Hubbry Logo
4-Fluoromethamphetamine4-FluoromethamphetamineMain
Open search
4-Fluoromethamphetamine
Community hub
4-Fluoromethamphetamine
logo
8 pages, 0 posts
0 subscribers
Be the first to start a discussion here.
Be the first to start a discussion here.
4-Fluoromethamphetamine
4-Fluoromethamphetamine
4-Fluoromethamphetamine
View on Wikipedia
from Wikipedia
4-Fluoromethamphetamine
Ball-and-stick model of the 4-fluoromethamphetamine molecule
Legal status
Legal status
  • AU: S9 (Prohibited substance)
  • CA: Schedule I[1]
  • DE: Anlage II (Authorized trade only, not prescriptible)
  • UK: Class A
  • US: Unscheduled
Identifiers
  • (RS)-1-(4-Fluorophenyl)-N-methylpropan-2-amine
CAS Number
PubChem CID
ChemSpider
UNII
CompTox Dashboard (EPA)
ECHA InfoCard100.254.220 Edit this at Wikidata
Chemical and physical data
FormulaC10H14FN
Molar mass167.227 g·mol−1
3D model (JSmol)
  • Fc1ccc(cc1)CC(NC)C
  • InChI=1S/C10H14FN/c1-8(12-2)7-9-3-5-10(11)6-4-9/h3-6,8,12H,7H2,1-2H3 checkY
  • Key:YCWZPIHKUYZTFM-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

4-Fluoromethamphetamine (4-FMA) is a stimulant drug related to methamphetamine and 4-fluoroamphetamine. It has been reported to be sold as a designer drug, but little is known about its pharmacology or toxicology.[2] It was first detected from legal highs sold in Japan in 2006 and became illegal to sell or to possess for the purpose of distribution (although not to simply possess for personal use) in Japan in 2008.[3] It was initially reported to be contained as an ingredient in some of the range of party pills sold internationally by the Israeli company Neorganics from around 2006 onwards, but this was later shown to be incorrect and this ingredient was eventually identified as the closely related compound 2-fluoromethamphetamine.[4]

Pharmacology

[edit]

4-FMA is a CYP450 inhibitor. It reduces the metabolism of methamphetamine, which has the effect of increasing its potency, duration and systemic toxicity while also reducing its cellular toxicity.[5]

[edit]

Australia

[edit]

4-FMA is considered a Schedule 9 substance in Australia under the Poisons Standard (October 2015).[6] A Schedule 9 substance is a substance which may be abused or misused, the manufacture, possession, sale or use of which should be prohibited by law except when required for medical or scientific research, or for analytical, teaching or training purposes with approval of Commonwealth and/or State or Territory Health Authorities.[6]

Canada

[edit]

As of 1996, 4-FMA is a controlled substance in Canada, due to being an analog of methamphetamine.[1]

China

[edit]

As of October 2015 4-FMA is a controlled substance in China.[7]

Finland

[edit]

Scheduled in the "government decree on narcotic substances, preparations and plants" and is therefore illegal.[8]

United States

[edit]

As a close analog of scheduled controlled substance,[2] sale or possession of 4-FMA could be potentially be prosecuted under the Federal Analogue Act if intended for human consumption.[9]

See also

[edit]

References

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

4-Fluoromethamphetamine

View on Grokipedia
from Grokipedia

4-Fluoromethamphetamine (4-FMA), chemically known as 1-(4-fluorophenyl)-N-methylpropan-2-amine, is a synthetic and a fluorinated of with the molecular formula C10H14FN. As a novel psychoactive substance, it exhibits and entactogenic effects akin to other amphetamines, primarily through interactions with monoamine systems, though specific pharmacological profiles remain incompletely characterized due to limited . In preclinical models, 4-FMA demonstrates locomotor stimulation, albeit weaker than , and shares discriminative stimulus effects with classical s, indicating subjective similarity in perceptual and reinforcing properties. It has been detected in recreational drug markets and is controlled under Schedule I in certain U.S. states, reflecting concerns over abuse potential and toxicity, including hepatotoxic effects observed mediated by metabolism. Reports associate its use with risks such as cardiovascular strain and potential for severe adverse events, underscoring the hazards of unregulated novel s.

History

Discovery and Early Research

4-Fluoromethamphetamine (4-FMA), a para-fluorinated analog of , was likely first synthesized during late 20th-century structure-activity relationship (SAR) studies on substituted amphetamines, though precise documentation of its initial preparation remains limited before the early 2000s. Such investigations typically involved modifying the phenyl ring of (1-phenyl-N-methylpropan-2-amine) with halogens like to probe alterations in potency, selectivity for release, and metabolic stability, building on foundational work with non-methylated analogs. The fluorine substitution at the para position parallels earlier explorations with (4-FA), synthesized in the early 1940s as part of analog research devoid of therapeutic intent. Unlike , developed in 1893 for potential medicinal use before recreational diversion, 4-FMA appears absent from pre-2000 pharmacological screening programs, with no peer-reviewed reports of systematic early evaluation. Sparse data from analog studies indicate fluorinated methamphetamine derivatives, including para-substituted variants, exhibit methamphetamine-like locomotor stimulation and discriminative stimulus effects in preclinical models, informing SAR without advancing clinical development. These findings underscore empirical efforts to map causal relationships between molecular modifications and activity, prioritizing mechanistic insight over application.

Emergence as a Designer Drug

4-Fluoromethamphetamine (4-FMA) emerged as a novel psychoactive substance (NPS) in the illicit drug market during the early , primarily through online vendors selling it as a and analog to . By 2011, it was documented among derivatives offered in pill form on global markets, with reports from multiple countries indicating its availability as an alternative to regulated amphetamines. Users and vendors described it as producing euphoric and energizing effects akin to but with potentially reduced due to the fluorine substitution, driving initial interest amid crackdowns on substances like , which faced EU-wide controls in December 2010 following its rise in popularity from 2007 onward. Detections of 4-FMA in drug seizures and testing began surfacing in and by 2012, as reported to the Office on Drugs and Crime (UNODC), with instances noted in , , , , and the . This timeline aligned with user migration from banned synthetic stimulants, including cathinones and earlier fluoroamphetamines like (which entered European markets around 2007), as recreational consumers sought chemically novel compounds to circumvent emerging analog legislation. The substance's structural deviation from controlled precursors enabled temporary evasion of specific prohibitions, though its low initial prevalence limited comprehensive early warning data from systems like the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA). Market drivers included the rapid proliferation of NPS following regulatory gaps post-2010, with 4-FMA ranking among the top-reported phenethylamines in UNODC questionnaires by 2012, reflecting 18 notifications across regions. Its appeal stemmed from anecdotal reports of balanced properties without the intensity of , attracting users in recreational settings, though verified seizure quantities remained modest compared to established drugs like .

Chemistry

Molecular Structure and Properties

4-Fluoromethamphetamine (4-FMA), also known as 1-(4-fluorophenyl)-N-methylpropan-2-amine, possesses the molecular formula C₁₀H₁₄FN and a molecular weight of 167.23 g/mol.7-9-3-5-10(11)6-4-9/h3-6%2C8%2C12H%2C7H2%2C1-2H3) The compound is structurally derived from by substitution of a atom at the 4-position of the phenyl ring, resulting in a para-fluorinated analog. This modification distinguishes it from (C₁₀H₁₅N), which lacks the , and from (4-FA; C₉H₁₂FN), which omits the N-methyl group on the . The substitution enhances the compound's relative to unsubstituted , attributable to the electronegative properties of that influence and intermolecular interactions in the aromatic system. Physical properties such as remain undetermined for the form, though the compound is typically handled as a salt in analytical contexts. Limited data on indicate typical behavior for derivatives, with in organic solvents and formation of salts for aqueous handling, though specific values are not well-documented in available chemical databases. Stability under standard storage conditions aligns with that of similar phenethylamines, requiring protection from light and moisture to prevent degradation, as inferred from general analytical protocols for fluorinated analogs.

Synthesis and Precursors

4-Fluoromethamphetamine (4-FMA) is typically synthesized through of 4-fluorophenylacetone (also known as 4-fluorophenyl-2-propanone) with , employing reducing agents such as in methanolic solution under acidic conditions. This method mirrors established routes for production, where the precursor undergoes formation followed by reduction to yield the secondary product. An alternative pathway involves the reduction of 4-fluoroephedrine, a fluorinated analog of , which serves as a direct precursor via and stereospecific conversion to the N-methylated . Clandestine laboratories adapt these approaches using readily available reagents, though selective para-fluorination of non-fluorinated precursors remains uncommon due to technical difficulties in achieving without specialized equipment. Key precursors include 4-fluorophenylacetone, classified as an analytical reference standard for synthesis monitoring, and 4-fluoroephedrine, both of which are subject to scrutiny under international precursor control frameworks analogous to those for phenyl-2-propanone. Impurities arising from incomplete reactions or suboptimal purification in illicit production—such as residual ketones, diastereomeric byproducts, or over-reduced amines—have been characterized in forensic contexts via gas chromatography-mass spectrometry (GC-MS) analysis of seized materials, aiding in route attribution.

Pharmacology

Mechanism of Action

4-Fluoromethamphetamine (4-FMA) acts primarily as a substrate at the (DAT), (NET), and (SERT), facilitating the efflux of , , and serotonin into the synaptic cleft while concurrently inhibiting their , thereby elevating extracellular monoamine levels. This dual mechanism of release promotion and uptake blockade mirrors that of , where the compounds enter monoaminergic neurons via the transporters and trigger vesicular monoamine transporter 2 (VMAT2)-mediated depletion of cytosolic stores, leading to reverse transport. The para-fluoro substitution on the phenyl ring introduces electronic and that modulate transporter interactions compared to unsubstituted , potentially enhancing and altering binding kinetics without fundamentally changing the substrate profile. In vitro assessments reveal 4-FMA exhibits markedly higher potency at NET (30- to 40-fold greater than at DAT or SERT), with comparable affinities at DAT and SERT, suggesting a noradrenergic bias that may contribute to pronounced sympathomimetic stimulation. Structure-activity relationship studies on fluorinated amphetamines indicate that para-halogenation generally preserves or slightly augments DAT affinity relative to amphetamine analogs, correlating with enhanced locomotor and reinforcing effects, though direct EC50 values for 4-FMA-induced release remain sparsely documented. Binding data for related para-fluorinated phenethylamines show moderate interactions with serotonin receptors (5-HT1A, 5-HT2A, 5-HT2C), but these occur at higher concentrations than transporter effects, implying minimal direct serotonergic receptor-mediated contributions to primary actions. Direct pharmacological profiling of 4-FMA is limited owing to its emergence as a designer drug post-2010, with inferences drawn from analogs like (4-FA), which demonstrates balanced monoamine release (NET-favored but equipotent across transporters at submicromolar levels) absent strong affinity for hallucinogenic targets such as 5-HT2A agonists. This profile underscores 4-FMA's classification among substituted amphetamines prioritizing transporter-mediated efflux over receptor agonism, distinguishing it from entactogens or psychedelics with prominent postsynaptic signaling.

Pharmacokinetics and Metabolism

4-Fluoromethamphetamine (4-FMA) is metabolized primarily in the liver by enzymes, with catalyzing N-demethylation to the (4-FA). and also participate in its biotransformation, as inhibition of these isoforms shifts the concentration-response profile in hepatoma cell models. This metabolic route resembles that of , where -mediated N-demethylation produces . The resulting metabolites, including 4-FA, are excreted renally and detectable in , supporting in intoxication cases, though human kinetics specific to 4-FMA remain uncharacterized. In vitro evidence points to potential CYP450 inhibition by 4-FMA itself, which could prolong exposure to co-administered substrates like . Human pharmacokinetic data are scarce owing to 4-FMA's emergence as a rather than a pharmaceutical; user reports describe oral onset within 20–40 minutes and total duration of 4–8 hours, implying efficient gastrointestinal absorption akin to other amphetamines. Variability in activity, including poor metabolizer phenotypes, likely influences clearance rates, as observed with . No quantitative measures of , , or plasma have been reported for 4-FMA.

Effects

Subjective and Psychological Effects

Users report that 4-fluoromethamphetamine (4-FMA) elicits a blend of and entactogenic effects, characterized by , heightened focus, and subtle enhancement, distinguishing it from the more purely stimulation of and the pronounced serotonergic entactogenesis of . These subjective experiences position 4-FMA intermediate in profile, with greater emphasis on motivational drive at moderate doses (e.g., 50-100 mg oral) compared to analogs like (4-FA). Euphoria manifests dose-dependently, often described as a warm, rolling sensation akin to at thresholds above 125 mg, attributed to combined and serotonin release, though less intense and shorter-lived than with . Enhanced focus and cognitive productivity are frequently noted during the peak phase (2-5 hours post-oral ingestion), facilitating tasks requiring sustained attention, yet users characterize it as a suboptimal due to inconsistent clarity. Mild empathy augmentation promotes sociability and emotional openness, particularly in social contexts, without the profound interpersonal bonding of entactogens. Adverse psychological effects include anxiety and , which intensify at higher doses (e.g., >150 mg) or with rapid routes like , where onset accelerates to 5-15 minutes but heightens emotional volatility. These negative states are exacerbated by polydrug combinations, such as with or psychedelics, potentially leading to acute distress or delusional thinking. Compared to 4-FA, 4-FMA exhibits lower psychedelic potential, with minimal visual distortions or introspective depth, favoring functional stimulation over hallucinatory elements. Experience variability arises from administration route and set/setting; oral dosing yields smoother, longer-lasting effects (total duration 4-8 hours, aftereffects up to 12 hours), while shortens duration (3-6 hours) but amplifies initial intensity and risk of unease. Self-reported accounts highlight context-dependent outcomes, including post-peak cognitive fatigue or regretful realizations, underscoring individual differences in tolerance and expectation.

Physical and Physiological Effects

4-Fluoromethamphetamine (4-FMA), as a , elicits sympathomimetic effects including elevated and , mirroring patterns seen in intoxication and related fluorinated analogs. Emergency department data on (4-FA), a demethylated structural relative often confounded with 4-FMA in illicit samples, document (heart rates exceeding 100 beats per minute in over 70% of cases), (systolic pressures above 140 mmHg in approximately 50% of presentations), and associated symptoms like agitation and diaphoresis as hallmarks of an exaggerated . These cardiovascular responses stem from peripheral alpha- and beta-adrenergic stimulation, with empirical observations from intoxication cases indicating peak effects within 1-2 hours post-ingestion at doses of 100-200 mg. Hyperthermia and disrupted represent additional physiological perturbations, with body temperatures rising to 38-40°C in acute exposures akin to 4-FMA, exacerbated by environmental factors in recreational settings. derivatives, including fluorinated variants, impair heat dissipation via and increased metabolic rate, contributing to risks documented in case series of polydrug events involving physical exertion. Pupillary dilation () and tremors are consistently reported in fluoroamphetamine intoxications, with light reflex attenuation observed in driving-under-influence cases involving 4-FA at serum concentrations of 0.05-0.2 mg/L. Appetite suppression occurs prominently, with anorectic effects persisting for 4-8 hours post-administration, attributable to central and noradrenergic enhancement observed in amphetamine-class . Tactile sensitivity may heighten mildly, though empirical data from analog studies indicate this is subdued relative to entactogens like , with users noting enhanced skin perception without pronounced sensory euphoria in self-reports corroborated by stimulant profiles.

Toxicity and Health Risks

Acute Toxicity

In acute intoxications, 4-fluoromethamphetamine (4-FMA) primarily elicits sympathomimetic toxicity, manifesting as , , agitation, and , consistent with its structural similarity to and other amphetamine derivatives. These effects arise from its potent inhibition of monoamine transporters, leading to elevated catecholamine levels, though direct human case series for isolated 4-FMA exposures remain limited, with most reports involving polydrug contexts. Cardiovascular complications predominate in documented presentations, including exaggerated elevations observed in related fluoroamphetamine intoxications, potentially moderated by fluorine substitution's impact on metabolic defluorination and reduced serotonergic potency relative to non-fluorinated analogs like . One retrospective analysis of cases noted frequent headaches and , attributing these to alpha-adrenergic agonism, with 4-FMA possibly contributing in misidentified exposures due to analytical overlap. Hepatotoxicity has been evidenced , where 4-FMA exposure to human hepatocytes induced dose-dependent , disrupting cellular integrity through and pathways, mediated by enzymes , , and CYP3A4. This metabolic activation generates reactive intermediates that elevate activity and compromise , suggesting acute liver injury risk at high doses, though human confirmations are absent. Overdose presentations occasionally include severe outcomes like unresponsiveness and respiratory depression in polydrug scenarios, as in a reported case combining 4-FMA with 3-MMC, necessitating urgent supportive care. Postmortem analyses have identified 4-FMA in 13 stimulant-related fatalities, primarily acute intoxications without chronic indicators, underscoring its contribution to cardiovascular collapse but highlighting a paucity of isolated lethality data compared to . No (LD50) has been established for 4-FMA in animal or human models, limiting precise dose-response extrapolations. Rare combination reports suggest potential for serotonin syndrome-like symptoms, but these lack verification for 4-FMA monotherapy.

Long-Term and Chronic Risks

Chronic administration of and its analogs has been associated with , characterized by long-term depletion of in striatal regions and leading to neuronal damage, as demonstrated in preclinical models where repeated dosing reduced density by up to 50%. Given 4-FMA's structural similarity as a fluorinated derivative, with comparable potency at transporters, analogous mechanisms may contribute to cumulative monoamine system impairment, though the fluorine substitution could alter and bioactivation pathways, potentially mitigating or exacerbating toxicity relative to unsubstituted . Direct longitudinal data on 4-FMA remain unavailable, limiting causal inferences. Repeated sympathomimetic effects from 4-FMA, including elevated heart rate and blood pressure akin to those of amphetamine-class stimulants, may impose chronic cardiovascular strain, with epidemiological patterns in chronic users showing elevated incidence of and . Fluorinated variants like 4-FA have produced acute cardiac complications such as in case reports, suggesting a class predisposition to cumulative myocardial remodeling under sustained exposure, though 4-FMA-specific chronic outcomes are undocumented. In vitro assays indicate 4-FMA elicits via , , and metabolism, involving reactive intermediates that compromise viability, which could manifest as progressive liver dysfunction in scenarios of frequent dosing. Heavy users, including those employing methamphetamine analogs, exhibit cognitive deficits in executive function and memory per and neuropsychological assessments, potentially extending to 4-FMA through shared monoaminergic disruption; however, user self-reports occasionally describe perceived productivity gains, contrasting empirical findings and likely attributable to acute stimulation rather than sustained benefit. Preclinical fluorinated data, such as for 3-FMA, further support risks of accumulation and microglial activation with repeated use.

Overdose and Emergency Presentations

Overdose presentations of 4-fluoromethamphetamine (4-FMA) remain rare in clinical and forensic records, with documented cases predominantly involving polydrug intoxication that confounds direct attribution of symptoms or outcomes to 4-FMA alone. A fatal intoxication reported in 2025 involved 4-FMA alongside 2-methylmethcathinone, O-desmethyltramadol, and bromazolam, where postmortem toxicology confirmed multi-substance contributions to respiratory depression and cardiovascular collapse, highlighting the challenges in isolating 4-FMA's role. Similarly, other postmortem analyses have detected 4-FMA in blood and urine via ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS), often in combination with other novel psychoactive substances (NPS), with blood concentrations varying based on unpublished forensic data from intoxication and fatality scenarios. Toxicological confirmation of 4-FMA has occurred in and samples from suspected driving-under-the-influence (DUI) and acute intoxication incidents since the early 2010s, typically through targeted screening for analogs, though specific symptomatic details are sparse due to co-ingestants. Clinical management mirrors that of sympathomimetic overdoses, emphasizing supportive care including benzodiazepines for agitation or seizures, external cooling for , intravenous fluids for hydration, and continuous monitoring for arrhythmias or ; no 4-FMA-specific antidotes exist. Outcomes generally favor survival with prompt intervention, as isolated 4-FMA fatalities are uncommon compared to opioids, with poison center and data reflecting low lethality in NPS exposures overall.

Dependence and Abuse Potential

Addiction Liability

4-Fluoromethamphetamine (4-FMA) exhibits high abuse potential through its capacity to enhance release in the mesolimbic reward pathway, mirroring the mechanisms of Schedule I stimulants like . This neurochemical action promotes and motivational effects akin to those observed in other substituted amphetamines, where extracellular surges drive behavioral . Preclinical studies on fluorinated methamphetamine analogs demonstrate self-administration in rodent models, underscoring their reinforcing properties. For example, 3-fluoromethamphetamine (3-FMA) elicited robust intravenous self-administration in rats at 0.1 mg/kg/infusion under fixed-ratio schedules, with intake escalating over sessions and producing locomotor sensitization indicative of reward pathway activation. Although direct self-administration data for 4-FMA remains unavailable, its regioisomeric similarity to 3-FMA and production of methamphetamine-like discriminative stimulus effects in rats (ED50 = 7.38 mg/kg for locomotor activity) imply comparable reinforcing efficacy, warranting caution in extrapolating abuse liability. Related fluorinated amphetamine 4-fluoroamphetamine (4-FA) elevates subjective drug liking and wanting in s following acute 100 mg dosing, with peak effects at 1 hour correlating to heightened abuse risk via reward anticipation rather than impulsivity. Genetic vulnerabilities to addiction, including variants in (DAT1) and receptor genes that modulate clearance and signaling, extend to 4-FMA without evidence of distinct mechanisms, as no compound-specific pharmacogenomic data contradicts generalized amphetamine models. Limited epidemiological data on 4-FMA precludes definitive human reinforcement profiles, but analog evidence supports empirical classification alongside high-potency stimulants.

Withdrawal and Tolerance

Tolerance to 4-fluoromethamphetamine (4-FMA) develops rapidly upon repeated use, typically within days, as neuroadaptations in the diminish responsiveness, requiring progressively higher doses to elicit comparable and entactogenic effects. This tolerance buildup aligns with patterns observed in analogs, where chronic exposure leads to downregulation of transporters and receptors. User reports indicate that -specific tolerance halves within 3–7 days of , with full dissipation to baseline requiring 1–2 weeks, while entactogenic components may persist longer. Cross-tolerance exists with other , reducing their efficacy following 4-FMA exposure. Withdrawal from 4-FMA, following abrupt cessation after prolonged use, manifests as psychological and physical rebound symptoms including depression, profound fatigue, , irritability, and intense cravings, akin to those in dependence but potentially attenuated by 4-FMA's partial serotonergic activity. These effects stem from depleted monoamine stores and hypersensitive postsynaptic receptors, with drawn from analog studies and aggregated user cessation accounts. Acute withdrawal phase endures 7–14 days, during which symptoms peak in the first week before subsiding, though protracted and mood disturbances may extend beyond. Dependence liability is moderate, primarily psychological, with risk elevated by the drug's rewarding profile but limited by sparse clinical data on chronic human use.

International Controls

4-Fluoromethamphetamine (4-FMA) is not explicitly scheduled under the 1971 , which lists in Schedule II but does not include fluorinated analogs such as 4-FMA. This absence reflects broader challenges in international drug control treaties, which focus on predefined lists rather than rapidly evolving new psychoactive substances (NPS), often leaving coverage to national implementations or analog provisions where applicable domestically. As an NPS, 4-FMA has been monitored by the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) since at least 2010, when it was first detected and reported through the EU Early Warning System in collaboration with . The United Nations Office on Drugs and Crime (UNODC) similarly tracked it via global questionnaires on NPS by 2012, noting its emergence alongside other synthetic stimulants. These monitoring efforts, including EMCDDA-Europol annual reports and UNODC's Early Warning Advisory, have documented 4-FMA in seizures, user reports, and forensic cases, but have not led to a WHO critical review or Commission on Narcotic Drugs recommendation for international scheduling as of 2024. UNODC reports highlight ongoing detections, such as in post-mortem analyses and the Early Warning System from 2020 to 2023, underscoring 4-FMA's persistence despite lacking binding global controls. This gap in coverage for structural analogs of controlled amphetamines has prompted risk assessments at the regional level, informing national bans rather than uniform international prohibition.

United States

In the , 4-fluoromethamphetamine (4-FMA) is not explicitly scheduled as a controlled substance under the federal as of October 2025. However, it falls under the purview of the (21 U.S.C. § 813), which deems substances with substantially similar chemical structures and pharmacological effects to Schedule I or II controlled substances—such as (Schedule II)—to be treated equivalently when manufactured, distributed, or possessed with intent for human consumption. This applicability has enabled federal prosecutions for 4-FMA distribution and possession in cases involving new psychoactive substances (NPS). The (DEA) has authority under emergency scheduling provisions (21 U.S.C. § 811(h)) to temporarily place NPS like 4-FMA into Schedule I if evidence of imminent hazard emerges, though no such action has been taken specifically for 4-FMA to date. 4-FMA lacks any currently accepted medical use in treatment in the United States, consistent with evaluations of analogous fluorinated amphetamines. Scheduling efforts for related fluorinated stimulants provide context for potential future controls on 4-FMA. In June 2025, the DEA proposed permanent placement of —a demethylated analog of 4-FMA—into Schedule I, citing its high abuse potential, absence of accepted medical use, and lack of safety for use under medical supervision, with public comments closing on July 3, 2025. This mirrors the three-factor analysis under the for emerging stimulants detected in NPS markets, and similar scrutiny applies to 4-FMA given its structural proximity to and reports of forensic detection in U.S. drug seizures alongside other synthetic amphetamines. The DEA's Special Surveillance List, updated in 2025, tracks such NPS for abuse patterns, informing potential emergency or permanent scheduling. State-level regulations vary, with some jurisdictions explicitly enumerating 4-FMA as a . In , it is classified as a Schedule I substance under § 54.1-3446 of the Code of Virginia, prohibiting its manufacture, distribution, or possession. Louisiana similarly lists 4-FMA in Schedule I pursuant to R.S. 40:964, subjecting it to the same penalties as other high-abuse-potential drugs without medical utility. Other states, such as , address 4-FMA through broader analog provisions and synthetic drug statutes (e.g., Fla. Stat. § 893.03), which incorporate federal analog interpretations and ban structural variants of controlled amphetamines, though without explicit naming. Forensic analyses of NPS seizures by agencies like the DEA have identified fluorinated methamphetamines, including analogs like 4-FMA, in materials misrepresented as legal highs or , underscoring ongoing enforcement focus.

European Union and Specific Countries

In the , 4-fluoromethamphetamine (4-FMA) is monitored by the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) through its on new psychoactive substances, with detections linked to its emergence as a following national bans on related fluoroamphetamines in the . While not subject to EU-wide scheduling under Council Decisions, national authorities have imposed controls based on its structural similarity to controlled amphetamines and reports of substitution use, including potential cardiovascular risks inferred from intoxication data on analogous compounds presenting with and in emergency settings. In the , 4-FMA was classified as a under the Opium Act in 2017 or 2018, extending prohibitions from similar fluoroamphetamines like (banned in May 2017) to address deliberate evasion via analogs and mitigate associated health harms from recreational use. The controls 4-FMA under the , which criminalizes the production, supply, and possession with intent to supply any substance intended for human consumption that produces psychoactive effects, irrespective of specific naming; this blanket approach targeted novel stimulants like 4-FMA to curb market proliferation post-2010s detections. Germany regulates 4-FMA via the New Psychoactive Substances Act (NpSG) enacted in 2016, which prohibits substances exhibiting abuse potential akin to narcotics but not previously listed under the Narcotics Act (BtMG), with controls justified by of stimulant diversion and toxicity risks from related fluorinated amphetamines reported in forensic and clinical contexts.

Other Jurisdictions

In , 4-fluoromethamphetamine (4-FMA) was classified as a in October 2015 under regulations targeting new psychoactive substances, following initial detections in illicit markets. This scheduling aligned with broader efforts to regulate synthetic stimulants amid rising synthetic drug production in . In , 4-FMA is designated a Schedule 9 prohibited substance under the Poisons Standard, effective from October 2015, subjecting it to designer drug provisions that enable provisional bans on novel psychoactive substances pending full legislative review. Enforcement emphasizes border controls and analog restrictions, with detections linked to online sales of . regulates 4-FMA as a controlled substance since 1996, treating it as an analog to under the , which prohibits possession, trafficking, and production of structurally similar stimulants without distinguishing the N-methyl group explicitly. This analog approach reflects precautionary controls on fluorinated amphetamine variants detected sporadically in forensic samples. Data on controls in and remain limited, with no widespread scheduling reported; however, 4-FMA has appeared in international drug seizures, often alongside precursors, prompting regional focus on disruptions rather than end-product bans. In parts of beyond , such as where 4-FMA was first marketed as a legal high in 2006, subsequent detections have led to de facto prohibitions under general laws, though enforcement varies by prioritizing precursor chemicals like 4-fluoroephedrine over the synthesized compound.

Research Developments

Preclinical Studies

investigations have established hepatotoxic potential for 4-fluoromethamphetamine (4-FMA). A 2021 study exposed primary hepatocytes, HepaRG cells, and HepG2 cells to 4-FMA concentrations from 37 μM to 30 mM over 24 hours, yielding EC50 values for of 2.21 mM, 5.59 mM, and 9.57 mM, respectively, as measured by . Toxicity involved CYP2E1-mediated bioactivation (with inhibition shifting response curves rightward, indicating toxification), alongside detoxification by and ; downstream effects included mitochondrial membrane depolarization, ATP depletion, elevated reactive oxygen and nitrogen species, compromised thiol defenses, heightened initiator and effector caspase activity promoting and , and loss of plasma membrane integrity. Pharmacological profiling in rodents confirms 4-FMA's stimulant-like actions via monoamine systems. In male Swiss-Webster mice subjected to open-field assays, 4-FMA elicited dose-dependent locomotor stimulation (ED50 = 7.38 mg/kg), though maximal activity counts (2200–3980) were lower than methamphetamine's (5905–7758), with potency ranking below 2-fluoromethamphetamine but comparable to other positional isomers. This profile aligns with prior indications of 4-FMA as a substrate-type releaser at dopamine, serotonin, and norepinephrine transporters, favoring serotonergic activity relative to some amphetamine analogs (lower DAT:SERT inhibition ratio). Discriminative stimulus assays in male Sprague-Dawley rats trained to recognize further delineate 4-FMA's neuropharmacology. Under a fixed-ratio 10 , 4-FMA produced full substitution (ED50 = 0.71 mg/kg), mirroring methamphetamine's effects and implying shared mechanisms of monoamine efflux underlying abuse-related cues, distinct from but overlapping with serotonergic profiles of analogs like . No preclinical data on carcinogenicity or long-term exist.

Human and Epidemiological Data

Limited human data exist on 4-fluoromethamphetamine (4-FMA), primarily from sporadic case reports of acute intoxications and forensic detections, reflecting its status as a niche novel psychoactive substance with no dedicated randomized controlled trials due to regulatory scheduling and ethical constraints on studying controlled stimulants. Intoxication cases often involve polydrug use, complicating attribution, but isolated detections link 4-FMA to severe outcomes including and cardiovascular strain, with symptoms such as , , and agitation reported in emergency settings, potentially more pronounced than with unsubstituted due to fluorination's influence on and receptor interactions. No large-scale clinical cohorts document long-term effects, underscoring data gaps compared to established stimulants like , where extensive epidemiological records exist. Epidemiological surveillance reveals low prevalence, with 4-FMA appearing infrequently in global monitoring. United Nations Office on Drugs and Crime international control exercises in 2024 identified 4-FMA in only one sample across participating labs, indicating minimal circulation relative to . Seizure data from the (2020-2023) and similarly show niche persistence post-bans, often as an in ecstasy or markets rather than a primary . Wastewater analyses in the detected 4-FMA on just one occasion in early 2023, contrasting with widespread signals and highlighting its limited population-level footprint. U.S. laboratory data from 2022 noted co-occurrence with other fluoroamphetamines in positives, but overall detections remain rare, suggesting harm profiles—self-reported by users as milder than for functional stimulation—are unverified by robust population studies and may reflect in anecdotal accounts.

References

  1. https://pubchem.ncbi.nlm.nih.gov/compound/4-Fluoromethamphetamine
  2. https://pubmed.ncbi.nlm.nih.gov/34655687/
  3. https://pubmed.ncbi.nlm.nih.gov/40553972/
  4. https://law.justia.com/codes/alabama/title-20/chapter-2/article-2/section-20-2-23/
  5. https://pmc.ncbi.nlm.nih.gov/articles/PMC3965957/
  6. https://pubmed.ncbi.nlm.nih.gov/35562170/
  7. https://researchonline.ljmu.ac.uk/id/eprint/7405/
  8. https://www.unodc.org/documents/scientific/NPS_Report.pdf
  9. https://onlinelibrary.wiley.com/doi/abs/10.1111/add.12932
  10. https://www.chemspider.com/Chemical-Structure.9919721.html
  11. https://www.sciencedirect.com/science/article/abs/pii/S0300483X21003103
  12. https://www.swgdrug.org/Monographs/4-FMA.pdf
  13. https://www.scirp.org/journal/paperinformation?paperid=30439
  14. https://www.sciencedirect.com/science/article/abs/pii/S0924977X14003599
  15. https://www.caymanchem.com/product/9003642/4-fluorophenylacetone
  16. https://academic.oup.com/jat/article/38/5/295/2797981
  17. https://www.sciencedirect.com/science/article/pii/S1570023221001550
  18. https://www.sciencedirect.com/science/article/abs/pii/S0022356525398307
  19. https://pubmed.ncbi.nlm.nih.gov/31785931/
  20. https://psychonautwiki.org/wiki/4-FMA
  21. https://erowid.org/experiences/exp.php?ID=118262
  22. https://pmc.ncbi.nlm.nih.gov/articles/PMC9512775/
  23. https://onlinelibrary.wiley.com/doi/full/10.1002/emp2.12813
  24. https://www.sciencedirect.com/science/article/abs/pii/S037907381100171X
  25. https://www.researchgate.net/publication/237823004_Combination_effects_of_amphetamines_under_hyperthermia_-_the_role_played_by_oxidative_stress
  26. https://pmc.ncbi.nlm.nih.gov/articles/PMC4835722/
  27. https://www.unodc.org/res/scientists/ewa/Current_NPS_Threats_VI.pdf
  28. https://academic.oup.com/jat/article-pdf/41/7/573/19593619/bkx031.pdf
  29. https://www.researchgate.net/publication/355255342_4-Fluoromethamphetamine_4-FMA_induces_in_vitro_hepatotoxicity_mediated_by_CYP2E1_CYP2D6_and_CYP3A4_metabolism
  30. https://pmc.ncbi.nlm.nih.gov/articles/PMC9640761/
  31. https://www.jneurosci.org/content/18/1/419
  32. https://www.sciencedirect.com/science/article/pii/S0014488621001849
  33. https://pmc.ncbi.nlm.nih.gov/articles/PMC2631950/
  34. https://www.sciencedirect.com/science/article/pii/S2352007825000290
  35. https://emedicine.medscape.com/article/812518-treatment
  36. https://jpet.aspetjournals.org/article/S0022-3565%2825%2939830-7/abstract
  37. https://onlinelibrary.wiley.com/doi/10.1111/adb.12846
  38. https://link.springer.com/article/10.1007/s00213-018-4931-7
  39. https://pmc.ncbi.nlm.nih.gov/articles/PMC4465863/
  40. https://pmc.ncbi.nlm.nih.gov/articles/PMC9332474/
  41. https://jamanetwork.com/journals/jamapsychiatry/fullarticle/2608759
  42. https://pubmed.ncbi.nlm.nih.gov/16128721/
  43. https://www.incb.org/documents/Psychotropics/conventions/convention_1971_en.pdf
  44. https://www.euda.europa.eu/system/files/media/publications/documents/644/EMCDDA-Europol_Annual_Report_2010A_281336.pdf
  45. https://www.unodc.org/LSS/Substance/Details/b0d8f5a3-cf4f-4a27-9955-7936dda56389
  46. https://www.oas.org/ext/en/security/early-warnings-system/moduleid/6827/id/1032/lang/1/controller/item/action/download
  47. https://docs.un.org/en/E/CN.7/2024/7
  48. https://www.sciencedirect.com/science/article/pii/S2468170921000424
  49. https://www.sciencedirect.com/science/article/pii/S2667118222000113
  50. https://www.legislation.gov.uk/ukpga/2016/2/contents
  51. https://harmreductionjournal.biomedcentral.com/articles/10.1186/s12954-022-00704-7
  52. https://www.researchgate.net/publication/51098890_Detection_of_the_synthetic_drug_4-fluoroamphetamine_4-FA_in_serum_and_urine
  53. https://www.unodc.org/roseap/uploads/documents/Publications/2023/Synthetic_Drugs_in_East_and_Southeast_Asia_2023.pdf
  54. https://www.abf.gov.au/help-and-support-subsite/CustomsNotices/2018-32.pdf
  55. https://www.canada.ca/en/health-canada/services/publications/healthy-living/new-psychoactive-substances-canada-2023.html
  56. https://www.incb.org/documents/PRECURSORS/TECHNICAL_REPORTS/2017/E_ebook_with_annexes.pdf
  57. https://pubmed.ncbi.nlm.nih.gov/25624004/
  58. https://www.netce.com/course/content/novel-psychoactive-substances-emerging-drugs-of-abuse/96913/2952
  59. https://www.unodc.org/documents/scientific/Summary_report_2024-2_SM_final.pdf
  60. https://research.vu.nl/files/226374832/International_snapshot_of_new_psychoactive_substance_use.pdf
  61. https://www.aegislabs.com/wp-content/uploads/2024/01/Aegis-Clinical-Update-7.2022.pdf
Add your contribution
Related Hubs
User Avatar
No comments yet.