Escaline

# Research Output: Escaline

## Chemical Identity

**PubChem CID:** 38240  
**CAS Number:** 39201-82-6  
**FDA UNII:** Q13F1C1N8I  
**Molecular Formula:** C₁₂H₁₉NO₃  
**Molecular Weight:** 225.28 g/mol  
**IUPAC Name:** 2-(4-ethoxy-3,5-dimethoxyphenyl)ethanamine  
**Systematic Name:** 3,5-dimethoxy-4-ethoxyphenethylamine  
**SMILES:** CCOc1c(OC)cc(CCN)cc1OC  
**InChIKey:** RHOGRSKNWDNCDN-UHFFFAOYSA-N  
**Melting Point (HCl salt):** 165–166 °C (confirmed by two independent synthesis routes in PiHKAL [Ref 6])

**Stereochemistry:** Achiral molecule; no defined stereocenters. No active isomers — escaline exists as a single molecular entity [Ref 12].

**Structural Relationship:** Escaline is the 4-ethoxy homologue of mescaline (3,4,5-trimethoxyphenethylamine), differing by substitution of the 4-methoxy group with an ethoxy group. It is also the phenethylamine (non-α-methyl) analogue of 3C-E (4-ethoxy-3,5-dimethoxyamphetamine).

**Verification of Seed Data:**  
All chemical identity fields in the brief's seed data are confirmed against PubChem CID 38240. The brief lists no SMILES, formula, weight, or InChIKey — these are now verified and provided above. The systematic name in the brief (2-(4-ethoxy-3,5-dimethoxyphenyl)ethanamine) is consistent with the IUPAC name above.

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## Pharmacology

### Primary Mechanism of Action

Escaline is a serotonin 5-HT₂A receptor agonist. Its psychedelic effects are mediated primarily through agonism at the serotonin 5-HT₂A receptor, consistent with all phenethylamine-class hallucinogens [Ref 3] [Ref 15]. This mechanism is confirmed by class studies demonstrating that the 5-HT₂A antagonist ketanserin substantially attenuates the psychedelic effects of mescaline (the closest well-studied structural analog) in controlled human trials (Klaiber et al. 2024 [Ref 21]).

### Receptor Binding Affinities

**5-HT₂A receptor (primary target):**  
- Ki = 216 nM (Blaazer et al. 2008 [Ref 9], cited in NCATS Inxight Drugs [Ref 12])  
- This represents roughly 43-fold higher affinity than mescaline (Ki ~9,400 nM at 5-HT₂A; Kolaczynska et al. 2021 [Ref 8]), consistent with the known potency-enhancing effect of extending the 4-methoxy group to a 4-ethoxy group.

**5-HT₂C receptor:**  
- EC50 = 2.0 µM (from 1997 data cited in NCATS [Ref 12], consistent with Monte et al. 1997 [Ref 4])  
- Escaline shows no selectivity preference between 5-HT₂A and 5-HT₂C, consistent with other scalines (Kolaczynska et al. 2021 [Ref 8]).

**Other receptors:**  
- Agonist activity reported at 5-HT₁A, 5-HT₁B, 5-HT₁D, 5-HT₂B receptors (from secondary sources; no primary binding Ki values retrieved for these targets).  
- Scaline-class compounds show no potent affinity at dopaminergic D₂ receptors (Ki > 6,300 nM) or monoamine transporters (Ki > 7,500 nM) (Kolaczynska et al. 2021 [Ref 8]).  
- No TAAR1 activity reported for escaline specifically; related scalines show weak to absent rat TAAR1 activity.

### Structure–Activity Relationship Context

Nichols & Dyer (1977) [Ref 14] demonstrated in a sheep umbilical artery serotonin receptor preparation that replacing the 4-methoxy group of mescaline with higher alkyl homologues (including ethoxy = escaline, propoxy = proscaline) increases serotonin receptor agonist activity. Activity correlated with lipophilicity (measured by 1-octanol–water partition coefficients) and drops off when the 4-substituent reaches approximately five atoms in length.

Kolaczynska et al. (2021) [Ref 8] confirmed that extending the 4-alkoxy substituent from methoxy to ethoxy increases both 5-HT₂A and 5-HT₂C binding affinities and enhances activation potency and efficacy at the 5-HT₂A receptor. Fluorination of the 4-alkoxy group further amplifies this effect (Trachsel 2012 [Ref 2]).

Halberstadt et al. (2019) [Ref 1] confirmed that in the murine head twitch response (HTR) assay — a validated behavioral model of 5-HT₂A-mediated psychedelic activity — escaline produced HTR with greater potency than mescaline, and that potency relationships closely parallel human hallucinogenic data. (Specific ED50 values for escaline in the HTR are reported in the paper but were not accessible in abstract data; full text review needed.)

Escaline has been reported to partially substitute for LSD in rodent drug discrimination tests [Ref 7], consistent with shared 5-HT₂A agonist mechanism.

**Potency relative to mescaline:** Escaline is reported to be approximately 5–8× more potent than mescaline in human psychoactive effects [Ref 2] [Ref 7]. This is consistent with the ~43-fold improvement in 5-HT₂A binding affinity and typical phenethylamine potency–receptor affinity relationships.

### Pharmacokinetics

**No published human pharmacokinetic studies exist for escaline.** The following is extrapolated from mescaline data (the closest studied structural analog) with appropriate caution flagging.

**Mescaline reference PK (oral):**  
- Tmax: ~2 hours (Klaiber et al. 2024 [Ref 21]; Mueller et al. 2025 [Ref 10])  
- Plasma elimination half-life: ~3.5 hours (Klaiber et al. 2024 [Ref 21]; Ley et al. 2023 [Ref 22])  
- PK is dose-proportional from 100–800 mg (Mueller et al. 2025 [Ref 10])  
- Oral bioavailability: not formally quantified in available sources

**Escaline-specific PK inferences:**  
Shulgin (PiHKAL #72 [Ref 6]) noted that escaline has a faster onset than mescaline ("within the first hour"), suggesting somewhat quicker absorption or distribution. Effect duration is described as 8–12 hours in PiHKAL [Ref 6], consistent with mescaline's 8–14-hour range at equivalent subjective doses.

**Metabolic pathway:** No published data on escaline's specific metabolism. Mescaline undergoes oxidative deamination and N-acetylation as primary metabolic routes (Madrid-Gambín et al. 2023 [Ref 17]). Phenethylamines of this class are substrates for MAO-A. CYP enzyme involvement for escaline is unstudied; extrapolation from mescaline suggests limited CYP involvement and primary MAO-mediated metabolism.

⚠️ **FLAG FOR HUMAN REVIEW:** All PK data above for escaline is structural analog inference from mescaline. No escaline-specific human PK studies exist. Onset and duration values in the seed data are not verified against published sources.

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## History

### First Synthesis and Early Research

Escaline (3,5-dimethoxy-4-ethoxyphenethylamine) was first synthesized and described in the scientific literature by Benington, Morin, and Clark in 1954 [Ref 18]. (An earlier attribution to "Grace, 1934" appears in some secondary sources; however, this could not be verified through primary literature searches and may be inaccurate or refer to a structurally related compound — see Gaps & Flags.)

The first systematic pharmacological characterization appeared in David E. Nichols and Dyer's 1977 publication in the Journal of Medicinal Chemistry (PMID 836502 [Ref 14]), which demonstrated increased serotonin agonist activity compared to mescaline and established the lipophilicity–activity relationship for the 4-substituted mescaline analog series.

### Shulgin and Human Documentation

Alexander Shulgin independently prepared escaline and documented the first detailed human bioassays in PiHKAL: A Chemical Love Story (1991) [Ref 6], where it appears as compound #72. Shulgin described two synthesis routes and noted that escaline produced "powerful and complex intoxication" qualitatively similar to mescaline but with a quicker onset and absence of nausea.

### Research Chemical Era

Escaline entered the research chemical market in the 2000s–2010s as a structural analog of mescaline. NMR spectral analysis of grey-market phenethylamine samples confirmed the presence of escaline and related scalines in materials sold through internet vendors (Chapman & Avanes 2015 [Ref: PeakAL report]). The 2012 review by Trachsel [Ref 2] used escaline as a reference compound for psychoactive potency in comparing fluorinated phenethylamine analogs.

### Regulatory History

- **United States:** Scheduling status under DEA is complex. Escaline is listed as DEA Schedule I controlled substance #7930. However, even if not specifically scheduled, it would qualify as a controlled substance analogue under the Federal Analogue Act (21 U.S.C. § 813) as substantially similar to mescaline (Schedule I).
- **Sweden:** Classified as illegal as of January 26, 2016.
- **United Kingdom:** Covered by the Psychoactive Substances Act 2016 (effective May 26, 2016), which broadly prohibits all psychoactive substances not otherwise exempted. Escaline is not specifically listed under the Misuse of Drugs Act 1971.
- **Germany:** Reportedly covered under the Neue-psychoaktive-Stoffe-Gesetz (NpSG, New Psychoactive Substances Act) as of November 2016; however, direct verification that escaline is specifically listed was not achieved in this research pass.
- **Canada:** Not currently listed as a controlled substance (as of 2025).
- **Australia:** Not specifically scheduled; would potentially fall under broad analogue or emerging drug provisions, but specific scheduling status was not verified.

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## Subjective Effects

All subjective effect data for escaline is derived from Shulgin's PiHKAL bioassays [Ref 6] and secondary sources referencing those accounts. No published controlled human studies on escaline's subjective effects exist.

**From Shulgin's PiHKAL #72 (primary observer account):**

*Dose tested:* 40–60 mg oral (HCl salt)  
*Duration:* 8–12 hours  
*Onset:* Described as "within the first hour," faster than mescaline

**Qualitative description:** Shulgin characterized escaline as producing a "powerful and complex intoxication." Notably:
- Similar qualitative content to mescaline
- Motor incoordination at higher doses (rational muscular activity impaired)
- Analgesia noted
- Intellectual and sensory enhancement at 60 mg ("rational analysis and insight")
- Tachycardia documented
- Muscle tension
- Dehydration
- Sleep disturbance ("nightmare quality sleep" in some subjects)
- Residual tiredness and low energy the following day
- Less nausea than mescaline was explicitly noted

**Mescaline clinical reference (Ley et al. 2023 [Ref 22]; Klaiber et al. 2024 [Ref 21]):**  
Controlled trials of mescaline (500 mg) in healthy subjects found comparable subjective effects to LSD (100 µg) and psilocybin (20 mg) at equiactive doses, with dose-dependent increases in altered consciousness. Given escaline's 5–8× potency advantage over mescaline, similar effects would be expected at correspondingly lower doses.

**Effects taxonomy (from DB, consistent with PiHKAL descriptions):**  
The broad effect domains listed in the seed data (visual hallucinations, thought connectivity, body sensations, personal insight, time alteration) are consistent with the 5-HT₂A-mediated psychedelic phenomenology documented for the mescaline class in clinical trials [Ref 22] [Ref 21].

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## Safety & Toxicity

### Acute Toxicity

**No published LD₅₀ data exists for escaline in any species.** The toxic dose is unknown. No published case reports of escaline overdose or fatal poisoning were identified in any database searched (PubMed, OpenAlex, ClinicalTrials.gov).

**Cardiovascular effects:** Mescaline produces dose-dependent increases in systolic and diastolic blood pressure and heart rate (Klaiber et al. 2024 [Ref 21]). Given structural similarity and shared mechanism, escaline is expected to produce similar cardiovascular stimulation. Tachycardia was explicitly documented in Shulgin's escaline bioassays [Ref 6].

**Nausea:** Shulgin noted escaline produces less nausea than mescaline. Mescaline produces emesis particularly at high doses (Klaiber et al. 2024 [Ref 21]).

### Psychological Risks

No controlled data on escaline-specific psychological adverse events. Class-level risks include:
- Acute anxiety and panic reactions — documented for 5-HT₂A psychedelics
- Hallucinogen Persisting Perception Disorder (HPPD) — documented for phenethylamine 5-HT₂A agonists (25I-NBOMe: Schetz et al. 2022 [Ref: found in search])
- Psychosis precipitation in vulnerable individuals — class risk for all 5-HT₂A agonists

### Organ Toxicity

No published data on escaline-specific organ toxicity. No hepatotoxic, nephrotoxic, or cardiotoxic effects reported in available literature. Dehydration was noted by Shulgin [Ref 6].

⚠️ **FLAG FOR HUMAN REVIEW:** The seed data states "toxic dose is unknown" — this is confirmed by absence of published LD₅₀ or overdose data. All safety-critical dose thresholds are unverified against published sources.

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## Harm Reduction

### Testing and Identification

**Colorimetric reagent results specific to escaline:** No published colorimetric reaction results found for escaline with standard harm reduction reagents (Marquis, Mecke, Simon's, Froehde). This is a gap in available published data. General guidance: phenethylamine-class substances can be difficult to distinguish from each other by colorimetric testing alone.

**NMR confirmation:** Chapman & Avanes (2015) reported ¹H NMR spectra for grey-market phenethylamines including scalines, confirming the existence of escaline in unregulated markets [Ref: PeakAL report].

### General Harm Reduction Principles

No escaline-specific published harm reduction protocols exist. General psychedelic harm reduction principles apply:
- Set and setting
- Dose titration (start low given higher potency than mescaline)
- Avoid combination with serotonergic drugs, especially tramadol (see Interactions)
- Do not drive or operate machinery
- Have a sober sitter available for high doses
- Avoid in individuals with personal or family history of psychosis

### Contraindications

No peer-reviewed contraindication data specific to escaline. Class-level contraindications from 5-HT₂A agonist literature:
- Severe cardiovascular disease (due to blood pressure and heart rate elevation; Klaiber 2024 [Ref 21])
- Personal or family history of psychosis/schizophrenia
- Concurrent use of MAOIs, SSRIs, tramadol, or other serotonergic agents

---

## Tolerance & Dependence

### Tolerance Development

No escaline-specific published data. Class mechanism well-established:  
Repeated administration of 5-HT₂A psychedelics produces rapid, progressive tolerance via receptor downregulation in the frontal cortex (de la Fuente Revenga et al. 2022 [Ref 11]). Tolerance to the murine HTR develops within 24 hours of a single administration and is blocked by the 5-HT₂A antagonist M100907, confirming receptor-mediated mechanism. Tolerance is not produced by beta-arrestin-2 knockout, suggesting a signaling mechanism independent of beta-arrestin-2.

The seed data's tolerance profile (buildup: almost immediately after ingestion; half-life: 3 days; full reset: 7 days) is consistent with class-level 5-HT₂A data and is reasonable as class inference, though no escaline-specific studies confirm these values.

### Cross-Tolerance

Bidirectional cross-tolerance exists between serotonergic hallucinogens (Halberstadt 2015 [Ref 15]; de la Fuente Revenga et al. 2022 [Ref 11]). Cross-tolerance between escaline and LSD, psilocybin, mescaline, and other 5-HT₂A agonists is expected. Cross-tolerance with nonpsychedelic 5-HT₂A agonists (e.g., lisuride) was not observed in murine studies, suggesting psychedelic-specific mechanisms [Ref 11].

### Dependence Liability

No escaline-specific dependence data published. 5-HT₂A agonists as a class do not produce classical dependence. Psychedelic phenethylamines show no rewarding effects in murine conditioned place preference or self-administration models (Nadal-Gracátos et al. 2026 [Ref found in search]). The seed data classification as "not habit-forming" is consistent with class-level evidence, though no escaline-specific studies confirm this.

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## Interactions

### Tramadol — DANGEROUS

**Mechanism:** Tramadol inhibits the serotonin reuptake transporter (SERT) in vitro (HEK293 cells; Baldo 2018 [Ref 16]) and also has weak 5-HT₂A agonist properties. Combined with escaline's strong 5-HT₂A agonist activity and indirect serotonin enhancement, this combination creates significant serotonin toxicity (serotonin syndrome) risk. Serotonin syndrome can manifest as hyperthermia, clonus, agitation, rhabdomyolysis, and, in severe cases, death. The interaction severity listed in the seed data ("dangerous") is supported by the pharmacological mechanism established by Baldo (2018) [Ref 16].

⚠️ **FLAG: Safety-critical.** Confirmed mechanistic basis; no escaline-specific case reports in literature, but class risk is well-established.

### Cannabis — Unknown

No published data on escaline + cannabis pharmacological interactions. Cannabis modulates CB₁/CB₂ receptors with indirect serotonin effects; the interaction with 5-HT₂A agonists is pharmacologically plausible but unstudied for escaline specifically.

### Class-Level Interaction Risks

- **MAOIs:** Potentially fatal. MAO inhibition would reduce metabolic clearance of escaline and elevate serotonergic tone.  
- **SSRIs/SNRIs:** May reduce psychedelic effects (via 5-HT₂A downregulation from chronic serotonin elevation) or increase serotonin syndrome risk.  
- **Lithium:** Combined use with classic psychedelics has been associated with seizure risk in case reports (not escaline-specific).  
- **Other 5-HT₂A agonists:** Additive effects; avoid combining.

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## Legal Status

| Jurisdiction | Status | Notes |
|---|---|---|
| United States | Schedule I (DEA #7930) | Positional isomer classification; also covered by Analogue Act |
| Sweden | Illegal | Since January 26, 2016 |
| United Kingdom | Covered by PSA 2016 | Blanket prohibition; not specifically listed in Misuse of Drugs Act 1971 |
| Germany | Reportedly NpSG-covered | Coverage claimed but specific listing not directly verified |
| Canada | Not controlled | As of 2025 |
| Australia | Not specifically scheduled | Status unverified; may be covered by state-level analogue provisions |
| European Union | Varies by member state | No EU-wide specific scheduling found |

⚠️ **FLAG FOR HUMAN REVIEW:** The DEA Schedule I listing (#7930) should be verified against the current DEA Orange Book. Germany NpSG coverage was not directly verified from primary legislative sources.

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## Clinical Trials

**No clinical trials found** for escaline on ClinicalTrials.gov. A search for "escaline mescaline analog phenethylamine psychedelic" returned zero results. Escaline has not been studied in any registered clinical trial. Its closest analog mescaline has been studied in several recent Swiss/European Phase I trials (Klaiber 2024 [Ref 21]; Ley 2023 [Ref 22]).

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## Community Feedback Analysis

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

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## Gaps & Flags

### Critical Missing Data (Safety)

1. ⚠️ **No published LD₅₀ or toxic dose data for escaline** — the seed data notes "toxic dose is unknown." Confirmed absent from all databases searched. Cannot be estimated from structure alone.

2. ⚠️ **No published human pharmacokinetic data for escaline** — Tmax, Cmax, t½, bioavailability, and metabolic pathway are all unstudied. All PK data in this report is extrapolated from mescaline (structural analog).

3. ⚠️ **Dose range discrepancy (HIGH PRIORITY):** The seed data dose ranges (Light: 30–50 mg, Common: 50–100 mg, Strong: 100–150 mg, Heavy: 150+ mg) substantially exceed Shulgin's PiHKAL data (40–60 mg active range). Shulgin is the primary source for escaline human dose data. A "common" dose of 50–100 mg is consistent with PiHKAL (40–60 mg is presumably the "sweet spot" not the full range); however, "heavy" at 150+ mg is far above any documented human dose in the literature. This discrepancy requires editorial review. **The PsychonautWiki dose range (which appears to be the source of the seed data) is community-derived with a disclaimer that it may not be accurate.** The generation agent should propose a dose update that reconciles PiHKAL (primary) with community data.

4. ⚠️ **Onset discrepancy:** The seed data states onset = 90–120 minutes. Shulgin's PiHKAL explicitly states that escaline's onset is "quicker (within the first hour)" than mescaline. Mescaline itself has Tmax ~2 hours in clinical trials. A 90–120 minute onset for escaline (which is faster-acting than mescaline) seems inconsistent with both PiHKAL and the mescaline PK reference data. This warrants editorial review.

5. ⚠️ **Grace (1934) reference uncertainty** — Some secondary sources attribute the first description of escaline to "George S. Grace, 1934." This could not be verified through primary literature search; the oldest confirmed published description is Benington et al. 1954. The Grace 1934 attribution may be an error propagated through secondary sources, or it may refer to a related compound. Flag for editorial verification.

6. ⚠️ **DEA Schedule I #7930 classification basis** — Some secondary sources state escaline is classified as a "positional isomer of 3,4,5-trimethoxyamphetamine (TMA)." This classification basis is chemically questionable (escaline is a phenethylamine, not an amphetamine). The actual basis for DEA scheduling should be verified against official DEA sources.

### Data Absent from Literature (Not Safety-Critical)

- No published human subjective effects studies (only Shulgin's self-experiment record)
- No escaline-specific HPPD case reports
- No escaline-specific adverse event reports
- No escaline-specific drug discrimination data (only HTR animal data)
- Colorimetric reagent test results not published
- Specific HTR ED50 values for escaline (in Halberstadt 2019 paper, but not accessible from abstract alone)
- No data on escaline effects in clinical populations
- Metabolic pathway and CYP involvement unstudied
- Reproductive/developmental toxicity: no data

### Reliance on Structural Analogy

The following sections rely substantially on structural inference from mescaline rather than escaline-specific data: Pharmacokinetics, Metabolic Pathway, Dependence Liability, Harm Reduction protocols, CYP interactions. These are flagged throughout the document.