4-HO-DPT

Claim in safety — inconclusiveinconclusiveworking →

The parent compound DPT produced proconvulsant effects at doses exceeding 20 mg/kg in micesupported

Proconvulsant at high doses. acsptsci.3c00137

Claim in safety — inconclusiveinconclusiveworking →

Claim in safety — inconclusiveinconclusiveworking →

Tolerance develops rapidly — effectively immediately following a single administration — through 5-HT₂A receptor downregulation mediated by β-arrestin2 internalization following Gq activationpartially supported

Beta-arrestin-biased ligands block psychedelic effects and induce receptor downregulation and tachyphylaxis. s41467-023-44016-1

A notable finding from Smith et al. (2014): daily DPT administration in mice did not produce tolerance to head-twitch responses, unlike the phenethylamine hallucinogens DOI and 2C-T-7supported

Tolerance develops to DOI/2C-T-7 HTR but not to DPT or DIPT. jpet.114.219337

Claim in safety — inconclusiveinconclusiveworking →

Tramadol inhibits human SERTsupported

Tramadol inhibits human SERT in HEK293 cells. s00204-018-2244-6

Combined with a serotonergic tryptamine that acts as a SERT substrate (as DPT does), this combination substantially increases synaptic serotonin concentrations, raising serotonin syndrome risksupported

High binding-to-uptake ratios indicate substrate behavior at both transporters. s00702-009-0308-8

Additionally, tramadol lowers seizure threshold, and at high doses of DPT-class compounds, proconvulsant effects have been observed in micesupported

Proconvulsant at high doses. acsptsci.3c00137

Combined with SERT substrate activity (demonstrated for DPT), MAOI co-administration could produce severe serotonin toxicitysupported

High binding-to-uptake ratios indicate substrate behavior at both transporters. s00702-009-0308-8

4-HO-DPT is presumed to act primarily through 5-HT₂A receptor agonism based on structural analogy and class-level SAR data showing that all tested 4-hydroxy-N,N-dialkyltryptamines activate 5-HT₂A, 5-HT₂B, and 5-HT₂C receptorssupported

4-HO-DPT is a full/partial agonist at 5-HT2A/2B/2C with more selectivity at 5-HT2A over 5-HT2C. acsptsci.0c00176

Classification as a 5-HT₂A agonist rests on three convergent lines of evidence: (1) all 4-hydroxy-N,N-dialkyltryptamines tested by Klein et al. (2021) acted as full or partial agonists at 5-HT₂A, 5-HT₂B, and 5-HT₂C; (2) the parent compound DPT is a confirmed 5-HT₂A full agonist (Ki = 152 nM, EC50 = 445 nM in TRUPATH biosensor assay); and (3) the 4-hydroxyl group on the indole ring enhances rather than diminishes 5-HT₂A activity, conferring psilocin-like hallucinogenic properties demonstrated in LSD-trained rat discrimination.supported

SAR of 17 tryptamines with 4-hydroxy or 4-acetoxy groups. 4-HO-DPT is a full/partial agonist at 5-HT2A/2B/2C with more selectivity at 5-HT2A over 5-HT2C. acsptsci.0c00176

Classification as a 5-HT₂A agonist rests on three convergent lines of evidence: (1) all 4-hydroxy-N,N-dialkyltryptamines tested by Klein et al. (2021) acted as full or partial agonists at 5-HT₂A, 5-HT₂B, and 5-HT₂C; (2) the parent compound DPT is a confirmed 5-HT₂A full agonist (Ki = 152 nM, EC50 = 445 nM in TRUPATH biosensor assay); and (3) the 4-hydroxyl group on the indole ring enhances rather than diminishes 5-HT₂A activity, conferring psilocin-like hallucinogenic properties demonstrated in LSD-trained rat discrimination.supported

In vitro: 5-HT2A full agonist (Ki=152 nM, EC50=445 nM), 5-HT1B partial agonist (Ki=8081 nM), 5-HT1A partial agonist (Ki=1640 nM). acsptsci.3c00137

Classification as a 5-HT₂A agonist rests on three convergent lines of evidence: (1) all 4-hydroxy-N,N-dialkyltryptamines tested by Klein et al. (2021) acted as full or partial agonists at 5-HT₂A, 5-HT₂B, and 5-HT₂C; (2) the parent compound DPT is a confirmed 5-HT₂A full agonist (Ki = 152 nM, EC50 = 445 nM in TRUPATH biosensor assay); and (3) the 4-hydroxyl group on the indole ring enhances rather than diminishes 5-HT₂A activity, conferring psilocin-like hallucinogenic properties demonstrated in LSD-trained rat discrimination.supported

4-hydroxy group produces LSD-like effects in drug discrimination. pmid:10514296

Wallach et al. (2023) demonstrated that 5-HT₂A–Gq efficacy, rather than β-arrestin2 recruitment, predicts psychedelic potential as measured by head-twitch response magnitude in micesupported

5-HT2A-Gq (not beta-arrestin2) efficacy predicts psychedelic potential. s41467-023-44016-1

The N,N-dipropyl substitution on the tryptamine nitrogen confers approximately 129-fold selectivity for 5-HT₂A over 5-HT₂C relative to psilocin, with concurrently enhanced efficacy at 5-HT₂B.partially supported

4-HO-DPT is a full/partial agonist at 5-HT2A/2B/2C with more selectivity at 5-HT2A over 5-HT2C. Bulkier N-alkyl groups reduce potency at 5-HT2C. acsptsci.0c00176

For the parent compound DPT, Tyagi et al. (2023) reported binding at 5-HT₁A (Ki = 1,640 nM, partial agonist at ~52% maximal response) and 5-HT₁B (Ki = 8,081 nM, partial agonist at ~85% maximal response)supported

5-HT1B partial agonist (Ki=8081 nM), 5-HT1A partial agonist (Ki=1640 nM). acsptsci.3c00137

Fantegrossi et al. (2008) demonstrated that the 5-HT₁A antagonist WAY-100635 produced surmountable antagonism of DPT-elicited head-twitch responses, while the 5-HT₂A antagonist M100907 produced insurmountable blockade — indicating 5-HT₁A plays a modulatory rather than primary role.supported

5-HT2A receptor is primary site of action; 5-HT1A plays modulatory role. pmid:17905422

DPT acts as a substrate (not inhibitor) at the serotonin uptake transporter (SERT), with KI for [³H]5-HT uptake inhibition = 0.594 ± 0.12 μM in human platelets, and at the vesicular monoamine transporter 2 (VMAT2, KI = 19 ± 2.3 μM)supported

DPT inhibits [3H]5-HT uptake at SERT (KI=0.594 uM) and VMAT2 (KI=19 uM). High binding-to-uptake ratios indicate substrate behavior at both transporters. s00702-009-0308-8

The pattern established by Klein et al. (2021) is clear: increasing N-alkyl bulk enhances 5-HT₂A over 5-HT₂C selectivity and increases 5-HT₂B efficacy. 4-HO-DPT appears substantially less potent than psilocin on a milligram-per-milligram basis (common oral dose 60–90 mg vs 10–25 mg for psilocin), though this potency difference has not been established in controlled conditions.supported

Bulkier N-alkyl groups reduce potency at 5-HT2C. All compounds induce head twitches in mice. acsptsci.0c00176

Selectivity: 4-hydroxylation enhances 5-HT₂A selectivity over 5-HT₂Csupported

4-HO-DPT is a full/partial agonist at 5-HT2A/2B/2C with more selectivity at 5-HT2A over 5-HT2C. acsptsci.0c00176

Hallucinogenic character: Gerasimov et al. (1999) demonstrated that 4-hydroxy tryptamine analogs achieve potency at 5-HT₂A comparable to DOI in LSD-trained rat discrimination, supporting enhanced hallucinogenic propertiessupported

4-hydroxy group produces LSD-like effects in drug discrimination. pmid:10514296

Claim in comparative-pharmacology — inconclusiveinconclusiveworking →

Prodrug relationship: Glatfelter et al. (2022) confirmed that 4-acetoxy tryptamines act as prodrugs that deacetylate to the corresponding 4-hydroxy compounds in vivosupported

4-acetoxy and 4-hydroxy compounds showed similar pharmacological effects. acsptsci.2c00177

DPT fully substitutes in rats trained to discriminate LSD, psilocybin, and MDMA, supporting classification within the psychedelic behavioral profilesupported

DPT tested in head-twitch and drug discrimination (LSD, psilocybin, MDMA cues). 5-HT2A receptor is primary site of action. pmid:17905422

In the [³⁵S]GTPγS binding assay, DPT ranked below 5-MeO-DMT and 5-MeO-DALT but above alpha-methyltryptamine in G-protein activation potencysupported

Rank order of tryptamine potency in GTPgammaS assay: 5-MeO-DMT > 5-MeO-DALT > 5-MeO-AMT > 5-MeO-MIPT > 5-MeO-DIPT > DPT >= AMT. pmid:18057721

Soskin, Grof, and Richards (1973) published a double-blind study of DPT (15–30 mg intramuscular) as a psycholytic therapy adjunct for alcoholism at the Maryland Psychiatric Research Center (Spring Grove State Hospital)supported

Clinical study on low-dose DPT (15-30 mg) as adjunct in psychotherapy for alcoholism. Double-blind study, 18 patients, 72 DPT sessions and 64 placebo sessions. pmid:4575167

Bates in 1977 at Kansas State University, reported as compound "4b" in a paper describing synthetic routes to psilocin analogs via 6,7-dihydroindol-4(5H)-one intermediatessupported

First synthesis of 4-HO-DPT (compound 4b). Synthesis of multiple psilocin analogs including N,N-dialkyl and N,N-cycloalkyl variants. jhet.5570140113

Chapman (2017) published NMR spectral data for 4-HO-DPT fumarate salt obtained from grey-market research chemical vendors, confirming chemical identity and purity of commercially available materialsupported

1H NMR spectra of 43 alleged psychedelic tryptamines from grey-market vendors. Spectra consistent with compounds as labelled. Includes tryptamines with 4-hydroxy substitution and various N-alkyl patterns. isomerdesign-5-supp

Sammeta et al. (2020) reported the first single-crystal X-ray diffraction structure of 4-HO-DPT hydrochloride, definitively establishing the three-dimensional molecular geometry.supported

Single-crystal X-ray diffraction structure of 4-HO-DPT hydrochloride salt. First crystal structure of this specific salt form. s2414314620015461

Claim in history — inconclusiveinconclusiveworking →

These studies were part of the broader psycholytic therapy movement spanning the 1950s–1970s in the United States and Europe. 4-HO-DPT itself has never been administered in any published clinical trial or formal human study.supported

Comprehensive review of psycholytic therapy 1949-1970s, led by Hanscarl Leuner in Germany. Various tryptamines employed at 30 European clinical centers in serial lower-dose sessions. fpsyt.2022.1020505

Claim in history — inconclusiveinconclusiveworking →

The addition of the 4-hydroxyl group to the indole ring is expected to modify these values — specifically, Klein et al. (2021) demonstrated that 4-hydroxylation within the N,N-dialkyltryptamine series enhances 5-HT₂A selectivity relative to 5-HT₂C by approximately 129-fold compared to psilocin.partially supported

4-HO-DPT is a full/partial agonist at 5-HT2A/2B/2C with more selectivity at 5-HT2A over 5-HT2C. acsptsci.0c00176

Wallach et al. (2023) established that 5-HT₂A–Gq efficacy correlates with head-twitch response magnitude in mice, while β-arrestin2-biased agonists at 5-HT₂A block psychedelic effects and induce receptor downregulation (tachyphylaxis)supported

5-HT2A-Gq (not beta-arrestin2) efficacy predicts psychedelic potential. Beta-arrestin-biased ligands block psychedelic effects and induce receptor downregulation and tachyphylaxis. s41467-023-44016-1

Klein et al. (2021) confirmed that 4-hydroxy-N,N-dialkyltryptamines including analogs structurally similar to 4-HO-DPT produce head-twitch responses in mice, consistent with 5-HT₂A-mediated psychedelic-like activitysupported

All compounds induce head twitches in mice. acsptsci.0c00176

For DPT specifically, Fantegrossi et al. (2008) demonstrated that head-twitch responses were insurmountably blocked by the selective 5-HT₂A antagonist M100907.supported

5-HT2A receptor is primary site of action; 5-HT1A plays modulatory role. pmid:17905422

In the [³⁵S]GTPγS binding assay in rat brain membranes, DPT produced measurable G-protein activation, ranking below 5-MeO-DMT and 5-MeO-DALT in potency but above alpha-methyltryptaminesupported

Rank order of tryptamine potency in GTPgammaS assay: 5-MeO-DMT > 5-MeO-DALT > 5-MeO-AMT > 5-MeO-MIPT > 5-MeO-DIPT > DPT >= AMT. pmid:18057721

Increasing N-alkyl chain length within this series has been shown to alter receptor selectivity profiles, particularly enhancing 5-HT₂A over 5-HT₂C selectivity.supported

Bulkier N-alkyl groups reduce potency at 5-HT2C. acsptsci.0c00176

The freebase is a solid with a melting point of 96–97 °C, first reported by Repke et al. (1977) and independently confirmed by Shulgin (1997)supported

Melting point of 4-HO-DPT freebase: 96-97 degrees C. jhet.5570140113

Sammeta et al. (2020) characterized the hydrochloride salt by single-crystal X-ray diffraction; Chapman (2017) obtained NMR data for the fumarate salt form.supported

Single-crystal X-ray diffraction structure of 4-HO-DPT hydrochloride salt. First crystal structure of this specific salt form. s2414314620015461

Sammeta et al. (2020) characterized the hydrochloride salt by single-crystal X-ray diffraction; Chapman (2017) obtained NMR data for the fumarate salt form.supported

1H NMR spectra of 43 alleged psychedelic tryptamines from grey-market vendors. Includes tryptamines with 4-hydroxy substitution and various N-alkyl patterns. isomerdesign-5-supp

First synthesized by Repke, Ferguson, and Bates in 1977 as a psilocin analog, 4-HO-DPT remained largely uninvestigated after Alexander Shulgin reported only a possible threshold effect at 20 mg oral and noted the compound's synthetic difficultysupported

First synthesis of 4-HO-DPT (compound 4b). Synthesis of multiple psilocin analogs including N,N-dialkyl and N,N-cycloalkyl variants. jhet.5570140113

The compound emerged on grey-market research chemical vendor sites substantially later than most substituted tryptamines, and its crystal structure was not resolved until 2020.supported

Single-crystal X-ray diffraction structure of 4-HO-DPT hydrochloride salt. First crystal structure of this specific salt form. s2414314620015461

Serotonergic psychedelics as a class are not considered habit-forming; tolerance develops rapidly through 5-HT₂A receptor downregulation and resets within approximately 7 dayspartially supported

Beta-arrestin-biased ligands block psychedelic effects and induce receptor downregulation and tachyphylaxis. s41467-023-44016-1

Soskin, Grof, and Richards (1973): Double-blind study of DPT (15–30 mg intramuscular) as a psycholytic therapy adjunct for alcoholism at the Maryland Psychiatric Research Center. This remains the only controlled human study of DPT in a therapeutic context.supported

Clinical study on low-dose DPT (15-30 mg) as adjunct in psychotherapy for alcoholism. Double-blind study, 18 patients, 72 DPT sessions and 64 placebo sessions. pmid:4575167

Claim in clinical-evidence — inconclusiveinconclusiveworking →

Claim in neuroscience — inconclusiveinconclusiveworking →

The finding that daily DPT does not produce tolerance to HTR in mice — does this extend to 4-HO-DPT, and what molecular mechanism differentiates tryptamine from phenethylamine tachyphylaxis?supported

Tolerance develops to DOI/2C-T-7 HTR but not to DPT or DIPT. Tryptamine-derived hallucinogens may have reduced tolerance potential vs phenethylamines. jpet.114.219337

Transporter interactions: DPT (the parent compound) acts as a substrate at SERT (KI = 0.594 μM) and VMAT2 (KI = 19 μM). If conserved in 4-HO-DPT, this substrate behavior could produce transient monoamine release.supported

DPT inhibits [3H]5-HT uptake at SERT (KI=0.594 uM) and VMAT2 (KI=19 uM). High binding-to-uptake ratios indicate substrate behavior at both transporters. s00702-009-0308-8

Claim in pharmacokinetic-detail — not_supportednot supportedworking →

The N,N-dipropyl substitution — which confers high 5-HT₂A/2C selectivity — may underlie a perceptual emphasis over the introspective depth typical of psilocinsupported

4-HO-DPT is a full/partial agonist at 5-HT2A/2B/2C with more selectivity at 5-HT2A over 5-HT2C. acsptsci.0c00176