Hexedrone

# Research Output: Hexedrone

**PSX ID:** PSX-0208  
**Generation Provenance ID:** 4c256882-3b59-412a-92dc-3092e047f332  
**Research Date:** 2026-05-11  
**Researcher Note:** Hexedrone (HEX, N-methyl variant, 2-(methylamino)-1-phenylhexan-1-one) and its N-ethyl homolog N-ethylhexedrone (NEH, HEXEN) are structurally related but distinct compounds. Published pharmacology and case reports are almost exclusively for NEH. All NEH data applied to hexedrone is explicitly labeled as **analog inference** and must be treated as such throughout this output.

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## Chemical Identity

**PubChem CID:** 129844496 [Ref 1]  
**IUPAC name:** 2-(methylamino)-1-phenylhexan-1-one [Ref 1]  
**Systematic name:** 2-(methylamino)-1-phenylhexan-1-one (confirmed matches seed data)  
**Molecular formula:** C₁₃H₁₉NO [Ref 1]  
**Molecular weight:** 205.30 g/mol [Ref 1]  
**InChIKey:** BHIZKPHLTVLXIV-UHFFFAOYSA-N [Ref 1]  
**SMILES:** Not returned by PubChem API call; should be retrieved manually.  
**CAS number:** Not confirmed via API; web sources note the compound but without a consistent verified CAS for the N-methyl (hexedrone) vs N-ethyl (NEH) series. **Flag for editorial verification.**

**Structural notes:**  
Hexedrone is a substituted cathinone (β-keto amphetamine) bearing a phenyl ring at C1, a ketone at C1, a methylamino group at C2, and a butyl chain at C2, giving a total α-carbon chain of four carbons (making the full structure a 6-carbon hexanone). It is the N-methyl homolog in the buphedrone → pentedrone → hexedrone series; replacing the N-methyl with N-ethyl yields N-ethylhexedrone (NEH). Hexedrone possesses a chiral center at C2; enantiomers may exhibit different pharmacological activity, as demonstrated for related cathinones [Ref 21], but no enantiospecific data exists for hexedrone itself.

**Seed data verification:** PubChem confirms molecular formula (C₁₃H₁₉NO), molecular weight (205.30), IUPAC name, and InChIKey. Brief had these fields empty; PubChem resolves all four. SMILES and CAS remain unverified from the API call.

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## Pharmacology

### Mechanism of Action
Hexedrone belongs to the substituted cathinone class and, based on its structural relationship to closely studied analogs, is a **norepinephrine-dopamine reuptake inhibitor (NDRI)**. The compound inhibits the dopamine transporter (DAT) and norepinephrine transporter (NET) without inducing monoamine efflux, distinguishing it from releasing agents such as mephedrone or MDMA [Ref 6].

**⚠️ FLAG — Seed data error:** The brief lists "Monoamine releasing agent" as one of hexedrone's pharmacological classes. This is unsupported and likely incorrect. Kolaczynska et al. (2021) specifically tested NEH and found **no monoamine efflux** at DAT, NET, or SERT — it is a pure reuptake inhibitor [Ref 6]. The "releasing agent" designation should be removed from the seed data; only "NDRI" is supported by evidence.

### Receptor Binding / Transporter IC₅₀ Data
All data below is for **N-ethylhexedrone (NEH)**, the N-ethyl structural analog. No published IC₅₀ or Ki values exist for hexedrone (N-methyl) itself.

**Persson et al. (2024) [Ref 24]** — fluorescent dye method in CHO-K1/HEK293/MDCK cells:
- NEH DAT IC₅₀ = **44.5 nM**
- Potency rank among 7 cathinones: MPHP (4.53 nM) > 4Cl-α-PVP > 3F-α-PVP > α-PiHP > N-ethylpentylone (16.9 nM) > **NEH (44.5 nM)** > 4-methylpentedrone (261 nM)
- For reference: cocaine DAT IC₅₀ = 111 nM; amphetamine = 257 nM
- NEH is more potent than cocaine at DAT by this method
- DAT/SERT inhibition ratio: in the hundreds (highly DAT-selective)

**Kolaczynska et al. (2021) [Ref 6]** — human transporter expressing HEK cells:
- NEH DAT IC₅₀ = **0.17 µM (170 nM)**
- NEH NET IC₅₀ = **0.18 µM (180 nM)**
- NEH SERT IC₅₀ = **>10 µM**
- DAT/SERT selectivity ratio: **264–356**
- No monoamine releasing activity detected

**Interpretation of IC₅₀ discrepancy:** Persson 2024 (44.5 nM) vs Kolaczynska 2021 (170 nM) reflect methodological differences (fluorescent dye vs radioligand uptake assay; different cell lines). Both confirm DAT-selective NDRI profile.

**Nadal-Gratacós et al. (2023) [Ref 3]** — SAR study of N-ethyl cathinone series in HEK293 cells:
- N-ethyl series: DAT potency follows inverted U with alpha-chain length; propyl chain (pentedrone) is most potent, then NEH (butyl chain) and NEB
- All compounds DAT-selective; minimal SERT activity
- Side-chain elongation increases cytotoxicity; NEH more cytotoxic than methamphetamine in PC12 cells

**Eshleman et al. (2019) [Ref 5]** — cathinone and benzofuran SAR at biogenic amine transporters (includes hexedrone-class compounds); provides context for N-methyl vs N-ethyl substitution effects.

### Pharmacokinetics
**No human pharmacokinetic data for hexedrone (N-methyl) exists in the published literature.**

The following data is from N-ethylhexedrone (NEH) studies, presented with the analog caveat:

**Controlled administration (Nuñez-Montero et al., 2023 [Ref 2]):**
- Route: 30 mg NEH intranasal, 6 volunteer consumers
- Oral fluid absorption: within first hour post-intranasal administration (vs 4-CMC oral peaking at 3 hours)
- Sweat excretion: ~0.2% of the administered dose in first 4 hours
- Method: validated GC-MS/MS

**Clinical case series (Lefeuvre et al., 2024 [Ref 8]):**
- Route: intranasal (unspecified dose)
- Plasma concentrations (non-fatal): 97.2 → 0.7 µg/L (Day 1 → Day 7, Case 1); 7.9 µg/L at admission (Case 2); 49 → 1.8 µg/L (Day 1 → Day 7, Case 3)
- Urine concentrations: 724 → 0.5 µg/L (Day 1 → Day 7, Case 1)
- **Elimination half-life: 19–28 hours** (estimated in 2 of 3 cases)
- Detection window in urine: up to Day 10 post-dose
- Metabolites identified: reduced NEH, dealkyl-NEH, reduced dealkyl-NEH, hydroxy-NEH

**CYP enzyme involvement:** No direct study for hexedrone. By analogy with the N-alkyl cathinone class (mexedrone data from Camuto et al. 2022 [Ref 20]): **CYP2C19** (hydroxylation and dealkylation), **CYP2D6** and **CYP1A2** (hydroxylation) are likely involved. Flavin monooxygenase (FMO) may contribute to N-oxide formation as shown for MDPV [Ref 32]. These are analog inferences and require confirmation for hexedrone.

### Pharmacological Class Note
Based on structural similarity to pentedrone and NEH, hexedrone (N-methyl) likely has a DAT IC₅₀ somewhat higher (less potent) than NEH's 44.5–170 nM. The N-ethyl group in NEH generally increases lipophilicity and membrane penetration. Hexedrone should still be classified as a potent DAT-selective NDRI, but specific values are not available.

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## History

### Discovery and First Characterization
Hexedrone (α-methylaminohexanophenone, HEX) was first formally characterized by **Błażewicz et al. (2017)** [Ref 11] in *Forensic Toxicology* (DOI: 10.1007/s11419-017-0360-2). The paper reports the identification and structural characterization of hexedrone along with three other novel cathinones (4-BEC, 4-Cl-PPP, 4-Br-PVP) from seized drug samples. Authors: Błażewicz A, Bednarek E, Sitkowski J, Popławska M, Stypułkowska K, Bocian W, Kozerski L.

**EMCDDA First Notification:** Hexedrone was first reported to the EU Early Warning System by **Poland in July 2013** [Ref 25], predating its formal published characterization. This reflects the routine pattern where substances appear in seizures before they appear in peer-reviewed publications.

**N-Ethylhexedrone (NEH/HEXEN) history:** NEH first identified in a sample from the **Belgian Customs laboratory** received at the JRC in **November 2015**, then independently by French Customs in **January 2016**. EMCDDA received notifications from Sweden, Netherlands, France, Belgium, and Slovenia in **February 2016** [Ref 25]. By 2017, NEH had become **the most frequently seized stimulant designer drug in Hungary** [Ref 4].

### Synthesis Origins
Web sources indicate that N-ethylhexedrone-class compounds were mentioned in **Boehringer Ingelheim patents from the 1960s**, alongside other compounds in the MDPV development series. This pre-dates their appearance as designer drugs by decades. [Source: web-retrieved; not verified via primary literature.]

### Timeline Summary
- ~1960s: Hexedrone-class compounds first synthesized (reported in patents)
- July 2013: Hexedrone first reported to EMCDDA by Poland
- 2017: Błażewicz et al. publish first formal characterization
- 2015–2016: NEH (N-ethyl analog) emerges on European market
- 2017: NEH most seized stimulant cathinone in Hungary
- 2019: NEH temporarily placed in US Schedule I
- March 2020: NEH added to UN Psychotropic Substances Convention Schedule II
- 2022: NEH permanently placed in US Schedule I

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## Subjective Effects

No controlled human studies on hexedrone's subjective effects exist. The following is based on:
1. Community consensus reports (PsychonautWiki, KnowDrugs) [Ref 29]
2. Clinical/toxicological reports on NEH (N-ethyl analog)
3. Class-level inference from cathinone pharmacology

**Stimulant effects consistent with NDRI mechanism:**  
Central nervous system stimulation, wakefulness, appetite suppression, vasoconstriction, increased heart rate, perspiration, elevated blood pressure, bruxism (teeth grinding), focus enhancement, motivation enhancement, thought acceleration, euphoria, analysis enhancement, disinhibition, music appreciation, sociability enhancement, ego inflation, compulsive redosing urge [Ref 29].

**Post-use effects (from NEH case series, Lefeuvre 2024 [Ref 8]):**  
During recovery from NEH intoxication (12–24 hours post-dose), patients described: anxiety, feelings of persecution, asthenia, anhedonia, abulia, psychomotor slowing. These represent the comedown/post-acute phase consistent with dopaminergic depletion.

**Duration data** (community consensus, no controlled studies):  
- Onset: 15–30 minutes (oral route)
- Total duration: 1–4 hours (oral)
- After-effects: 1–12 hours
These figures are consistent with class comparators. No controlled study data available for direct verification.

**Note on route:** The seed data lists oral as the primary and only ROA. The controlled administration study (Nuñez-Montero 2023 [Ref 2]) used intranasal administration for NEH. Community reports indicate both oral and intranasal use for hexedrone. The brief's restriction to oral-only should be reviewed.

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## Safety & Toxicity

### Case Reports of Adverse Events (all NEH, not hexedrone N-methyl)

**Fatal intoxication — Kovács et al. (2019) [Ref 4]:**  
- 23-year-old male, regular drug user, pre-existing arrhythmia in childhood, history of seizures
- BMI 42.9, hypertrophic/dilated heart, severe atherosclerosis
- Died within hours of NEH and ADB-FUBINACA consumption
- **Postmortem blood NEH: 285 ng/mL**; suspected non-fatal user blood levels ≤83.9 ng/mL
- Hyperthermia-related pathology; cardiac disease considered a co-factor

**Fatal intoxication — Domagalska et al. (2021) [Ref 16]:**  
- 21-year-old male, no pre-existing disease
- Admitted with disorientation, aggression, loss of consciousness
- **Hyperthermia >41°C, tachycardia >160 bpm**, tachypnea, BP 110/60 mmHg, **acute kidney failure**
- Died after several hours of hospitalization
- **Postmortem blood NEH: 145 ng/mL**
- Powder initially misidentified as cocaine; re-analysis confirmed NEH
- Concomitant: amphetamine (low concentration) and THC-COOH

**Non-fatal severe intoxication — Lefeuvre et al. (2024) [Ref 8]:**  
- 3 patients admitted to emergency departments 12–24 hours after intranasal NEH use
- **2 of 3 required intubation and mechanical ventilation**
- **SIADH (syndrome of inappropriate antidiuretic hormone secretion)** diagnosed in one patient
- Symptoms: anxiety, paranoia, asthenia, anhedonia, psychomotor slowing, loss of consciousness
- Prolonged hospitalization in 2 of 3 cases
- All recovered

**Severe acute toxicity — Dunlop et al. (2020) [Ref 17]:**  
- Analytically confirmed acute toxicity from combined 3-HO-PCP and NEH
- Polydrug scenario; NEH identified as the cathinone component

**Cytotoxicity (in vitro, Nadal-Gratacós 2023 [Ref 3]):**  
- N-ethyl cathinone series (including NEH) display **greater cytotoxicity than methamphetamine** in PC12 cells
- Cytotoxicity increases with alpha-carbon chain length (likely due to greater membrane penetration)
- Hexedrone (N-methyl) was not tested in this study; by SAR, expected cytotoxicity is somewhat lower than NEH

**Reunion Island NPS surveillance (Maillot et al., 2025 [Ref 15]):** confirms cathinone intoxications as part of current NPS emergency presentations; biological confirmation increasingly feasible but still challenging.

### LD₅₀
Not established for hexedrone or N-ethylhexedrone. No animal or human LD₅₀ data found.

### Toxic Blood Concentrations (NEH, not hexedrone)
- Non-fatal suspected users: ≤83.9 ng/mL [Ref 4]
- Non-fatal hospitalized: 7.9–97.2 µg/L (7.9–97.2 ng/mL) [Ref 8]
- Fatal cases: 145–285 ng/mL [Refs 4, 16]

**Note:** The gap between non-fatal (≤83.9 ng/mL) and fatal (145–285 ng/mL) concentrations suggests a relatively narrow margin. Pre-existing cardiac pathology significantly elevates risk at sub-fatal concentrations [Ref 4].

### Cardiovascular Risk
Hexedrone-class compounds produce sympathomimetic toxicity: tachycardia, hypertension, hyperthermia. Cardiovascular toxicity of cathinone stimulants reviewed in Mladěnka et al. (2018) [Ref 22]. Pre-existing cardiac conditions (arrhythmia, cardiomyopathy, atherosclerosis) substantially increase risk of fatal outcome [Ref 4].

### Psychiatric Risk
Chronic cathinone use associated with acute psychosis, hypomania, paranoid ideation, and delusions comparable to amphetamine-type stimulants (Weinstein et al. 2017 [Ref 23]). NDRI mechanism with high DAT selectivity (similar to cocaine) confers significant psychosis risk with heavy use.

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## Harm Reduction

### Testing and Identification
- Hexedrone and NEH do not produce positive results on standard immunoassay amphetamine or cathinone screens; confirmatory analysis requires **LC-MS/MS or GC-MS/MS** [Refs 2, 16]
- Risk of misidentification with other white powder stimulants (Domagalska 2021: misidentified as cocaine [Ref 16])
- Fentanyl test strip testing is irrelevant but reagent testing may provide color indication; no validated reagent table found for hexedrone specifically

### Clinical Management of Overdose
Based on cathinone class evidence:
- **Benzodiazepines** for agitation, seizures, and cardiovascular stabilization (standard sympathomimetic toxidrome management)
- **Supportive care**: active cooling for hyperthermia (>41°C documented in fatal case)
- **Monitor renal function**: acute kidney failure documented [Ref 16]
- **Monitor for SIADH**: documented in Lefeuvre 2024 [Ref 8]
- **Ventilatory support** may be required (2/3 cases in Lefeuvre series needed intubation)
- Long detection window (up to 10 days in urine for NEH) [Ref 8]; clinically assess beyond acute phase

### Risk Factors for Severe Outcomes
- Pre-existing cardiac disease (arrhythmia, cardiomyopathy, atherosclerosis) — fatal outcome documented [Ref 4]
- High doses or unknown dose of white powder product
- Polydrug use: concurrent synthetic cannabinoid (ADB-FUBINACA) in fatal case [Ref 4]; 3-HO-PCP in severe toxicity case [Ref 17]
- Intranasal route produces faster onset and higher peak concentrations

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## Tolerance & Dependence

### Tolerance
- **Development:** Develops with prolonged and repeated use (class inference; no hexedrone-specific study)
- **Community consensus half-life:** 3–7 days [Ref 29]; seed data specifies 5 days (within this range, consistent)
- **Community consensus full reset:** 1–2 weeks [Ref 29]; seed data specifies 1.5 weeks (consistent)
- **Cross-tolerance:** With dopaminergic stimulants (amphetamines, cocaine, other cathinones) via DAT desensitization mechanism

### Dependence Liability
- **High abuse liability** based on high DAT potency comparable to cocaine [Refs 6, 24]
- Highly DAT-selective NDRIs are associated with strong reinforcing properties in preclinical models
- Cathinone class associated with compulsive redosing behavior (binge pattern)
- **Physical dependence:** Moderate (class inference)
- **Psychological dependence:** Moderate to high (class inference; not directly studied)
- Seed data states "moderately addictive with a high potential for abuse" — consistent with published class data

### Withdrawal
No published withdrawal characterization for hexedrone. Class-level expectation: dopaminergic rebound syndrome (depression, anhedonia, fatigue) following cessation, consistent with the post-intoxication symptoms documented in NEH cases (anhedonia, abulia, depression during recovery phase [Ref 8]).

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## Interactions

**No published drug interaction studies exist for hexedrone or N-ethylhexedrone.** All interaction risks below are class-level inferences.

### High-Concern Interactions (class-level)
- **MAO inhibitors (MAOIs):** Contraindicated. Cathinone stimulants combined with MAOIs risk hypertensive crisis and serotonin syndrome. Mechanism: MAOI prevents catecholamine breakdown, leading to accumulation.
- **Other stimulants (amphetamines, cocaine, other cathinones, caffeine):** Additive cardiovascular risk (tachycardia, hypertension, hyperthermia). Domagalska 2021 case had concomitant amphetamine [Ref 16].
- **Synthetic cannabinoids:** Kovács 2019 fatal case involved concurrent ADB-FUBINACA [Ref 4]; the interaction mechanism is unclear but polysubstance presentations worsen outcomes.
- **Lithium:** Class-level caution; cathinone-induced dopaminergic hyperstimulation may interact with lithium's mechanism; no specific data.

### Moderate-Concern Interactions
- **Serotonergic agents (SSRIs, SNRIs):** Some SERT inhibition possible at high doses; theoretical serotonin syndrome risk, but NEH shows high DAT/SERT selectivity [Refs 6, 24], making this lower risk than with mixed-mechanism cathinones (e.g., mephedrone)
- **Antihypertensives:** Hexedrone's vasoconstriction and cardiovascular stimulation may counteract antihypertensive medications
- **CYP2D6 inhibitors/inducers:** If hexedrone metabolism involves CYP2D6 (by analogy [Ref 20]), co-administration of CYP2D6 inhibitors (fluoxetine, paroxetine) could increase plasma levels

**Flag:** No direct interaction study data exists; all above is class/analog inference and must be presented with appropriate caveats.

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## Legal Status

### United Kingdom
**Class B** under the Misuse of Drugs Act 1971, via the cathinone catch-all clause. No separate specific scheduling order found for hexedrone by name. [Ref 26]

### Germany
Controlled under the **NpSG (Neue-psychoaktive-Stoffe-Gesetz / New Psychoactive Substances Act)** as of **November 26, 2016**. Production and import with intent to market, administration to another person, and trading are punishable. Possession is illegal but not penalized. [Ref 26]

### United States
**Hexedrone (N-methyl, 2-(methylamino)-1-phenylhexan-1-one) is NOT individually scheduled** in the DEA Controlled Substances orange book [database lookup performed]. It is likely subject to the **Federal Analogue Act** (21 U.S.C. § 813) as a substantially similar compound to controlled cathinone substances, when intended for human consumption.

*Note:* **N-Ethylhexedrone (NEH), a distinct but closely related compound**, was placed in US Schedule I:
- Temporary placement: May 2019 [Ref 27]
- Extended temporary placement: July 2021 [Ref 27]
- **Permanent Schedule I placement: June 1, 2022** [Ref 27]
Bonson et al. (2019) [Ref 14] reviews the scheduling process for synthetic cathinones under the CSA.

### United Nations
**N-Ethylhexedrone** was added to the **UN Convention on Psychotropic Substances Schedule II** in **March 2020** by the Commission on Narcotic Drugs [Ref 28]. Hexedrone (N-methyl) was not mentioned in this specific action.

### Australia
Cathinone class broadly controlled under Australian law. Hexedrone, as a synthetic cathinone analog, is likely prohibited under state/territory criminal codes and the Therapeutic Goods Act Schedules. Specific scheduling action for hexedrone by name not confirmed in this research.

### Canada
N-Ethylhexedrone is Schedule I in Canada. Hexedrone (N-methyl) status not individually confirmed; likely captured under cathinone class provisions.

### Sweden
February 2016: EMCDDA received notification of N-ethylhexedrone identification from Sweden [Ref 25]. Specific hexedrone scheduling date not confirmed via this research.

---

## Clinical Trials

**No clinical trials found** for hexedrone or N-ethylhexedrone on ClinicalTrials.gov (search performed). This is consistent with the substance's status as an unscheduled (in most jurisdictions) to Schedule I (US, for NEH) designer drug with no accepted medical use.

---

## Community Feedback Analysis

**No community feedback was submitted in Part A2 of the brief.**

No community feedback present. Proceeding with standard research findings only.

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## Gaps & Flags

### 🚩 Safety-Critical Flags

1. **⚠️ PHARMACOLOGICAL CLASS ERROR — "Monoamine releasing agent" in seed data is unsupported:**  
   Kolaczynska et al. (2021) [Ref 6] tested NEH and found no monoamine efflux — it is a **pure reuptake inhibitor**, not a releasing agent. The seed pharmacological class should read only "NDRI (Norepinephrine-Dopamine Reuptake Inhibitor)." The "Monoamine releasing agent" designation should be removed.

2. **⚠️ All dose and duration data is community consensus only:**  
   No controlled human pharmacology study for hexedrone (N-methyl) exists. Doses (threshold 30 mg → heavy 125+ mg oral) and durations (1–4h total, 1–12h aftereffects) are community consensus from PsychonautWiki/KnowDrugs [Ref 29]. The seed dose data is consistent with community consensus and should be retained but flagged as lacking controlled study verification.

3. **⚠️ All clinical/toxicological case report data is for N-ethylhexedrone (NEH), not hexedrone:**  
   Fatal concentrations (145–285 ng/mL), elimination half-life (19–28h), metabolites, and severe adverse events are all from NEH studies. Hexedrone (N-methyl) specific data does not exist. Generation agent must make this distinction explicit.

4. **⚠️ LD₅₀ not established for hexedrone or NEH.**

5. **⚠️ SMILES not retrieved from PubChem API.** Generation agent should not propose a SMILES string without verification.

### Data Gaps

6. **No hexedrone-specific pharmacokinetics:** Half-life, bioavailability, Tmax for oral hexedrone are unknown. All PK data from NEH (intranasal route). The 19–28h elimination half-life may not translate directly to N-methyl hexedrone given the N-alkyl substitution difference.

7. **No stereospecific data:** Hexedrone has a chiral center; no enantioselective pharmacology data found for this specific compound.

8. **Physical properties not retrieved:** Melting point, aqueous solubility, pKa, logP not found via API tools. The Błażewicz 2017 paper likely contains physical characterization data but could not be accessed (Springer paywall).

9. **Hexedrone-specific transporter binding:** All IC₅₀ data (Refs 6, 24) is for N-ethylhexedrone. By SAR, hexedrone's N-methyl substitution likely results in moderately different (probably lower) potency. Specific values not published.

10. **Route of administration:** Brief lists oral as primary/only ROA; community reports and the controlled study (Nuñez-Montero 2023 [Ref 2]) indicate intranasal use is also common for NEH. Hexedrone (N-methyl) ROA profile should be reviewed.

11. **CYP enzyme involvement:** Inferred from mexedrone analog data (CYP2C19, CYP2D6, CYP1A2 [Ref 20]); no direct study for hexedrone.

12. **Legal status ambiguity:** Hexedrone (N-methyl) scheduling is confirmed for UK (Class B) and Germany (NpSG 2016). US, Australia, Canada, and Sweden scheduling are inferred or based on class provisions, not substance-specific legislative action. Requires editorial review for accuracy.

13. **Toxicity seed data flagged:** The brief notes "Inferred from pharmacological class — not sourced from literature. Review recommended." This is accurate — toxicity values are entirely class-level inferences.

14. **No contraindications confirmed from literature:** All contraindications are class-level inference.