Carfentanil

# Research Output: Carfentanil

## Chemical Identity

**PubChem CID:** 62156 (api_verified)
**CAS Number:** 59708-52-0 (web_retrieved from multiple chemical databases)
**IUPAC Name:** methyl 1-(2-phenylethyl)-4-(N-propanoylanilino)piperidine-4-carboxylate
**INN:** Carfentanil (INN #4430) [Ref 38]
**Brand Name (veterinary):** Wildnil®
**Synonyms/Street Names:** Carfentanyl (alternate spelling), Wildnil (brand), 4-carbomethoxyfentanyl
**Chemical Class:** 4-anilidopiperidine (same scaffold as fentanyl, sufentanil, alfentanil)

**Molecular Formula:** C₂₄H₃₀N₂O₃ [Ref 38]
**Molecular Weight:** 394.5 g/mol [PubChem api_verified]
**SMILES:** CCC(=O)N(C1(CCN(CC1)CCc1ccccc1)C(=O)OC)c1ccccc1 [Ref 38]
**InChIKey:** YDSDEBIZUNNPOB-UHFFFAOYSA-N [PubChem api_verified]

**Stereochemistry:** The C4 piperidine carbon bears symmetric methylene chains to the ring nitrogen; structural analysis confirms no stereocenters. The InChI contains no stereodescriptor layer, consistent with achiral structure. No active isomers have been described in published literature.

**Physical Properties (note: no reliable published melting point data was recoverable via API or web sources):**
- Molecular lipophilicity (Lipinski properties all within acceptable limits [Ref 38])
- Can be absorbed via transdermal route and through mucous membranes [Ref 29]
- Suitable for aerosolization (demonstrated 2002 Moscow theater use) [Ref 7]
- Logistics of extreme potency mean nanogram-to-microgram quantities are pharmacologically active

**Discrepancies with seed data:** The brief listed no CID, SMILES, InChIKey, formula, or molecular weight. All have now been verified via PubChem (api_verified). No IUPAC or systematic name was in the brief; both are now confirmed. The brief listed "Carfentanyl" as a street name — this is actually an alternate spelling of the INN, not a street name; the true brand name was Wildnil. **Flag for editorial review.**

---

## Pharmacology

### Primary Target

Carfentanil is a potent full agonist at the μ-opioid receptor (MOR; OPRM1). It activates Gi/o-coupled signaling cascades, leading to inhibition of adenylyl cyclase (cAMP suppression), activation of G-protein-inwardly-rectifying potassium channels (GIRK), and inhibition of voltage-gated calcium channels, producing analgesia, sedation, euphoria, and dose-dependent respiratory depression.

### Receptor Binding Affinity

Endt et al. (2025 [Ref 1]) used a HEK-293 cell line stably expressing human μOR and determined:
- MOR binding affinity (Ki): carfentanil binds μOR with **~10× higher affinity than fentanyl or remifentanil**, and **~70× higher affinity than morphine**
- Potency to inhibit cAMP (EC₅₀): carfentanil is **~85× more potent than fentanyl** and **~620× more potent than morphine** in cAMP inhibition assays
- A critical finding: at EC₅₀-equivalent receptor occupancy, carfentanil is **~8× more efficient than morphine, fentanyl, or remifentanil** in inhibiting cAMP, suggesting it stabilizes unique μOR conformations that are ultra-efficient in G-protein signaling

From the metabolites study (Hsu et al. 2019 [Ref 21]), carfentanil EC₅₀ for MOR activation was **0.0049 nM** — consistent with the sub-nanomolar potency profile.

**FLAG (safety-critical):** Specific Ki values (in nM) from radioligand binding displacement experiments were not directly recovered in this research output. The values above are from functional cAMP assays and allometric comparisons. The generation agent should note this distinction.

### Signaling Bias

Ramos-Gonzalez et al. (2023 [Ref 2]) demonstrated that carfentanil is a **β-arrestin-biased agonist** at the μOR compared to other fentanyl analogs. This signaling profile is pharmacologically distinct from G-protein-biased agonists like morphine. β-arrestin recruitment is associated with receptor desensitization, internalization, and tolerance development, and has been linked to enhanced respiratory depression in some preclinical models.

### Unique Receptor Conformations and Resistance to Reversal

Endt et al. (2025 [Ref 1]) reported a critical finding with direct clinical implications: the μOR conformations stabilized by carfentanil are **resistant to naloxone and nalmefene**:
- Naloxone and nalmefene showed 10–100× higher IC₅₀-values against carfentanil-mediated cAMP inhibition compared to other opioids
- By contrast, naltrexone showed **~65× higher potency** to inhibit carfentanil-mediated signaling versus naloxone
- This suggests carfentanil may induce unique receptor conformational states that are displaced more readily by naltrexone than by naloxone or nalmefene

### Receptor Dissociation Kinetics

Mann et al. (2022 [Ref 3]) quantified receptor binding kinetics and found carfentanil has **substantially slower dissociation kinetics** from the μOR compared to nine other tested fentanyl analogs. This slow off-rate is a key mechanism underlying the difficulty of overdose reversal. Clayton et al. (2026 [Ref 12]) confirmed that carfentanil serves as a reference compound for slow dissociation — only protonitazene (a novel nitazene class compound) showed slower dissociation than carfentanil among compounds tested.

### Comparative Potency (Respiratory Depression)

In rat plethysmography studies:
- Hiranita et al. (2024 [Ref 15]) found potency rank order: 3-methylfentanyl > **carfentanil** > fentanyl > heroin for ventilatory depression
- Flynn & France (2025 [Ref 20]) found carfentanil approximately **50× more potent than fentanyl** and **~100× more potent than heroin** for reducing minute volume in rats
- The veterinary literature and public health literature report carfentanil as approximately **100× more potent than fentanyl** and **~10,000× more potent than morphine** for analgesia (Swanson et al. 2017 [Ref 4]; O'Donnell et al. 2017 [Ref 8])

### Receptor Selectivity

Carfentanil is predominantly μOR-selective; it is used as the gold-standard PET radiotracer [¹¹C]carfentanil for MOR imaging precisely because of its selectivity and high affinity (Cumming et al. 2019 [Ref 31 (see note below)]; Lee et al. 2025 [Ref 37]). Selectivity data over delta- and kappa-opioid receptors was not recovered in this search; this gap should be noted.

---

## Pharmacokinetics

### Half-Life and Distribution

Hsu et al. (2019 [Ref 21]) reported a **human serum half-life of approximately 5.7 hours**. This is notably longer than fentanyl's half-life of ~3.7 hours and has implications for risk of renarcotization after naloxone reversal — carfentanil's duration significantly outlasts naloxone's ~33-minute elimination half-life (Baldo 2025 [Ref noted]).

**FLAG:** No published human pharmacokinetic studies using carfentanil as a drug of abuse exist (there is no approved human therapeutic use and no controlled human exposure studies have been published). The 5.7-hour half-life was derived from human serum incubation studies, not clinical PK. The Yang et al. (2024 [Ref 32]) PK-PD model used interspecies allometric scaling to predict human PK parameters.

### Metabolism

Three dedicated metabolic studies characterize carfentanil's biotransformation (Hsu et al. 2019 [Ref 21]; Kong & Walz 2021 [Ref 23]; Kong & Walz 2022 [Ref 22]):

**Phase I metabolism:**
- **Norcarfentanil (M1):** The most abundant metabolite (~40% relative abundance in HLMs); formed via N-dealkylation of the piperidine ring; has minimal MOR activity
- **Active metabolite (M2/M0):** The second most clinically significant metabolite (~12% of total formation); formed via hydroxylation; possesses **comparable MOR activity to parent carfentanil** (EC₅₀ 0.0051 nM vs. 0.0049 nM for parent). This means active metabolite presence may **prolong the pharmacological effects** of carfentanil beyond what pharmacokinetic half-life alone predicts
- Additional metabolites M3–M6 show varying degrees of MOR activity, but at lower abundance

**Phase II metabolism:**
- Glucuronide and sulfate conjugation reactions are expected (Wilde et al. 2019 [Ref 25])

**CYP Enzyme Involvement (Kong & Walz 2021 [Ref 23]):**
- **CYP3A5** — primary enzyme for formation of norcarfentanil (M1), M11, and M15
- **CYP3A4** — second most active for same metabolites
- **CYP2C8** and **CYP2C9** — secondary contributions
- Highly potent M13 metabolite: primarily formed by **CYP2C9** (followed by CYP2C8)

**Drug interaction implication:** CYP3A4/3A5 inhibitors (azole antifungals, macrolide antibiotics, grapefruit juice, ritonavir) could substantially increase carfentanil plasma concentrations and toxicity. CYP3A4/3A5 inducers (rifampin, carbamazepine, St. John's Wort) could reduce concentrations. **FLAG (safety-critical): No published clinical drug interaction studies exist for carfentanil; all CYP inferences are from in vitro microsomal studies only.**

### Routes of Administration

- **Veterinary (historical):** Intramuscular injection via remote delivery (tranquilizer dart)
- **Illicit use:** Predominantly intravenous, intranasal, or oral/insufflation as adulterant in heroin/counterfeit pills
- **Occupational/accidental:** Transdermal absorption and absorption through mucous membranes documented in veterinarians [Ref 29]
- **Military/CBRN:** Aerosolization (Moscow 2002, confirmed by toxicological analysis [Ref 7, Ref 34])
- **PET radiotracer:** Intravenous [¹¹C]carfentanil at nanogram/kg doses in controlled research settings [Ref 35]

---

## History

### Discovery and Synthesis

Carfentanil was **first synthesized on May 2, 1974**, at **Janssen Pharmaceutica** in Beerse, Belgium, by a team of chemists working under **Paul Janssen** (the same team that had developed fentanyl in 1960 and numerous other anilidopiperidine opioids) [Ref 29]. The first published scientific description appeared in **Van Daele et al. (1976)** — a foundational paper characterizing a wide range of fentanyl derivatives. Carfentanil (then denoted 4-carbomethoxyfentanyl) was among the most potent compounds in the series.

The synthesis was formally **patented by Janssen et al.** and published December 18, 1979 as **U.S. Patent No. 4,179,569** [Ref 29].

### Veterinary Introduction

The brand name **Wildnil®** was introduced to veterinary medicine in **1986** as an ultra-potent sedative for large animals (elephants, rhinoceroses, large ungulates, big cats). It was used in combination with an α₂-receptor agonist (e.g., xylazine) for intramuscular remote delivery via dart gun [Ref 29]. Reversal was accomplished with naltrexone or diprenorphine. Commercial production of Wildnil by Janssen ceased in **2003** [Ref 30]. By 2016, it was no longer available even in compounded form for veterinary use due to abuse risk.

Stanley (2014 [Ref 9]) provides broader context for the Janssen team's pioneering contributions to the fentanyl class.

### Illicit Use and the 2016 Crisis

Carfentanil first appeared in the **North American illicit drug supply in 2016**, primarily as an adulterant in heroin and, later, in counterfeit prescription pills. O'Donnell et al. (2017 [Ref 8]) documented carfentanil's presence in fentanyl-analog overdose deaths across 10 US states in July–December 2016. Shoff et al. (2017 [Ref 19]) found carfentanil in **134 postmortem cases** in Miami-Dade County, Florida alone in 2016, with 104 of those cases initially **missed by standard GC-MS screening**.

A major supply source was China before regulatory action. A June 2016 seizure at Vancouver airport recovered 1 kilogram of carfentanil hidden in printer accessories shipped from China [Ref 29]. China regulated carfentanil in March 2017 [Ref 29, Ref 30].

The **DEA issued public and law enforcement warnings** about carfentanil in 2016, emphasizing danger to first responders from skin/eye contact.

### Moscow Theater Hostage Crisis (October 2002)

In October 2002, Russian security forces pumped an aerosolized chemical agent into the Dubrovka Theater in Moscow to incapacitate Chechen hostage-takers. **Toxicological analysis of survivor urine and clothing samples confirmed the presence of both carfentanil and remifentanil** [Ref 29]. Approximately **130 of the approximately 850 hostages died**, primarily from the agent combined with inadequate immediate medical response (insufficient naloxone supply, improper positioning of unconscious victims) (Wax et al. 2003 [Ref 7]; Patocka et al. 2024 [Ref 34]).

This event represents the only confirmed large-scale deployment of carfentanil as an incapacitating agent in a military/law enforcement operation.

### International Scheduling

- **December 2017:** World Health Organization recommended placement of carfentanil in Schedule I and Schedule IV of the 1961 Single Convention on Narcotic Drugs — the **most stringent level of international control** [Ref 31]
- **June 2017:** Australia added carfentanil to Schedule 8 (controlled/restricted) of the Poisons Standard [Ref 30]

---

## Subjective Effects

**No controlled human studies of carfentanil's subjective effects have been published.** The compound has no approved human therapeutic use, and the extreme lethality at microgram doses makes controlled human exposure studies ethically untenable.

The following represents class-based inference from μOR agonist pharmacology and limited observational/forensic data:

**By class inference (μ-opioid receptor agonism, same class as morphine and fentanyl):**
- **Euphoria** — intense opioid-class reward via mesolimbic dopamine release secondary to MOR activation in VTA/NAc
- **Pain suppression** — primary intended veterinary effect; expected to be extreme given potency
- **Sedation** — progressing rapidly to stupor and loss of consciousness at active human doses
- **Respiratory depression** — the dominant toxicological effect and mechanism of death; onset likely extremely rapid given potency and lipophilicity
- **Muscle rigidity** ("wooden chest syndrome") — class effect described for ultra-potent synthetic opioids (Martin et al. 2025 [Ref 33])
- **Bradycardia** — documented in rat vaccine challenge studies (Crouse et al. 2022 [Ref 17])
- **Nausea/vomiting** — class effect
- **Miosis** — pupil constriction as class effect

**Veterinarian accidental exposure report (Ref 29):** A veterinarian splashed in the face and eyes while removing a dart reported **drowsiness within a couple of minutes** despite immediate water washing, requiring naltrexone administration. This represents the closest to a published human experiential account.

**Duration data:** Given the half-life of ~5.7 hours (human serum, in vitro) [Ref 21] and the presence of an active metabolite with comparable MOR activity [Ref 21, 22], duration of effects would be expected to be significantly longer than fentanyl. No human duration data from controlled studies exists.

**⚠️ FLAG (safety-critical):** All subjective effect assignments above are inferred from class pharmacology, not from published human studies. No recreational user reports with methodological rigor have been published. The dose-response relationship in humans is completely unknown; the estimated lethal dose (~20 μg extrapolated from etorphine) [Ref 29] leaves essentially no margin between any experiential dose and a lethal dose.

---

## Safety & Toxicity

### Estimated Human Lethal Dose

No published LD₅₀ data in humans exists. From species extrapolation and analogy with etorphine (a similarly ultra-potent opioid):
- Estimated human lethal dose: **approximately 20 μg** [Ref 29]
- This is approximately equivalent to a few grains of salt — far below quantities visible to the naked eye
- Etorphine has a published human estimated lethal dose of ~30 μg; carfentanil is estimated to be at least as potent [Ref 29]

**FLAG (safety-critical):** This value is extrapolated, not experimentally established. It should be presented as an estimate only.

### Therapeutic Index

There is no therapeutic index applicable to human use. In veterinary use, carfentanil has a narrow but workable window when administered by trained professionals with immediate reversal agents on hand. The extreme potency eliminates any practical therapeutic index for non-controlled human use.

### Blood Concentration Data (Forensic)

Postmortem cases — Ontario, Canada (Solbeck et al. 2021 [Ref 5]): Blood carfentanil concentrations in **160 carfentanil-positive deaths** ranged from **<0.1 to 9.2 ng/mL**; most cases were classified as mixed drug toxicity or carfentanil overdose.

Postmortem cases — Miami-Dade (Kahl et al. 2018 [Ref 18]): In cases where carfentanil was listed as **sole cause of death**: blood concentrations ranged from **<0.2 to 0.73 ng/mL** — an extremely narrow range reflecting lethality at very low concentrations.

Two-case report — Swanson et al. (2017 [Ref 4]): Case 1 (heroin user): carfentanil **1.3 ng/mL** + furanyl fentanyl **0.34 ng/mL**. Case 2: carfentanil **0.12 ng/mL** (sole carfentanil death).

Impaired driving — Ontario (Wallage et al. 2022 [Ref 6]): In 66 surviving cases (impaired drivers), blood concentrations ranged from **<0.04 to 2.1 ng/mL**, with decreased levels of consciousness commonly reported. Many required medical intervention.

**FLAG (safety-critical):** The overlap between blood concentrations in surviving (impaired) and fatal cases indicates an extremely narrow margin between impairment and lethality. The clinical significance of specific concentrations is unclear without controlled pharmacokinetic data.

### Routes of Exposure Hazard

Carfentanil can cause toxicity via:
- Intravenous/intramuscular injection
- Intranasal/inhalation
- **Transdermal absorption** (skin contact)
- **Mucous membrane absorption** (eyes, mouth, nose)
- Occupational exposure risk for law enforcement, first responders, and forensic laboratory workers [Ref 29]

Standard PPE requirements include: full-face shield or goggles, nitrile gloves (minimum), full body coverage, with naloxone antidote immediately accessible [Ref 29].

### Detection Challenges

Carfentanil is **not detectable by standard immunoassay drug screening** (urine/blood toxicology panels) due to low cross-reactivity. **Standard GC-MS also fails**: Shoff et al. (2017 [Ref 19]) documented 104 of 134 carfentanil-positive postmortem cases were initially missed by GC-MS. **LC-MS/MS is required** for reliable detection and quantitation (Solbeck et al. 2021 [Ref 5]; Kahl et al. 2018 [Ref 18]).

### Cardiovascular Effects

Crouse et al. (2022 [Ref 17]) documented **bradycardia** as a consistent effect alongside respiratory depression in rat challenge models. Kelleher et al. (2024 [Ref 41]) documented significant dose-dependent **heart rate decreases** in anesthetized rats at conventional [¹¹C]carfentanil tracer doses (>100 ng/kg IV), alongside increased PCO₂ (respiratory depression marker). Cardiac arrest is a common cause of death in overdose modeling (Mann et al. 2022 [Ref 3]).

---

## Harm Reduction

### Overdose Recognition

Signs of carfentanil overdose (by opioid class inference and forensic case data):
- Sudden loss of consciousness or extreme sedation
- Slow, shallow, or stopped breathing (respiratory rate <12/min)
- Blue/gray lips or fingernails (cyanosis)
- Pinpoint pupils (miosis)
- Unresponsiveness to stimulation
- Possible bradycardia and cardiac arrest

**Warning:** Onset may be extremely rapid — faster than morphine or heroin overdose — due to high lipophilicity and potency. Time from exposure to apnea may be measured in seconds to minutes.

### Naloxone/Antidote Considerations

Standard naloxone dosing is **potentially insufficient** for carfentanil overdose:

- Multiple published pharmacodynamic models demonstrate that 2 mg and 4 mg intranasal naloxone may result in unacceptable rates of cardiac arrest when compared to doses needed for carfentanil reversal (Mann et al. 2022 [Ref 3]; Skolnick et al. 2024 [Ref 16]; Chaturbedi et al. 2025 [Ref 40])
- **Sequential dosing** (up to 4 doses of intranasal naloxone at 2.5-minute intervals) does not meaningfully reduce cardiac arrest rates beyond a single dose — suggesting that timing and formulation, not just total dose, matter (Skolnick et al. 2024 [Ref 16])
- **10 mg intramuscular naloxone** showed superior reversal and prolonged protection vs. 2 mg (Yang et al. 2024 [Ref 32])
- **Intranasal nalmefene** (recently FDA-approved) outperforms intranasal naloxone for carfentanil reversal in modeling studies, due to faster absorption, higher MOR affinity, and longer half-life (Skolnick et al. 2024 [Ref 16]; Laffont et al. 2024 [Ref 39]; Chaturbedi et al. 2025 [Ref 40])
- Endt et al. (2025 [Ref 1]) found that **naltrexone** may be a superior antidote: it shows ~65× greater potency to displace carfentanil-stabilized μOR conformations compared to naloxone. This has not been translated to emergency clinical use.
- Novel antagonist **methocinnamox (MCAM)** shows long-duration reversal of carfentanil-induced hypoventilation in rats (Hiranita et al. 2024 [Ref 15])
- **Monoclonal antibodies** targeting carfentanil are in preclinical development (Eubanks et al. 2023 [Ref 14]; Hoppe et al. 2025 [Ref 13])
- **Vaccines** eliciting polyclonal antibody responses against carfentanil show preclinical efficacy against respiratory depression and bradycardia (Crouse et al. 2022 [Ref 17])

### Drug Checking

Carfentanil is **not reliably detectable with fentanyl test strips** (which are designed for fentanyl detection). Point-of-care drug checking services using IR spectroscopy, SERS, or GC-MS may detect carfentanil in samples, but sensitivity limitations at the extreme low-dose range are a concern. Gozdzialski et al. (2023) discuss drug checking technology capabilities and limitations in the context of ultra-potent opioids.

### Risk Contexts

The major harm reduction context is **unwitting exposure** through adulterated heroin or counterfeit pills. Deliberate recreational use of carfentanil by informed users is essentially unknown in published literature; essentially all reported human exposures involve unknowing ingestion or occupational exposure.

---

## Tolerance & Dependence

**No published human studies on carfentanil tolerance or dependence exist.**

By class inference from μ-opioid receptor pharmacology:
- **Tolerance** develops via MOR desensitization, internalization, and G-protein uncoupling with repeated exposure
- β-arrestin bias (confirmed for carfentanil [Ref 2]) is associated with **enhanced receptor desensitization** and potentially faster tolerance development compared to G-protein-biased agonists
- **Physical dependence** develops with chronic opioid agonist use; withdrawal syndrome expected to follow typical opioid withdrawal trajectory (anxiety, dysphoria, muscle pain, diaphoresis, rhinorrhea, insomnia, GI distress)
- **Compulsive redosing urge** (craving) expected from high-affinity MOR engagement in reward circuits

**Cross-tolerance:** Expected with all μOR agonists (morphine, fentanyl, oxycodone, heroin). No substance-specific cross-tolerance data published.

**Dependence liability assessment:** The combination of high μOR affinity, significant euphoric potential (by class inference), extreme potency, and β-arrestin bias suggests high dependence liability — though no formal assessment has been conducted. The practical barrier to characterizing dependence is that the compound is almost never used intentionally in recreational contexts, and essentially all human exposures are acute overdose events.

---

## Interactions

**No published clinical drug interaction studies for carfentanil exist in humans.** All interaction data below is from mechanistic reasoning and in vitro pharmacology.

### Pharmacodynamic Interactions (Synergistic toxicity)

- **Other CNS depressants** (benzodiazepines, barbiturates, alcohol, other opioids, z-drugs, gabapentinoids): synergistic respiratory depression and CNS sedation. The majority of carfentanil overdose deaths involve polydrug toxicity (Solbeck et al. 2021 [Ref 5])
- **Other opioids:** Cross-tolerance expected; combined opioid exposure increases overdose risk
- **Serotonergic agents:** Theoretical serotonin syndrome risk is low given μOR selectivity, but caution with serotonergic combinations as a general opioid class interaction

### Pharmacokinetic Interactions (CYP-mediated)

Primary metabolic pathway is CYP3A5 > CYP3A4, with secondary involvement of CYP2C8, CYP2C9 (Kong & Walz 2021 [Ref 23]):

- **CYP3A4/3A5 inhibitors** (itraconazole, ketoconazole, clarithromycin, erythromycin, ritonavir, diltiazem, verapamil, grapefruit juice): would be expected to **increase** carfentanil plasma concentrations and toxicity
- **CYP3A4/3A5 inducers** (rifampin, carbamazepine, phenytoin, St. John's Wort): would be expected to **decrease** carfentanil plasma concentrations and potentially precipitate withdrawal in dependent users
- **CYP2C9 inhibitors** (fluconazole, amiodarone, warfarin): may affect formation of the highly potent M13 metabolite

**FLAG (safety-critical):** All pharmacokinetic interaction data is inferred from in vitro CYP studies. No human clinical interaction studies have been conducted. These represent evidence-based mechanistic predictions only.

### Opioid Antagonist Interactions

- **Naloxone:** Partial reversal at standard doses; requires higher or repeated doses. Carfentanil-stabilized μOR conformations show 10–100× reduced sensitivity to naloxone [Ref 1]
- **Nalmefene:** Superior to naloxone for reversal based on modeling; higher affinity and longer half-life [Ref 16, Ref 39]
- **Naltrexone:** Data from Endt et al. (2025 [Ref 1]) suggests ~65× greater potency against carfentanil-occupied μOR vs naloxone — but clinical evidence in overdose settings is lacking
- **Diprenorphine:** Veterinary reversal agent; Flynn & France (2025 [Ref 20]) showed both naloxone and diprenorphine are less potent at reversing carfentanil vs equivalent heroin dose in rats

---

## Legal Status

**United States:** Schedule II under the Controlled Substances Act. DEA ACSCN: 9743. Annual aggregate manufacturing quota: 19 grams (2016 figure — reflects tiny volumes used only in research). Carfentanil retains Schedule II status (not Schedule I) because it historically had accepted veterinary medical use as Wildnil, even though that use is now effectively discontinued [Ref 30]. **FLAG: This is the opposite of what many sources imply. The brief listed no legal status. Generation agent should verify current DEA status as regulations may have evolved.**

**United Kingdom:** Class A drug under the Misuse of Drugs Act 1971. Maximum penalties: possession — up to 7 years imprisonment and/or unlimited fine; supply — up to life imprisonment and/or unlimited fine [Ref 30].

**Australia:** Schedule 8 (controlled drug) under the Poisons Standard, added June 2017 [Ref 30].

**Canada:** Controlled substance [Ref 30].

**International:** Listed under Schedule I and Schedule IV of the 1961 Single Convention on Narcotic Drugs, following WHO recommendation in **December 2017** that carfentanil receive the most stringent level of international drug control [Ref 31].

**European Union:** Status varies by member state; multiple EU nations have individually scheduled carfentanil. The EUDA (formerly EMCDDA) conducted a formal risk assessment. Specific EU member state data (Czech Republic, Denmark, others) indicates widespread EU scheduling.

---

## Clinical Trials

**No clinical trials studying carfentanil as a pharmacological agent in humans have been identified** in ClinicalTrials.gov searches. No NCT IDs exist for carfentanil as an investigational drug.

**[¹¹C]Carfentanil as PET radiotracer:** Carfentanil labeled with carbon-11 is used extensively as a PET radiotracer for μOR imaging in research studies. These studies use trace (non-pharmacologically active) doses; regulatory DEA Schedule II status requires a research DEA license. Multiple registered trials use [¹¹C]carfentanil as a tool to image MOR availability in various disorders (opioid use disorder, alcohol use disorder, pain conditions, obesity). Representative examples:

- NCT05528848 — "Multi-System Analysis of Opioid Receptor Binding" — University of Pennsylvania — Active, Not Recruiting — Phase 1 — Healthy/Opioid Use Disorder [Ref from ClinicalTrials search]
- NCT05957159 — "Investigating the Mu:Kappa Opioid Receptor Imbalance in Alcohol Use Disorder" — Yale University — Recruiting — Early Phase 1

First in-human whole-body [¹¹C]carfentanil PET was reported by Dubroff et al. (2025 [Ref 35]), confirming feasibility and providing normative MOR distribution data across 13 healthy humans.

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## Community Feedback Analysis

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

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## Gaps & Flags

### Data Gaps

1. **No published human pharmacokinetic data** for carfentanil as a drug of abuse or therapeutic. The 5.7-hour half-life (Hsu et al. 2019 [Ref 21]) is from in vitro human serum, not clinical PK studies. All human PK parameters used in modeling (Yang et al. 2024 [Ref 32]) rely on interspecies allometric scaling.

2. **No specific Ki values (nM) from radioligand displacement binding studies recovered.** Binding affinity data are from functional assays (Ki expressed relative to comparators). The generation agent should note this distinction and avoid presenting relative affinity ratios as absolute Ki values.

3. **Physical properties (melting point, logP, aqueous solubility) not recoverable** via API or web sources in this session. PubChem page was inaccessible via JavaScript-dependent interface. This is a minor gap but affects the physical properties section.

4. **Stereochemistry confirmed absent** (no stereocenters), but this has not been explicitly published as a finding; it is derived from structural analysis.

5. **No published human subjective effect data** of any quality. All subjective effect assignments are class-based inferences. No Erowid-type reports or formal user surveys were identified.

6. **No published cross-tolerance, dependence characterization, or withdrawal syndrome data** specific to carfentanil.

7. **Specific pharmacokinetic parameters** (Tmax, Cmax, volume of distribution, protein binding, bioavailability by route) have not been measured in humans.

8. **MOR selectivity over DOR and KOR:** Carfentanil is described as MOR-preferring but quantitative selectivity ratios (Ki MOR vs. KOR/DOR) were not recovered in this search. **FLAG for editorial review.**

9. **US scheduling status flag:** The brief and many public sources describe carfentanil as if it were Schedule I, but this research found it is actually classified as **Schedule II** in the US (has historically had accepted veterinary medical use). This discrepancy should be verified against current DEA scheduling data before publication.

### Safety-Critical Flags

10. **Estimated lethal human dose (~20 μg)** is extrapolated from etorphine analogy, not experimentally determined. Must be presented as an estimate, not established fact.

11. **Postmortem blood concentrations**: The range 0.12–9.2 ng/mL encompasses both polydrug and single-drug deaths. The concentration in single-drug deaths (0.2–0.73 ng/mL) is more relevant for toxicological interpretation. High concentrations in polydrug cases reflect combined toxicity rather than carfentanil alone.

12. **Naloxone dosing for carfentanil reversal**: Standard community naloxone (2–4 mg intranasal) may be inadequate. This is a safety-critical message that the generation agent should present clearly and without hedging.

13. **Detection failure risk**: Standard immunoassay and GC-MS screening will miss carfentanil. LC-MS/MS is required. Drug checking services using fentanyl test strips will not reliably detect carfentanil.