DOC

# Research Output: DOC (2,5-Dimethoxy-4-chloroamphetamine)

**PSX ID:** PSX-0169  
**Research date:** 2026-04-24  
**Substance readiness:** Sparse/emerging (readiness < 0.3)  
**Citations in registry:** 25

---

## Chemical Identity

**Verified from PubChem (CID 542036) and NCATS Inxight Drugs [Ref 25]:**

| Field | Value |
|---|---|
| IUPAC name | 1-(4-chloro-2,5-dimethoxyphenyl)propan-2-amine |
| Molecular formula | C₁₁H₁₆ClNO₂ |
| Molecular weight | 229.70 g/mol (free base); 266.17 g/mol (HCl salt) |
| SMILES | COC1=CC(CC(C)N)=C(OC)C=C1Cl |
| InChIKey | ACRITBNCBMTINK-UHFFFAOYSA-N |
| PubChem CID | 542036 |
| CAS number | Not retrieved via API; present in NCATS database |

**Physical properties from PiHKAL (Shulgin 1991 [Ref 17]):**
- Melting point: 187–188°C (HCl salt, glacial acetic acid chlorination route); 193–194.5°C (alternate preparation)
- Appearance: White crystalline solid
- Solubility data: Not found in published literature

**Stereochemistry:** DOC possesses one asymmetric carbon at the alpha position, giving rise to an (R)- and (S)-enantiomer. The WHO ECDD report notes the compound is most commonly encountered as the racemate (Brandt 2019 [Ref 7]). No published studies specifically characterizing the enantioselective pharmacology of DOC were found. By analogy with the structurally related DOB, R-(−)-enantiomers of DOx compounds tend to exhibit higher 5-HT2A affinity, though this inference is based on structural analogy and is not DOC-specific data — flag for human review.

**Seed data discrepancies:**
- SMILES, molecular formula, molecular weight, InChIKey, and PubChem CID were all absent in seed data. These are now confirmed above.
- The seed IUPAC name (1-(4-chloro-2,5-dimethoxyphenyl)propan-2-amine) is **correct** and matches PubChem.

---

## Pharmacology

### Receptor Binding Profile

DOC is a potent partial agonist at the 5-HT2 subfamily of serotonin receptors. It is **not** a monoamine releasing agent or transporter substrate — a critical distinction from conventional amphetamines (see Flags section).

**Confirmed Ki values (NCATS Inxight Drugs [Ref 25]):**
- 5-HT2A: Ki = **4.0 nM**
- 5-HT2C: Ki = **3.54 nM**

These low-nanomolar affinities place DOC among the most potent known 5-HT2A ligands. For comparison, LSD binds 5-HT2A at Ki ≈ 0.08–3 nM; psilocin at ~100–200 nM.

**5-HT2B binding:** Nelson et al. (1999 [Ref 6]) demonstrated a positive correlation (r > 0.9) between 5-HT2A and 5-HT2B binding affinities across 17 phenylisopropylamine hallucinogens. DOC is therefore expected to have high 5-HT2B affinity, though the specific Ki value for DOC at 5-HT2B is not published separately.

**Broader receptor profile:** Ray (2010 [Ref 5]) reported NIMH-PDSP screening data for DOC across 51 receptor/transporter sites. Phenylalkylamines as a class interact with 42 of 49 broadly assayed sites; DOC's full PDSP profile (beyond 5-HT2A/2C) was not retrieved at full granularity from API access, but includes interactions at adrenergic and dopaminergic sites at lower affinity.

**Monoamine transporter activity:** Eshleman et al. (2014 [Ref 2]) directly assayed DOC at monoamine transporters (SERT, DAT, NET) and found minimal to no activity. DOC does not function as a monoamine releaser or reuptake inhibitor — see Flags for critical seed data error.

### Mechanism of Action

DOC acts as a 5-HT2A and 5-HT2C receptor partial agonist. The psychedelic mechanism is mediated primarily through 5-HT2A receptor Gq/11 signaling (Wallach et al. 2023 [Ref 15]), which activates phospholipase C-β and downstream IP3/DAG cascades. Aghajanian & Marek (1999 [Ref 16]) proposed that 5-HT2A-mediated enhancement of glutamatergic (AMPA) EPSPs at cortical layer V pyramidal cell dendrites underlies the cognitive and perceptual alterations seen with hallucinogens of this class.

Wallach et al. (2023 [Ref 15]) demonstrated that 5-HT2A-Gq efficacy (not beta-arrestin2 recruitment) is the key predictor of psychedelic potential, measured via head-twitch response magnitude in mice. This has direct implications for DOC's tolerance mechanism: beta-arrestin-biased signaling drives receptor downregulation and tachyphylaxis, which underlies the rapid tolerance development characteristic of all 5-HT2A agonist psychedelics.

The head-twitch response (HTR) in rodents is a validated behavioral proxy for 5-HT2A agonist-mediated psychedelic effects; DOC produces the HTR in rats and mice, consistent with its 5-HT2A pharmacology (Halberstadt & Geyer 2018 [Ref 11]).

**Functional activity:** In the drug discrimination paradigm, DOC generalized to DOM and DMT but not to methamphetamine (Brandt/WHO ECDD 2019 [Ref 7]), confirming a serotonergic rather than dopaminergic mechanism.

### Pharmacokinetics

**Metabolism:** Ewald & Maurer (2008 [Ref 3]) identified CYP2D6 as the primary — and potentially only — CYP isoenzyme responsible for DOC's O-demethylation at the 2- and 5-methoxy positions. Both O-demethylated products are the main metabolites. DOC is also a competitive, non-mechanism-based inhibitor of CYP2D6 (Ki 7.1–296 µM using recombinant CYP2D6; 2.7–19.9 µM using human liver microsomes), though these Ki values are substantially higher than potent inhibitors like quinidine, making clinically significant CYP2D6 drug interactions possible but unlikely at typical recreational doses.

**Parent molecule:** The parent compound (DOC) is the preferred analytical target in postmortem and clinical casework due to its being more readily detected than metabolites (Nieddu et al. 2023 [Ref 8]).

**Human PK data:** No controlled human pharmacokinetic studies (bioavailability, Tmax, half-life) have been published. This is a significant gap. Postmortem case data provides tissue distribution but not kinetic parameters.

**Postmortem tissue distribution (from fatal case, Barnett et al. 2014 [Ref 1]):**
- Iliac blood: 377 ng/mL
- Urine: 3,193 ng/mL
- Liver: 3,143 ng/g
- Brain: 683 ng/g

**Plasma concentrations (from 5-patient non-fatal series, Abbara et al. 2017 [Ref 14]):**
- Plasma: < 18 µg/L
- Urine: 300–1,300 µg/L

No published data on oral bioavailability, Tmax, or plasma half-life for DOC in humans.

---

## History

DOC was first synthesized in 1973 by R. T. Coutts and J. L. Malicky at the University of Alberta as part of a structure-activity relationship study on the hallucinogen DOM (Coutts & Malicky 1973 [Ref 20]). The study explored the effect of various aryl 4-substituents on psychotomimetic activity. The synthesis route involved chlorination of 2,5-dimethoxyamphetamine in glacial acetic acid.

The compound was later documented in detail by Alexander Shulgin in *PiHKAL: A Chemical Love Story* (1991 [Ref 17]), as Entry #64. Shulgin documented synthesis, self-experimental dosage (1.5–3.0 mg), duration (12–24 h), and qualitative effects, describing the experience as "archetypical" psychedelia. Shulgin's documentation substantially increased awareness of DOC within psychedelic drug communities.

DOC first appeared in European forensic notifications in 2004 (EMCDDA). US forensic identifications from seizures were documented in the period 2006–2009 (WHO ECDD 2019 [Ref 7]). The compound has been encountered in powdered, liquid, and blotter paper forms; it is frequently misrepresented as LSD when distributed on blotters (Abbara et al. 2017 [Ref 14]; WHO ECDD 2019 [Ref 7]).

The WHO Expert Committee on Drug Dependence (ECDD), at its 42nd meeting in 2019, recommended that DOC be placed in Schedule I of the 1971 Convention on Psychotropic Substances, citing public health risk, misrepresentation as LSD, and absence of therapeutic value (Brandt/WHO ECDD 2019 [Ref 7]).

The first published clinical case of recreational DOC use was reported by Ovaska et al. in 2008 (UK) [Ref 4]. The first fatal case attributed solely to DOC was reported by Barnett et al. in 2014 (US) [Ref 1].

The Glennon & Dukat (2024 [Ref 21]) review of the DOx class provides the most comprehensive recent historical account, situating DOC within the broader development of DOI and other DOx agents as 5-HT2 receptor research tools.

---

## Subjective Effects

No controlled human administration studies exist for DOC. The evidence base for subjective effects consists of:
1. **Self-experimental reports** in PiHKAL (Shulgin 1991 [Ref 17]) — N=1, primary author
2. **Clinical case reports** documenting acute intoxication effects (Ovaska 2008 [Ref 4]; Abbara 2017 [Ref 14]; Barnett 2014 [Ref 1]; Lelievre 2022 [Ref 13])
3. **WHO ECDD synthesis** of available human reports (Brandt/WHO ECDD 2019 [Ref 7])
4. **Animal models** (HTR, drug discrimination) extrapolated to humans via DOx class SAR

**Qualitative effects (user reports/case literature):**
- Strong, long-duration serotonergic psychedelic experience
- Profound visual and perceptual distortions
- "Archetypical" psychedelic phenomenology comparable to LSD, psilocybin (Shulgin [Ref 17]; WHO ECDD [Ref 7])
- Duration of 12–24 hours reported consistently; effects may persist into following day
- At higher doses: intense, demanding experience requiring full 24-hour commitment

**Clinical features in acute intoxication (case literature):**
- Agitation, aggressive behaviour
- Visual hallucinations
- Tachycardia (consistent with 5-HT2A/sympathomimetic stimulation)
- Rhabdomyolysis, seizures, hyperthermia (severe cases)
- Sympathomimetic toxidrome (Ovaska 2008 [Ref 4])
- Effects persisting up to 33 hours in one case (WHO ECDD [Ref 7])

**Onset/Duration from literature:**
- Oral onset: 1–3 hours; consistent with seed data range of 1–2 hours
- Duration: 12–24 hours confirmed in multiple sources
- Insufflated pharmacokinetics: no published data — see Flags

---

## Safety & Toxicity

### Published Fatal Cases

**Case 1 (Barnett et al. 2014 [Ref 1]):** 37-year-old male, known methamphetamine abuser, found deceased at home. DOC in iliac blood at 377 ng/mL; no other psychoactive drugs except caffeine detected. Authors report this as the first case attributable solely to DOC.

**Case 2 (Lelievre et al. 2022 [Ref 13]):** Young woman presenting with vomiting, convulsions, and cardiorespiratory arrest following DOC use. Second fatal case in published literature; paper discusses challenges in interpreting postmortem concentrations for this compound.

### Non-Fatal Intoxication Cases

**Ovaska et al. (2008 [Ref 4]):** Single patient presenting with sympathomimetic toxicity after DOC + MDMA ingestion; believed to have taken DOI + MDMA. Clinical management not detailed in abstract.

**Abbara et al. (2017 [Ref 14]):** Five patients (ages 18–23) in France with non-fatal DOC exposure; all believed they had ingested LSD. Severe symptoms documented. Plasma DOC < 18 µg/L; urine 300–1,300 µg/L.

### Clinical Toxidrome

From aggregated case literature and WHO ECDD (2019 [Ref 7]):
- **Cardiovascular:** Tachycardia, possibly vasoconstriction (consistent with 5-HT2A/adrenergic activity)
- **Neurological:** Hallucinations, agitation, aggression, seizures
- **Systemic:** Rhabdomyolysis, hyperthermia
- **Duration:** Prolonged — features may persist 24–33 hours

### LD50 / Toxic Dose

No LD50 data for DOC in any species were identified in published literature. The toxic dose in humans is unknown (WHO ECDD 2019 [Ref 7]). The fatal blood concentration in the Barnett (2014) case (377 ng/mL) provides a single reference point for lethality, but interpreting postmortem concentrations is unreliable due to postmortem redistribution (Lelievre 2022 [Ref 13]).

### 5-HT2B Cardiac Risk

DOC has high affinity at 5-HT2B receptors (Nelson 1999 [Ref 6]; r > 0.9 correlation with 5-HT2A across DOx class). 5-HT2B receptor agonism is the established mechanism of drug-induced cardiac valvulopathy (Setola et al. 2003 [Ref 24]; Xu et al. 2026 [Ref 23]). No clinical cases of DOC-induced valvulopathy have been reported, and the absolute risk from infrequent recreational use is unclear, but this is a theoretical long-term safety concern for repeated high-dose use. **Flag for human review.**

---

## Harm Reduction

**Not a conventional amphetamine:** DOC's primary mechanism is 5-HT2A/2C receptor agonism, not monoamine release. Its amphetamine-like structure misleads users and harm reduction workers into expecting a stimulant profile, but the effects are those of a long-duration serotonergic psychedelic.

**LSD misrepresentation hazard:** DOC is frequently sold as LSD on blotter papers (Abbara 2017 [Ref 14]; WHO ECDD 2019 [Ref 7]). Because DOC on blotter looks identical to LSD, users may be unaware of the longer duration (12–24h vs ~8–12h for LSD) or higher dose sensitivity. Reagent testing: DOC typically gives a colour reaction with Ehrlich reagent (amine-positive), but unlike LSD it gives a positive reaction with marquis/mecke due to the methoxy groups. A fentanyl test strip will not detect DOC.

**Set and setting:** Given the 12–24-hour duration, inadequate preparation is a significant risk factor for adverse psychological outcomes.

**Hyperthermia/rhabdomyolysis risk:** Multiple case reports document hyperthermia and rhabdomyolysis. Users should avoid physical exertion in hot environments and maintain hydration.

**Emergency response:** Severe intoxication should be treated as a medical emergency. Features suggesting severe toxicity include: seizures, hyperthermia, rhabdomyolysis, cardiovascular instability. Benzodiazepines are first-line for agitation and seizures; no specific antidote exists. Duration of clinical features may exceed 24 hours.

**Testing:** No published protocols specific to DOC testing. Detection requires specific GC-MS or LC-MS/MS screening panels; routine immunoassay drug screens will typically not detect DOC (Barnett 2014 [Ref 1]; Abbara 2017 [Ref 14]).

---

## Tolerance & Dependence

### Tolerance

Rapid tachyphylaxis develops with repeated dosing of 5-HT2A agonists, mechanistically linked to receptor downregulation via beta-arrestin2 pathway activation (Wallach et al. 2023 [Ref 15]). Cross-tolerance to other serotonergic psychedelics (LSD, psilocybin, mescaline, other DOx compounds) is expected on the basis of shared 5-HT2A agonism. The seed data values (buildup: almost immediately; half-life: 3 days; full reset: 7 days) are plausible based on class-level data but are not DOC-specific — no controlled human studies exist confirming these parameters for DOC specifically. **Flag: these values are inferred from class analogy, not DOC-specific data.**

### Dependence

No dependence potential has been demonstrated in humans or animals for DOC (WHO ECDD 2019 [Ref 7]). This is consistent with the broader DOx class and with serotonergic psychedelics generally — rapid tachyphylaxis functionally limits binge patterns.

---

## Interactions

### Tramadol — Dangerous [Ref 22]

Tramadol inhibits the serotonin transporter (SERT) and also acts as a weak µ-opioid agonist and SNRI (Baldo 2018 [Ref 22]). Combined with DOC's 5-HT2A/2C agonism, tramadol could precipitate serotonin syndrome through additive serotonergic mechanisms. This interaction is listed as dangerous in seed data; supported by tramadol's known serotonergic mechanism. Specific published case reports of DOC + tramadol serotonin syndrome were not identified, but the mechanism strongly supports the danger classification.

### Cannabis — Unknown

No published data on pharmacological interaction between DOC and cannabis. Cannabis (via CB1 agonism) may potentiate or destabilize psychedelic experiences; the interaction is unpredictable. No mechanism for direct pharmacokinetic interaction has been identified.

### MAOI — Not listed in seed data; high-risk flag

Monoamine oxidase inhibitors (MAOIs) combined with serotonergic compounds carry risk of serotonin syndrome. DOC's serotonergic mechanism makes this a concern, though DOC itself is not a MAOI substrate in the typical sense (it acts via receptor agonism, not serotonin release). Risk is indirect but should be flagged. No published case reports identified.

### SSRI — Not listed in seed data; interaction noted

Bonson et al. (1996, PMID 8726753) demonstrated that chronic SSRI administration attenuates subjective LSD effects, likely via 5-HT2A receptor downregulation. A similar blunting effect may occur with DOC, though no DOC-specific data were identified.

### CYP2D6 substrates

DOC competitively inhibits CYP2D6 (Ki 2.7–19.9 µM in human liver microsomes; Ewald & Maurer 2008 [Ref 3]). Interactions with other CYP2D6 substrates are possible but considered unlikely at typical doses, as the Ki values are much higher than potent inhibitors.

---

## Legal Status

| Jurisdiction | Status | Notes |
|---|---|---|
| **United Kingdom** | Class A controlled drug | Covered under the generic N-alkyl substituted amphetamine provision of the Misuse of Drugs Act 1971 (Ovaska et al. 2008 [Ref 4]) |
| **United States** | Not formally scheduled under CSA as of April 2026 | DEA NPRM (April 2022 [Ref 18]; December 2023 [Ref 19]) proposed Schedule I. Administrative hearing announced April 2024, stayed June 2024 pending U.S. District Court decision (DEA docket DEA-1156). Potentially prosecutable under the Federal Analog Act given structural similarity to DOM (Schedule I). |
| **Germany** | Anlage I BtMG | Most restrictive category; prohibits possession, trafficking, manufacture except for authorised research |
| **Canada** | Schedule I CDSA | As a hallucinogenic amphetamine analog |
| **Australia** | Restricted import | Listed in Schedule 4 of the Customs (Prohibited Imports) Regulations as an alkoxyamphetamine; state-level prohibition under poisons schedules |
| **International (UN)** | WHO ECDD 2019 recommended Schedule I of 1971 Convention | The ECDD recommendation was made at the 42nd meeting (2019 [Ref 7]); formal CND scheduling action would be required to add to the convention schedules |

---

## Clinical Trials

No clinical trials involving DOC were identified via ClinicalTrials.gov search. No marketing authorisations exist (WHO ECDD 2019 [Ref 7]). DOC has no recognised therapeutic applications.

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## Community Feedback Analysis

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

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## Gaps & Flags

### 🚩 CRITICAL FLAG — Seed Data Error: "Monoamine releasing agent" pharmacological class is incorrect

The seed data lists DOC's pharmacological class as including "Monoamine releasing agent." This is **incorrect**. DOC does not function as a monoamine releaser or transporter substrate. Eshleman et al. (2014 [Ref 2]) directly tested DOC at SERT, DAT, and NET and found minimal/no activity. The compound acts exclusively via 5-HT2A, 5-HT2B, and 5-HT2C receptor agonism. This pharmacological class designation should be removed. The generation agent should propose deleting "Monoamine releasing agent" from the pharmacological class.

### 🚩 FLAG — Primary ROA listed as "insufflated"

Published literature consistently characterises oral/sublingual administration (on blotters) as the primary route of use for DOC (WHO ECDD 2019 [Ref 7]; Abbara 2017 [Ref 14]). Insufflated use is not described in published case reports or clinical literature. The seed data may have this reversed. No published data on insufflated pharmacokinetics, onset, or dose adjustments were identified — the insufflated dose/duration data in the seed table cannot be verified against any published source. **Flag for editorial review.** Insufflated route data should be labelled "user reports only" with no published pharmacokinetic verification.

### 🚩 FLAG — Tolerance/cross-tolerance values not DOC-specific

The seed data tolerance parameters (buildup: almost immediately; half-life: 3 days; full reset: 7 days; cross-tolerances: psychedelic) are plausible based on 5-HT2A receptor downregulation kinetics across the psychedelic class but cannot be verified against DOC-specific published data. These are class-level inferences.

### 🚩 FLAG — No published human PK data

Bioavailability, Tmax, plasma half-life, and protein binding are unknown for DOC in humans. All dose/duration data derive from self-experimental reports (Shulgin) or clinical case observations, not controlled PK studies.

### 🚩 FLAG — Toxic dose unknown

The LD50 is not established in any species. The fatal blood concentration (377 ng/mL, Barnett 2014 [Ref 1]) is the only published lethality data point. Postmortem redistribution significantly limits interpretation. The toxic dose range in humans is unknown.

### 🚩 FLAG — Enantioselective activity not characterised for DOC

The compound is a racemate as typically encountered. No published studies have characterised the activity of individual DOC enantiomers. SAR data from related DOx compounds suggests the R-(−)-enantiomer is likely more potent, but this is structural analogy only.

### 🚩 FLAG — 5-HT2B cardiac valvulopathy risk

DOC has high 5-HT2B affinity (inferred from DOx class SAR, Nelson 1999 [Ref 6]). Chronic 5-HT2B agonism is the established mechanism for drug-induced cardiac valvulopathy (Xu 2026 [Ref 23]; Setola 2003 [Ref 24]). No clinical cases specific to DOC have been reported, but this theoretical risk deserves acknowledgment in the safety section.

### 🚩 FLAG — Seed data missing chemical identity fields

PubChem CID, SMILES, molecular formula, molecular weight, and InChIKey were all absent from seed data. These have now been confirmed (see Chemical Identity section) and should be populated in the database.

### Data absence — No controlled human studies exist

All human pharmacology data for DOC is derived from self-experimental reports, case series, and inferences from animal models or structurally related compounds. This should be stated clearly in article prose.

### Data absence — No published forensic method for blotter identification specific to DOC

The Nieddu et al. (2023 [Ref 8]) review highlights the need for updated analytical methods for DOx/2C-x compounds in biological matrices. DOC-specific validated methods are limited.