4-HO-EPT

Bergh et al. (2024) identified unique 4-HO-EPT metabolites in a human postmortem blood sample from a case of suspected EPT or 4-HO-EPT intoxicationsupported

unique metabolites identified in human postmortem blood with suspected 4-OH-EPT intoxication. dta.3668

Claim in safety — inconclusiveinconclusiveworking →

Claim in safety — inconclusiveinconclusiveworking →

Claim in safety — inconclusiveinconclusiveworking →

Claim in safety — inconclusiveinconclusiveworking →

Hallucinogen persisting perception disorder (HPPD): Persistent visual disturbances following 5-HT₂A agonist psychedelic use have been documented across the classsupported

HPPD attributed to drugs with agonistic effects on 5-HT2A receptors. Majority of HPPD cases linked to 5-HT2A agonists. j.euroneuro.2014.05.008

Tolerance to the behavioral effects of 5-HT₂A agonist psychedelics develops rapidly — a single dose induces measurable tolerance within 24 hours — through 5-HT₂A receptor downregulation in the frontal cortexpartially supported

Repeated DOI induces progressive HTR decrease... 5-HT2AR downregulation in frontal cortex. acschemneuro.2c00170

Cross-tolerance extends to structurally distinct 5-HT₂A agonist psychedelics (demonstrated between DOI and LSD) but not to non-psychedelic 5-HT₂A agonists such as lisuride.supported

Cross-tolerance between DOI and LSD. No cross-tolerance with non-psychedelic 5-HT2AR agonist lisuride. acschemneuro.2c00170

Tramadol: Tramadol inhibits serotonin reuptake and stimulates serotonin release, in addition to weak mu-opioid agonismsupported

Tramadol inhibits serotonin reuptake and stimulates serotonin release; risk increased when combined with serotonergic agents. 0897190013504957

Co-administration would be expected to dramatically prolong and intensify the experience while creating serious serotonin syndrome risksupported

Evaluates drug-drug interaction risks and serotonin toxicity between psychedelic serotonergic substances and SSRIs/MAOIs. s00213-021-05876-x

SSRIs and SNRIs: Serotonergic antidepressants produce bidirectional interactions with 5-HT₂A agonist psychedelics: pharmacodynamic antagonism (chronic SSRI use downregulates 5-HT₂A, potentially blunting psychedelic effects) and theoretical serotonin toxicity risk at high doses.supported

Evaluates drug-drug interaction risks and serotonin toxicity between psychedelic serotonergic substances and SSRIs/MAOIs. s00213-021-05876-x

Claim in safety — inconclusiveinconclusiveworking →

The primary psychedelic mechanism is agonism at the 5-HT₂A receptor (Ki = 546 nM), confirmed by the compound's 4-hydroxytryptamine scaffold and by class-wide evidence that hallucinogen-like behavioral effects — specifically the head-twitch response in rodents — produced by 4-hydroxytryptamines are abolished by selective 5-HT₂A antagonists. 4-HO-EPT itself induces head-twitch response in mice, directly confirming hallucinogenic potential.partially supported

Psilocin HTR absent in 5-HT2A knockout mice. Locomotor-decreasing effects blocked by 5-HT1A antagonist. 0269881110388326

The primary psychedelic mechanism is agonism at the 5-HT₂A receptor (Ki = 546 nM), confirmed by the compound's 4-hydroxytryptamine scaffold and by class-wide evidence that hallucinogen-like behavioral effects — specifically the head-twitch response in rodents — produced by 4-hydroxytryptamines are abolished by selective 5-HT₂A antagonists. 4-HO-EPT itself induces head-twitch response in mice, directly confirming hallucinogenic potential.supported

4-hydroxy and 4-acetoxy tertiary tryptamines had nanomolar affinity for 5-HT2A and 5-HT1A; only tertiary amines induced head twitch response. acsptsci.2c00177

Meaningful 5-HT₁A co-agonism (Ki = 163 nM) is present. 5-HT₁A activation attenuates psychedelic intensity and contributes anxiolytic and hypothermic effects, as characterized for the structurally related compound psilocin.supported

Locomotor-decreasing effects blocked by 5-HT1A antagonist. Confirms multi-receptor pharmacology of 4-hydroxy tryptamines. 0269881110388326

Claim in pharmacology — inconclusiveinconclusiveworking →

Claim in pharmacology — not_supportednot supportedworking →

Addition of the 4-hydroxyl group substantially increases 5-HT₂A affinity relative to the unsubstituted parent compound, as established across the tryptamine class.supported

4-hydroxylated derivatives showed 25-380-fold selectivity for 5-HT2A over 5-HT1A. pmid:2139186

Addition of the 4-hydroxyl group substantially increases 5-HT₂A affinity relative to the unsubstituted parent compound, as established across the tryptamine class.supported

4-substituted compounds showed high selectivity for 5-HT2AR. EPT described as partial agonist at 5-HT2A. jpet.122.001454

Metabolic pathways have been characterized in vitro using pooled human liver microsomes (pHLM) and in vivo from a postmortem human blood case. In vitro, the primary pathway is double bond formation, accompanied by N-dealkylation (yielding N-ethyltryptamine and N-propyltryptamine fragments), hydroxylation, and carbonylationsupported

4-OH-EPT metabolism dominated by double bond formation, N-dealkylation, hydroxylation, and carbonylation in vitro; unique metabolites identified in human postmortem blood. dta.3668

The in vivo metabolic pattern diverges: hydroxylation predominates over double bond formation, consistent with the in vitro/in vivo metabolic shift observed for the parent compound EPT in rat models.supported

in vivo rat studies show shift to indole ring hydroxylation with N-dealkyl metabolites and glucuronide conjugate. bkaa060

Claim in pharmacology — inconclusiveinconclusiveworking →

Claim in pharmacology — inconclusiveinconclusiveworking →

Tolerance develops rapidly through 5-HT₂A receptor downregulation, and the compound is not considered habit-formingsupported

Repeated DOI induces progressive HTR decrease... 5-HT2AR downregulation in frontal cortex. acschemneuro.2c00170

The compound displays moderate affinity at the 5-HT₂A receptor (Ki = 546 nM), substantially weaker than psilocin (Ki ≈ 100–200 nM in comparable assays), and produces effects lasting 3–7 hours by the oral route at doses in the 15–60 mg range.partially supported

Receptor binding profiles of tryptamine psychedelics with various N,N-dialkyl substitutions including ethyl-propyl (4-OH and 4-AcO-EPT). acsptsci.2c00222

Claim in summary — inconclusiveinconclusiveworking →

Claim in summary — inconclusiveinconclusiveworking →

Claim in summary — inconclusiveinconclusiveworking →

The resulting 5-HT₁A:5-HT₂A selectivity ratio (~1:3) is considerably less selective than prototypical 4-hydroxytryptamines, consistent with larger N-alkyl groups preferentially reducing 5-HT₂A affinity.supported

4-hydroxylated derivatives showed 25-380-fold selectivity for 5-HT2A over 5-HT1A. N,N-dialkyl groups larger than diisopropyl markedly reduced affinity. pmid:2139186

The meaningful 5-HT₁A co-agonism may contribute sedative and anxiolytic components, as established for other 4-hydroxytryptaminessupported

Locomotor-decreasing effects blocked by 5-HT1A antagonist. Confirms multi-receptor pharmacology of 4-hydroxy tryptamines. 0269881110388326

Claim in summary — inconclusiveinconclusiveworking →

A human postmortem case with suspected intoxication has been documented, but the causal role of the compound remains unestablishedsupported

unique metabolites identified in human postmortem blood with suspected 4-OH-EPT intoxication. dta.3668

The sole published metabolic data derive from Bergh et al. (2024), who characterized 4-HO-EPT metabolism using pooled human liver microsomes (pHLM) and confirmed metabolite formation in vivo from a postmortem human blood sample.supported

Characterization of major metabolites of EPT, 4-OH-EPT, and 5-MeO-EPT via human liver microsomes and postmortem blood. dta.3668

This shift parallels observations for the parent compound EPT, where in vitro alkyl hydroxylation shifts to indole ring hydroxylation in vivo in rat models.supported

in vivo rat studies show shift to indole ring hydroxylation with N-dealkyl metabolites and glucuronide conjugate. bkaa060

Psilocin (4-HO-DMT), the closest well-characterized structural analog, has been reviewed systematically for clinical pharmacokineticssupported

Systematic review of psilocin pharmacokinetics as active metabolite of psilocybin. Post-hoc analysis. s40262-024-01454-4

4-HO-EPT does not appear in routine forensic drug screening panelssupported

undetected by routine drug screening. s00204-020-02693-7

Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →

Bergh et al. (2024) identified unique metabolites suitable as forensic markers for confirming 4-HO-EPT exposuresupported

unique metabolites identified in human postmortem blood with suspected 4-OH-EPT intoxication. dta.3668

Schüller et al. validated a 96-well electromembrane extraction UHPLC-MS/MS method capable of quantifying 20 tryptamine analogs in whole blood, providing a scalable approach for forensic detection of EPT-class compounds.partially supported

EME-UHPLC-MS/MS method for simultaneous extraction and analysis of 20 tryptamines from whole blood including EPT analogs. Method validated for 16 tryptamines 5-500 nM range. j.talo.2022.100171

Glatfelter et al. (2023) characterized the binding profile of 4-HO-EPT via radioligand displacement at cloned human receptors:supported

Receptor binding profiles of tryptamine psychedelics with various N,N-dialkyl substitutions including ethyl-propyl (4-OH and 4-AcO-EPT). acsptsci.2c00222

The 5-HT₂A affinity of 546 nM is notably weaker than psilocin (Ki ≈ 100–200 nM in comparable assays), consistent with the established structure-activity relationship whereby increasing the size of N,N-dialkyl substituents progressively reduces 5-HT₂A bindingsupported

N,N-dialkyl groups larger than diisopropyl markedly reduced affinity. pmid:2139186

McKenna et al. (1990) demonstrated that 4-hydroxylated tryptamines typically exhibit 25–380-fold selectivity for 5-HT₂A over 5-HT₁A; 4-HO-EPT's ratio of approximately 1:3 (5-HT₁A:5-HT₂A = 163:546 nM) represents a marked departure from this pattern, indicating that the ethyl-propyl substitution erodes 5-HT₂A selectivity more than 5-HT₁A affinity.supported

4-hydroxylated derivatives showed 25-380-fold selectivity for 5-HT2A over 5-HT1A. N,N-dialkyl groups larger than diisopropyl markedly reduced affinity. pmid:2139186

The corresponding 4-acetoxy prodrug 4-AcO-EPT shows substantially weaker 5-HT₂A affinity (Ki = 2,459 nM), consistent with 4-acetoxy compounds functioning as partial prodrugs that require in vivo hydrolysis to the active 4-hydroxy form.supported

4-acetoxy analogues showed somewhat weaker binding affinities but similar target profiles vs 4-hydroxy comparators. acsptsci.2c00222

Claim in receptor-pharmacology — not_supportednot supportedworking →

Claim in neuroscience — inconclusiveinconclusiveworking →

The compound's meaningful 5-HT₁A co-agonism (Ki = 163 nM) may modulate these effects through engagement of inhibitory 5-HT₁A autoreceptors on raphe nuclei and postsynaptic 5-HT₁A receptors in cortical and limbic regions, potentially attenuating the intensity of 5-HT₂A-driven cortical destabilization.supported

Locomotor-decreasing effects blocked by 5-HT1A antagonist. Confirms multi-receptor pharmacology of 4-hydroxy tryptamines. 0269881110388326

Claim in neuroscience — inconclusiveinconclusiveworking →

Claim in neuroscience — inconclusiveinconclusiveworking →

The 5-HT₂A affinity of 4-HO-EPT (Ki = 546 nM) is approximately 3–5× weaker than psilocin, consistent with the systematic reduction in 5-HT₂A affinity produced by increasing N,N-dialkyl bulk beyond the N,N-dimethyl optimumsupported

N,N-dialkyl groups larger than diisopropyl markedly reduced affinity. pmid:2139186

The 5-HT₂A affinity of 4-HO-EPT (Ki = 546 nM) is approximately 3–5× weaker than psilocin, consistent with the systematic reduction in 5-HT₂A affinity produced by increasing N,N-dialkyl bulk beyond the N,N-dimethyl optimumsupported

Receptor binding profiles of tryptamine psychedelics with various N,N-dialkyl substitutions including ethyl-propyl (4-OH and 4-AcO-EPT). acsptsci.2c00222

McKenna et al. (1990) established that N,N-dialkyl groups larger than diisopropyl markedly reduce affinity at both 5-HT₂A and 5-HT₁Asupported

N,N-dialkyl groups larger than diisopropyl markedly reduced affinity. pmid:2139186

The closely related 4-acetoxy form (4-AcO-EPT) functions as a presumed prodrug; acetylation of the 4-hydroxyl group produces a more stable compound that undergoes in vivo hydrolysis to yield 4-HO-EPT, paralleling the psilocybin-to-psilocin conversion established across the 4-substituted tryptamine class.supported

4-acetoxy analogues showed somewhat weaker binding affinities but similar target profiles vs 4-hydroxy comparators. acsptsci.2c00222

The crystal structure of the closely related 4-AcO-EPT fumarate salt has been determined by single-crystal X-ray diffraction, but equivalent structural data for 4-HO-EPT itself are not availablesupported

Single-crystal X-ray diffraction structure of 4-AcO-EPT fumarate salt. s2414314623007794

The closely related 4-acetoxy prodrug analog 4-AcO-EPT has been characterized by X-ray crystallography as its fumarate salt, confirming that academic synthesis and solid-state characterization of the EPT tryptamine series are well established.supported

Single-crystal X-ray diffraction structure of 4-AcO-EPT fumarate salt; asymmetric unit consists of singly protonated tryptammonium cation, fumarate dianion, fumaric acid. s2414314623007794

Claim in history — inconclusiveinconclusiveworking →

The only published data involving human exposure consist of the metabolite identification from a postmortem blood case reported by Bergh et al. (2024)supported

unique metabolites identified in human postmortem blood with suspected 4-OH-EPT intoxication. dta.3668