Deschloroetizolam

# Research Output: Deschloroetizolam

---

## Chemical Identity

**PubChem CID:** 827322 (confirmed via API lookup) [Ref 1 — PubChem database]

**Molecular Formula:** C₁₇H₁₆N₄S (confirmed; matches seed data) [Ref 1]

**Molecular Weight:** 308.4 g/mol (confirmed; matches seed data) [Ref 1]

**IUPAC Name:** 4-ethyl-13-methyl-7-phenyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.0²,⁶]trideca-2(6),4,7,10,12-pentaene (confirmed; matches seed data) [Ref 1]

**InChIKey:** JIOBORXCOGMHSV-UHFFFAOYSA-N (confirmed via PubChem and chemical database crosscheck) [Ref 1, Ref 28]

**SMILES:** CCC1=CC2=C(S1)N3C(=NN=C3CN=C2C4=CC=CC=C4)C [Ref 28]

**CAS Number:** 40054-73-7 (confirmed via multiple chemical databases) [Ref 19, Ref 28]

**Alternate Name:** Etizolam-2 [Ref 19]

**Drug Class — CORRECTION FLAGGED:** The seed data classifies deschloroetizolam's chemical class as "Benzodiazepine core, Thienodiazepine." This is imprecise. Published literature consistently classifies it as a **thienotriazolodiazepine** — it contains a fused thiophene ring, a benzodiazepine ring, AND a triazolo ring, making it more precisely a thienotriazolodiazepine rather than a simple thienodiazepine. This distinction is made in Huppertz et al. 2015 [Ref 14], Edinoff et al. 2022 [Ref 1/original PubMed search], and the CFSRE monograph [Ref 19]. The seed characterization is acceptable as a broader grouping but "thienotriazolodiazepine" is the accurate chemical class designation used in forensic toxicology literature.

**Seed data discrepancy:** The seed data lacks a SMILES string and InChIKey in the database record, though both are now confirmed via PubChem and chemical registries.

---

## Pharmacology

### Mechanism of Action

Deschloroetizolam is a positive allosteric modulator (PAM) of the GABA-A receptor, acting at the classical benzodiazepine binding site located at the α+/γ2- subunit interface [Ref 22]. Like other benzodiazepines and thienotriazolodiazepines, it potentiates the inhibitory effect of GABA without directly activating the receptor. This mechanism enhances chloride ion conductance, causing neuronal hyperpolarization and CNS depression.

Subunit selectivity dictates the clinical effect profile: α1-containing receptors mediate sedation and hypnosis; α2- and α3-containing receptors mediate anxiolysis and muscle relaxation; α5-containing receptors mediate cognitive impairment (Trincavelli et al. 2012 [Ref 22]). No published deschloroetizolam-specific subunit binding affinity data exists; the above is inferred from class-level evidence.

**Relationship to etizolam:** Deschloroetizolam is the dechlorinated analog of etizolam, differing only by the absence of a chlorine atom at the 2'-position of the phenyl ring [Ref 14, Ref 19]. Etizolam is the approved thienotriazolodiazepine marketed in Japan and India for anxiety and insomnia; deschloroetizolam has never received any regulatory approval anywhere.

### Binding Affinity Data

**No published Ki or EC50 values exist for deschloroetizolam at any receptor.** This is a significant data gap.

By structural analogy: etizolam has documented activity at the benzodiazepine binding site of GABA-A receptors in rat cerebral cortex, displacing ³H-diazepam from synaptosomal membranes (Takehara et al. 1990 [Ref 23]). Deschloroetizolam is expected to share this binding site but with reduced affinity due to the missing 2'-chloro substituent.

Potency relative to other designer benzodiazepines: El Balkhi et al. 2020 [Ref 4] analyzed 197 user trip reports for 10 designer BZDs and derived a comparative potency score. Deschloroetizolam ranked among the **least potent** of the designer benzodiazepines analyzed, alongside metizolam, nifoxipam, and pyrazolam. Flubromazepam, flubromazolam, clonazolam, and meclonazepam were substantially more potent. The chemical structure analysis confirmed this ranking — the 2'-chloro substituent on etizolam increases its potency, and its absence reduces deschloroetizolam's potency relative to the parent compound [Ref 4].

**⚠️ FLAG FOR HUMAN REVIEW:** All potency and binding data for deschloroetizolam relies on structural analogy to etizolam and trip-report analysis. No controlled human pharmacodynamic or animal receptor binding studies have been published.

### Pharmacokinetics

**Human data exists from ONE published study:**

Ameline et al. 2018 (Part II) [Ref 15] documented deschloroetizolam in oral fluid (saliva) after a single controlled self-administration of **6 mg oral deschloroetizolam** by a researcher volunteer. Saliva was collected using a NeoSal device over 18 hours post-ingestion. Key findings:

- **Peak saliva concentration:** Achieved at approximately **30 minutes** post-ingestion
- **Rapid initial decline** following the peak
- **Detection window in saliva:** Traces detectable for the full **18-hour** observation period
- **Self-reported effects during study:** Tiredness, dizziness, difficulty speaking, problems with concentration

No blood or urine concentration-time profile from a controlled human study has been published (Part I of this series was referenced in the title structure but not located in indexed literature as of this research date).

Greenblatt & Greenblatt 2019 [Ref 5] reference the existence of "single-volunteer studies" documenting deschloroetizolam half-life data, attributing it to a similar self-experiment format used by Moosmann and Auwärter for other designer benzodiazepines [Ref 26]. The specific half-life figure was not recoverable from the available abstract.

**Seed duration data:** The seed data provides onset 15–30 minutes, come-up 30–60 minutes, peak 3–4 hours, offset 3–4 hours, aftereffects 3–6 hours, total 8–10 hours. The 30-minute peak saliva concentration from the Ameline study is broadly consistent with the 15–30 minute onset range, though the 8–10 hour total duration is not independently verified by published data and derives from community consensus.

### Metabolism

Huppertz et al. 2015 [Ref 14] performed in vitro Phase I metabolite identification using human liver microsomes (HLM) for deschloroetizolam. Identified metabolites:

- At least **one monohydroxylated metabolite**
- **One dihydroxylated metabolite**

Methods: NMR spectroscopy, GC-EI-MS, LC-MS/MS, LC-Q-ToF-MS, and IR spectroscopy were used for parent compound characterization; HLM incubation identified the in vitro metabolites.

Wu & Fu 2022 [Ref 12] note that designer benzodiazepines including deschloroetizolam undergo Phase I and II metabolism similar to traditional benzodiazepines, but "their specific metabolic pathways and the influence of genetic polymorphisms are yet to be clarified."

**CYP enzyme inference:** By analogy to etizolam, CYP2C19 and CYP3A4 are the likely principal metabolic enzymes. Yamamoto et al. 2017 [Ref 21] demonstrated in a 16-participant clinical study that etizolam is a dual substrate of CYP2C19 and CYP3A4: CYP2C19 poor metabolizers had 2.65× higher etizolam AUC; adding itraconazole (CYP3A inhibitor) produced a 6.18× AUC increase in poor metabolizers vs. extensive metabolizers. This pharmacogenomic vulnerability is expected to apply to deschloroetizolam by structural analogy, though no direct data exists.

---

## History

### Original Synthesis and Patent Origins

Deschloroetizolam's chemical foundation traces to Yoshitomi Pharmaceutical Industries (Japan), which filed patent **US 3,904,641** (published September 9, 1975) covering a family of triazolothienodiazepine compounds including structural analogs that form the basis of the etizolam/deschloroetizolam class. Authors: Nakanishi M, Tahara T, Araki K, Shiroki M [Ref 20]. A subsequent patent **EP 0776892A1** (1997) was also attributed to Yoshitomi for related compounds [Ref 19].

Etizolam itself received regulatory approval in Japan in 1983 for anxiety and sleep disorders; it has never been approved in the US, UK, or EU. Deschloroetizolam is the direct structural analog lacking the 2'-chloro substituent and has **never been approved as a pharmaceutical in any jurisdiction** [Ref 5, Ref 6, Ref 19].

### Appearance in Illicit Markets

Deschloroetizolam was **first identified in the UK illicit drug supply in 2014** [Ref 19]. The CFSRE monograph (2021) documents this emergence. The compound appeared as part of the broader wave of designer benzodiazepines that entered NPS markets starting around 2007, intensifying after 2012 as traditional substances became scheduled [Ref 3, Ref 6].

Łukasik-Głębocka et al. 2015 [Ref 10] listed deschloroetizolam among the designer benzodiazepines known to be available on the market, confirming its established presence by late 2015. Bäckberg et al. (STRIDA project) [Ref 8] detected deschloroetizolam in one acute intoxication case in Sweden, with the STRIDA data covering 2012–2016.

### Market Context

Designer BZDs are typically sold online as research chemicals, tablets, blotters, or powders at prices far below pharmaceutical benchmarks. Some are sold as counterfeit pharmaceutical benzodiazepines or used as adulterants in other drugs [Ref 3]. Deschloroetizolam's relatively low potency among designer BZDs [Ref 4] may explain its comparatively rare appearance in severe intoxication case reports.

---

## Subjective Effects

All human effects data for deschloroetizolam derives from **user-report sources** (trip reports) and one self-administration study; no controlled human pharmacological studies exist.

### From Self-Experiment (Ameline et al. 2018 [Ref 15])
6 mg oral dose produced (self-reported): tiredness, dizziness, difficulty speaking, and problems with concentration. These represent typical CNS depressant effects consistent with GABA-A modulation.

### From Trip Report Analysis (El Balkhi et al. 2020 [Ref 4])
197 trip reports analyzed across 10 designer BZDs, with deschloroetizolam included (≥15 trip reports with ≥2 accounts of experienced effects). Effects were described as similar to prescription benzodiazepines. Comparative findings:

- **Anxiolytic:** Less anxiolytic than pyrazolam (most anxiolytic of the analyzed DBZDs); anxiolytic effects present
- **Hypnotic/Sedating:** Less hypnotic than flubromazolam (most hypnotic)
- **Euphoric:** Less euphoric than etizolam (most euphoric); some euphoria reported
- **Amnesic:** Less amnesic than flubromazolam and clonazolam
- **Overall potency score:** Among the lowest of the analyzed designer BZDs

### From Review Literature (Edinoff et al. 2022 [Ref 1])
Described effects in the class: sedation, anxiolysis, muscle relaxation, euphoria (less pronounced than etizolam), and amnesia (less pronounced than triazolobenzodiazepines).

### Duration (Seed Data — Community Consensus)
- Onset: 15–30 minutes
- Come-up: 30–60 minutes
- Peak: 3–4 hours
- Offset: 3–4 hours
- Aftereffects: 3–6 hours
- Total: 8–10 hours

**⚠️ FLAG:** Duration data is from community consensus, not controlled human studies. The 30-minute saliva peak in Ameline et al. [Ref 15] confirms rapid absorption but cannot validate the full duration profile.

### Dose (Seed Data — Community Consensus)
- Threshold: 1 mg (oral)
- Light: 2–4 mg (oral)
- Common: 4–6 mg (oral)
- Strong: 6–12 mg (oral)
- Heavy: 12+ mg (oral)

The 6 mg self-experiment dose [Ref 15] falls in the "common/strong" range per the seed data and produced noticeable CNS depression. Greenblatt & Greenblatt 2019 [Ref 5] and El Balkhi et al. 2020 [Ref 4] both classify deschloroetizolam as a lower-potency designer BZD, which is consistent with the seed dose ranges being higher than those for clonazolam or flubromazolam.

**⚠️ FLAG FOR HUMAN REVIEW:** Dose data is derived from community consensus (Dose data: community_consensus_large/medium per seed). No published controlled human dose-response studies exist.

---

## Safety & Toxicity

### LD50 / Acute Toxicity
No published LD50 or acute toxicity threshold data exists for deschloroetizolam in any species. This is a complete data gap.

### Adverse Events in Literature

Brunetti et al. 2021 [Ref 2] included deschloroetizolam in their scoping review of 12 designer BZDs, covering 49 reports total (1 drug offense, 2 self-administration studies, 3 outpatient admissions, 44 ED admissions, 63 DUID cases, 141 deaths across all 12 drugs). The review notes etizolam, flualprazolam, flubromazolam, and phenazepam were "implicated in the majority of adverse events, drug offenses and deaths," with deschloroetizolam represented in the smaller fraction of documented cases.

Bäckberg et al. 2019 (STRIDA) [Ref 8]: One confirmed deschloroetizolam case among 217 NPS BZD intoxication cases in Sweden (2012–2016). The single-substance NPS BZD cases (n=24) showed CNS depression as the predominant sign; 7/24 required ICU monitoring; all responded positively to flumazenil treatment. The majority of cases (89%) involved multiple substances.

Pettersson Bergstrand et al. 2018 [Ref 16]: Deschloroetizolam detected at 5 ng/mL in one urine sample from the STRIDA acute intoxication database; no clinical details available from this publication for that specific case.

### Fatalities
**No fatalities specifically attributable to deschloroetizolam alone have been published in the indexed literature.** Given its low potency ranking [Ref 4] and infrequent appearance in severe adverse event reports [Ref 2], this is consistent but should not be interpreted as evidence of safety.

### Polydrug Interaction Risk
The primary acute lethality risk for designer benzodiazepines is **CNS depression synergy with other depressants** — particularly opioids, alcohol, and other sedatives. Greenblatt & Greenblatt 2019 [Ref 5] state: "Mortality or serious morbidity associated with misuse or overdosage with designer BZs occurs almost exclusively when they are combined with other psychoactive substances." This class-level risk applies directly to deschloroetizolam.

Manchester et al. 2017 [Ref 6] note that illicitly obtained benzodiazepines have been found to contain opiates, which together can lead to respiratory depression and death.

**⚠️ FLAG FOR HUMAN REVIEW:** The seed toxicity data states "Acute: high; Chronic: high; Notes: low toxicity, potentially lethal when mixed with depressants." There is an internal inconsistency in the seed data — "Acute: high" and "low toxicity" are contradictory. Published literature supports "low acute toxicity when taken alone; potentially lethal in polydrug combinations." This should be corrected by editorial review.

### Psychological Risks
Rapid development of psychological and physical dependence (within days of regular use) is documented at the class level [Ref 1, Ref 13]. Designer BZDs carry the same risk profile as traditional benzodiazepines for dependence, tolerance, rebound anxiety, and withdrawal.

---

## Harm Reduction

### Detection and Testing
- Deschloroetizolam shows **cross-reactivity in standard immunoassay urine drug screens** (CEDIA, EMIT II Plus, HEIA, KIMS II), allowing detection in routine screening. KIMS II and CEDIA showed highest reactivity (Pettersson Bergstrand et al. 2016 [Ref 7]).
- Confirmatory identification requires LC-MS/MS or LC-HRMS (Pettersson Bergstrand et al. 2018 [Ref 16]).
- Not all immunoassays may detect deschloroetizolam reliably at low doses; a negative screen does not exclude intoxication [Ref 5].
- Fentanyl test strips do not detect benzodiazepines. Reagent test kits may identify the benzodiazepine class but cannot distinguish deschloroetizolam from other BZDs.

### Overdose Response
Flumazenil (a competitive GABA-A benzodiazepine-site antagonist) reverses designer benzodiazepine effects, including deschloroetizolam. The STRIDA data (Bäckberg et al. 2019 [Ref 8]) confirmed positive flumazenil response in all NPS BZD cases presenting to Swedish hospitals. Farcas et al. 2025 [Ref 24] reviewed evidence for pre-hospital flumazenil use in BZD-involved overdose.

**Caution:** Flumazenil in BZD-dependent individuals can precipitate acute withdrawal and seizures. Its use requires clinical judgment.

### Contraindications
No substance-specific contraindications are published for deschloroetizolam. Class-level contraindications apply:
- Other CNS depressants (opioids, alcohol, other BZDs, GHB, antihistamines) — additive respiratory depression
- CYP3A4 inhibitors (itraconazole, ketoconazole, HIV protease inhibitors) — may significantly increase plasma levels by analogy to etizolam [Ref 21]
- CYP2C19 poor metabolizer status — may significantly increase plasma levels by analogy to etizolam [Ref 21]
- Respiratory compromise, myasthenia gravis, sleep apnea

---

## Tolerance & Dependence

### Tolerance Development
The seed data states: "Buildup: within a couple of days of continuous use; Full reset: 10.5 days." This aligns with the general pattern for designer benzodiazepines described across the review literature [Ref 1, Ref 3, Ref 11].

Molecular mechanism: Chronic benzodiazepine use causes downregulation of GABA-A receptor α subunits (Vinkers et al. 2012 [Ref 27]) and compensatory glutamatergic sensitization (Navarrete et al. 2026 [Ref 13]). This underlies both tolerance and the withdrawal hyperexcitability syndrome.

### Cross-Tolerance
Cross-tolerance with all benzodiazepines and thienodiazepines is expected and documented at the class level. Seed data correctly identifies "benzodiazepine, thienodiazepine" cross-tolerances.

### Dependence
Physical and psychological dependence formation is described as "extremely physically and psychologically addictive" in the seed data. The class-level evidence supports high physical dependence potential for regular/chronic use of any benzodiazepine or analog. Treatment: gradual taper using a long-acting benzodiazepine with concurrent psychological support (Navarrete et al. 2026 [Ref 13]).

### Withdrawal
Benzodiazepine withdrawal syndrome can be severe and potentially life-threatening (seizures) with abrupt cessation after prolonged regular use. This risk applies to deschloroetizolam by class membership [Ref 13]. No published case series of deschloroetizolam-specific withdrawal exist.

---

## Interactions

### Established Class-Level Interactions

| Interacting substance | Mechanism | Severity |
|---|---|---|
| Alcohol | Additive GABA-A enhancement + CNS depression | High — potentially lethal |
| Opioids | Additive respiratory depression via distinct receptors | High — potentially lethal |
| Other benzodiazepines/sedatives | Additive GABA-A enhancement | High |
| GHB/GBL | Additive CNS depression | High |
| CYP3A4 inhibitors (azole antifungals, ritonavir, etc.) | Reduced deschloroetizolam metabolism → increased plasma levels | Moderate–High |
| CYP2C19 inhibitors (omeprazole, fluoxetine) | Reduced metabolism via polymorphic enzyme | Moderate |
| Antihistamines (first-gen), antipsychotics, muscle relaxants | Additive sedation | Moderate |
| Stimulants (amphetamines, cocaine, MDMA) | May mask sedation, promoting redosing and overdose | Moderate |

Evidence basis: Etizolam CYP data (Yamamoto et al. 2017 [Ref 21]); class-level polydrug interactions (Greenblatt & Greenblatt 2019 [Ref 5]; Manchester et al. 2017 [Ref 6]).

**⚠️ FLAG FOR HUMAN REVIEW:** All interaction severity ratings are inferred from class-level evidence. No deschloroetizolam-specific interaction studies exist.

---

## Legal Status

### United States
Deschloroetizolam is **NOT** currently listed in the DEA Controlled Substances schedules at the federal level [Ref 25]. Five closely related designer benzodiazepines (clonazolam, diclazepam, etizolam, flualprazolam, flubromazolam) were permanently placed in Schedule I effective April 1, 2026 [Ref 25], but deschloroetizolam was NOT included in this action.

However, with etizolam now a Schedule I substance, deschloroetizolam is **likely subject to prosecution under the Federal Analog Act** (21 U.S.C. § 813) when intended for human consumption, as it is substantially similar in chemical structure and pharmacological effect to etizolam.

**State-level:** Alabama placed deschloroetizolam in Schedule I effective July 15, 2024 [web-retrieved, unverified by primary source].

### United Kingdom
Controlled under the **Psychoactive Substances Act 2016** (effective May 26, 2016). It is illegal to produce, supply, or import deschloroetizolam for human consumption. The ACMD had previously recommended designer benzodiazepines including deschloroetizolam for control [Ref 28].

### Germany
Controlled under the **NpSG (Neue-psychoaktive-Stoffe-Gesetz)** — specifically scheduled as of **July 18, 2019** for deschloroetizolam, though the broader NpSG framework has been in force since November 26, 2016.

### Sweden
Classified as a **hazardous substance (hälsofarlig vara)** since **October 15, 2015**. This is one of the earliest national controls for deschloroetizolam [Ref 28].

### Russia
**Schedule III controlled substance** since **2017** [web-retrieved].

### Switzerland
Placed under national control **approximately April 2017** alongside other benzodiazepine derivatives [web-retrieved].

### Canada
Deschloroetizolam is **not scheduled** under the Controlled Drugs and Substances Act. However, sale for human consumption without regulatory approval violates the Food and Drugs Act.

### Australia
**Status unclear from published sources.** Etizolam is Schedule 4 in Australia. Analog act provisions may apply to deschloroetizolam, but this was not confirmed by primary sources.

---

## Clinical Trials

**No clinical trials have been registered for deschloroetizolam** on ClinicalTrials.gov (confirmed by direct search). The compound has never been investigated in any sponsored clinical study, consistent with its research chemical / designer drug status.

---

## Community Feedback Analysis

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

---

## Gaps & Flags

### Critical Data Gaps

1. **No published human receptor binding affinity data (Ki/EC50)** for deschloroetizolam at any receptor. All potency estimates are by structural analogy or user-report analysis.

2. **No controlled human pharmacodynamic study.** Only one published human exposure study exists (Ameline et al. 2018, Part II — saliva only). No blood, plasma, or urine PK data from controlled studies is indexed in the literature.

3. **No published elimination half-life in humans.** The Greenblatt review mentions half-life data from a "single-volunteer study" but the specific value is not recoverable from available abstracts.

4. **No LD50 or animal toxicity data specific to deschloroetizolam.**

5. **No case fatalities attributable solely to deschloroetizolam.** The available literature does not document a single-substance deschloroetizolam death.

6. **Part I of the Ameline self-experiment series** (likely covering blood/urine concentrations) was not located in indexed databases as of this research date. The companion paper's data on blood concentrations and half-life cannot be confirmed.

7. **No published CYP enzyme data specific to deschloroetizolam.** CYP2C19 and CYP3A4 involvement is inferred from etizolam analog data.

### Seed Data Flags for Human Review

8. **⚠️ SAFETY-CRITICAL — Toxicity field inconsistency:** Seed data lists "Acute: high; Chronic: high; Notes: low toxicity." "High" acute toxicity and "low toxicity" are mutually contradictory. Based on published literature, the accurate characterization is: *low intrinsic acute toxicity when taken alone; potentially lethal in polydrug combinations with CNS depressants.* This should be corrected.

9. **⚠️ Chemical class terminology:** Seed data uses "Thienodiazepine" but published literature consistently uses "thienotriazolodiazepine" for deschloroetizolam and etizolam. The triazolo ring is a defining structural feature. The seed data class should be updated to "Thienotriazolodiazepine."

10. **⚠️ SMILES and InChIKey missing from database:** PubChem CID 827322 was confirmed but the SMILES and InChIKey fields are empty in the seed data. Both values are now confirmed: InChIKey = JIOBORXCOGMHSV-UHFFFAOYSA-N; SMILES = CCC1=CC2=C(S1)N3C(=NN=C3CN=C2C4=CC=CC=C4)C.

11. **⚠️ Duration data (seed):** Total duration of 8–10 hours is from community consensus, not controlled studies. The 30-minute saliva peak from Ameline 2018 is the only human PK anchor point. Duration values should remain community consensus until PK studies are available.

12. **⚠️ Dose data (seed):** Common dose 4–6 mg oral is plausible given the 6 mg self-experiment dose produced clear CNS effects. These values are from community consensus. The low-potency ranking from trip report analysis [Ref 4] is broadly consistent with the dose range being higher than for more potent designer BZDs (e.g., clonazolam at 0.5–2 mg common).

13. **⚠️ US Legal Status:** The seed data should reflect that deschloroetizolam is NOT currently federally scheduled in the US, but its parent compound etizolam was permanently scheduled in April 2026. The Federal Analog Act creates a practical legal prohibition for human use contexts.

14. **⚠️ All effect intensity/frequency values are missing** from the seed (13/13 effects lacking values). The effect profile is supported by class-level and trip-report evidence and should be completed by the generation agent with appropriate confidence framing.

---

*Research conducted: May 9, 2026. Substance readiness: Sparse/emerging — published primary literature is very limited. Generation agent should rely heavily on class-level (thienotriazolodiazepine/benzodiazepine) evidence with explicit labeling of analog inferences.*