3C-E

# Research Output: 3C-E

## Chemical Identity

**Verified from PubChem (CID 44350137) [Ref N/A — database lookup]:**
- **IUPAC name:** 1-(4-ethoxy-3,5-dimethoxyphenyl)propan-2-amine
- **Molecular formula:** C₁₃H₂₁NO₃
- **Molecular weight:** 239.31 g/mol
- **InChIKey:** AHLXCGRWNKUNTQ-UHFFFAOYSA-N
- **PubChem CID:** 44350137

**From secondary web sources (psychedelicsdaily.com) [Ref 21]:**
- **CAS number:** 146849-92-5
- **SMILES:** CCOc1c(cc(cc1OC)CC(C)N)OC

> **Note on SMILES:** The PubChem API call returned CID, formula, MW, and InChIKey but did not return a SMILES string. The SMILES above was retrieved from a secondary web source and is consistent with the IUPAC name; it should be verified directly via PubChem SID or ChemSpider before committing to the database.

**Structural description:** 3C-E is 1-(4-ethoxy-3,5-dimethoxyphenyl)propan-2-amine — the α-methylated (amphetamine) homolog of escaline (1-(4-ethoxy-3,5-dimethoxyphenyl)ethan-2-amine). It belongs to the 3C sub-family of mescaline analogs, in which the 4-position methoxy group of mescaline is homologated to an ethoxy group, and the aminoethyl chain is extended to a 2-aminopropyl (amphetamine) chain. This distinguishes it from TMA (3,4,5-trimethoxyamphetamine), which retains methoxy at all three positions, and from the 2,5-dimethoxy (DOx/2Cx) series, which carries methoxy groups at positions 2 and 5 rather than 3 and 5.

**Stereochemistry:** 3C-E has a chiral center at the α-carbon of the aminopropyl chain. All published studies and PiHKAL experimentation used racemic mixtures. No published data on isolated enantiomers of 3C-E specifically exist. By analogy with other phenylisopropylamines, the (R) enantiomer is expected to have higher intrinsic activity at the human 5-HT₂A receptor — Parrish et al. (2005 [Ref 20]) demonstrated this pattern across a series of phenylisopropylamine/phenethylamine pairs, with (R) isomers showing higher phospholipase C activation.

**Seed data alignment:**
- Formula, MW, InChIKey: **Confirmed** against PubChem
- PubChem CID: **Confirmed** (44350137, not in brief)
- SMILES: **Not in brief** — obtained from secondary source, requires verification
- CAS: **Not in brief** — 146849-92-5 from secondary source

---

## Pharmacology

### Primary Mechanism

3C-E is a serotonin 5-HT₂A receptor agonist. This is inferred from:

1. **Structural class membership:** 3C-E is an α-methylated mescaline analog (3C series). The mescaline/TMA series is pharmacologically characterized as acting via 5-HT₂A agonism, with no significant monoamine-releasing activity — Matsumoto et al. (2014 [Ref 5]) demonstrated via in vivo microdialysis that TMA (3,4,5-trimethoxyamphetamine), the direct parent scaffold of 3C-E, produces **no detectable changes** in extracellular 5-HT or dopamine levels in rat brain, distinguishing it mechanistically from MDMA and other empathogenic amphetamines.

2. **In vivo behavioral data:** Halberstadt et al. (2019 [Ref 1]) directly tested 3C-E in the mouse head-twitch response (HTR) assay, which is an established 5-HT₂A receptor-mediated behavior. Key findings:
   - 3C-E induced dose-dependent HTR in C57BL/6J mice
   - For the 3,4,5-substituted series (mescaline → TMA), replacing the 4-methoxy with an ethoxy group (mescaline → escaline; TMA → 3C-E) **increased potency** in the HTR assay
   - TMA was approximately twice as potent as mescaline in HTR
   - 3C-E showed higher HTR potency than TMA (consistent with increased lipophilicity of the ethoxy group improving receptor affinity)
   - By contrast, the 2,4,5-regioisomeric series (TMA-2 and its alkoxy analogs MEM and MPM) did **not** show potency increases upon 4-alkoxy homologation, demonstrating distinct SAR between the 3,4,5- and 2,4,5-substituted series

3. **Alpha-methylation potency enhancement:** Parrish et al. (2005 [Ref 20]) demonstrated that phenylisopropylamine analogs (amphetamines) have significantly higher intrinsic activities for 5-HT₂A receptor-mediated phospholipase C activation compared to their phenethylamine counterparts. This directly explains the greater potency of 3C-E versus its parent escaline.

4. **Hallucinogenic potency correlation:** Halberstadt et al. (2020 [Ref 19]) established a strong positive correlation (r = 0.9448) between HTR potency in mice and reported hallucinogenic potency in humans across 36 compounds, supporting the translational relevance of 3C-E's HTR activity as a predictor of human psychedelic effects.

### Receptor Selectivity Profile

**No published in vitro binding affinity data (Ki or EC₅₀) at specific receptors exist specifically for 3C-E.** This is a critical gap.

By structural analogy with the 3,4,5-trimethoxy/alkoxy amphetamine series:
- **5-HT₂A agonism** — primary psychedelic mechanism (demonstrated by HTR data [Ref 1])
- **5-HT₂C agonism** — likely co-present, as is typical for phenethylamine/amphetamine hallucinogens; exact contribution to effects unknown
- **Monoamine transporters (DAT/SERT/NET)** — negligible activity based on TMA microdialysis data [Ref 5]
- **MAO inhibition** — TMA showed no meaningful MAO-A or MAO-B inhibition [Ref 5]; 3C-E expected similar
- **α₂-adrenergic, D₂, TAAR1** — tested for related 2,5-dimethoxy alkoxy series [Ref 2] but not for 3,5-dimethoxy series specifically

**FLAG — Safety critical:** No published Ki/EC₅₀ binding data exist for 3C-E at any receptor. All mechanistic claims rely on class inference from TMA/mescaline data. Generation agent should clearly label this as structural analogy, not direct measurement.

### Pharmacokinetics

**No published human pharmacokinetic data exist for 3C-E.** The following is inferred from structural analogy with TMA and related compounds:

- **Metabolism:** Likely involves hepatic O-demethylation/O-deethylation of the alkoxy groups, catalyzed predominantly by CYP2D6. Ewald & Maurer (2008 [Ref 4]) identified CYP2D6 as the sole isoenzyme responsible for the main metabolic steps of TMA-2 and related 2,5-dimethoxy amphetamine derivatives. A similar pathway is anticipated for 3C-E's methoxy and ethoxy groups, though this is class inference, not direct measurement.
- **CYP2D6 inhibition:** The related DOx/TMA-2 compounds are non-mechanism-based competitive CYP2D6 inhibitors with Ki values of 2.7–19.9 µM in human liver microsomes [Ref 4] — inhibition of CYP2D6 substrates is pharmacologically possible but unlikely at typical doses.
- **Oral bioavailability:** Not published; assumed moderate by class analogy
- **Duration:** 8–12 hours per PiHKAL [Ref 10] (Shulgin's primary report); secondary community sources suggest 8–14 hours

**FLAG:** No pharmacokinetic studies in humans or animals have been published for 3C-E. All PK claims require structural analogy labeling.

---

## History

3C-E was **first synthesized by Alexander Shulgin** and documented as **entry #25 in PiHKAL: A Chemical Love Story** (Shulgin & Shulgin, 1991 [Ref 8, Ref 10]). The compound's conception arises from Shulgin's systematic exploration of the mescaline pharmacophore: escaline (2C-E's mescaline-series phenethylamine analog) extended by α-methylation to the three-carbon amphetamine chain. Shulgin described 3C-E as "Escaline (or E) re-extended again to a 3-carbon chain amphetamine," framing it as a conceptual bridge in his exploration of phenethylamine space.

The "3C" naming convention Shulgin used designates the three-carbon (propan-2-amine) chain, distinguishing these compounds from their phenethylamine (2C-) counterparts. 3C-E is thus the amphetamine homolog of escaline.

The synthesis described in PiHKAL [Ref 10] proceeds via:
1. Ethylation of syringaldehyde (3,5-dimethoxy-4-hydroxybenzaldehyde) to give 3,5-dimethoxy-4-ethoxybenzaldehyde
2. Henry reaction with nitroethane (and ammonium acetate catalyst) to form the corresponding nitrostyrene intermediate
3. Lithium aluminum hydride (LAH) reduction to yield the racemic amine as its hydrochloride salt (white crystalline solid)

There is **no institutional or clinical history** for 3C-E. It was not developed by any pharmaceutical company and has never entered clinical investigation. It emerged as a research chemical in the online market subsequent to PiHKAL's publication. No specific dates of market appearance are documented in the published literature.

**Legal/regulatory history:**
- Germany: Controlled under NpSG (Neue-psychoaktive-Stoffe-Gesetz) effective November 26, 2016 [Ref 22]
- UK: Prohibited under the Psychoactive Substances Act 2016 [Ref 22]
- US: No specific scheduling; potential Federal Analogue Act applicability as a mescaline structural/pharmacological analog [Ref 22]

---

## Subjective Effects

### Primary Source: PiHKAL Entry #25 (Shulgin, 1991) [Ref 10]

Shulgin recorded the following experiential notes (paraphrased from PiHKAL text):

**At 40 mg (oral):**
- Unusual mental state characterized by a strong sense of control but with an underlying quality of unreality
- Effects required moderate sensory input to become apparent
- Experience resolved by hour 8 with minimal residual effects
- Notable: mild teeth clenching (bruxism)

**At 60 mg (oral):**
- Initial phase (first hour): significant body discomfort, pre-nausea sensations, tremor-like feelings
- Progression to strong visual phenomena: "bright colors, distinct shapes — jewel-like" with closed eyes
- Complex fantasy elements and altered perception of reality at peak
- The experience was described as reaching high intensity

**Shulgin's overall assessment:** *"A fascinating compound, but for most subjects a little too heavy on the body."*

This characterization — notable body load relative to visual/cognitive richness — is consistent with the broader class-level finding that mescaline and its analogs are frequently described as producing prominent physical sensations alongside psychedelic effects. The Halberstadt et al. (2019 [Ref 1]) study confirmed that 3C-E is pharmacologically active via 5-HT₂A (HTR assay), consistent with psychedelic-type effects in humans.

### Effect Profile (Community-Based Data)

The seed data's 55 effect slugs are all sourced from `community_consensus_large/medium` provenance with no published primary source. These effects are consistent with the broader serotonergic phenethylamine psychedelic class and align with Shulgin's qualitative reports, but none have been validated in controlled human studies. Key effects consistent with published class pharmacology include:
- **Geometry, visual drifting, color enhancement, internal hallucinations** — consistent with 5-HT₂A agonism
- **Stimulation, wakefulness, muscle tension, bruxism** — consistent with amphetamine scaffold (though not via monoamine release per Ref 5)
- **Body high, spontaneous body sensations, temperature dysregulation** — consistent with PiHKAL body load reports
- **Anxiety, thought loops, confusion** — documented risk at higher doses across serotonergic psychedelic class

### Duration Data

| Source | Onset | Peak | Offset | Aftereffects | Total |
|--------|-------|------|--------|--------------|-------|
| PiHKAL (Shulgin) [Ref 10] | Not stated | — | — | — | 8–12 h |
| Seed data (DB, oral) | 1–2 h | 4–8 h | 3–6 h | 3–6 h | 10–16 h |
| psychedelicsdaily.com [Ref 21] | 30–60 min | — | — | 2–16 h | 8–14 h |

**FLAG — Discrepancy:** The seed data total duration of 10–16 hours exceeds PiHKAL's primary reported range of 8–12 hours. The seed data onset of 1–2 hours appears longer than the 30–60 minutes reported in secondary community sources. The PiHKAL figure (8–12h) represents the only primary source. These values should be reviewed against community experience for accuracy; the DB total duration range may be appropriately conservative or may reflect outlier reports.

No controlled pharmacokinetic studies exist to adjudicate these figures.

---

## Safety & Toxicity

### Toxic Dose / LD₅₀
- **No LD₅₀ data exist for 3C-E in any species.** The toxic dose is unknown.
- No overdose case reports specifically involving 3C-E have been identified in the peer-reviewed literature.
- The seed data note "toxic dose is unknown" — this is confirmed.

### Body Load
The most consistently documented safety concern specific to 3C-E is its significant **body load** — Shulgin's own characterization was that it is "for most subjects a little too heavy on the body" [Ref 10]. This includes pre-nausea sensations, tremors/trembling, and body discomfort at higher doses.

### Class-Level Adverse Effect Profile

No 3C-E-specific adverse event data exist. Based on the broader serotonergic phenethylamine class [Ref 9]:
- **Cardiovascular effects:** Pupil dilation, tachycardia, hypertension, and vasoconstriction are typical adverse sympathomimetic effects of serotonergic psychedelics
- **Hyperthermia:** Risk increases with physical activity and high ambient temperature
- **Seizure risk:** Possible at high doses; documented with related phenethylamine psychedelics
- **Psychological adverse effects:** Acute anxiety, panic, and confusion — dose-dependent
- **HPPD:** Hallucinogen persisting perception disorder has been reported with the broader psychedelic class; generally low prevalence and often self-resolving [Ref 16]

### Toxicological Note
Matsumoto et al. (2014 [Ref 5]) demonstrated that TMA (3,4,5-trimethoxyamphetamine), the direct structural parent of 3C-E, does **not** release 5-HT or dopamine in rat brain and does not significantly inhibit MAO. This distinguishes 3C-E from empathogenic amphetamines (MDMA, PMA) in terms of monoamine toxicity risk profile — the serotonin syndrome risk with 3C-E is expected to arise primarily from 5-HT₂A receptor agonism in combination with serotonergic drugs, rather than from monoamine release or MAO inhibition.

**FLAG — Safety critical:** All toxicity data for 3C-E is inferred from structural analogy with TMA and mescaline class compounds. No 3C-E-specific safety studies exist.

---

## Harm Reduction

### Interactions

**Dangerous interaction — Tramadol [seed data verified]:**
Tramadol is a serotonergic opioid that inhibits the serotonin transporter (SERT) and has been associated with serotonin syndrome risk when combined with serotonergic agents [Ref 7, Ref 13]. The FDA issued a Drug Safety Communication in 2016 specifically linking tramadol to serotonin toxicity risk [Ref 13]. Combining tramadol (SERT inhibitor) with 3C-E (5-HT₂A agonist + potential indirect serotonergic activity) creates a pharmacodynamic interaction risk. The seed data's classification of this interaction as **dangerous** is pharmacologically well-supported [Ref 7].

**Cannabis interaction — Unknown:**
The seed data classifies the cannabis interaction as unknown. No published studies exist on this combination specifically for 3C-E. Anecdotally, cannabis may intensify anxiety and perceptual effects during psychedelic experiences; this interaction is often listed as "caution" for serotonergic psychedelics generally but the pharmacological mechanism is not well characterized. The "unknown" classification is appropriate.

**Other interactions inferred from class:**
- **MAOIs:** Risk of serotonergic effects potentiation; extreme caution advised by class analogy
- **SSRIs/SNRIs:** May reduce psychedelic effects (5-HT₂A downregulation with chronic use); acute combination may increase serotonergic burden
- **Lithium:** Combined with psychedelics, lithium has been associated with seizure risk; classified as dangerous for LSD/proscaline class
- **Stimulants (amphetamines):** May intensify cardiovascular effects
- **CYP2D6 inhibitors (fluoxetine, paroxetine, bupropion):** May prolong effects by inhibiting metabolism [Ref 4] — this is class inference from DOx compounds

### Testing and Identification
- Reagent testing colors for 3C-E: No published reference data identified in the academic literature. Community sources (Erowid, Bunk Police) may have data but were not verified via academic APIs.
- The PeakAL report [Ref 12] acquired 1H NMR spectra of grey-market phenylethanamines including "four para-substituted 3,5-dimethoxyphenylethanamines (mescaline analogues)" which likely includes 3C-E, but the paper is not open-access and specific NMR data for 3C-E was not confirmed.

### Key Harm Reduction Points
- Shulgin's body load warning is a primary harm reduction signal: start significantly below the stated common dose
- Long duration (8–12 h minimum) requires set/setting planning and time safety
- No published antidote or reversal agent; benzodiazepines may be used for acute anxiety/agitation per general psychedelic emergency protocols
- Cross-tolerance with other serotonergic psychedelics means effects will be attenuated if taken within days of LSD, psilocybin, or other phenethylamine psychedelics [Ref 15]

---

## Tolerance & Dependence

### Tolerance
Cross-tolerance among serotonergic psychedelics is well documented and is mediated by 5-HT₂A receptor downregulation in frontal cortex. de la Fuente Revenga et al. (2022 [Ref 15]) demonstrated using the DOI/LSD HTR model that:
- Tolerance to HTR develops as rapidly as 24 hours after a single administration
- Cross-tolerance occurs between different psychedelic 5-HT₂A agonists (DOI and LSD)
- Non-psychedelic 5-HT₂A agonists (lisuride) do not produce cross-tolerance with psychedelics
- Mechanism is 5-HT₂A receptor activation-dependent and independent of β-arrestin-2

The seed data states tolerance builds "almost immediately after ingestion," with half-life of 3 days and full reset at 7 days, with cross-tolerance to the psychedelic class. These figures are **consistent with published data** for the psychedelic class [Ref 15] and align with general understanding of serotonergic psychedelic tolerance, though they have not been verified specifically for 3C-E.

Earlier work (Buckholtz et al. 1990 [Ref cited in Ref 15]) showed 5-HT₂ receptor downregulation with repeated LSD administration, though mescaline (10 mg/kg × 5–10 days) did not produce the same downregulation. This is noteworthy: mescaline may have a different tolerance profile than the indole hallucinogens. Whether 3C-E (a mescaline homolog with amphetamine chain) shares mescaline's profile or more resembles DOI/LSD in this regard is unknown — **FLAG for editorial review.**

### Dependence
The seed data states 3C-E is "not habit-forming." This is consistent with the class: serotonergic psychedelics generally have very low dependence liability, are not positively reinforcing in animal models, and rapid tolerance development limits compulsive use. No 3C-E-specific dependence data exist.

---

## Legal Status

| Jurisdiction | Status | Notes |
|---|---|---|
| United States | Not specifically scheduled | Potential Schedule I analog under Federal Analogue Act (mescaline analog); mescaline is Schedule I. FAA requires proof of intent for human consumption to prosecute [Ref 22] |
| United Kingdom | Illegal | Prohibited under Psychoactive Substances Act 2016 (blanket ban on psychoactive substances not otherwise exempted) [Ref 22] |
| Germany | Controlled | Scheduled under Neue-psychoaktive-Stoffe-Gesetz (NpSG) effective November 26, 2016. Possession is illegal but not penalized; production, import, distribution, and administration are criminal offenses [Ref 22] |
| Australia | Unconfirmed for 3C-E specifically | Mescaline is Schedule 9 (Prohibited Substance) under the Poisons Standard; 3C-E as a close analog would likely fall under analog provisions, but this could not be confirmed via available sources |
| Canada | Unconfirmed for 3C-E specifically | Mescaline is Schedule III under the Controlled Drugs and Substances Act (CDSA); analog status of 3C-E not confirmed |
| Sweden | Likely controlled | Country with broad NPS scheduling; specific date/instrument not confirmed |

**FLAG:** Australia and Canada scheduling for 3C-E specifically could not be confirmed in the published literature or accessible legal databases. The generation agent should note these as unconfirmed and recommend verification.

---

## Clinical Trials

No clinical trials for 3C-E have been registered on ClinicalTrials.gov or any other database. A search returned zero results [Step 9].

No clinical trials for mescaline analogs of the 3C series appear in any registry.

---

## Community Feedback Analysis

**No community feedback was submitted.** (Brief Part A2 is empty.)

---

## Gaps & Flags

### Critical Gaps

1. **No in vitro receptor binding data (Ki/EC₅₀) for 3C-E** at any receptor target. All receptor pharmacology claims require explicit labeling as "class inference from TMA/mescaline analogs."

2. **No human pharmacokinetic data** — no bioavailability, Tmax, half-life, volume of distribution, or clearance data. CYP enzyme involvement is inferred by analogy with DOx/TMA-2 compounds.

3. **No LD₅₀ or human toxicology data** — toxic dose is genuinely unknown. No case reports of overdose or serious adverse events specifically involving 3C-E in the peer-reviewed literature.

4. **SMILES not confirmed via PubChem API** — obtained from secondary web source; requires verification against PubChem SID or ChemSpider.

5. **CAS number (146849-92-5) not confirmed via PubChem CAS lookup** — retrieved from secondary source only.

### Safety-Critical Flags

6. **Dose range discrepancy [FLAG FOR REVIEW]:**
   - PiHKAL primary source: 30–60 mg oral
   - Seed data (DB): common 40–60 mg; strong 60–80 mg; heavy 80+ mg; threshold 20 mg
   - psychedelicsdaily.com: threshold 15–25 mg; common 35–50 mg; strong 50–70 mg+
   - The seed data's "heavy" dose category (80+ mg) **exceeds PiHKAL's stated maximum (60 mg)** with no documented source for this range. Given Shulgin's warning about body load at 60 mg, the 80+ mg "heavy" categorization is potentially dangerous if it normalizes very high doses. **Recommend editorial review and conservative curation.**

7. **Duration discrepancy [FLAG FOR REVIEW]:**
   - PiHKAL: 8–12 hours (primary source)
   - Seed data: 10–16 hours total (oral)
   - psychedelicsdaily.com: 8–14 hours total; onset 30–60 minutes (vs. seed data's 1–2 hours)
   - The upper bound of 16 hours in seed data exceeds all documented primary sources. The onset range (1–2 h in seed data vs. 30–60 min in secondary sources) is worth verifying.

8. **Primary ROA listed as "insufflated" [FLAG FOR REVIEW]:**
   - PiHKAL exclusively documents oral administration for 3C-E
   - No published data on intranasal bioavailability, onset, or dosing for 3C-E
   - The insufflated ROA and its dose/duration data (threshold 15 mg, common 35–60 mg, onset 5–90 min) appear to be derived from community experience without published backing
   - Listing insufflated as the *primary* ROA is unusual and requires editorial justification; oral should likely be primary

9. **Mescaline tolerance vs. indole psychedelic tolerance [FLAG FOR REVIEW]:**
   - Buckholtz et al. (1990) found mescaline did not produce 5-HT₂ downregulation with repeated use, unlike LSD
   - Whether the 7-day full reset tolerance schedule (seed data) applies specifically to 3C-E or is derived from indole psychedelic tolerance norms is unclear
   - No specific tolerance data for 3C-E exist

10. **Australia and Canada legal status unconfirmed** for 3C-E specifically.

11. **No published stereochemical analysis** of 3C-E enantiomers — all reported use involves racemates.

12. **No analytical forensic data** (GC-MS, HPLC, reagent test colors) confirmed for 3C-E in peer-reviewed publications.