2-Aminoindane

# Research Output: 2-Aminoindane (2-AI)

**PSX ID:** PSX-0010  
**Generation Provenance ID:** aedff97e-81b4-4408-adaf-0c69d49eb79d  
**Research Date:** 2026-05-10  

---

## Chemical Identity

### Verified Data (PubChem CID 76310 [Ref via database_lookup])

| Property | Value | Source |
|---|---|---|
| IUPAC Name | 2,3-dihydro-1H-inden-2-amine | PubChem CID 76310 |
| CAS Number | 2975-41-9 | Jurowski & Frydrych 2026 [Ref 4] |
| Molecular Formula | C₉H₁₁N | PubChem CID 76310 |
| Molecular Weight | 133.19 g/mol | PubChem CID 76310 |
| InChIKey | LMHHFZAXSANGGM-UHFFFAOYSA-N | PubChem CID 76310 |
| SMILES (canonical) | NC1Cc2ccccc2C1 | Derived from IUPAC; matches PubChem structure |
| PubChem CID | 76310 | Confirmed by API lookup |

### Physical Properties (ChemicalBook, CAS 2975-41-9 [web_retrieved])

| Property | Value |
|---|---|
| Melting Point | 33–34°C |
| Boiling Point | 103–105°C |
| Density | 1.024 g/mL at 25°C |
| Flash Point | 212°F (100°C) |
| pKa | 9.21 ± 0.20 (predicted) |
| Water Solubility | Slightly soluble |
| Refractive Index | n₂₀/D 1.561 |

**Physical appearance:** Due to its low melting point (33–34°C), 2-AI exists as a liquid at typical room temperature. The hydrochloride salt (CAS 2338-18-3) is a solid more suitable for handling and storage.

### Stereochemistry

2-AI is **achiral** — the C2 carbon of the indane scaffold is flanked symmetrically by two –CH₂– bridges connected to the same aromatic ring, creating a plane of symmetry. No stereoisomers exist. This distinguishes 2-AI from amphetamine-class analogs that have a chiral center at the α-carbon.

### Discrepancies with Seed Data

The brief's chemical data block leaves SMILES, molecular formula, molecular weight, and PubChem CID blank. All four are now verified:
- SMILES: NC1Cc2ccccc2C1
- Formula: C₉H₁₁N
- MW: 133.19
- CID: 76310

---

## Pharmacology

### Mechanism of Action

2-AI acts primarily as a **norepinephrine transporter (NET) substrate**, causing release of norepinephrine (NE) from presynaptic terminals. Its activity at the dopamine transporter (DAT) is weak, and its serotonin transporter (SERT) activity is minimal. This profile makes 2-AI a selective noradrenergic releasing agent rather than a broad monoamine releaser like MDMA.

**Source:** Simmler et al. 2014 [Ref 1] characterized the pharmacology of 2-AI, MDAI, 5-IAI, piperazines, and pipradrol derivatives at human monoamine transporters (NET, DAT, SERT) expressed in HEK293 cells using both uptake inhibition and efflux assays. The key finding was that "2-AI interacted with the NET" — specifically as a substrate that induces norepinephrine efflux.

### α₂-Adrenoceptor Activity — CRITICAL FINDING

Halberstadt et al. 2019 [Ref 11] studied 2-AI and ring-substituted derivatives (5-MeO-AI, MMAI, MDAI) across 29 receptor and transporter binding sites. 2-AI demonstrated particularly high affinity at **α₂-adrenoceptor subtypes**:

| Receptor | Ki (nM) | Classification |
|---|---|---|
| α₂C-adrenoceptor | **41 nM** | High affinity |
| α₂A-adrenoceptor | **134 nM** | Moderate affinity |
| α₂B-adrenoceptor | **211 nM** | Moderate affinity |

This α₂-adrenoceptor activity is **not present in the brief's pharmacological class or pharmacology JSONB** and represents a significant omission. α₂-Adrenoceptors are autoreceptors that regulate norepinephrine release; agonism at these receptors would inhibit further NE release (negative feedback), which could modulate the stimulant/cardiovascular profile of 2-AI. The high affinity at α₂C (41 nM) is comparable to therapeutic agents used for α₂-adrenoceptor-related indications.

Ring-substituted derivatives (MDAI, MMAI) showed higher SERT activity relative to NET/DAT, while 2-AI itself retains predominantly NET/α₂ activity (Halberstadt et al. 2019 [Ref 11]).

### TAAR1 Binding

The Simmler 2014 [Ref 1] study also investigated trace amine-associated receptor 1 (TAAR1) binding. For 2-AI specifically, the published abstract notes TAAR1 was assessed. Full quantitative TAAR1 data for 2-AI was not recoverable from available abstracts. Based on structural analogy and class comparison with MDAI/5-IAI (which interact with TAAR1), 2-AI may have some TAAR1 affinity, but this requires verification against the full Simmler 2014 dataset.

### Comparison with Class Analogs

The pharmacological distinction between 2-AI and its methylenedioxy derivative MDAI is critical:

| Compound | Primary Transporter | Drug Discrimination |
|---|---|---|
| 2-AI | NET (releasing) | Does NOT substitute in MDMA-trained rats; partial LSD (weak) [Ref 20] |
| MDAI | SERT/NET (releasing) | Fully substitutes in MDMA-trained rats [Ref 20] |
| 5-IAI | SERT/NET | MDMA-like |

**Source:** Nichols et al. 1990 [Ref 20] — the founding pharmacological characterization.

### ⚠️ PHARMACOLOGICAL CLASSIFICATION FLAG

The brief classifies 2-AI as:
- "Monoamine releasing agent" — **partially supported** (NET releasing confirmed; DAT releasing weak)
- "Dopamine releasing agent" — **poorly supported** by available literature; Simmler 2014 shows weak DAT activity
- "Norepinephrine releasing agent" — **well-supported**
- "Norepinephrine-dopamine reuptake inhibitor" — **incorrect framing**; the mechanism is substrate-mediated release, not reuptake inhibition
- Psychoactive class "Entactogen" — **challenged** by Nichols 1990; 2-AI does not substitute in MDMA-trained rats

**Recommendation for generation agent:** Flag pharmacological class for editorial review. "Norepinephrine releasing agent" is well-supported; "Dopamine releasing agent" and "Entactogen" are not supported by the primary literature for 2-AI specifically (they are better applied to MDAI).

### Pharmacokinetics

No published human pharmacokinetic data exists for 2-AI specifically.

**In vitro metabolism (Manier et al. 2020 [Ref 3]):**
- **Human liver microsomes (pHLM):** 2-AI left **unmetabolized** — no oxidative metabolism detected. This is unusual and contrasts with its N-methyl analog NM-2-AI, which undergoes hydroxylation.
- **Human liver S9 fraction (pS9):** 2-AI forms an **acetyl conjugate** via N-acetylation
- **NAT2 specificity:** Activity screening showed 2-AI is acetylated **exclusively by NAT2** (N-acetyltransferase 2), which is **polymorphically expressed** in humans. Slow NAT2 acetylators would have reduced acetylation capacity, potentially leading to higher plasma concentrations of unchanged 2-AI.
- **Rat urine (in vivo):** Both hydroxylated metabolites and acetylated metabolites detected. Hydroxylation in rat urine was not seen in pHLM, suggesting species-specific or in vivo-specific oxidative pathways.

**Class PK data:**

From MDAI rat study (Palenicek et al. 2016 [Ref 23]):
- Brain/serum ratio: ~4 (high CNS penetration)
- Tmax: ~30 min post-SC dose in serum and brain
- Near-zero concentrations by 6h post-dose
- Lung tissue accumulation noted

From MEAI rat study (Shimshoni et al. 2018 [Ref 8]):
- Oral bioavailability: ~25% at 10 mg/kg; non-linear — increases ~500% at 90 mg/kg
- Plasma/brain half-life: 0.5–0.7h
- Total clearance: 2.8 L/h/kg (extensive)
- Metabolites: N-acetyl-MEAI and 5-hydroxy-N-acetyl-AI (via NAT and oxidation)

**Implication:** The NAT2 polymorphism finding (Manier 2020) is safety-relevant. Slow acetylators may experience higher systemic exposure to unchanged 2-AI, potentially exaggerating both effects and toxicity.

**2-AI as active metabolite:** Tirri et al. 2023 [Ref 12] demonstrated in mice that the main active metabolite of NM-2-AI (N-methyl-2-aminoindane) is **2-AI itself**. This means users consuming NM-2-AI are pharmacologically being exposed to 2-AI.

---

## History

### Origin and Early Development

Aminoindane derivatives were first investigated for **bronchodilating and analgesic properties** in the 1970s — predating their use as psychoactive research chemicals. The specific development of aminoindanes as psychoactive agents began in the early 1990s.

The **founding publication** is:

> Nichols DE, Brewster WK, Johnson MP, Oberlender R, Riggs RM. "Nonneurotoxic tetralin and indan analogues of 3,4-(methylenedioxy)amphetamine (MDA)." *J Med Chem.* 1990;33(2):703–710. [Ref 20, PMID 1967651]

This paper, from the laboratory of **David E. Nichols at Purdue University**, studied four cyclic analogs of MDA/MDMA including the parent aminoindane scaffold (2-AI, compound 5a in the paper) and MDAI (compound 3a). The Nichols group coined the concept of **"entactogens"** — drugs that facilitate emotional communication and introspection — and sought to develop non-neurotoxic analogs of MDMA for potential psychotherapy applications.

Key findings of Nichols 1990 [Ref 20]:
- 2-AI (unsubstituted aminoindane) did NOT substitute in MDMA-trained rats
- MDAI (methylenedioxy derivative) fully substituted in MDMA-trained rats
- Neither MDAI nor the tetralin analog produced serotonin neurotoxicity at 40 mg/kg SC

**1991:** 5-IAI (5-iodo-2-aminoindane) was synthesized by Nichols' group as a non-neurotoxic rigid analog of p-iodoamphetamine.

**1991–1996:** Further Nichols-group publications investigated MDAI's mechanism of neurotoxicity prevention and its utility as a pharmacological tool for studying serotonin neurotoxicity of MDMA (Johnson et al. 1991 [Ref 9]; Sprague et al. 1996 [Ref 21]).

### Market Emergence

**2010:** Following the UK government's banning of mephedrone and other synthetic cathinones in April 2010, MDAI and related aminoindanes appeared rapidly on the recreational drug market as legal alternatives (Gallagher et al. 2012 [Ref 14]; Pinterova et al. 2017 [Ref 2]). 2-AI emerged in this same wave as a research chemical.

The Pinterova 2017 review [Ref 2] states that aminoindanes "increased rapidly in popularity on the recreational drug market, particularly after mephedrone and other synthetic cathinones were banned in the UK in 2010."

---

## Subjective Effects

### Published Descriptions

**No controlled human studies of 2-AI have been published.** All subjective effect data is derived from:
1. User reports (Erowid, PsychonautWiki — community/anecdotal)
2. Class inference from MDAI human study (Angerer et al. 2024 [Ref 18])

**MDAI human study (Angerer et al. 2024 [Ref 18])** — the closest available controlled human data for the aminoindane class:
- MDAI (3 mg/kg, 180–228 mg) produced effects "comparable with those of 125 mg MDMA"
- Increased blood pressure (similar to 125 mg MDMA)
- Did NOT significantly increase heart rate or body temperature (unlike MDMA)
- Elevated cortisol and prolactin (endocrine activation)
- Detected in serum ~20 min post-ingestion; remained detectable ≥4 days
- Urine detection ≥6 days post-dose

**User report summary (PsychonautWiki, web_retrieved):** 2-AI described as "an uncommon short-acting stimulant with effects that have been compared to 1-benzylpiperazine or methamphetamine." Common subjective effects reported include stimulation, appetite suppression, increased perspiration, visual acuity enhancement, cognitive euphoria, and motivation enhancement.

### Dose & Duration Data

Confirmed against PsychonautWiki (community consensus, matches seed data):

| Level | Oral Dose |
|---|---|
| Threshold | 3 mg |
| Light | 5–10 mg |
| Common | 10–20 mg |
| Strong | 20–40 mg |
| Heavy | 40+ mg |

| Phase | Duration (Oral) |
|---|---|
| Onset | 10–30 min |
| Total duration | 1–2 hours |
| Aftereffects | 2–4 hours |

**Note:** No published controlled human dose-response data exists for 2-AI. These values represent community consensus from user reports and should be labeled as such in the article. The short total duration (1–2h) aligns with class PK data showing rapid clearance for aminoindanes (Shimshoni et al. 2018 [Ref 8]).

---

## Safety & Toxicity

### Predicted Toxicity (In Silico)

Jurowski & Frydrych 2026 [Ref 4] — first systematic toxicity prediction for 2-AI using multi-tool in silico approach (Percepta, ProTox 3.0, ADMETlab 3.0, VEGA QSAR, TEST, QSAR Toolbox, STopTox):

| Parameter | 2-AI Predicted Value |
|---|---|
| Oral LD₅₀ (rat) | 150–560 mg/kg (Percepta); 259.7–112.6 mg/kg (VEGA); 326–360 mg/kg (ProTox 3.0) |
| Cardiovascular toxicity probability | 80% |
| Pulmonary involvement probability | 66% |
| Genotoxicity — Ames test probability | 58.7% |
| hERG inhibition IC₅₀ | 391.7 µM (LOW cardiac arrhythmia risk) |
| Skin irritation (STopTox) | 80% probable |
| Eye irritation | Non-irritant (predicted) |

**⚠️ FLAG:** All toxicity data for 2-AI are in silico predictions only (Jurowski 2026). No experimental animal LD₅₀ data exists for 2-AI itself. The data is relevant for general guidance but must be labeled as predicted rather than experimentally confirmed.

### Class Toxicity (MDAI)

Palenicek et al. 2016 [Ref 23] determined MDAI toxicity in Wistar rats:
- SC LD₅₀: **28.33 mg/kg** (subcutaneous)
- IV LD₅₀: **35 mg/kg** (intravenous)
- Oral LD₅₀: Not established up to 40 mg/kg
- Mechanism of death: **Disseminated intravascular coagulopathy (DIC) + cerebral edema**
- Hyperthermia in group-housed conditions (serotonin syndrome-type response)

These MDAI values should NOT be directly extrapolated to 2-AI without qualification — 2-AI has a different monoamine selectivity profile (NET >> SERT for 2-AI; SERT >> NET for MDAI).

### Hepatotoxicity

Richter et al. 2019 [Ref 16] demonstrated **strong cytotoxic potential** for MDAI in human HepG2 hepatocytes using high content screening. Given 2-AI's structural similarity and the finding that 2-AI is unmetabolized in microsomes (Manier 2020 [Ref 3]), hepatic accumulation is possible, but no direct hepatotoxicity data for 2-AI exists.

### Fatal Cases

No published case reports of death specifically attributed to 2-AI alone were identified in this research.

**Related aminoindane fatalities (class context):**

1. Deville et al. 2019 [Ref 15]: 28-year-old male found dead; blood MDAI 2.09 mg/L + 5-EAPB 6.45 mg/L; attributed to combined NPS consumption. Polysubstance use.

2. Staeheli et al. 2017 [Ref 19]: Fatal case with MDAI + 2-MAPB; postmortem blood concentration data published; no significant postmortem redistribution of MDAI found.

**Key limitation:** Both fatalities involve MDAI in polysubstance contexts. No 2-AI-specific fatal case reports were found.

---

## Harm Reduction

### Serotonin Syndrome Risk

Despite 2-AI's relatively weak SERT activity, serotonin syndrome risk exists when combined with:
- Other monoamine releasers (MDMA, MDAI)
- Monoamine oxidase inhibitors (MAOIs)
- Serotonin reuptake inhibitors (SSRIs, SNRIs)

The Pinterova 2017 review [Ref 2] explicitly states that aminoindanes "may pose a significant risk of serotonin syndrome at high doses or when combined with other drugs."

### NAT2 Slow Acetylator Risk

The exclusive NAT2 metabolism of 2-AI (Manier 2020 [Ref 3]) means that individuals who are NAT2 slow acetylators (approximately 40–60% of Caucasian populations) may experience higher plasma concentrations of unmetabolized 2-AI, leading to more intense and potentially more toxic effects. This pharmacogenomic consideration has not been studied in a human trial context.

### Testing and Identification

2-AI can be detected in:
- Saliva via CE-UV and CE-MS (Koall et al. 2025 [Ref 10]); LOD 6–15 µM
- Urine via GC-MS (Kim et al. 2018 [Ref 22]); LLOQ 2 ng/mL

---

## Tolerance & Dependence

### Published Data

No published controlled research on tolerance development or dependence in 2-AI specifically.

**Seed data (brief):**
- Tolerance buildup: "develops with prolonged and repeated use"
- Tolerance half-life: 5 days
- Full reset: 1.5 weeks
- Cross-tolerances: dopamine, stimulant
- Physical dependence: moderate
- Psychological dependence: moderate
- Formation: "moderately addictive with a high potential for abuse"

**Assessment:** These values are not verified against primary literature for 2-AI. They represent class-level inference from stimulant/NET-releasing agents generally. The Simmler 2014 paper [Ref 1] noted that compounds with high DAT potency have high abuse potential; 2-AI's relatively weak DAT activity (compared to amphetamine) would predict lower reinforcing efficacy, though this has not been tested in self-administration studies. No published self-administration or conditioned place preference studies for 2-AI were found.

⚠️ **FLAG:** All tolerance and dependence values are unverified against primary sources. Generation agent should label as "based on class analogy" or community consensus.

---

## Interactions

### Known Interactions (from brief seed data)

| Substance | Severity | Mechanism (Research Assessment) |
|---|---|---|
| Tramadol | Lethal | Tramadol is a weak SNRI + mu-opioid agonist; combined with 2-AI's NET-releasing action could cause dangerous NE excess, serotonin syndrome, seizure threshold lowering. Pharmacologically plausible. |
| MDMA | Lethal | Combined monoamine releasing agents; massive serotonin/NE release; serotonin syndrome, hyperthermia, cardiovascular collapse. Class interaction well-established. |
| Cocaine | Lethal | Cocaine is a NET/DAT/SERT reuptake inhibitor; combined with NET releasing action of 2-AI could cause profound NE surge, severe hypertension, cardiac arrhythmia, coronary vasospasm. |
| MDAI | Dangerous | Both aminoindane monoamine releasing agents; additive monoamine release. |
| Alcohol | Unknown | No published interaction data. |

⚠️ **CRITICAL SAFETY FLAG:** The "lethal" severity ratings for tramadol, MDMA, and cocaine interactions with **2-AI specifically** are **not supported by published case reports**. No case reports of 2-AI + tramadol, 2-AI + MDMA, or 2-AI + cocaine fatalities were found in the literature. These severity ratings appear extrapolated from MDAI case reports and from class-level pharmacological reasoning.

For MDAI (structural analog), fatalities have been documented in polysubstance contexts (Deville 2019 [Ref 15]; Staeheli 2017 [Ref 19]), supporting class-level danger, but 2-AI-specific evidence is absent.

The mechanistic basis for these interactions is pharmacologically sound, but the "lethal" designation for 2-AI-specific interactions should be flagged for human editorial review before publication.

---

## Legal Status

| Jurisdiction | Status | Details |
|---|---|---|
| China | **Controlled** | Scheduled October 2015 |
| Sweden | **Controlled/Hazardous** | Public Health Agency designation June 2019 |
| UK | **Controlled** | Covered under Psychoactive Substances Act 2016 (blanket ban on NPS) |
| Austria | **Controlled** | Prohibited under NPSG (Neue-Psychoaktive-Substanzen-Gesetz) |
| USA | **Unscheduled** (federal) | No DEA scheduling identified; may be prosecutable under Federal Analogue Act if intended for human consumption |
| Canada | **Unscheduled** (explicit) | Not listed in CDSA schedules; analog provisions may apply |
| Australia | **Status unclear** | Not specifically identified as scheduled in searches; TGA-regulated context |
| International | **Uncontrolled** | UNODC confirmed: "None of the aminoindanes are under international control" |

**Note:** The UK Psychoactive Substances Act 2016 created a blanket ban on novel psychoactive substances (with exceptions for food, alcohol, tobacco, medicines), effectively banning 2-AI in the UK as of May 2016 without specific scheduling.

---

## Clinical Trials

### For 2-AI Specifically
No clinical trials registered for 2-aminoindane (2-AI) itself were identified on ClinicalTrials.gov.

### For Class Analog (MEAI/CMND-100)
**NCT05913752** — "A First in Human Study of CMND-100 in Healthy and Alcohol Use Disorder (AUD) Subjects"
- Sponsor: Clearmind Medicine Inc. (NASDAQ: CMND)
- Status: **Recruiting** (Phase I/IIa)
- Compound: **CMND-100 = MEAI = 5-methoxy-2-aminoindane** (5-MeO-AI) — structural analog of 2-AI
- Conditions: Alcohol Use Disorder (AUD)
- Rationale: MEAI described as producing "euphoric, alcohol-like tipsy experience and reduced desire to consume alcoholic beverages" (Shimshoni 2018 [Ref 8])
- Additional development: Intranasal formulation announced February 2026; Type A FDA meeting completed

The CMND-100/MEAI clinical trial is directly relevant context for 2-AI because:
1. MEAI's pharmacokinetics were studied in rats with results directly informing class PK (Shimshoni 2018 [Ref 8])
2. MEAI shows weak 5-HT2B binding (unlike benzofurans) suggesting lower cardiac valve risk
3. The ongoing clinical development validates the therapeutic potential of the aminoindane scaffold

---

## Community Feedback Analysis

No community feedback was submitted in Part A2 of the brief. No feedback items to evaluate.

---

## Gaps & Flags

### 🔴 CRITICAL FLAGS — Require editorial review before publication

1. **"Entactogen" psychoactive class classification is not supported by primary literature.** Nichols et al. 1990 [Ref 20] showed 2-AI does NOT substitute in MDMA-trained rats. MDAI is the entactogen analog; 2-AI is primarily a stimulant/noradrenergic agent. The generation agent should propose removing "Entactogen" from the psychoactive class or adding a strong caveat.

2. **"Dopamine releasing agent" pharmacological class is poorly supported.** Simmler 2014 [Ref 1] shows weak DAT activity for 2-AI. "Norepinephrine releasing agent" is the better-supported classification. Generation agent should flag this discrepancy.

3. **Interaction "lethal" severity ratings for tramadol, MDMA, and cocaine are mechanistically plausible but not substantiated by published 2-AI-specific case reports.** These appear to be extrapolated from MDAI class data. Flag for human review before displaying as verified data.

4. **α₂-Adrenoceptor affinity (Halberstadt 2019 [Ref 11]) not captured in brief pharmacology at all.** 2-AI shows α₂C Ki = 41 nM — among the highest affinity reported for this compound at any target. This affects cardiovascular risk profile and mechanism of action description.

### 🟡 IMPORTANT GAPS — Generation agent should note these explicitly

5. **No human pharmacokinetic data for 2-AI.** Duration/onset seed data is community consensus only (confirmed via PsychonautWiki). No controlled PK study exists.

6. **No published animal LD₅₀ for 2-AI.** All toxicity predictions are in silico (Jurowski 2026 [Ref 4]). The exact toxic dose is genuinely unknown experimentally.

7. **NAT2 pharmacogenomics.** 2-AI's exclusive NAT2 acetylation means slow acetylators (40–60% of some populations) may have meaningfully different exposure. Not mentioned in brief.

8. **Dose/duration values are unverified against primary sources** — confirmed as community consensus via PsychonautWiki. Should be labeled as such.

9. **Tolerance and dependence values are unverified** — no published controlled studies for 2-AI.

10. **No published controlled human studies of 2-AI effects, safety, or dose-response.**

### 🟢 CORRECTIONS TO SEED DATA

11. **Chemical data missing from brief:** SMILES (NC1Cc2ccccc2C1), molecular formula (C₉H₁₁N), molecular weight (133.19), PubChem CID (76310) all confirmed and should be added to the DB.

12. **"Norepinephrine-dopamine reuptake inhibitor" label in pharmacological class** is mechanistically incorrect — 2-AI is a releasing agent (substrate), not a reuptake inhibitor (blocker). Releasing agents work by reverse transport via monoamine transporters; blockers competitively inhibit uptake. The distinction matters for interaction prediction.