least **five deaths** reported in the 2C class literature
- Presentations consistent with **serotonin toxicity** or **sympathomimetic toxidrome**
- Excited delirium was the consistent finding among 2C-related fatalities
- Treatment: primarily supportive; urgent intervention for excited delirium, hyperthermia, and seizures

Gil-Martins et al. (2025) [Ref 5] comprehensively reviewed 2C and NBOMe drug toxicodynamics, including cardiovascular complications (hypertension, arrhythmia) and neurotoxicity, consistent with 5-HT₂A activation and sympathomimetic effects.

Luethi and Liechti (2020) [Ref 8] note that designer drugs including serotonergic phenethylamines may produce undetected intoxications in routine toxicology due to non-standard screening targets.

### Cardiovascular

Sympathomimetic effects are expected via 5-HT₂A-mediated vasoconstrictive and adrenergic activation. Published 2C-B human data (Papaseit et al. 2018 [Ref 16]) confirmed increased blood pressure and heart rate after 10–20 mg oral doses. 2C-C is expected to produce similar cardiovascular effects at the relatively higher doses needed.

---

## Harm Reduction

### Testing and Identification

Validated forensic LC-MS/MS detection method (Kerrigan et al. 2014 [Ref 21]) achieves LOD 0.5 ng/mL in urine, linear range 0.5–100 ng/mL. Reagent-based colorimetric tests (e.g., Marquis, Mecke) are commonly used for field identification of 2C compounds — these are not specific to 2C-C but can indicate the 2C-class.

### Contraindications and Combinations

- **Tramadol: dangerous** (seed data interaction, confirmed by brief). Mechanism: tramadol is a serotonin and norepinephrine reuptake inhibitor with mu-opioid agonist activity; coadministration with a 5-HT₂A agonist significantly elevates serotonin syndrome risk (Mason & Blackburn 1997 [Ref 30]; Roulet et al. 2021). 5-HT₂A agonism combined with tramadol's serotonin reuptake inhibition creates a dual serotonergic burden. ⚠️ **FLAG:** The specific mechanism of 2C-C + tramadol danger has not been tested in a published study — the interaction is inferred from tramadol's known serotonergic mechanism and class-level 5-HT₂A agonist risk.
- **Cannabis: unknown** (seed data interaction). Cannabis (THC) modulates serotonergic and dopaminergic tone; potential for enhanced psychological distress or psychosis has been suggested in community reports but is unstudied for 2C-C specifically.
- **MAOIs:** Class-level contraindication for 5-HT₂A agonists — MAOI coadministration could cause serotonin syndrome and dangerously amplify psychedelic effects. Not in seed data but should be flagged.
- **SSRIs/SNRIs:** May reduce or alter psychedelic effects via 5-HT₂A receptor downregulation; serotonin syndrome risk at high doses (class-level).
- **Stimulants:** Combined cardiovascular stress (hypertension, tachycardia) from additive sympathomimetic effects.
- **Lithium:** Class-level contraindication (seizure risk reported with phenethylamine hallucinogens and lithium).

### Emergency Response

Based on class-level data (Dean et al. 2013 [Ref 6]):
- Supportive care is primary
- Urgent management of hyperthermia, seizures, and excited delirium
- Benzodiazepines for agitation
- Avoid physical restraint in excited delirium without sedation
- 5-HT₂A antagonists (e.g., cyproheptadine) may be considered for serotonin toxicity

---

## Tolerance & Dependence

### Tolerance Mechanism

Tolerance to 5-HT₂A agonist-mediated behavioral effects (head-twitch response in rodents) develops rapidly — within 24 hours of a single dose and progressively with repeated dosing. Mechanism involves **5-HT₂A receptor downregulation** in frontal cortex. This tolerance is:
- Blocked by 5-HT₂A antagonist pretreatment (de la Fuente Revenga et al. 2022 [Ref 9])
- Independent of β-arrestin2 (de la Fuente Revenga et al. 2022 [Ref 9])

### Cross-Tolerance

Cross-tolerance exists between 5-HT₂A agonist psychedelics. Smith et al. (2014) [Ref 10] showed that phenethylamine hallucinogens (DOI, 2C-T-7) develop insurmountable cross-tolerance, including cross-tolerance to tryptamines. Phenethylamine-derived hallucinogens develop tolerance more rapidly than tryptamine-derived ones — a clinically relevant distinction suggesting 2C-class drugs (including 2C-C) have greater tolerance liability than psilocybin or DMT.

### Abuse Potential and Dependence

Kim et al. (2021) [Ref 1] demonstrated that 2C-C produced:
- **Conditioned place preference** (dose-dependent) in mice — indicator of reward/reinforcing properties
- **Increased self-administration** in rats — stronger indicator of abuse potential

This is a significant finding: despite the conventional characterization of psychedelics as having low abuse potential, 2C-C showed preclinical abuse signals in rodents. Gil-Martins et al. (2025) [Ref 5] also examined abuse potential across 2C and NBOMe drugs.

**However**, the seed data characterizes 2C-C as "not habit-forming" under dependence formation. This characterization is based on the broader class consensus for serotonergic psychedelics. The Kim et al. (2021) rodent data represents an important **FLAG** for the generation agent: there is a discrepancy between the conventional "low abuse potential" framing and published rodent self-administration data. The generation agent should present this nuance.

No physical withdrawal syndrome has been documented for 2C-C or the 2C class.

---

## Interactions

### Tramadol (Dangerous)
Tramadol inhibits serotonin and norepinephrine reuptake and has weak mu-opioid agonism. Combined with a 5-HT₂A agonist, the risk of serotonin syndrome is substantially elevated. Tramadol itself can cause serotonin syndrome when combined with other serotonergic drugs (Mason & Blackburn 1997 [Ref 30]). The "dangerous" classification in the seed data is pharmacologically sound. Specific combined human data does not exist for 2C-C + tramadol specifically. ⚠️ **FLAG:** Safety-critical value based on class-level pharmacology, not 2C-C-specific published data.

### Cannabis (Unknown)
No published interaction data for 2C-C + cannabis. Cannabis has complex effects on serotonergic tone via CB1 receptors. Interaction unpredictability warrants caution label. ⚠️ **FLAG:** No supporting published data.

### MAOIs (Class-Level Contraindication — Not in Seed Data)
All 5-HT₂A agonists carry a class-level contraindication with MAO inhibitors. The generation agent should consider adding this interaction.

### SSRIs and Antidepressants
Chronic SSRI/SNRI use downregulates 5-HT₂A receptors and may blunt psychedelic effects; acute high-dose combinations raise serotonin syndrome risk. Class-level only; no 2C-C-specific data.

### Lithium
Lithium carbonate combined with serotonergic psychedelics has been associated with seizure risk in case reports (class-level warning from community harm reduction resources). No 2C-C-specific data.

---

## Legal Status

| Jurisdiction | Status | Notes |
|---|---|---|
| **United States** | Schedule I | Food and Drug Administration Safety and Innovation Act (FSSIA), July 2012. Explicitly controls 2C-C and other named 2C compounds. Federal Analogue Act may also apply pre-2012. |
| **United Kingdom** | Class A | Misuse of Drugs Act 1971, as amended in 2002 with catch-all provisions covering 2,5-dimethoxyphenethylamine derivatives. |
| **Canada** | Schedule III | Controlled Drugs and Substances Act, Schedule III item 35, catch-all for 2C-phenethylamines (1-amino-2-phenylethane structure with 2' and 5' alkoxy groups). |
| **Sweden** | Health hazard | Classified as "health hazard" under the Act on Prohibition of Certain Goods Dangerous to Health since March 1, 2005. Sale and possession illegal. |
| **China** | Controlled | Government decree on psychoactive substances, October 2015. |
| **Australia** | Likely Schedule 9 | Not confirmed in searches. 2C-I is confirmed Schedule 9 (TGA Poisons Standard); 2C-C likely falls under same classification by class but specific listing was not confirmed. ⚠️ **FLAG for verification.** |
| **European Union** | Varies by country | No unified EU-wide control. Individual member state scheduling applies. |
| **UN Conventions** | Not scheduled | Not specifically listed under 1971 Convention on Psychotropic Substances. |

---

## Clinical Trials

**No clinical trials found.** Search of ClinicalTrials.gov for "2C-C phenethylamine psychedelic" returned zero results. No registered trials, no completed trials, no investigational status.

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## Community Feedback Analysis

**No community feedback submitted** (Part A2 of brief is empty).

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## Gaps & Flags

### Safety-Critical Values Not Verified Against Published Sources

1. **⚠️ Tramadol interaction (dangerous):** Pharmacologically sound but no 2C-C + tramadol-specific human or animal study exists. Based on tramadol's serotonergic mechanism and class-level 5-HT₂A agonist risk.

2. **⚠️ Strong/Heavy dose ranges (50–90 mg, 90+ mg):** Shulgin's PiHKAL reports doses up to ~50 mg. Ranges above 50 mg (Strong: 50–90 mg; Heavy: 90+ mg) originate from community consensus (PsychonautWiki), not published clinical data. These are plausible given pharmacology but cannot be verified against a primary source. Flag for editorial review.

3. **⚠️ Australia Schedule 9 status:** Listed as likely Schedule 9 based on class extrapolation from 2C-I; could not confirm 2C-C's explicit listing in the TGA Poisons Standard during this research session.

4. **⚠️ Specific 5-HT₂A/₂C Ki values for 2C-C:** Eshleman et al. (2014) contains these values in the primary text, but the numerical Ki values (in nM) are not available via abstract retrieval. The generation agent should note that Ki data exists in the primary literature but specific numbers cannot be cited without full-text confirmation. Do not use fabricated values.

5. **⚠️ High-dose neurotoxicity thresholds in rodents:** Kim et al. (2021) demonstrates neurotoxicity at "high doses" in rodents, but specific mg/kg thresholds producing neurotoxicity are not provided in the available abstract. Human relevance is uncertain.

### Data Gaps (No Published Data)

- **Human pharmacokinetics:** No Tmax, Cmax, half-life, bioavailability, or CYP metabolism data for 2C-C in humans.
- **LD₅₀:** Not determined for any species.
- **Controlled human study:** No published controlled dosing or clinical study with human subjects for 2C-C.
- **Stereochemistry:** 2C-C has no chiral center; it is a single achiral compound. No active isomer considerations.
- **Physical chemistry details:** Melting point of HCl salt (220–222°C) confirmed from PiHKAL. Solubility, pKa, log P, stability data not found in published literature.
- **CYP enzyme identification:** No published data on which CYP enzymes metabolize 2C-C.
- **MAO as metabolic pathway:** Assumed from class structure but no 2C-C-specific metabolic studies found.
- **Cannabis interaction:** No data; unknown.
- **2C-C-specific MAOI contraindication study:** None; inferred from class mechanism.
- **Therapeutic index:** Unknown.

### Contradictions Between Sources

1. **Abuse potential framing vs. rodent self-administration data:** Seed data characterizes 2C-C as "not habit-forming." Kim et al. (2021) [Ref 1] found conditioned place preference and self-administration in rodents, indicating abuse potential. These are not mutually exclusive (rodent models differ from human harm potential), but the generation agent should present this nuance rather than resolving it as a simple yes/no.

2. **Dose range: Shulgin vs. community consensus:** PiHKAL entry #22 documents 20–40 mg as the dose range with some reports up to 50 mg. The community-consensus dose structure extends to 90+ mg (Heavy). The "light" range (15–30 mg) in the community data is lower than Shulgin's minimum of 20 mg, and the "strong/heavy" ranges exceed Shulgin's reported maximum. The common range (30–50 mg) is well-supported by PiHKAL. Higher ranges lack primary-source verification.

### Areas Relying on Structural Analogy

- All pharmacokinetic claims (metabolism, CYP involvement, half-life) are based on structural analogy to 2C-B
- MAOI and lithium contraindications are class-level inferences
- Australia legal status is inferred from class scheduling of related 2C compounds
- Cardiovascular risk magnitude is estimated from 2C-B human study (Papaseit et al. 2018)