2C-B-FLY

Physical dependence does not occursupported

Hallucinogens are physiologically safe and do not produce dependence or addiction. pmid:14761703

This mechanism is detectable within 24 hours of a single administration and operates independently of β-arrestin-2 recruitmentsupported

Tolerance after single dose... Tolerance mechanism independent of beta-arrestin-2. acschemneuro.2c00170

2C-B-FLY carries an identified risk for vasoconstriction, ischemia, and hypertension due to its potent 5-HT₂B and 5-HT₂A receptor activitysupported

2C-B-FLY indicates predominant hallucinogenic properties and risk for vasoconstriction. bph.13128

Transient blood pressure and heart rate elevations are expected based on the parent compound 2C-B, which produced measurable pressor effects at 20 mg oral in controlled settings.supported

2C-B induced transient pressor effects. cpt.2958

2C-B-FLY demonstrates potential MAO-A inhibition, an unusual property for a phenethylamine psychedelic that elevates the risk of serotonin syndrome in polydrug contextssupported

2C-B-FLY among drugs tested. MAO inhibition cannot be excluded as pharmacological contributor. dta.2494

Tolerance to 2C-B-FLY's effects develops rapidly via 5-HT₂A receptor downregulation in the frontal cortexsupported

DOI caused 5-HT2AR downregulation in frontal cortex. Tolerance after single dose. acschemneuro.2c00170

Administration of 2C-B-FLY produces cross-tolerance with LSD, psilocybin, mescaline, and other 5-HT₂A agonists.partially supported

Cross-tolerance between DOI and LSD. acschemneuro.2c00170

Serotonergic hallucinogens as a class do not produce physical dependence and are not associated with compulsive use patternssupported

Hallucinogens are physiologically safe and do not produce dependence or addiction. pmid:14761703

This risk is compounded by 2C-B-FLY's dual mechanism: direct 5-HT₂A/₂B/₂C agonism combined with potential MAO-A inhibition.supported

2C-B-FLY among drugs tested. MAO inhibition cannot be excluded as pharmacological contributor. dta.2494

Claim in safety — inconclusiveinconclusiveworking →

As a weak serotonin-norepinephrine reuptake inhibitor and μ-opioid agonist, tramadol combined with a serotonergic psychedelic that also inhibits MAO creates multiple converging mechanisms for serotonin accumulationsupported

2C-B-FLY among drugs tested. MAO inhibition cannot be excluded as pharmacological contributor. dta.2494

MAOIs (monoamine oxidase inhibitors) are contraindicated. 2C-B-FLY itself shows MAO-A inhibitory potential; adding exogenous MAO inhibition risks precipitating serotonin syndrome.supported

2C-B-FLY among drugs tested. MAO inhibition cannot be excluded as pharmacological contributor. dta.2494

Because 2C-B-FLY is primarily metabolized by CYP2D6, co-administration with potent CYP2D6 inhibitors (fluoxetine, paroxetine, quinidine, bupropion) may impair clearance and prolong or intensify effectssupported

2C-B-fly WAS metabolised in HLM by CYP2D6 j.toxlet.2018.07.018

Cardiovascular disease: The identified vasoconstriction risk and expected pressor effects make uncontrolled hypertension, coronary artery disease, peripheral vascular disease, and cerebrovascular disease relative-to-absolute contraindications depending on severity.supported

2C-B-FLY indicates predominant hallucinogenic properties and risk for vasoconstriction. bph.13128

Cardiovascular disease: The identified vasoconstriction risk and expected pressor effects make uncontrolled hypertension, coronary artery disease, peripheral vascular disease, and cerebrovascular disease relative-to-absolute contraindications depending on severity.supported

2C-B induced transient pressor effects. cpt.2958

Concurrent serotonergic medications: MAOIs, SSRIs, SNRIs, tramadol, triptans, and lithium are contraindicated due to serotonin syndrome risk and other pharmacodynamic interactions.supported

2C-B-FLY among drugs tested. MAO inhibition cannot be excluded as pharmacological contributor. dta.2494

2C-B-FLY is a serotonergic psychedelic whose primary pharmacological action is partial agonism at the serotonin 5-HT₂A receptor, the receptor subtype responsible for the hallucinogenic effects of 2C-B, LSD, psilocin, and other classical psychedelicspartially supported

They stimulate 5-HT2A receptors especially on neocortical pyramidal cells. pmid:14761703

The compound also shows potent activity at 5-HT₂B and 5-HT₂C receptors and binds trace amine-associated receptor 1 (TAAR1)supported

very potently interacted with 5-HT2 receptors and bound TAAR1. bph.13128

The conformational constraint imposed by the tetrahydrobenzodifuran ring system forces the oxygen atoms into a fixed geometry that models the active binding conformation of the 2,5-dimethoxy groups at 5-HT₂ receptorssupported

Tetrahydrobenzodifuran functionalities employed as conformationally restricted bioisosteres of aromatic methoxy groups in hallucinogenic phenylalkylamines. pmid:8709129

2C-B-FLY is not a monoamine releasersupported

The benzodifuran 2C-B-FLY was not a monoamine releaser bph.13128

Its pharmacological profile indicates predominantly hallucinogenic properties and a risk for vasoconstriction arising from potent 5-HT₂B activity.supported

2C-B-FLY indicates predominant hallucinogenic properties and risk for vasoconstriction. bph.13128

Hepatic metabolism has been characterized in vitro. 2C-B-FLY is metabolized by hepatic enzymes — a critical distinction from its aromatic analog Bromo-DragonFLY, which is resistant to hepatic metabolismsupported

Bromo-dragonfly was not metabolised in HLM or HLC in vitro systems. In contrast, 2C-B-fly WAS metabolised in HLM by CYP2D6 and HLC j.toxlet.2018.07.018

The primary metabolic enzyme is CYP2D6 in human liver microsomes, with additional metabolism occurring in human liver cytosolsupported

2C-B-fly WAS metabolised in HLM by CYP2D6 and HLC j.toxlet.2018.07.018

MAO-A also metabolizes 2C-B-FLY, producing an aldehyde intermediate trapped in vitro using methoxyamine.supported

MAO-A also metabolized 2C-B-fly (aldehyde metabolite). j.toxlet.2018.07.018

Studies of related FLY compounds (2C-E-FLY, 2C-EF-FLY, 2C-T-7-FLY) confirm Phase I metabolism via CYP2D6, CYP3A4, and FMO3, with N-acetylation by NAT1 and NAT2, and deamination by both MAO-A and MAO-Bsupported

Phase I by CYP2D6, 3A4, FMO3. N-acetylation by NAT1, NAT2. MAO-A and B deamination detected. dta.2675

Interindividual variation in metabolism is anticipated due to CYP2D6 polymorphisms — poor metabolizers may experience prolonged or intensified effects.supported

Interindividual variation possible from CYP polymorphisms. dta.2675

First synthesized in 1996 by Monte, Nichols, and colleagues at Purdue University as a molecular probe of the active binding conformation of phenylalkylamine hallucinogens at the 5-HT₂A receptor, 2C-B-FLY entered the research chemical market in the mid-2000s and was first reported to the EMCDDA early warning system in 2007partially supported

Tetrahydrobenzodifuran functionalities employed as conformationally restricted bioisosteres of aromatic methoxy groups in hallucinogenic phenylalkylamines. pmid:8709129

2C-B-FLY acts as a partial agonist at 5-HT₂A receptors with potent activity at 5-HT₂B, 5-HT₂C, and trace amine-associated receptor 1 (TAAR1)partially supported

The benzodifuran 2C-B-FLY was not a monoamine releaser, very potently interacted with 5-HT2 receptors and bound TAAR1. bph.13128

In the mouse head-twitch response assay — validated as a predictor of human hallucinogenic potency (r = 0.9448, n = 36) — 2C-B-FLY (ED₅₀ = 1.79 μmol/kg) is approximately equipotent with 2C-B (ED₅₀ = 2.43 μmol/kg)supported

Strong positive correlation (r=0.9448) between HTR potencies in mice and reported hallucinogenic potencies in humans (n=36). j.neuropharm.2019.107933

In the mouse head-twitch response assay — validated as a predictor of human hallucinogenic potency (r = 0.9448, n = 36) — 2C-B-FLY (ED₅₀ = 1.79 μmol/kg) is approximately equipotent with 2C-B (ED₅₀ = 2.43 μmol/kg)supported

The tetrahydrobenzodifurans DOB-FLY (ED50=0.67 μmol/kg) and 2C-B-FLY (ED50=1.79 μmol/kg) were approximately equipotent with their non-rigid counterparts. j.neuropharm.2018.10.037

Unlike Bromo-DragonFLY, 2C-B-FLY is hepatically metabolized via CYP2D6 and MAO-A.supported

2C-B-fly WAS metabolised in HLM by CYP2D6 and HLC... MAO-A also metabolized 2C-B-fly (aldehyde metabolite). Bromo-dragonfly was not metabolised in HLM or HLC in vitro systems. j.toxlet.2018.07.018

The expected experiential profile — visual distortions, altered cognition, mood intensification, and entactogenic qualities at certain doses — is inferred from class pharmacology and the parent compound's controlled human datasupported

Double-blind placebo-controlled within-subjects study n=22. 2C-B (20mg) vs psilocybin (15mg). 2C-B elicited psychedelic alterations. cpt.2958

2C-B-FLY carries vasoconstriction and hypertension risk via potent 5-HT₂B agonism, and demonstrates potential MAO-A inhibition, elevating serotonin syndrome risk in polydrug contextspartially supported

2C-B-FLY indicates predominant hallucinogenic properties and risk for vasoconstriction. bph.13128

2C-B-FLY carries vasoconstriction and hypertension risk via potent 5-HT₂B agonism, and demonstrates potential MAO-A inhibition, elevating serotonin syndrome risk in polydrug contextssupported

2C-B-FLY among drugs tested. MAO inhibition cannot be excluded as pharmacological contributor. dta.2494

Rapid tolerance develops via 5-HT₂A receptor downregulation within 24 hours of a single dose, with complete cross-tolerance across serotonergic psychedelicspartially supported

Tolerance after single dose. Cross-tolerance between DOI and LSD. DOI caused 5-HT2AR downregulation in frontal cortex. acschemneuro.2c00170

The foundational work by Monte and colleagues established that the tetrahydrobenzodifuranyl aminoalkane series — including compounds structurally equivalent to 2C-B-FLY — exhibited activities at 5-HT₂A, 5-HT₂B, and 5-HT₂C receptors that equaled or surpassed those of the conformationally flexible parent compoundssupported

Compound 7b had ED50=61 nmol/kg in rat LSD discrimination and Ki in nanomolar to subnanomolar range at 5-HT2A, 2B, 2C receptors. pmid:8709129

Rickli and colleagues characterized 2C-B-FLY's receptor pharmacology in the context of novel psychoactive benzofurans, identifying very potent interactions at 5-HT₂A, 5-HT₂B, and 5-HT₂C receptors, TAAR1 binding, and the absence of monoamine transporter activitysupported

2C-B-FLY was not a monoamine releaser, very potently interacted with 5-HT2 receptors and bound TAAR1. bph.13128

For the closely related DOB-FLY (the α-methyl amphetamine analog), Schultz and colleagues reported Ki = 1.0 nM and EC₅₀ = 13 nM at the rat 5-HT₂A receptorsupported

Parent difuranyl compound has Ki=1.0 nM, EC50=13 nM at 5-HT2A. j.bmc.2008.04.030

The HTR assay has been validated as a robust predictor of human hallucinogenic potency, with a correlation coefficient of r = 0.9448 across 36 compounds.supported

Strong positive correlation (r=0.9448) between HTR potencies in mice and reported hallucinogenic potencies in humans (n=36). j.neuropharm.2019.107933

First, the tetrahydrobenzodifurans (FLY compounds) are approximately equipotent with their flexible parent compounds — conformational constraint alone does not increase in vivo potencysupported

The tetrahydrobenzodifurans DOB-FLY (ED50=0.67 μmol/kg) and 2C-B-FLY (ED50=1.79 μmol/kg) were approximately equipotent with their non-rigid counterparts. j.neuropharm.2018.10.037

Second, full aromatization of the fused rings (as in the DragonFLY series) produces a substantial potency increase, with Bromo-DragonFLY approximately 9-fold more potent than 2C-B-FLY in this assay.supported

The benzodifurans DOB-DFLY (ED50=0.20 μmol/kg)... 2C-B-FLY (ED50=1.79 μmol/kg) j.neuropharm.2018.10.037

Pottie and colleagues investigated biased agonism in the related benzodifuran scaffold (Bromo-DragonFLY and N-benzyl NPS), finding markedly different β-arrestin 2 vs. miniGαq responses that indicate functional selectivity within this structural classsupported

Bromo-DragonFLY showed markedly different responses in the two bioassays suggesting biased agonism. j.bcp.2020.114251

Across the 2C/FLY compound series tested, IC₅₀ values ranged 10–125 μM for MAO-A and 1.7–180 μM for MAO-Bpartially supported

IC50 values ranged from 10-125 microM for MAO-A. dta.2494

The closest available proxy comes from the N-benzyl analog 2C-B-Fly-NBOMe in male Wistar rats (subcutaneous administration, 1 mg/kg): peak serum concentrations were detected at 30 minutes post-dose, with peak brain tissue concentrations at 60 minutes (171 ng/g brain tissue)supported

2C-B-Fly-NBOMe (1 mg/kg s.c.) in male Wistar rats. Peak serum concentrations 30 min, brain tissue 60 min post-dose (171 ng/g). fphar.2023.1120419

Noble and colleagues demonstrated that 2C-B-FLY is metabolized by hepatic enzymes, in marked contrast to Bromo-DragonFLY, which is resistant to metabolism in both HLM and HLC preparations.supported

Bromo-dragonfly was not metabolised in HLM or HLC in vitro systems. In contrast, 2C-B-fly WAS metabolised in HLM by CYP2D6 and HLC j.toxlet.2018.07.018

CYP2D6 is the principal cytochrome P450 isoform responsible for Phase I metabolism in human liver microsomessupported

2C-B-fly WAS metabolised in HLM by CYP2D6 j.toxlet.2018.07.018

Studies of structurally related FLY compounds (2C-E-FLY, 2C-EF-FLY, 2C-T-7-FLY) expand the known enzymatic involvement to include CYP3A4 and FMO3 for Phase I reactions, and confirm NAT1 and NAT2 for N-acetylationsupported

Phase I by CYP2D6, 3A4, FMO3. N-acetylation by NAT1, NAT2. dta.2675

Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →

Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →

CYP2D6 polymorphisms introduce significant potential for interindividual variation in 2C-B-FLY metabolismsupported

Interindividual variation possible from CYP polymorphisms. dta.2675

Claim in neuroscience — inconclusiveinconclusiveworking →

The following neural mechanisms are inferred from its classification as a serotonergic psychedelic acting primarily through 5-HT₂A agonism.supported

They stimulate 5-HT2A receptors especially on neocortical pyramidal cells. Activation leads to increased cortical glutamate levels. pmid:14761703

These effects have been demonstrated for structurally related phenethylamines and are expected to apply to 2C-B-FLY based on its 5-HT₂A agonist activity.supported

They stimulate 5-HT2A receptors especially on neocortical pyramidal cells. In vivo imaging shows hallucinogens increase prefrontal cortical metabolism. pmid:14761703

Does 2C-B-FLY exhibit biased agonism at 5-HT₂A (β-arrestin vs. Gαq pathway preference)? Related benzodifuran compounds show functional selectivity, but 2C-B-FLY has not been directly tested.supported

Bromo-DragonFLY showed markedly different responses in the two bioassays suggesting biased agonism. j.bcp.2020.114251

Claim in neuroscience — inconclusiveinconclusiveworking →

Its distinguishing structural feature is the incorporation of the 2- and 5-methoxy groups into a tetrahydrobenzodifuran (tetrahydrobenzo[1,2-b:4,5-b']difuran) ring system, which constrains the oxygen atoms into a fixed spatial orientation relative to the aromatic ringsupported

Tetrahydrobenzodifuran functionalities employed as conformationally restricted bioisosteres of aromatic methoxy groups in hallucinogenic phenylalkylamines. pmid:8709129

The compound occupies a key position in the structure-activity relationship hierarchy of the FLY series. 2C-B-FLY is the ethylamine (non-α-methylated) member, while DOB-FLY is its α-methylamphetamine counterpart, and Bromo-DragonFLY is the fully aromatic benzodifuran analogsupported

The tetrahydrobenzodifurans DOB-FLY (ED50=0.67 μmol/kg) and 2C-B-FLY (ED50=1.79 μmol/kg)... benzodifurans DOB-DFLY (ED50=0.20 μmol/kg) and 2C-B-DFLY (ED50=1.07 μmol/kg) j.neuropharm.2018.10.037

Claim in chemistry — inconclusiveinconclusiveworking →

Claim in chemistry — inconclusiveinconclusiveworking →

The ethylamine-to-amphetamine conversion (2C-B-FLY → DOB-FLY; ED₅₀ 1.79 → 0.67 μmol/kg) produces a ~2.7-fold potency increase — consistent with the established observation that α-methylation increases phenethylamine hallucinogen potency by slowing metabolic deamination and increasing CNS penetration.supported

The tetrahydrobenzodifurans DOB-FLY (ED50=0.67 μmol/kg) and 2C-B-FLY (ED50=1.79 μmol/kg) j.neuropharm.2018.10.037

Bromo-DragonFLY (ED₅₀ = 0.20 μmol/kg) is approximately 9-fold more potent than 2C-B-FLY (ED₅₀ = 1.79 μmol/kg) in the HTR assaysupported

The benzodifurans DOB-DFLY (ED50=0.20 μmol/kg)... 2C-B-FLY (ED50=1.79 μmol/kg) j.neuropharm.2018.10.037

The most safety-relevant comparative finding is the metabolic divergence. 2C-B-FLY is cleared hepatically via CYP2D6 and MAO-A, producing identifiable metabolites in human liver microsomes and cytosolsupported

2C-B-fly WAS metabolised in HLM by CYP2D6 and HLC, main biotransformations being monohydroxylation and N-acetylation. MAO-A also metabolized 2C-B-fly (aldehyde metabolite). j.toxlet.2018.07.018

Bromo-DragonFLY is resistant to metabolism in both preparations and additionally functions as a competitive MAO-A inhibitor (Ki = 0.352 μM)supported

Bromo-dragonfly was not metabolised in HLM or HLC in vitro systems... Bromo-dragonfly is competitive inhibitor of MAO-A (Ki=0.352 microM). j.toxlet.2018.07.018

Mallaroni and colleagues conducted a randomized, placebo-controlled, crossover study comparing 2C-B (20 mg oral) with psilocybin (15 mg oral) in healthy volunteerssupported

Double-blind placebo-controlled within-subjects study n=22. 2C-B (20mg) vs psilocybin (15mg). cpt.2958

The absence of clinical data is typical for novel psychoactive substances that emerged from medicinal chemistry research programs rather than drug development pipelines. 2C-B-FLY was synthesized as a structural probe for receptor pharmacology, not as a therapeutic candidate, and no pharmaceutical sponsor has pursued its clinical development.supported

Tetrahydrobenzodifuran functionalities employed as conformationally restricted bioisosteres of aromatic methoxy groups in hallucinogenic phenylalkylamines. pmid:8709129

No controlled human studies have characterized the subjective effects directly; all experiential data derive from community reports and pharmacological inference from the parent compound.supported

Double-blind placebo-controlled within-subjects study n=22. 2C-B (20mg) vs psilocybin (15mg). cpt.2958

Claim in effects-overview — inconclusiveinconclusiveworking →

Claim in history — inconclusiveinconclusiveworking →