2C-E
2C-E, or 2,5-dimethoxy-4-ethylphenethylamine, is a synthetic psychedelic phenethylamine belonging to the 2C family of compounds first synthesized by chemist Alexander Shulgin.[1] Developed as part of Shulgin's exploration of psychoactive substances, it was documented in his 1991 book PiHKAL: A Chemical Love Story, where synthesis methods and qualitative effects were described.[1] 2C-E primarily acts as a partial agonist at serotonin 5-HT2A, 5-HT2B, and 5-HT2C receptors, inducing alterations in perception, visual and auditory hallucinations, and euphoric mood states in human users.[2] Oral doses of 10-25 mg typically produce peak effects within 2 hours, with physiological changes including elevated heart rate and body temperature, and subjective intensity correlating with dose.[3] Effects are generally well-tolerated in experienced recreational users at moderate doses but carry risks of nausea, confusion, and residual hallucinations.[3] Recreational use has been linked to severe adverse outcomes, including fatalities from overdose and toxic leukoencephalopathy.[4] In the United States, 2C-E is scheduled as a DEA List I controlled substance, reflecting its high potential for abuse and lack of accepted medical use.[5]History
Synthesis and Discovery
2C-E, or 2,5-dimethoxy-4-ethylphenethylamine, was first synthesized in 1977 by American chemist Alexander Shulgin during his independent research on psychoactive phenethylamines.[6] Shulgin, who had previously worked at Dow Chemical Company developing pesticides and later focused on novel psychoactive compounds, prepared 2C-E as part of the 2C series to explore substitutions at the 4-position of the aromatic ring for enhanced hallucinogenic potency.[7] The initial synthesis employed a multi-step process starting with Friedel-Crafts acylation of 1,4-dimethoxybenzene derivatives to form the corresponding ketone, followed by reduction and amination to yield the phenethylamine.[8] Shulgin's approach prioritized empirical bioassay over theoretical prediction, testing small doses on himself to assess qualitative effects before scaling documentation. This method contrasted with institutional research constrained by regulatory oversight, allowing direct causal inference from synthesis to psychopharmacology.[9]Documentation in PiHKAL
In PiHKAL: A Chemical Love Story, published in 1991 by Alexander T. Shulgin and Ann Shulgin, 2C-E (2,5-dimethoxy-4-ethylphenethylamine) is cataloged as entry #24 among the documented phenethylamines.[8] The entry delineates a multi-step synthesis commencing with the Friedel-Crafts acylation of 1,4-dimethoxybenzene using acetyl chloride and anhydrous aluminum chloride in dichloromethane to produce 2,5-dimethoxyacetophenone, followed by Clemmensen reduction to 2,5-dimethoxyethylbenzene, Vilsmeier formylation to the 4-ethylbenzaldehyde derivative, nitrostyrene formation via Henry reaction, and final reduction with lithium aluminum hydride to yield the target amine as its hydrochloride salt.[8] Shulgin specifies oral dosages of 10–25 mg, with a threshold at approximately 10 mg, common effective range at 15–20 mg, and heavier doses exceeding 25 mg; the duration is reported as 8–12 hours.[8] He designates 2C-E as one of the "magical half-dozen" phenethylamines deemed particularly noteworthy for their qualitative depth, emphasizing its profound visual distortions, enhanced pattern recognition, and introspective intensity, though with a pronounced steep dose-response curve that heightens risks of anxiety or overwhelm at upper levels.[8] Personal and volunteer accounts in the entry recount experiences such as vivid eidetic imagery (e.g., animated environmental overlays) and emotionally charged insights, underscoring its potential for both aesthetic enhancement and therapeutic challenge.[8] Shulgin also notes homologues like DOET (longer-acting and more potent) and 2CE-5ETO (extended duration of 2–3 times, dosed at 10–15 mg).[8]Chemistry
Molecular Structure and Properties
2C-E, systematically named 2-(4-ethyl-2,5-dimethoxyphenyl)ethanamine, is a member of the 2C series of phenethylamine derivatives.[10] Its molecular formula is C₁₂H₁₉NO₂, corresponding to a molecular weight of 209.29 g/mol.[10] The core structure consists of a benzene ring with methoxy substituents (-OCH₃) at the ortho and meta positions relative to the ethylamine side chain (positions 2 and 5), an ethyl group (-CH₂CH₃) at the para position (position 4), and a β-phenethylamine moiety (-CH₂CH₂NH₂) attached to the ring.[10] The free base of 2C-E exists as a colorless oil at room temperature.[11] The hydrochloride salt, commonly used for handling and administration, crystallizes as white solids.[11] Alexander Shulgin reported the melting point of the hydrochloride salt to be 208.5–210.5 °C following recrystallization.[11] The salt exhibits solubility in polar solvents such as dimethylformamide (20 mg/mL), dimethyl sulfoxide (20 mg/mL), ethanol (30 mg/mL), and phosphate-buffered saline (5 mg/mL at pH 7.2).[12] Density of the free base has been estimated at approximately 1.0 g/cm³.[13]Synthesis Methods
The synthesis of 2C-E (2,5-dimethoxy-4-ethylphenethylamine) follows a multi-step procedure originally detailed by Alexander Shulgin, involving electrophilic aromatic substitution, reduction, formylation, nitroaldol condensation, and reductive amination.[8] The process begins with the acetylation of 1,4-dimethoxybenzene using acetyl chloride and anhydrous aluminum chloride in dichloromethane, yielding 2,5-dimethoxyacetophenone (111.6 g from 110 g starting material, distilled at 147–150 °C under water pump vacuum).[8] This ketone is then reduced to 2,5-dimethoxy-1-ethylbenzene via the Wolff-Kishner reaction, employing hydrazine hydrate, potassium hydroxide, and triethylene glycol at reflux (210 °C) for 3 hours, producing 22.0 g of the ethylbenzene derivative (distilled at 120–140 °C under water pump vacuum).[8] Formylation at the 4-position occurs via the Vilsmeier-Haack reaction with stannic chloride and dichloromethyl methyl ether in dichloromethane at 0 °C followed by heating, affording 2,5-dimethoxy-4-ethylbenzaldehyde (5.9 g, mp 47–48 °C, distilled at 90–110 °C/0.2 mmHg).[8] The aldehyde undergoes a Henry reaction with nitromethane and anhydrous ammonium acetate on a steam bath for 2 hours, forming 2,5-dimethoxy-4-ethyl-β-nitrostyrene (13.4 g, mp 99–100 °C after recrystallization from methanol).[8] Final reduction of the nitrostyrene to the phenethylamine is achieved using lithium aluminum hydride (LAH) in tetrahydrofuran (THF), with the reaction cooled to 0 °C, refluxed, and then acidified with sulfuric acid or hydrochloric acid, yielding 2C-E hydrochloride (3.87–7.7 g after crystallization from isopropyl alcohol/ether).[8] Yields vary across steps, with overall efficiency limited by the sequential transformations typical of phenethylamine syntheses.[8] No alternative peer-reviewed synthetic routes specific to 2C-E were identified in chemical literature, though analogous methods for substituted phenethylamines employ similar strategies.[14]Pharmacology
Pharmacodynamics
2C-E acts predominantly as an agonist at serotonin 5-HT2 receptors, with the 5-HT2A subtype mediating its primary hallucinogenic effects through activation of Gq-coupled signaling pathways that increase phospholipase C activity, intracellular calcium release, and downstream neuronal excitability in cortical regions.[15] [16] This receptor interaction profile aligns with classical serotonergic psychedelics, where 5-HT2A agonism disrupts default mode network integrity and enhances sensory processing, contributing to altered perception and cognition.[17] Binding studies demonstrate 2C-E's high affinity for 5-HT2A and 5-HT2C receptors, though specific Ki values for the parent 2C-E remain in the low nanomolar to submicromolar range, lower than N-benzyl derivatives like NBOMe analogs which exhibit enhanced potency.[18] [19] It displays negligible affinity for dopamine D1-D3 receptors and minimal inhibition of monoamine transporters (DAT, NET, SERT), with IC50 values exceeding 10 μM, distinguishing it from entactogenic or stimulant phenethylamines.[17] [20] At lower concentrations, 2C-E may exhibit mild stimulant-like actions via weak adrenergic α1 and α2A receptor interactions or trace amine-associated receptor 1 (TAAR1) modulation, though these contribute less to its overall pharmacodynamic signature compared to serotonergic effects.[17] [21] Functional assays confirm partial agonism at 5-HT2A, with efficacy comparable to other 2C-series compounds but without significant β-arrestin recruitment bias observed in some newer psychedelics.[22]Pharmacokinetics
2C-E exhibits limited documented pharmacokinetic profiles in humans, primarily due to its status as a research chemical with sparse clinical investigation. Following oral self-administration of doses ranging from 6.5 to 25 mg, maximal concentrations in saliva—a proxy for plasma levels—occur approximately 2 hours post-ingestion, indicating relatively rapid absorption and distribution into systemic circulation.[2][3] Animal studies provide insight into metabolism, with rat models showing primary biotransformation via O-demethylation at the 2- or 5-methoxy positions, yielding monodemethylated metabolites.[23] Subsequent pathways include oxidation of the 4-ethyl group to a carboxylic acid, N-acetylation of the phenethylamine chain, and reduction of intermediate aromatic aldehydes to alcohols, facilitating urinary elimination.[23] Excretion occurs predominantly via urine, as evidenced by detectable parent compound and metabolites in rat urine samples analyzed by gas chromatography-mass spectrometry.[23] Human elimination half-life remains uncharacterized, though structural analogs like 2C-B display short half-lives of 1.1–2.5 hours in rodents and humans, suggesting potentially comparable rapid clearance for 2C-E.[24] No data on tissue distribution or bioavailability are available, reflecting the compound's understudied nature outside recreational contexts.Usage and Dosage
Routes of Administration
2C-E is most commonly administered orally, either swallowed in capsule form or dissolved in a liquid vehicle such as water or juice, with typical dosages ranging from 10 to 25 mg as documented by its synthesizer Alexander Shulgin.[11] Oral ingestion produces effects with an onset of 20 to 90 minutes and a total duration of 6 to 10 hours, reflecting the compound's pharmacokinetics as a phenethylamine derivative that undergoes hepatic metabolism.[3] This route is preferred for its reliability and reduced risk of immediate tissue irritation compared to alternatives.[25] Intranasal insufflation (snorting) represents a secondary route, often employing doses of 5 to 15 mg of the powdered hydrochloride salt, which yields a faster onset of 5 to 15 minutes but intensifies the initial intensity of effects.[26] Users report significant nasal burning and discomfort during insufflation, attributable to the compound's acidity and poor solubility in mucosal environments, potentially leading to higher bioavailability but increased risk of local tissue damage.[25] Empirical accounts indicate that insufflation may shorten overall duration slightly while amplifying acute sensory distortions, though it is less favored due to pain and inconsistent absorption.[27] Rectal administration has been anecdotally reported, typically involving suppository forms or dissolved solutions at doses approximately half those of oral intake (e.g., 5 to 12.5 mg), purportedly enhancing bioavailability by bypassing first-pass metabolism and accelerating onset to 15 to 30 minutes.[28] Limited data exists on this method's efficacy and safety for 2C-E specifically, with potential for gastrointestinal irritation or variable absorption based on formulation. Other routes, such as sublingual or intravenous, are rarely documented and lack standardized dosing, rendering them inadvisable absent controlled pharmacokinetic studies.[29] Vaporization is not viable due to the compound's thermal instability and low volatility as a solid phenethylamine.[1]Dosage Guidelines
2C-E is typically administered orally in doses ranging from 10 to 25 mg, as documented by Alexander Shulgin in PiHKAL based on personal and exploratory trials.[8] This range corresponds to perceptual thresholds and full psychedelic effects, with a noted steep dose-response curve where small increments can significantly intensify visuals and introspection.[8] User reports aggregated by Erowid classify oral dosages as follows: threshold effects at 2–5 mg, light at 5–10 mg, common at 10–15 mg, strong at 15–30 mg, and heavy at 25–40 mg or higher.[30] These levels reflect variability in subjective intensity, with common doses producing vivid open- and closed-eye visuals, enhanced pattern recognition, and emotional depth lasting 6–10 hours, while stronger doses may induce overwhelming geometric hallucinations or anxiety.[30] [8] An observational study of recreational users reported average intakes of 10–20 mg, with medium effects at 15–25 mg and high at 25–40 mg, confirming the narrow therapeutic window and potential for exceptional doses up to 100 mg in tolerant individuals, though such extremes risk acute distress.[6]| Dose Level | Oral Range (mg) | Typical Duration (hours) |
|---|---|---|
| Threshold | 2–5 | 4–6 |
| Light | 5–10 | 6–8 |
| Common | 10–15 | 6–10 |
| Strong | 15–30 | 8–12 |
| Heavy | 25+ | 10+ |