EDMA

3,4-Ethylenedioxy-N-methylamphetamine (EDMA) is a synthetic substituted amphetamine and chemical analog of 3,4-methylenedioxymethamphetamine (MDMA), belonging to the phenethylamine class of psychoactive substances.^[1]^[2] With the molecular formula C₁₂H₁₇NO₂, EDMA features an ethylenedioxy group on the benzene ring, distinguishing it structurally from MDMA's methylenedioxy moiety.^[2]^[3] As an analytical reference standard, it is primarily utilized in forensic and research contexts to study amphetamine derivatives.^[1] EDMA functions as a monoamine releaser, stimulating the efflux of serotonin and dopamine from rat brain synaptosomes at concentrations of 1 μM, suggesting potential entactogenic and stimulant properties akin to but potentially less potent than those of MDMA.^[1] Though lesser-known and not widely reported in recreational use, its synthesis and characterization highlight ongoing interest in structure-activity relationships among ring-substituted amphetamines for pharmacological evaluation.^[1]

Chemistry

Chemical structure and properties

3,4-Ethylenedioxy-N-methylamphetamine (EDMA) is a synthetic derivative of the phenethylamine class, structurally analogous to 3,4-methylenedioxymethamphetamine (MDMA) but featuring an ethylenedioxy substituent at the 3 and 4 positions of the benzene ring. This substituent forms a six-membered 1,4-dioxane ring fused to the aromatic system via -O-CH₂-CH₂-O- linkages, distinguishing it from the five-membered methylenedioxy ring in MDMA. The side chain attached to position 1 of the benzene ring is -CH₂-CH(CH₃)-NHCH₃, conferring amphetamine-like properties. The molecular formula of EDMA is C₁₂H₁₇NO₂, with a molar mass of 207.27 g/mol.^[4]^[3] The SMILES notation for EDMA is CC(Cc1ccc2c(c1)OCCO2)NC, representing the connectivity of its atoms.^[4] Experimental physical properties are sparsely documented due to EDMA's status as a lesser-known research chemical. The hydrochloride salt form appears as a crystalline solid with ≥98% purity in commercial preparations.^[1] One analytical certificate reports a melting point of 151–154 °C for the hydrochloride salt.^[5] Solubility data for the salt indicate moderate to good dissolution in polar aprotic solvents (DMF: 25 mg/mL; DMSO: 30 mg/mL) and alcohols (ethanol: 10 mg/mL; methanol: 1 mg/mL), as well as in phosphate-buffered saline (10 mg/mL).^[1] The free base likely exhibits oil-like consistency typical of many amphetamines, though specific boiling point, density, or logP values remain unreported in available sources.

Synthesis methods

3,4-Ethylenedioxy-N-methylamphetamine (EDMA) is synthesized via methods that typically involve N-methylation of the primary amine precursor 1-(3,4-ethylenedioxyphenyl)-2-aminopropane or multi-step routes from related intermediates.^[6] One reported procedure for the racemic compound begins with the formation of the ethyl carbamate intermediate using ethyl chloroformate (0.14 mL, 1.47 mmol) and triethylamine (0.4 mL) in anhydrous diethyl ether under nitrogen atmosphere at room temperature for 1 hour, yielding 79%.^[6] This is followed by reduction with lithium aluminum hydride (0.13 g, 3.40 mmol) in anhydrous tetrahydrofuran at 0°C, then reflux for 3 hours under nitrogen, with quenching using diethyl ether, water, and sodium hydroxide, affording EDMA in 11% yield with a melting point of 150–151°C.^[6] Enantioselective synthesis of (S)-(+)-EDMA and (R)-(-)-EDMA employs a sequence starting from nitroalkene 5.^[6] Reduction of 5 with iron powder in acetic acid at reflux for 3 hours produces ketone 6 in 78% yield.^[6] Reductive amination of 6 with (S)-(-)- or (R)-(+)-α-methylbenzylamine and sodium triacetoxyborohydride in 1,2-dichloroethane at room temperature for 24 hours forms the corresponding imine reduction products (S,S-(-)-7 or R,R-(+)-7) in 50% yield.^[6] Hydrogenation using 10% palladium on carbon at 50 psi for 40 hours yields the primary amines (S-(+)-8 or R-(-)-8) in 73% yield.^[6] Protection as the tert-butyl carbamate with di-tert-butyl dicarbonate in dichloromethane at room temperature for 1 hour, followed by reduction with lithium aluminum hydride in tetrahydrofuran at 0°C then reflux for 4 hours, provides (S)-(+)-EDMA in 72% yield (melting point 192–194°C, >98% enantiomeric purity by 1H NMR with chiral shift reagent) and (R)-(-)-EDMA in 67% yield.^[6] These methods adapt strategies common to phenethylamine synthesis, emphasizing reductive processes under inert conditions to achieve the target structure.^[6]

Pharmacology

Pharmacodynamics

EDMA primarily exerts its effects through interaction with monoamine transporters, acting as a substrate-type releaser that promotes the efflux of serotonin (5-HT), dopamine (DA), and norepinephrine (NE) from presynaptic neurons.^[6] This mechanism involves reversal of the transporters—serotonin transporter (SERT), dopamine transporter (DAT), and norepinephrine transporter (NET)—facilitating non-exocytotic release of neurotransmitters into the synaptic cleft, similar to other substituted amphetamines.^[6] In vitro assays demonstrate that the racemic mixture of EDMA induces release with EC₅₀ values of 117 nM at SERT, 597 nM at DAT, and 325 nM at NET, indicating a preference for serotonergic activity over dopaminergic or noradrenergic effects.^[6] The S-(+)-enantiomer is markedly more potent, with EC₅₀ values of 91 nM (SERT), 276 nM (DAT), and 239 nM (NET), whereas the R-(-)-enantiomer shows substantially reduced activity (EC₅₀ 573 nM at SERT, 14,600 nM at DAT, 1,952 nM at NET), highlighting stereoselectivity in transporter interactions.^[6] Compared to MDMA, EDMA exhibits moderately lower potency as a releaser across transporters, being approximately twice less effective at SERT (MDMA EC₅₀ 61 nM) and showing greater selectivity for SERT relative to DAT and NET.^[6] No data on receptor binding affinities or secondary mechanisms, such as agonist activity at postsynaptic receptors, have been reported; effects are attributable to enhanced synaptic monoamine levels.^[6] Pharmacological studies remain limited, with available evidence derived primarily from transporter release assays in cell models.^[6]

Pharmacokinetics

Limited pharmacokinetic data exists for ethylenedioxymethamphetamine (EDMA), a synthetic phenethylamine analog of 3,4-methylenedioxymethamphetamine (MDMA). No controlled studies have characterized its absorption, distribution, metabolism, or excretion in humans or preclinical models. Anecdotal reports from self-experimentation indicate oral bioavailability sufficient for pharmacological effects, with no activity observed at 200 mg and threshold subjective effects at 250 mg administered per os, suggesting onset times comparable to amphetamines but without quantitative measures of peak plasma concentration or time to maximum concentration.^[6] These observations derive from uncontrolled personal accounts rather than rigorous pharmacokinetic assessments, limiting their reliability for establishing precise ADME parameters. Further empirical research is required to elucidate EDMA's handling in biological systems, particularly given its structural homology to MDMA, for which nonlinear pharmacokinetics and CYP2D6-mediated metabolism are well-documented.^[7]

Effects

Subjective physical effects

Users report mild physical sensations following oral administration of EDMA at doses of 150–250 mg, primarily manifesting as paresthesia—a tingling or flooding sensation—onset within 30 minutes.^[8] This sensory effect is subtle and does not escalate to pronounced tactile enhancement or body euphoria characteristic of related compounds like MDMA.^[8] At higher doses around 200–250 mg, individuals experience hints of nystagmus or slight eye muscle tension, alongside increased alertness without significant cardiovascular changes such as elevated blood pressure or pronounced stimulation.^[8] Notably absent are common amphetamine-associated physical side effects, including teeth clenching, appetite suppression, or persistent eye jiggle (nystagmus).^[8] These reports indicate a low body load, with effects resolving to baseline within 3–5 hours and no residual physical aftereffects.^[8] Pharmacological studies corroborate the mild profile, showing EDMA induces weaker serotonin release compared to MDMA, potentially contributing to subdued physical activation.^[6] Human experiential data remains limited to exploratory self-reports, as no controlled clinical trials assess subjective physical responses.^[8]

Subjective psychological effects

Subjective psychological effects of EDMA (3,4-ethylenedioxy-N-methylamphetamine, also known as MDMC) are characterized as mild psychedelia in exploratory reports by chemist Alexander Shulgin, who synthesized and tested the compound. At oral dosages of 150-250 mg, effects include sensory alterations such as paresthesia (tingling sensations), nystagmus (involuntary eye movements), and hypnagogic imagery (mild, dream-like visuals), with minimal additional psychological changes reported.^[8] These differ markedly from the intense empathogenic and euphoric states induced by MDMA, lacking enhanced emotional openness, introspection, or prosocial bonding.^[8] The onset occurs within 1-2 hours, peaking around 2-3 hours post-ingestion, with a total duration of 3-5 hours before residual effects subside.^[8] Shulgin noted no significant entactogenic or stimulant-driven mood elevation, attributing the subdued profile to the ethylenedioxy ring substitution altering receptor interactions compared to methylenedioxy analogs. Anecdotal evidence from Shulgin's qualitative assessments, derived from self-administration and small-group trials, represents the primary data available, as no controlled human studies on EDMA's psychological effects have been published.^[8] This limits generalizability, with potential variability due to individual factors like set, setting, and purity.

Aftereffects and duration

The duration of EDMA's subjective effects is reported as 3 to 5 hours following oral administration of 150 to 250 mg.^[9] These effects are described as mild and primarily psychedelic, including paresthesia, nystagmus, difficulty focusing, and minor visual distortions such as colored patterns with eyes closed, without notable entactogenic or empathogenic qualities akin to MDMA.^[9] Onset typically occurs within 1 hour, with a plateau phase leading to gradual resolution.^[10] Aftereffects of EDMA are poorly documented due to the compound's obscurity and reliance on limited self-experimental reports rather than controlled clinical studies. No severe comedown or protracted "crash" is mentioned in primary accounts, consistent with its weaker stimulant and serotonergic profile compared to related amphetamines. Potential residual symptoms may include mild fatigue, transient mood lowering, or insomnia, persisting for several hours post-resolution, though these inferences draw from class-wide patterns in methylenedioxy-substituted phenethylamines rather than EDMA-specific data.^[9] The scarcity of empirical evidence underscores the need for caution, as individual variability in metabolism and dose could amplify risks like dehydration or neurochemical depletion observed in analogs.^[11]

Toxicity and health risks

Acute toxicity and overdose

Limited published data exists on the acute toxicity of 3,4-ethylenedioxymethamphetamine (EDMA), a lesser-known amphetamine analog primarily encountered as a research chemical with infrequent recreational use.^[4] No peer-reviewed reports of confirmed human overdoses or detailed toxicological profiles specific to EDMA have been identified, reflecting its obscurity compared to structurally related compounds like MDMA.^[6] Pharmacological studies indicate EDMA acts as a monoamine releaser, stimulating efflux of serotonin and dopamine from synaptosomes at concentrations around 1 μM, which may predispose users to sympathomimetic and serotonergic adverse effects in overdose scenarios.^[1] Potential manifestations could include elevated heart rate, hypertension, hyperthermia, agitation, and seizures, analogous to amphetamine class toxicity, though empirical verification in EDMA-exposed individuals is absent.^[6] Animal data on lethality or dose-response thresholds remain unreported, limiting risk assessment.^[12] Management of suspected EDMA overdose would follow general protocols for amphetamine-like substances, emphasizing supportive care such as cooling for hyperthermia, benzodiazepines for agitation or seizures, and monitoring for cardiovascular instability or rhabdomyolysis. However, without established pharmacokinetic parameters or antidote-specific interventions for EDMA, treatment relies on symptom palliation rather than targeted reversal. Polydrug interactions, common in recreational contexts, would further complicate presentation and outcomes.^[6]

Long-term health effects

Limited human data exists on the long-term health effects of 3,4-ethylenedioxy-N-methylamphetamine (EDMA), a synthetic entactogen structurally related to MDMA but with an expanded ethylenedioxy ring, owing to its rarity in recreational and clinical contexts. Preclinical rodent studies have found that EDMA, administered at doses up to 50 mg/kg subcutaneously, does not induce long-term depletion of brain serotonin (5-HT) or dopamine levels, nor does it cause histopathological evidence of neurotoxicity such as axonal degeneration observed with MDMA analogs. This contrasts with MDMA's established serotonergic neurotoxicity in similar models, attributed to EDMA's reduced potency as a monoamine releaser and weaker metabolic activation to toxic intermediates.^[6] In vitro assays confirm EDMA's activity as a serotonin releaser via the serotonin transporter (SERT), but with lower efficacy than MDMA, potentially mitigating risks of chronic 5-HT axon damage.^[6] No longitudinal human cohort studies or case reports document cognitive impairments, mood disorders, or structural brain changes specifically linked to EDMA use, unlike the deficits in memory, executive function, and increased depression risk reported in heavy MDMA users. Animal behavioral assays further suggest EDMA lacks the mescaline-like hallucinogenic or strong stimulant properties that could contribute to persistent perceptual alterations. Potential indirect long-term risks mirror those of other amphetamine derivatives, including cardiovascular strain from repeated sympathomimetic activation, though EDMA's diminished locomotor and discriminative stimulus effects in rats indicate lower abuse liability and thus reduced cumulative exposure.^[6] Biosynthetic enzyme studies in rats show no sustained alterations in tryptophan hydroxylase or tyrosine hydroxylase activity post-EDMA administration, supporting absence of dopaminergic or serotonergic synthetic deficits. Overall, the pharmacological profile implies a lower neurotoxic potential than MDMA, but the absence of epidemiological data precludes definitive assessment of human outcomes like psychiatric sequelae or organ pathology from chronic or high-dose use.^[13]

Dependence potential and withdrawal

Limited empirical data exist on the dependence potential of ethylenedioxymethamphetamine (EDMA), a structural analog of 3,4-methylenedioxymethamphetamine (MDMA) featuring an expanded ethylenedioxy ring.^[6] Pharmacological studies indicate EDMA acts primarily as a monoamine releaser, with EC₅₀ values of 117 nM at the serotonin transporter (SERT), 597 nM at the dopamine transporter (DAT), and 325 nM at the norepinephrine transporter (NET), rendering it less potent at DAT and NET than MDMA (EC₅₀ values of 75 nM and 72 nM, respectively).^[6] This reduced DAT affinity, which correlates with reinforcing effects in preclinical models of drug self-administration for stimulants, suggests EDMA may possess lower abuse liability than classical amphetamines or even MDMA, though no direct self-administration or reinforcement studies have been conducted.^[6]^[14] No verified reports of physical dependence or compulsive use patterns specific to EDMA appear in the literature, consistent with its obscurity as a recreational substance and the absence of widespread clinical or epidemiological data.^[6] The S-enantiomer of EDMA exhibits greater potency (SERT EC₅₀ = 91 nM, DAT EC₅₀ = 276 nM), potentially contributing to subjective reward via serotonergic mechanisms, but overall transporter selectivity favors serotonin release over dopamine, limiting euphoric reinforcement typically associated with addiction vulnerability.^[6] Withdrawal symptoms following EDMA cessation have not been documented in human or animal studies. Given the compound's pharmacological profile, any withdrawal, if present, would likely manifest psychologically—such as dysphoria or fatigue—rather than through severe physical signs like those seen in opioid or alcohol dependence, mirroring patterns observed in serotonergic entactogens with minimal DAT involvement.^[6]^[14] Further research is required to assess long-term use risks, as current knowledge derives primarily from in vitro transporter assays rather than behavioral or clinical outcomes.^[6]

History

Discovery and initial research

3,4-Ethylenedioxymethamphetamine (EDMA), a homolog of 3,4-methylenedioxymethamphetamine (MDMA) featuring an expanded ethylenedioxy ring, was first synthesized by chemist Alexander T. Shulgin during his extensive exploration of psychoactive phenethylamines in the latter half of the 20th century. Shulgin's work focused on modifying the ring-substituted amphetamine scaffold to probe variations in psychoactive effects, with EDMA representing an attempt to alter the dioxole ring size for potential changes in potency and selectivity.^[6] Initial research consisted primarily of Shulgin's self-experimentation and small-scale human trials, as documented in his 1991 book PiHKAL. These trials established an effective oral dosage range of 150–250 mg, yielding subjective effects akin to MDMA—including enhanced empathy and sensory openness—but reportedly milder in intensity, with a total duration of 3–5 hours. Shulgin noted the compound's lower potency compared to MDMA, attributing this possibly to steric effects from the larger ring.^[15] Subsequent pharmacological investigations in the late 1980s confirmed EDMA's mechanism involves promoting the release of serotonin and dopamine from neuronal terminals, consistent with its structural similarity to MDMA, though with potentially reduced efficacy at monoamine transporters. These early studies laid the groundwork for understanding EDMA's entactogenic profile, though limited due to the compound's obscurity relative to MDMA.^[16]

Documentation and analogs

3,4-Ethylenedioxy-N-methylamphetamine (EDMA) is documented primarily in pharmacological research examining structure-activity relationships among entactogenic amphetamines, where it serves as a homolog of 3,4-methylenedioxy-N-methylamphetamine (MDMA) featuring an expanded six-membered ethylenedioxy ring fused to the benzene moiety.^[6] This structural modification has been explored in studies synthesizing such compounds to assess their potential emergence as designer drugs, with EDMA demonstrating serotonin and dopamine release from rat brain synaptosomes at 1 μM concentrations, indicative of a mechanism akin to MDMA but potentially with altered potency and selectivity.^[1] Documentation in peer-reviewed literature dates to at least the mid-2010s, focusing on synthetic routes starting from appropriately substituted benzodioxane precursors and evaluating neurochemical effects rather than early therapeutic or recreational contexts.^[6] Analogs of EDMA include the β-keto derivative 3,4-ethylenedioxymethcathinone (EDMC), which shares the ethylenedioxy substitution and has been synthesized alongside EDMA to probe cathinone-class variants with stimulant and empathogenic potential.^[6] These ethylenedioxy homologs represent a subclass of ring-expanded phenethylamine derivatives, differing from standard methylenedioxy compounds by increased ring strain relief and modified lipophilicity, which may influence metabolism and receptor interactions.^[12] Further related structures encompass ethylenedioxy variants of methylone (a β-keto MDMA analog), investigated for their presence in illicit formulations and comparative toxicity profiles in preclinical models.^[6] Such analogs highlight efforts to evade regulatory controls on MDMA-like substances while preserving core pharmacological actions, though empirical data on human effects remain limited due to controlled synthesis for research purposes.

Legal status and societal impact

Regulatory classification

In the United States, 3,4-ethylenedioxy-N-methylamphetamine (EDMA) is not explicitly enumerated in the schedules of the Controlled Substances Act (CSA). However, owing to its close structural similarity to 3,4-methylenedioxymethamphetamine (MDMA)—differing primarily in the replacement of the five-membered methylenedioxy ring with a six-membered ethylenedioxy ring—and its comparable pharmacological profile as a serotonin and dopamine releaser, EDMA qualifies as a "controlled substance analogue" under the Federal Analogue Act (21 U.S.C. § 813).^[17] This provision treats such analogues as Schedule I controlled substances when substantially similar in chemical structure and effect to a Schedule I substance like MDMA, and when intended for human consumption rather than legitimate research or industrial use. MDMA itself has been classified as Schedule I since 1985 due to its high potential for abuse and lack of accepted medical use.^[18] Internationally, regulatory approaches vary, often capturing EDMA through provisions for designer amphetamines or novel psychoactive substances (NPS). In Taiwan, EDMA is explicitly designated as a controlled drug under the national schedules, subjecting its possession, manufacture, and distribution to penalties akin to those for other amphetamine derivatives.^[19] In jurisdictions without specific listings, enforcement typically relies on analog clauses or blanket bans on psychoactive phenethylamines, reflecting concerns over abuse liability similar to MDMA. EDMA's obscurity in mainstream drug markets—primarily appearing in research contexts—has limited explicit scheduling, but its entactogenic effects prompt scrutiny under anti-NPS frameworks in Europe and elsewhere.^[6]

Recreational use and availability

3,4-Ethylenedioxy-N-methylamphetamine (EDMA) exhibits limited recreational use, confined largely to niche communities exploring research chemicals as alternatives to more established entactogens like MDMA. Users report mild empathogenic effects, including enhanced sociability and sensory appreciation, attributed to its action as a serotonin releaser at concentrations around 1 µM in synaptosomal assays, with comparatively weaker dopamine release.^[1] These properties stem from its structural analogy to MDMA, featuring an ethylenedioxy ring substitution, though clinical or large-scale user data on subjective experiences remain scarce due to its obscurity.^[6] Availability of EDMA is primarily through specialized chemical suppliers catering to forensic, pharmacological, and analytical research needs, where it is distributed as a hydrochloride salt with purity exceeding 98%.^[1] ^[20] It does not appear in mainstream illicit markets or consumer-oriented formulations, unlike MDMA, and detections in harm reduction testing programs, such as those in Spain, are infrequent, often as trace adulterants or experimental submissions rather than primary substances.^[21] This restricted distribution aligns with its status as an uncommon synthetic, with no evidence of widespread production or trafficking for recreational purposes.^[15]