DOI

# Research Output: DOI (2,5-Dimethoxy-4-iodoamphetamine)
**PSX-0170 | Generation Provenance: c928c5e8-e35d-486c-ab7d-336b1cc44f4a**
**Research Date: 2026-05-03**

---

## Chemical Identity

**Confirmed via PubChem CID 1229 [Ref 3 cross-reference]:**

| Field | Value | Source |
|---|---|---|
| IUPAC name | 1-(4-iodo-2,5-dimethoxyphenyl)propan-2-amine | PubChem CID 1229 |
| Molecular formula | C₁₁H₁₆INO₂ | PubChem CID 1229 |
| Molecular weight | 321.15 g/mol (free base) | PubChem CID 1229 |
| InChIKey | BGMZUEKZENQUJY-UHFFFAOYSA-N | PubChem CID 1229 |
| CAS (free base) | 64584-34-5 | Psychedelic Science Review [Ref 28] |
| CAS (HCl salt) | 42203-78-1 | Cayman Chemical [Ref 20] |
| PubChem CID | 1229 | PubChem direct lookup |
| SMILES (likely) | CC(N)Cc1cc(OC)c(I)cc1OC | Derived from IUPAC; **unconfirmed by API** |
| Systematic name | 1-(4-iodo-2,5-dimethoxyphenyl)propan-2-amine | Confirmed |

**Notes and discrepancies with seed data:**
- Seed data left SMILES, molecular formula, molecular weight, and InChIKey blank. All four are now populated from PubChem CID 1229.
- The SMILES above is derived from the IUPAC name. The PubChem canonical SMILES could not be retrieved via API due to a JavaScript-rendered page; **should be confirmed by a human editor against PubChem CID 1229 before publication.**
- Both CAS numbers (free base and HCl salt) are valid; the seed data CID field was empty.
- The brief's systematic name "1-(4-iodo-2,5-dimethoxyphenyl)propan-2-amine" is **confirmed correct** per PubChem.

---

## Pharmacology

### Receptor Binding Profile

DOI is a potent, direct serotonin receptor agonist. Published Ki values at human serotonin receptors [Ref 28]:

| Receptor | Ki (nM) | Activity |
|---|---|---|
| 5-HT₂A | 0.65 | Full agonist |
| 5-HT₂C | 2.36 | Agonist |
| 5-HT₂B | 20.2 | Agonist |

The radioligand [¹²⁵I]-R-(−)-DOI labels 5-HT₂A sites in rat cortex with KD = 0.63 nM and Bmax = 2.5 pmol/g tissue (McKenna & Peroutka 1989 [Ref 5]). This was a landmark paper establishing DOI as the prototypical 5-HT₂A radioligand.

Ray (2010) [Ref 3] confirmed in the NIMH-PDSP receptorome study that DOI, like other phenylalkylamines, is less selective than generally believed, interacting with 42 of 49 broadly assayed sites (though 5-HT₂A/2C are the primary high-affinity targets). Full receptor affinity tables are in the Ray (2010) supplementary data.

The active enantiomer is R-(−)-DOI, as evidenced by the McKenna & Peroutka (1989) [Ref 5] use of [¹²⁵I]-R-(−)-DOI as the reference radioligand and the exclusive use of (R)-DOI in anti-inflammatory studies (Nau et al. 2013 [Ref 2]; Flanagan et al. 2019 [Ref 14]).

### Mechanism of Action

DOI acts primarily as a full agonist at 5-HT₂A and 5-HT₂C receptors. Its hallucinogenic effects are now understood to require 5-HT₂A-mediated **non-canonical Gᵢ signalling** rather than classical Gq/PLC signalling (Xu et al. 2026 [Ref 4]), a major recent finding. A derivative, DOI-NBOMe, was identified as a Gq-biased derivative lacking hallucinogenic properties while retaining therapeutic potential.

DOI also signals through the canonical Gq pathway, activating phospholipase C (PLC), IP3/DAG, and downstream MAP kinase and CaMKII pathways (Desouza et al. 2021 [Ref 6]). These signalling cascades upregulate plasticity-associated genes including *Arc*, *Bdnf1*, *Cebpb*, *Egr2*, *Egr1*, and *cFos* in the rodent neocortex; CREB phosphorylation is a key mediator.

The **5-HT₂A-mGluR2 heteromeric complex** is necessary for the full hallucinogenic behavioral response. Moreno et al. (2011) [Ref 22] demonstrated that mGluR2 knockout mice show abolished head-twitch response and undetectable high-affinity DOI binding sites. The hallucinogen-specific gene egr-2 is not induced in mGluR2 KO mice, while c-fos (shared with non-hallucinogens) is still induced.

DOI enhances dopamine D2 receptor signalling via **D2-5-HT₂A heteroreceptor complexes** in ventral and dorsal striatum; DOI and LSD (but not non-hallucinogenic 5-HT₂A agonists) specifically increase D2 receptor density and high-affinity agonist binding (Borroto-Escuela et al. 2014 [Ref 9]).

At the 5-HT₂A level, DOI stimulates **neuroendocrine release** of ACTH, corticosterone, oxytocin, prolactin, and renin via hypothalamic CRF and oxytocin neurons (Van de Kar et al. 2001 [Ref 13]).

In the **claustrum-ACC circuit**, Anderson et al. (2024) [Ref 8] found that DOI's effects on EPSCs are mediated by 5-HT₂C (not 5-HT₂A) receptors, and that 5-HT and DOI have *opposing* effects on synaptic transmission in this circuit. This challenges the canonical view that 5-HT₂A is the sole mediator of psychedelic effects across all brain circuits.

**5-HT₂A vs. 5-HT₂C locomotor effects:** Halberstadt et al. (2009) [Ref 12] showed DOI produces an inverted-U locomotor dose-response — lower doses (0.625–5 mg/kg) increase activity via 5-HT₂A, higher doses (≥10 mg/kg) decrease activity via 5-HT₂C. 5-HT₂A and 5-HT₂C thus exert opposing effects on locomotion.

### Anti-Inflammatory Effects

Nau et al. (2013) [Ref 2] demonstrated systemic (R)-DOI potently blocks TNF-α-induced proinflammatory gene expression (ICAM-1, VCAM-1, IL-6, IL-1β, MCP-1, CX3CL1) in rat aortic arch and intestine in vivo. This effect is mediated exclusively by 5-HT₂A receptors. Flanagan et al. (2019) [Ref 14] extended this to show (R)-DOI reverses established airway inflammation and structural remodeling in a chronic mouse asthma model.

Szabó (2015) [Ref 11] reviewed DOI's immunomodulatory potential alongside other serotonergic psychedelics, noting therapeutic prospects for atherosclerosis, asthma, rheumatoid arthritis, and multiple sclerosis.

### Neuroplasticity

Šabanović et al. (2024) [Ref 31] showed a single 2 mg/kg dose of (±)-DOI in mice:
- Increased brain volumes in multiple sensory and association areas (ex vivo MRI) at 24 hours
- Improved cognitive flexibility in a probabilistic reversal learning task **one week** after treatment
- Induced a novel "learning from reward omissions" strategy not typically seen in untreated mice
- These effects were time- and experience-dependent

Desouza et al. (2021) [Ref 6] confirmed DOI upregulates CREB-dependent neuroplasticity genes (Arc, Bdnf1, Cebpb, Egr1, Egr2, cFos) in rodent neocortex via MAP kinase and CaMKII downstream of 5-HT₂A.

### Pharmacokinetics

**⚠️ FLAG: No published human pharmacokinetic studies for DOI were found.** All PK data are absent from the primary literature. The following notes apply:

- **Route of administration:** Oral (primary); may also be administered via other routes in research settings
- **Onset (oral):** 1–2 hours (consistent with gastric absorption and peripheral distribution)
- **Duration (oral):** 16–24 hours per community consensus / PsychonautWiki; 16–30 hours per Shulgin's PiHKAL [Ref 19] — see dose section for full discussion
- **Metabolism:** No published DOI-specific CYP metabolism data found. As a substituted amphetamine, DOI is likely subject to CYP2D6-mediated aromatic hydroxylation and monoamine oxidase (MAO) catabolism of the amine, but this is **class-level inference only**. The iodine substituent may influence metabolic pathways differently from other DOx compounds.
- **Half-life:** Unknown from published data. Seed data states 6-day tolerance half-life (receptor-level), not plasma half-life.

### Classification Note: "Monoamine Releasing Agent"

**⚠️ FLAG FOR EDITORIAL REVIEW:** The seed data classifies DOI as a "monoamine releasing agent." The published literature does **not** support this classification. All peer-reviewed sources describe DOI as a **direct serotonin 5-HT₂A/2C agonist**, not as a monoamine transporter substrate or releaser. Unlike classical amphetamines, DOI does not appear to cause presynaptic monoamine release via transporter reversal. Ray (2010) [Ref 3] found no significant affinity at monoamine transporters (DAT, SERT, NET) in the NIMH-PDSP panel. This classification in the seed data is likely an error derived from DOI's amphetamine-like chemical scaffold. Recommend removal of "monoamine releasing agent" from pharmacological class.

---

## History

### Discovery and Synthesis

DOI was first synthesized in 1973 by R. Coutts and J. Malicky (Canadian Journal of Chemistry) [Ref 27] as part of a structure-activity relationship study of hallucinogenic analogs of DOM (2,5-dimethoxy-4-methylamphetamine). The paper synthesized a series of 4-substituted 2,5-dimethoxyamphetamine analogs to explore which substituents at the 4-position of the ring conferred hallucinogenic activity.

Alexander Shulgin subsequently documented DOI in greater detail in **PiHKAL: A Chemical Love Story** (1991) [Ref 19], including synthesis procedures, a personal dosing account, and characterization of the subjective effects in his psychonautical community. Shulgin described the dose range as 1.5–3 mg orally with a duration of 16–30 hours. PiHKAL is the primary early-literature source for human dose-response characterization.

The radioiodinated form, **[¹²⁵I]-R-(−)-DOI**, was developed as a radioligand in David E. Nichols' laboratory at Purdue University and rapidly became the field-standard radioligand for 5-HT₂A receptor characterization (McKenna & Peroutka 1989 [Ref 5]). This development transformed DOI from a niche research chemical into a ubiquitous pharmacological tool.

### Evolution as a Research Tool

By the 1990s–2000s, DOI had become arguably the most widely used pharmacological probe for 5-HT₂A receptor research:
- As a radioligand ([¹²⁵I]-DOI) for receptor characterization
- As a reference 5-HT₂A agonist for in vitro assays
- As the primary stimulus in the head-twitch response (HTR) animal model of hallucinogens

Canal & Morgan (2012) [Ref 1] published a comprehensive historical review of DOI and the HTR model, documenting its rise to prominence as the standard hallucinogen research tool.

### Recreational History

DOI has seen very limited recreational use due to its extremely long duration (16–30 hours) and high body load. Recreational use in the UK was documented circa 2007. A key harm reduction concern emerged at festivals where DOx compounds (including DOI) were sold as LSD — Martins et al. (2017) [Ref 36] documented DOx misrepresentation at the 2014 Boom Festival in Portugal.

---

## Subjective Effects

**No controlled human dose-response studies have been published for DOI.** All human effect data derives from self-reports, most famously Shulgin's accounts in PiHKAL [Ref 19], and community reports.

From Shulgin (PiHKAL) [Ref 19] and community sources:
- Psychedelic hallucinogen experience similar to but distinct from LSD
- More "energetic" and stimulating than LSD
- Greater body load (vasoconstriction, muscle tension, GI effects)
- Pronounced visual effects: hallucinations, color enhancement, tracers, distortions
- Empathy and emotional enhancement
- Long-lasting residual stimulation
- Difficulty sleeping for 1–2 days post-experience depending on dose
- Users describe the headspace as somewhat less complex than LSD

From the HTR animal model literature, DOI reliably produces dose-dependent 5-HT₂A-mediated behavioral responses. Halberstadt et al. (2020) [Ref 23] demonstrated a strong positive correlation (r = 0.9448) between HTR potency in mice and human hallucinogenic potency across 36 compounds, supporting translational validity of the animal model.

The following effects taxonomy is consistent with published preclinical literature and community reports:

**Perception:** External hallucinations, internal hallucinations, visual drifting, color alteration, color enhancement, after-images, tracers, object transformations, symmetrical texture repetition, visual diffraction, perspective distortion, depth perception distortion, brightness alteration, visual acuity enhancement, synesthesia, music enhancement

**Body:** Stimulation, wakefulness, pupil dilation, vasoconstriction, muscle tension, excessive sweating, bruxism, nausea, diarrhea, appetite suppression, spontaneous body sensations, dehydration sensation, abnormal heartbeat, involuntary body movements, sexual arousal enhancement, motor control enhancement, salivation, seizure threshold reduction

**Thinking:** Thought acceleration, thought connectivity, conceptual thinking, analysis enhancement, pattern recognition enhancement, cognitive euphoria, immersion enhancement, novelty enhancement, humor enhancement, memory suppression, thought loops, delusions

**Feeling:** Emotional enhancement, empathy enhancement, anxiety

**Transpersonal:** Existential realization, unity and interconnectedness, noetic insight

**Time:** Time alteration

**Awareness:** Personal insight

**Duration data** (oral route):
- Onset: 1–2 hours
- Come-up: 1.5–3 hours
- Total: 16–24 hours (PsychonautWiki/community consensus) — see Gaps & Flags for Shulgin discrepancy

---

## Safety & Toxicity

### Acute Toxicity

**No published LD50 data for DOI in humans exists.** The seed data correctly notes "toxic dose is unknown."

Animal model data: DOI has been used extensively in rodents at doses of 1–10 mg/kg IP/SC without reported mortality in the literature. The Tourette syndrome model uses DOI at 5 mg/kg IP as a 5-HT₂A/2C agonist to induce stereotyped behaviors (Li et al. 2019 [Ref implicitly cited in search results]).

**No confirmed human deaths from pure DOI ingestion** have been published as of the research date.

The [125I] radioiodinated version is a radiohazard, but this is distinct from recreational or research use of unlabeled DOI.

### Adverse Event Reports

**No published case reports of pure DOI overdose or serious adverse events were found.** The very long duration (16–30 hours) constitutes its primary safety risk in human use — prolonged psychedelic states can produce:
- Severe anxiety and panic
- Psychedelic crisis or "bad trip"
- Cardiovascular stress (vasoconstriction, elevated heart rate)
- Hyperthermia from stimulant effects
- Sleep deprivation sequelae

Related compound 25I-NBOMe (an N-benzyl derivative of 2C-I, not DOI itself) has documented severe toxicity cases including rhabdomyolysis, seizures, and fatalities (Halberstadt 2017 [Ref 24 context]). These are **not** attributable to DOI but reflect the risk profile of the phenethylamine hallucinogen class.

Martins et al. (2017) [Ref 36] documented cases of unintentional DOx consumption when DOx compounds were sold as LSD at festivals — representing a major real-world harm from adulteration.

### Psychological Risks

- Very long duration increases risk of prolonged adverse psychological states
- Potential for persistent psychosis in vulnerable individuals (no DOI-specific data; class inference)
- Seed data lists seizure threshold reduction as an effect, consistent with 5-HT₂A agonism (animal data)
- No HPPD (Hallucinogen Persisting Perception Disorder) case reports specific to DOI found

---

## Harm Reduction

**No published harm reduction studies specifically on DOI were found.** The following derives from pharmacological principles and class-level data:

- **Start low:** Given no published human dose-response data, and given the extreme duration, extreme caution is warranted with dosing
- **Reagent testing:** DOI should test positive with Ehrlich reagent (amine detection) but this is non-specific. Marquis reagent may show characteristic DOx color (orange-brown). **Drug checking services** are the gold standard (Martins et al. 2017 [Ref 36])
- **Adulteration risk:** DOx compounds including DOI have been sold as LSD on blotter paper — test all blotter with fentanyl test strips and reagent kits
- **Contraindications:** No published contraindication data specific to DOI. Based on mechanism, contraindicated with:
  - Monoamine oxidase inhibitors (MAOIs) — serotonin syndrome risk
  - Serotonergic drugs (tramadol, SSRIs, SNRIs) — additive serotonin activity
  - Cardiovascular conditions — due to vasoconstriction and potential arrhythmia risk
- **Cannabis interaction:** Listed as "unknown" in seed data — no published data found; likely increases anxiety given both compounds have anxiogenic potential at high doses
- **Setting:** Due to 16–30 hour duration, requires full-day (and possibly overnight) commitment in a safe environment

---

## Tolerance & Dependence

### Tolerance

De la Fuente Revenga et al. (2022) [Ref 21] provided the most comprehensive published data on DOI tolerance in mice:

- **Onset:** Tolerance to head-twitch response develops within **24 hours** of a single dose
- **Mechanism:** 5-HT₂A receptor downregulation in frontal cortex (confirmed by [³H]ketanserin binding)
- **Rate:** Progressive decrease with repeated (4-day) administration
- **Cross-tolerance:** Full cross-tolerance between DOI and LSD confirmed
- **Non-psychedelic 5-HT₂A agonists:** Lisuride (non-psychedelic 5-HT₂A agonist) does **not** cause cross-tolerance with DOI or LSD — tolerance appears psychedelic-specific
- **Mechanism independence:** Tolerance to HTR is independent of β-arrestin-2 signalling

Rangel-Barajas et al. (2014) [Ref 37] confirmed: **daily** DOI (5 mg/kg) produces tolerance; **every-other-day** (48 hours) does not — suggesting receptor recovery occurs within 48 hours in mice.

**Seed data tolerance values** (build: almost immediately; half-life: 6 days; full reset: 12 days; cross-tolerances: psychedelic) are:
- **"Almost immediately"**: Confirmed — tolerance observed within 24 hours in mice [Ref 21]
- **6-day half-life / 12-day full reset**: These specific values are not found in published literature — **FLAG as unverified; likely from community consensus, not controlled data**
- **Cross-tolerance with psychedelics**: Confirmed with LSD [Ref 21]

### Dependence

No evidence of physical dependence or withdrawal syndrome from DOI has been published. DOI appears **not habit-forming** based on:
- No rewarding properties documented (5-HT₂A agonism is not associated with dopamine-mediated reward)
- Very long duration and high body load make repeated use aversive
- Rapid tolerance development limits use frequency

---

## Interactions

### Tramadol (Dangerous — Seed Data)

The seed data classifies tramadol as a **dangerous** interaction. No specific DOI + tramadol combination study was found in the published literature. The danger is pharmacologically inferred:

- **Tramadol** is a serotonin-norepinephrine reuptake inhibitor (SNRI) and μ-opioid agonist that also has some serotonin releasing properties
- Combined with a potent 5-HT₂A/2C agonist like DOI, tramadol can significantly elevate serotonergic tone
- Risk: **serotonin syndrome** (hyperthermia, tachycardia, hypertension, myoclonus, diarrhea, potentially fatal)
- **⚠️ FLAG: No published primary source confirms DOI + tramadol specifically. This classification is mechanism-based class reasoning. The dangerous rating appears clinically justified but cannot cite a specific paper.**

### Cannabis (Unknown — Seed Data)

No published data on DOI + cannabis pharmacokinetic or pharmacodynamic interaction found. The "unknown" classification is appropriate.

### MAOI Class (Not in Seed Data — Should Be Flagged)

MAOIs dramatically increase serotonergic activity by blocking monoamine degradation. Combination with any 5-HT₂A agonist significantly increases serotonin syndrome risk. No specific DOI + MAOI study found, but this interaction risk applies to all serotonergic psychedelics and should be flagged as a contraindication.

### Vasoconstriction-Potentiating Drugs

Given DOI's vasoconstriction effect (via 5-HT₂A in smooth muscle — Florian & Watts 1998 [Ref 15]), combination with other vasoconstrictors (triptans, ergotamines) could potentiate cardiovascular risk.

---

## Legal Status

### United States

DOI is **currently NOT a federally scheduled controlled substance** in the United States as of May 2026. However, scheduling proceedings are active:

- **April 2022**: DEA published Notice of Proposed Rulemaking to place DOI and DOC in Schedule I [Ref 16]
- **December 2023**: Formal scheduling notice published
- **June 2024**: DEA Administrative Law Judge hearing **stayed** pending resolution of a U.S. District Court collateral matter [Ref 17]
- As of research date (May 2026): Scheduling proceedings remain stayed; DOI remains unscheduled at federal level
- **Note:** DOI may trigger state analogue acts in some jurisdictions

### Canada

DOI is listed as **Schedule III** under the Controlled Drugs and Substances Act as an analogue of amphetamine.

### United Kingdom

DOI is controlled under two frameworks:
1. **Misuse of Drugs Act 1971** — phenethylamine catch-all clause (amended 2002, Schedule 2 part 1(b&c)) covers all phenethylamine derivatives not specifically listed [Ref 34]
2. **Psychoactive Substances Act 2016** — blanket ban on all psychoactive substances not specifically exempt

### Sweden

DOI added to Schedule I (Förteckning I) as narcotics effective **August 30, 2007**.

### Finland

DOI classified as a psychoactive substance banned from the consumer market.

### Australia

Per earlier search data: DOI is not listed in the Standard for the Uniform Scheduling of Medicines and Poisons (SUSMP) — **tentatively unscheduled**, but this requires verification against the current SUSMP schedule.

### International

Sixteen phenethylamines are controlled under the UN 1971 Convention on Psychotropic Substances; DOI is not among them as of published data. It may be subject to national analogue laws in various countries.

---

## Clinical Trials

**No clinical trials for DOI were found** on ClinicalTrials.gov as of the search date. DOI is used exclusively as a preclinical research tool; no Phase I or II studies have been registered. This is consistent with its legal status (unscheduled in the US but proposed for Schedule I, which would restrict clinical use).

**Research directions that may eventually lead to clinical development:**
- (R)-DOI as an anti-inflammatory agent for asthma/IBD (Flanagan et al. 2019 [Ref 14]; Nau et al. 2013 [Ref 2])
- DOI-derived non-hallucinogenic therapeutics (e.g., DOI-NBOMe as Gq-biased agonist; Xu et al. 2026 [Ref 4])
- Cognitive flexibility enhancement for depression/OCD/addiction (Šabanović et al. 2024 [Ref 31])

---

## Community Feedback Analysis

No community feedback was submitted in Part A2 of the brief. This section is therefore empty per protocol.

**No community feedback submitted.**

---

## Gaps & Flags

### 🚩 Critical Flags (Safety-Critical or High-Impact)

1. **"Monoamine releasing agent" classification is likely incorrect.** Published literature uniformly describes DOI as a direct 5-HT₂A/2C agonist, not a monoamine transporter substrate or releasing agent. Ray (2010) NIMH-PDSP data found no significant monoamine transporter affinity. Recommend removing this pharmacological class designation pending editorial review. [SAFETY-ADJACENT — affects mechanistic understanding and interaction risk assessment]

2. **Tramadol interaction has no specific published source.** The "dangerous" classification is pharmacologically inferred (serotonin syndrome risk via additive serotonergic activity) but no primary study confirms this specific combination. Generation agent should note this as mechanism-inferred rather than empirically confirmed.

3. **SMILES not confirmed via direct API.** PubChem CID 1229 is confirmed, but the SMILES string was derived from the IUPAC name (CC(N)Cc1cc(OC)c(I)cc1OC) rather than fetched from the API. Needs human editor verification against PubChem before publication.

4. **US legal status is dynamic (as of May 2026).** Scheduling proceedings were stayed June 2024. Status should be verified at publication time — DOI may have been formally scheduled or proceedings may have concluded.

5. **No human pharmacokinetic data published.** Onset, peak, and offset times are from community reports only. Metabolism/CYP pathway is inferred from structural class.

### ⚠️ Notable Gaps

6. **Duration discrepancy:** Shulgin/PiHKAL [Ref 19] and Wikidoc report 16–30 hours total; seed data and PsychonautWiki report 16–24 hours. The Shulgin upper bound of 30 hours may reflect higher doses or individual variation. Community data source (PsychonautWiki) aligns with seed data. The 16–24 hour seed data value is reasonable but the generation agent should acknowledge the upper bound extends to ~30 hours at higher doses.

7. **Dose range discrepancy:** Shulgin (PiHKAL) gives active range as 1.5–3 mg; seed data has threshold at 0.5 mg, light at 0.5–1 mg. Shulgin's range omits the threshold/light tiers. Community reports (PsychonautWiki) align with seed data's lower dose tiers. The seed data dose structure appears reasonable, with Shulgin's "active" range corresponding to seed data's common-to-strong range. No controlled human dose-response study exists to adjudicate.

8. **Tolerance half-life (6 days) and full reset (12 days) are unverified** against published literature. These appear to be community-derived estimates. Published data only confirms rapid onset (<24 hours) and receptor-level mechanism. Flag for editorial review.

9. **No published LD50 for any species** — the seed data correctly notes "toxic dose is unknown."

10. **Australia legal status:** Early web search indicated unscheduled; this needs verification against current SUSMP.

11. **Stereochemistry:** R-(−)-DOI is the active enantiomer based on radioligand literature. No published comparative human study of R vs S enantiomers in humans was found. Most research uses racemic (±)-DOI.

12. **No controlled human studies** — all human effect data is from self-reports (Shulgin PiHKAL, community forums). DOI has essentially no clinical trial history.

13. **The Glennon & Dukat (2024) ACS P&TS review** [Ref 18] was confirmed via Crossref but the full text was inaccessible (403 error). This review is the most recent comprehensive pharmacological review of DOI; generation agent should note it exists and cite it, but detailed content from it is not incorporated here beyond what was confirmed accessible.

14. **Canada scheduling:** One source states Schedule III, another states Schedule I (as amphetamine analogue). Exact Schedule level for Canada should be verified.