DOET

# Research Output: DOET

## Chemical Identity

**Verified via PubChem (CID 27402) [Ref 9 context; PubChem database_lookup]:**

| Property | Value |
|---|---|
| Common name | DOET |
| Street name | Hecate |
| PubChem CID | 27402 |
| IUPAC name | 1-(4-ethyl-2,5-dimethoxyphenyl)propan-2-amine |
| Molecular formula | C₁₃H₂₁NO₂ |
| Molecular weight | 223.31 g/mol |
| InChIKey | HXJKWPGVENNMCC-UHFFFAOYSA-N |
| CAS number | 22004-32-6 |
| Melting point (HCl salt) | 194–195°C |

**Notes on seed data discrepancies:** The brief's seed data left SMILES, molecular formula, molecular weight, InChIKey, and PubChem CID blank. All of these have now been verified against PubChem CID 27402. The street name "Hecate" is confirmed. The systematic name 2,5-dimethoxy-4-ethylamphetamine is consistent with the IUPAC name and PubChem record.

**Synthesis route (from PiHKAL #66 [Ref 11]):** DOET is synthesized by combining 2,5-dimethoxy-4-ethylbenzaldehyde with ammonium acetate and nitroethane in glacial acetic acid under heat to form 1-(2,5-dimethoxy-4-ethyl)-2-nitropropene. This intermediate is then reduced using lithium aluminum hydride (LiAlH₄) in ether, followed by acid workup, basification, and conversion to the hydrochloride salt. The resulting white crystalline product has a melting point of 194–195°C.

**Stereochemistry:** DOET contains one chiral center (the alpha-carbon of the isopropylamine chain), giving rise to R-(−)- and S-(+)-enantiomers. The R-(−)-enantiomer is significantly more potent as a hallucinogen, while the S-(+)-enantiomer has weaker activity — the opposite of the amphetamine stimulant pattern (Snyder et al. 1974 [Ref 2]; Nichols 2022 [Ref 16]).

**Naming convention:** The name DOET was chosen by Shulgin to avoid confusion with DOE, which would abbreviate 2,5-dimethoxy-4-ethoxyamphetamine; the "T" distinguishes the ethyl (alkyl) from ether substituent. Shulgin also described DOET under the name "Hecate" in PiHKAL [Ref 11].

---

## Pharmacology

### Receptor Binding and Mechanism of Action

DOET is a serotonin 5-HT₂A and 5-HT₂C receptor agonist, the established primary mechanism for its psychedelic and hallucinogenic effects. It also acts at 5-HT₂B receptors. The following binding affinity data are widely cited (source attributed to Nelson et al. 1999 [Ref 23] and/or NIMH-PDSP via Ray 2010 [Ref 9]):

| Receptor | Ki (nM) |
|---|---|
| 5-HT₂A | ~12 nM |
| 5-HT₂C | ~108 nM |
| 5-HT₂B | Active (exact Ki for DOET not retrieved) |

**⚠️ FLAG: The Ki values of 12 nM (5-HT₂A) and 108 nM (5-HT₂C) are derived from secondary web sources (Wikipedia summary) citing Nelson et al. 1999 or NIMH-PDSP data. The primary tables from those studies (PMID 9933142 and the Ray 2010 open-access paper) could not be read directly due to access limitations. The generation agent should treat these values as probable but unconfirmed at the primary source level and label them accordingly until a direct extraction from Nelson et al. 1999 or Ray 2010 supplemental data is achieved.**

DOET belongs to the DOx (2,5-dimethoxy-4-substituted amphetamine) structural class. The foundational receptor pharmacology for this class was established by Glennon et al. (1984 [Ref 21]), who found a strong correlation (r = 0.938) between 5-HT₂ binding affinities of phenylalkylamines and their hallucinogenic potency in humans. Titeler, Lyon, and Glennon (1988 [Ref 22]) extended this with radioligand binding studies showing phenylisopropylamines display 10–100-fold higher affinities for 5-HT₂ than for 5-HT₁C, and 100–1000-fold higher affinities than for 5-HT₁A or 5-HT₁B (correlation with hallucinogenic potency r = 0.90).

Nelson et al. (1999 [Ref 23]) specifically examined 17 phenylisopropylamine hallucinogens at cloned human 5-HT₂A, 5-HT₂B, and 5-HT₂C receptors, finding high positive correlations (r > 0.9) between affinities at all three subtypes. This work implicated 5-HT₂A as the primary mediator.

At the 5-HT₂A receptor, DOx phenylisopropylamines function as partial agonists (Imax 22–58% relative to 5-HT); the corresponding phenylethylamine counterparts have substantially lower or undetectable efficacy. DOx compounds show greater relative efficacy at 5-HT₂C. DOI (a related DOx compound) has been demonstrated as a full 5-HT₂C agonist (Acuña-Castillo et al. 2002 [Ref 17]).

**5-HT₂B activity and cardiac valvulopathy risk:** High correlation between affinities at 5-HT₂A and 5-HT₂B has been documented for the DOx series (Hemanth et al. 2023 [Ref 26]; Glennon & Dukat 2024 [Ref 10]). Because 5-HT₂B receptor agonism is associated with cardiac valvulopathy (thickening of heart valves), the DOx class as a whole carries a theoretical cardiac risk under sustained or chronic use, analogous to that seen with norfenfluramine and MDA. This has not been specifically documented for DOET in clinical case reports, but is a class-level pharmacological concern [Ref 26].

**Biased agonism:** Serotonergic hallucinogens including DOx compounds demonstrate biased agonism at 5-HT₂A, with differential engagement of Gq/11 versus beta-arrestin signaling pathways. This bias has been proposed as relevant to the hallucinogenic mechanism, though the precise contribution of each pathway continues to be debated.

**Ray 2010 receptorome data [Ref 9]:** The NIMH-PDSP-based study (Ray 2010) demonstrated that phenylalkylamine psychedelics, while broadly believed to be selective for 5-HT₂A/5-HT₂C, in fact interact with 42 of 49 broadly assayed sites. Phenylalkylamines as a class show diverse multi-receptor interaction profiles that likely underlie qualitative differences among compounds.

**Animal behavioral confirmation:** Halberstadt, Powell, and Geyer (2013 [Ref 3]) confirmed DOET increases locomotor activity in C57BL/6J mice via 5-HT₂A receptor activation, a behavioral proxy for hallucinogen-like activity. The selective 5-HT₂A antagonist M100907 blocked locomotor hyperactivity produced by related compounds, confirming 5-HT₂A dependence. Wing, Tapson, and Geyer (1990 [Ref 4]) showed that in rats tested in a Behavioral Pattern Monitor, DOET (like other 5-HT₂ agonists) inhibited locomotor and investigatory behavior in novel environments; this effect was blocked by the 5-HT₂ antagonist ketanserin, confirming serotonin-mediated mechanism.

**Drug discrimination:** DOET fully substitutes for mescaline in drug discrimination paradigms at 0.3 mg/kg in rats (Winter 1975 [Ref 5]; Silverman & Ho 1980 [Ref 7]), confirming shared discriminative stimulus properties with serotonergic hallucinogens. Stimulants (d-amphetamine, cocaine) did not substitute for mescaline-trained animals, whereas DOET and DOM did.

### Pharmacokinetics

**Route of administration:** DOET is primarily used orally. Other routes are mentioned in user communities but have no published clinical data.

**Onset, peak, and duration (from PiHKAL [Ref 11]):**
- Onset: gradual, apparent within 2–3 hours
- Peak: 3–5 hours
- Total duration: 14–20 hours (dose-dependent)

**Metabolism:** The primary metabolic pathway for DOx compounds is CYP2D6-mediated O-demethylation at the 2- or 5-methoxy positions. Ewald and Maurer (2008 [Ref 14]) identified CYP2D6 as the sole isoenzyme involved in O-demethylation of DOC (a closely related DOx compound), producing O-demethylated metabolites. CYP2D6 is also a competitive inhibitor of DOx compounds (Ki values measured for DOC were 7.1–296 µM with recombinant CYP2D6 and 2.7–19.9 µM with human liver microsomes). By class analogy, DOET is expected to follow similar metabolic pathways, though DOET-specific in vitro or in vivo pharmacokinetic data have not been published.

**⚠️ FLAG: No published pharmacokinetic data (Tmax, half-life, bioavailability, Vd, clearance) exist specifically for DOET in humans or animals. All pharmacokinetic inferences are based on class analogy from related DOx compounds.**

**CYP2D6 phenotype implications:** CYP2D6 poor metabolizers may experience prolonged or intensified DOET effects; ultra-rapid metabolizers may have attenuated effects. This is an unverified inference from the class-level CYP2D6 dependence.

### Structure-Activity Relationship Context

DOET sits between DOM (4-methyl) and DOPR (4-propyl) in the DOx alkyl chain series. The ethyl substituent at position 4 provides significant 5-HT₂A affinity, with Ki of ~12 nM. By class, hydrophobicity of the 4-position substituent positively correlates with 5-HT₂A affinity (Hemanth et al. 2023 [Ref 26]). An important SAR principle documented by Nichols (2022 [Ref 16]) is that extension of the alpha-methyl group to an alpha-ethyl moiety abolishes hallucinogenic activity in phenylalkylamines — confirming that the alpha-methyl of DOET is essential for its psychedelic effects, and that the 4-position ethyl group is the SAR-relevant variable for potency within the DOx series.

---

## History

**Discovery and synthesis:**
Alexander Shulgin synthesized DOET while employed as a research chemist at Dow Chemical Company in the early 1960s. Shulgin had invented the closely related DOM (2,5-dimethoxy-4-methylamphetamine, later known as STP on the street) in 1963, and DOET is the direct ethyl homologue of DOM (Trout & Daley 2024 [Ref 24]; Glennon & Dukat 2024 [Ref 10]).

**Pharmaceutical development at Dow Chemical:**
In August 1966, Dow Chemical Company submitted research protocols to study DOET clinically as a potential pharmaceutical drug. Shulgin and colleagues found DOET to act as a remarkable "psychic energizer" at low, sub-hallucinogenic doses — enhancing mood, self-awareness, and cognitive flexibility without producing overt psychedelic effects at these doses. Dow commissioned Solomon H. Snyder at Johns Hopkins University to conduct formal clinical evaluation.

**Termination of development:**
The entire DOET pharmaceutical program was terminated following the DOM (STP) public health crisis in San Francisco in 1967, when DOM was distributed widely as "STP" at the Human Be-In, causing numerous adverse reactions attributable partly to the drug's unusually long duration and partly to misinformation about chlorpromazine (antipsychotic) treatment worsening rather than helping the response. The political fallout from DOM made clinical development of related DOx compounds untenable.

**Published clinical research:**
Snyder and colleagues nonetheless published three clinical studies of DOET between 1968 and 1974:
1. Snyder, Faillace, and Weingartner (1968 [Ref 19]) — DOM and DOET effects in normal subjects
2. Weingartner, Snyder, Faillace, and Markley (1970 [Ref 20]) — DOET cognitive effects (altered free associations)
3. Snyder, Weingartner, and Faillace (1971 [Ref 1]) — effects of varying doses in man
4. Snyder, Unger, Blatchley, and Barfknecht (1974 [Ref 2]) — stereospecific actions in man

The 1971 and 1974 papers were published in *Archives of General Psychiatry* (now *JAMA Psychiatry*).

**Jacob and Shulgin (1983 [Ref 8]):** Shulgin co-authored a study synthesizing and evaluating thio-analogues of DOM and DOET in man. The 5-thio isomers were found to be more potent than the 2-thio isomers, but both retained only about 1/10th the potency of the sulfur-free parent compounds. The dithio analogue of DOM was found to be without central activity.

**PiHKAL (1991 [Ref 11]):** Shulgin described DOET as #66 in PiHKAL (*Phenethylamines I Have Known and Loved*), co-authored with Ann Shulgin. The book entry provides the only comprehensive published account of higher-dose DOET effects.

**Regulatory history:**
- February 1973: DOET placed in Schedule I of the US Controlled Substances Act (DEA code 7399)
- 1971 (ongoing): DOET controlled under Schedule I of the UN Convention on Psychotropic Substances
- UK: Controlled as Class A under the generic phenethylamine clause of the Misuse of Drugs Act 1971
- Australia: Schedule 9 Prohibited Substance under the Poisons Standard (October 2015 or earlier)

---

## Subjective Effects

Published descriptions of DOET's effects come primarily from four sources: the Snyder-group clinical studies (which used sub-hallucinogenic doses), the Weingartner 1970 cognitive study, the Jacob & Shulgin 1983 thio-analogue paper (which confirms DOET's psychotomimetic character), and Shulgin's PiHKAL account (which covers the full dose range including fully psychedelic doses).

### Clinical Study Findings (Sub-Hallucinogenic Range)

**Snyder et al. 1968 [Ref 19]** — DOM and DOET in normal subjects at low doses:
- Both drugs increased self-awareness and produced mild euphoria
- No hallucinogenic or psychotomimetic effects were observed
- "Freed up" word associations without impairing memory or concentration
- DOM enhanced performance on serial learning tasks
- Altered perception of tachistoscopically presented TAT cards (DOM; inferred similar for DOET)

**Weingartner et al. 1970 [Ref 20]** — Specific DOET cognitive effects:
- Altered free word associations documented as a specific cognitive effect
- Consistent with DOET's low-dose profile as a cognitive enhancer without overt hallucinogenesis

**Snyder et al. 1971 [Ref 1]** — Doses 0.75–4 mg in normal male subjects:
- Mild euphoria
- Enhanced self-awareness
- Anxiety at higher doses within this range
- No hallucinogenic or psychotomimetic effects across a five-fold dosage range
- Talkativeness noted

**Snyder et al. 1974 [Ref 2]** — Stereospecific actions:
- Confirmed psychotropic activity is stereospecific
- R-(−) enantiomer substantially more potent
- **⚠️ FLAG: The 1971 and 1974 papers (PMID 4923215 and 4599412) returned no abstract via PubMed API; conclusions are drawn from secondary sources and the published citation record.**

### PiHKAL Dose-Range Descriptions (Full Psychedelic Range)

Shulgin [Ref 11] documents experience reports spanning 1–7 mg orally:

- **1 mg:** Gentle, relaxing; one subject noted relief from menstrual cramping. No psychedelic effects.
- **2.5 mg:** Visual disturbances, disorientation, body sensations (considered a low psychedelic threshold dose).
- **4 mg:** Mood-energizing effects; little or no hallucinogenic effect. Described as mood-enhancing without perceptual distortion.
- **6 mg:** Sensory enhancement, rich closed-eye visuals, no open-eye visual movement; "incredibly lovely" emotional openness, preserved intellectual clarity.
- **7 mg:** Strong emotional themes of love, eroticism, and divinity; openness; limited open-eye visuals; rich closed-eye imagery; some body load symptoms.

**Key character descriptors from PiHKAL [Ref 11]:**
- Predominantly introspective and emotional rather than dramatically visual at typical doses (2–6 mg)
- Preserved cognitive clarity at doses producing emotional depth
- Unusual menstrual cramp relief reported anecdotally (mechanism unknown; possibly via smooth muscle serotonin receptors)
- Shulgin noted approximately 50% success rate for menstrual cramp relief across multiple subjects

**Dose sensitivity note:** Shulgin emphasized substantial individual variation in response, consistent with the known involvement of CYP2D6 (a highly polymorphic enzyme) in DOx metabolism.

### Effect Domains (Based on Published Descriptions)

Based on published clinical and PiHKAL data, the following domains are documented or strongly inferred for DOET:

**Perception:** visual enhancement (color, sensory), geometry (closed-eye, higher doses), tracers possible at high doses; open-eye visuals less prominent than some psychedelics; music enhancement.

**Body:** stimulation (amphetamine-related), temperature dysregulation (hyperthermia documented in rats [Ref 6]), vasoconstriction/pressor effects (documented in rats [Ref 6]), muscle tension possible; appetite suppression expected from class.

**Thinking:** cognitive flexibility, analysis enhancement, creativity enhancement, thought connectivity; at lower doses: enhanced self-awareness, openness; at higher doses: thought acceleration possible.

**Feeling:** euphoria (low to moderate doses), emotional enhancement, empathy enhancement, emotional lability; anxiety at upper sub-hallucinogenic doses.

**Self:** disinhibition, sociability enhancement (low doses), communication enhancement.

**Time:** time alteration likely at psychedelic doses.

**Transpersonal/Noetic:** at highest PiHKAL doses (6–7 mg): noetic insight, existential realization, themes of unity.

**⚠️ FLAG: The full effect domain mapping above is primarily based on PiHKAL self-report and the limited clinical studies (which used sub-hallucinogenic doses). No controlled psychedelic-dose study of DOET in humans has been published.**

---

## Safety & Toxicity

### LD50 and Acute Toxicity
No LD50 data have been published specifically for DOET. The toxicity of DOET is not formally characterized in the published literature. **⚠️ FLAG: This is a critical data gap.**

### Cardiovascular Effects
Huang and Ho (1975 [Ref 6]) documented that DOET, like DOM, produces pressor (blood pressure-raising) action in rats. This effect was blocked by pretreatment with the serotonin antagonist cinanserin, confirming serotonin-mediated cardiovascular stimulation. The sympathomimetic cardiovascular profile is expected for DOx compounds as a class.

### Hyperthermic Effects
DOET increases rectal temperature in rats. This hyperthermic action was suppressed by pretreatment with cinanserin or methysergide (serotonin antagonists), confirming serotonin-mediated hyperthermia (Huang & Ho 1975 [Ref 6]).

### Cardiac Valvulopathy Risk (Class Concern)
A high correlation between DOx compound affinities at 5-HT₂A and 5-HT₂B receptors has been documented (Hemanth et al. 2023 [Ref 26]; Nelson et al. 1999 [Ref 23]). Since 5-HT₂B receptor agonism is mechanistically linked to cardiac valvulopathy (as established for fenfluramine and norfenfluramine), the DOx class theoretically carries a valvulopathy risk under sustained use. This has not been documented in clinical case reports for DOET specifically, but remains a pharmacologically grounded concern warranting a safety flag.

### Duration and Overdose Risk
DOET's extreme duration (14–20 hours) combined with its amphetamine-related cardiovascular effects (hypertension, hyperthermia) creates overdose risk if doses are stacked or if a user takes additional stimulants. The extended duration relative to subjective effects (which may plateau but adverse effects may persist) is a specific harm.

### Case Reports
No published case reports of DOET overdose, adverse events, or toxicological findings were identified in the literature search. The Wohlfarth et al. (2010 [Ref 18]) LC-MS/MS method includes DOET in a panel of 35 designer drugs for forensic serum screening, confirming it is considered by forensic toxicologists as a substance requiring coverage, but no detected cases appear in the accessible literature.

### Psychological Risks
The Snyder 1971 clinical studies [Ref 1] documented anxiety at higher sub-hallucinogenic doses (approaching 4 mg). At fully psychedelic doses (6–7 mg, PiHKAL [Ref 11]), the long duration (14–20 hours) creates prolonged vulnerability to anxiety, paranoia, or difficult psychological experiences, particularly in unsupported settings. These risks are inferred from class membership and duration.

---

## Harm Reduction

**Testing:** DOET does not have a reliable colorimetric reagent test profile distinct from other DOx compounds. Reagent tests (Marquis, Simon's, etc.) can identify the presence of amphetamine-type compounds but cannot distinguish DOET from other DOx or substituted amphetamines. HPLC or LC-MS testing (Wohlfarth et al. 2010 [Ref 18]) is required for definitive identification. Fentanyl test strips are relevant if DOET is obtained from uncontrolled sources.

**Dosage:** Given the extreme duration (14–20 hours), users should plan for a full day of impairment. Driving and operating machinery are contraindicated throughout. The narrow therapeutic window between sub-psychedelic (4 mg) and full psychedelic effects suggests caution with titration.

**Set and setting:** The 2–3 hour onset delay creates risk of re-dosing before effects are felt. The PiHKAL entry notes Shulgin's documentation of individual variability — what was sub-perceptual for one person was clearly psychedelic for another at the same dose.

**Contraindications (inferred from class):**
- Monoamine oxidase inhibitors (MAOIs): Additive serotonergic stimulation could increase cardiovascular effects; exact risk for DOET not documented, but class concern applies
- SSRIs/SNRIs: Could reduce psychedelic effects via 5-HT₂A downregulation; interaction data specific to DOET lacking
- Stimulants (amphetamines, cocaine): Additive cardiovascular effects (pressor, hyperthermic)
- Lithium: No DOET-specific data found. Lithium potentiation of hallucinogen effects has been documented anecdotally for LSD but no controlled data for DOx.
- Pre-existing cardiovascular conditions: Pressor and hyperthermic effects make DOET inadvisable for individuals with hypertension, arrhythmia, or cardiac valve disease

---

## Tolerance & Dependence

**Tolerance mechanism:** Tolerance to the effects of serotonergic hallucinogens develops rapidly via 5-HT₂A receptor downregulation in the frontal cortex. De la Fuente Revenga et al. (2022 [Ref 13]) demonstrated that repeated DOI administration (4 days) caused progressive decrease in head-twitch response (HTR), with measurable tolerance even 24 hours after a single administration. Tolerance development was blocked by the 5-HT₂A antagonist M100907, confirming 5-HT₂A receptor activation is required. Beta-arrestin-2 knockout did not affect tolerance development.

**Cross-tolerance:** Cross-tolerance occurs between DOET and other serotonergic hallucinogens (LSD, mescaline, DOM) due to shared 5-HT₂A mechanism (de la Fuente Revenga et al. 2022 [Ref 13]; drug discrimination literature [Refs 5, 7]). Non-psychedelic 5-HT₂A agonists (such as lisuride) do not produce cross-tolerance with psychedelic 5-HT₂A agonists, consistent with biased signaling mechanisms.

**Dependence liability:** No published evidence of physical dependence, withdrawal syndrome, or compulsive use behavior exists for DOET or for the DOx class in general. Like other classical psychedelics, DOET is not expected to produce physical dependence. Psychological dependence is theoretically possible but undocumented.

**Tolerance washout:** Rapid tolerance typically reverses within several days to a week for serotonergic hallucinogens, though precise DOET-specific data are absent.

---

## Interactions

**MAOIs:** No DOET-specific interaction data found. Class-level concern: MAOIs elevate monoamine levels, and the combination with a serotonin receptor agonist could produce additive or synergistic serotonergic effects. Unlike tryptamines (which are directly metabolized by MAO), DOx compounds are primarily metabolized by CYP2D6, so pharmacokinetic interaction with MAOIs may be less dramatic than with ayahuasca admixtures, but the pharmacodynamic combination remains potentially dangerous. **⚠️ FLAG: No primary literature specifically documents this interaction for DOET.**

**SSRIs/SNRIs:** By class inference, SSRIs and SNRIs may attenuate the subjective effects of DOET through 5-HT₂A receptor desensitization following chronic serotonin elevation. Bonson (1996) documented this effect for LSD; equivalent data for DOET do not exist.

**CYP2D6 inhibitors:** Fluoxetine, paroxetine, and other CYP2D6 inhibitors could inhibit DOET O-demethylation (the primary metabolic pathway), potentially prolonging and intensifying DOET effects. This is a pharmacokinetic inference from Ewald and Maurer (2008 [Ref 14]).

**Lithium:** No published interaction data for DOET. The lithium-hallucinogen interaction is anecdotally reported for LSD but no controlled studies exist for DOx compounds.

**Stimulants:** Additive cardiovascular effects (pressor, hyperthermic) are expected; concurrent use contraindicated.

**5-HT₂ antagonists (antipsychotics):** Ketanserin, risperidone, and other 5-HT₂A antagonists would be expected to block the hallucinogenic effects of DOET (this is confirmed in animal models for the DOx class [Refs 3, 4]). However, typical antipsychotics (e.g., chlorpromazine) may not be appropriate emergency treatments due to the pharmacological nuances of DOx compounds and the historical misuse of chlorpromazine during the DOM (STP) crisis.

---

## Legal Status

| Jurisdiction | Schedule/Class | Notes |
|---|---|---|
| United States | Schedule I (CSA) | DEA code 7399; placed February 1973 |
| International (UN) | Schedule I (1971 Convention) | Convention on Psychotropic Substances |
| United Kingdom | Class A (MDA 1971) | Via generic phenethylamine structural definition |
| Australia | Schedule 9 Prohibited | Under SUSMP Poisons Standard (from 2015 or earlier) |
| Canada | Likely Schedule III (CDSA) | Via analogue control; not explicitly listed; case-by-case determination |
| European Union | Varies by member state | Not EU-wide; some countries control via analogue provisions |

**⚠️ FLAG: Canadian and EU scheduling status could not be confirmed from a primary legal source. The Canada assessment is based on the CDSA analogue provision for amphetamine analogues; exact listing status should be verified with Health Canada.**

---

## Clinical Trials

No clinical trials were found for DOET on ClinicalTrials.gov (search conducted May 2026). The three clinical studies by Snyder and colleagues (1968–1974) represent the entirety of formally published controlled human research on DOET. There is no current registered clinical trial program for DOET.

---

## Community Feedback Analysis

No community feedback was submitted (Part A2 of the brief was empty).

---

## Dose and Duration Proposals

Per standing research directives, dose/duration data are proposed based on the evidence hierarchy.

**Dose:**
- **Threshold:** ~1 mg oral (relaxation, no psychedelic effects)
- **Light:** 1–2 mg oral
- **Common:** 2–4 mg oral
- **Strong:** 4–6 mg oral
- **Heavy:** 6–7+ mg oral

These ranges are derived from PiHKAL [Ref 11] combined with the Snyder clinical trials [Refs 1, 19] and reflect dose-response observations across multiple human subjects. The effective psychedelic range (2–6 mg) is remarkably low compared to most phenethylamine psychedelics, though markedly longer in duration.

**Duration:**
- **Onset:** 1–3 hours
- **Peak:** 3–5 hours
- **Total:** 14–20 hours

These figures are from PiHKAL [Ref 11] and are corroborated by the clinical trial contexts (which used sub-hallucinogenic doses with a similar onset profile).

**⚠️ FLAG: The 14–20 hour duration is Shulgin's self-report and reports of subjects at doses 2–7 mg. No pharmacokinetic study confirms the plasma half-life underlying this duration. The duration should be flagged as experience-based, not pharmacokinetically validated.**

---

## Gaps & Flags

### Critical Data Gaps

1. **LD50 / acute toxicity data absent:** No published LD50 or dose-response lethality data exist specifically for DOET in any species. Toxicity is formally "unknown." This is a safety-critical gap.

2. **Ki binding values not primary-source verified:** The 5-HT₂A Ki of ~12 nM and 5-HT₂C Ki of ~108 nM are from secondary sources citing Nelson et al. 1999 (PMID 9933142) and/or NIMH-PDSP data in Ray 2010 (PMID 20126400). Direct extraction from the primary tables was not achieved. These values appear credible but should be flagged as requiring primary-source confirmation.

3. **No published pharmacokinetic data for DOET:** Half-life, bioavailability, Cmax, Tmax, and volume of distribution are all unknown for humans. Duration estimates (14–20 h) are experience-based.

4. **Limited human psychedelic-dose data:** The Snyder clinical studies only used sub-hallucinogenic doses (≤4 mg). Shulgin's PiHKAL account is the primary source for full psychedelic dose effects, which is a single researcher's self-experimentation data.

5. **No documented adverse event case reports:** DOET does not appear in toxicological case literature despite 50+ years of existence as a controlled substance. This likely reflects genuine rarity of use rather than absence of risk.

6. **No MAOI interaction data specific to DOET:** Only class-level inference is available.

7. **Canadian scheduling not confirmed from primary source:** Assessed as likely controlled via CDSA analogue provisions, but exact status unverified.

8. **5-HT₂B valvulopathy risk:** DOx compounds as a class show high correlation between 5-HT₂A and 5-HT₂B affinities, suggesting theoretical cardiac valvulopathy risk. Not documented clinically for DOET. Should be noted as a safety concern in article content.

9. **Abstracts unavailable for Snyder 1971 and 1974 papers (PMID 4923215, 4599412):** PubMed returned these records without abstracts; content was inferred from secondary sources and citation context. Exact findings should be verified against full text.

10. **Snyder 1974 enantiomer data not confirmed from primary source:** The R-(−) > S-(+) potency relationship is inferred from secondary sources; the original paper (PMID 4599412) returned no abstract from PubMed.