2C-P

# Research Output: 2C-P

## Chemical Identity

**Verified via PubChem (CID 44350080):**
- **Systematic name (IUPAC):** 2-(2,5-dimethoxy-4-propylphenyl)ethanamine
- **Molecular formula:** C₁₃H₂₁NO₂
- **Molecular weight:** 223.31 g/mol
- **InChIKey:** PZJOKFZGPTVNBF-UHFFFAOYSA-N
- **PubChem CID:** 44350080
- **CAS number:** 207740-18-9 (web-retrieved; not returned by PubChem API — flag for verification)
- **SMILES:** Not returned by PubChem API. Derivable from name as CCCc1cc(CCN)c(OC)cc1OC — this should be verified against a primary chemical database before use in article prose.

**Seed data match:** The brief's systematic name ("2-(2,5-dimethoxy-4-propylphenyl)ethanamine") matches PubChem exactly. Formula, molecular weight, and InChIKey all confirmed. PubChem CID and SMILES were absent from the brief and are now provided. No discrepancies detected.

**FLAG (human review):** CAS number 207740-18-9 is web-retrieved only; SMILES is derived, not API-verified. Both should be cross-checked against CAS Common Chemistry or ChemSpider before publication.

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## Pharmacology

### Primary Mechanism

2C-P is a potent agonist at serotonin 5-HT₂A and 5-HT₂C receptors, the primary and secondary targets respectively mediating its psychedelic effects. This is established by structural membership in the 2,5-dimethoxyphenethylamine (2C-X) class and confirmed by rodent behavioral data (Kim et al. 2021 [Ref 1]; de la Fuente Revenga et al. 2022 [Ref 12]).

The 2,5-dimethoxy scaffold is essential for 5-HT₂A receptor activation in vivo — removal of either methoxy group significantly reduces head-twitch response in mice even when in vitro binding is only modestly reduced (Marcher-Rorsted et al. 2020 [Ref 25]). The 4-propyl substituent on the benzene ring increases lipophilicity and, consistent with SAR across the 2C class, likely contributes to higher receptor affinity and more prolonged effects compared to smaller 4-substituents. Across structurally related series (4-alkoxy phenethylamines), increasing 4-substituent size progressively increases 5-HT₂A/2C affinity (Kolaczynska et al. 2019 [Ref 27]).

**FLAG (human review):** No published primary study has reported specific Ki or EC50 values for 2C-P at 5-HT₂A or 5-HT₂C from a directly verifiable source in this research. A web-search summary cited EC50 values of 1–9 nM at 5-HT₂A for the "4-propyl analog" from an unnamed study — this claim could not be traced to a primary paper and should not be used in article prose until sourced. The Pottie et al. 2020 β-arrestin 2 study [Ref 18] covers 12 2C-X compounds and likely includes 2C-P, but the specific EC50 value for 2C-P was not confirmed from its abstract.

### Receptor Selectivity Profile

Across the 2C-X class, receptor interaction follows a consistent profile:
- **Primary:** 5-HT₂A agonist (nanomolar range affinity; partial agonist efficacy)
- **Secondary:** 5-HT₂C agonist (typically 2–14-fold lower affinity than 5-HT₂A) (Kolaczynska et al. 2019 [Ref 27])
- **Tertiary:** Weak TAAR1 activity has been described for related phenethylamines (Kolaczynska et al. 2019 [Ref 27]; Luethi et al. 2018 [Ref 20])
- **Monoamine transporters:** Little or no activity at DAT, SERT, NET in the phenethylamine 2C class (Kolaczynska et al. 2019 [Ref 27]; Luethi et al. 2018 [Ref 20])
- **MAO inhibition:** 2C-P was among 17 2C-series drugs tested by Wagmann et al. 2019 [Ref 3]; 13 of the 17 drugs showed MAO-A inhibition and 11 showed MAO-B inhibition. IC₅₀ values ranged 10–125 µM for MAO-A and 1.7–180 µM for MAO-B across the panel. Specific IC₅₀ values for 2C-P individually are not confirmed from the abstract — see full-text verification needed. The clinical significance of MAO inhibition at recreational doses is uncertain but cannot be excluded.

### Dopaminergic Effects

At high doses in rodents, 2C-P affects dopaminergic signaling: Kim et al. 2021 [Ref 1] found changes in D1 and D2 dopamine receptor expression and dopamine transporter phosphorylation in the nucleus accumbens and medial prefrontal cortex. These effects were not observed at low doses and are considered secondary or toxicity-associated rather than primary mechanism of action.

### 5-HT₂B Considerations

Related hallucinogenic phenethylamines show correlation between 5-HT₂A and 5-HT₂B binding affinity (Setola et al. 2005 [Ref not in primary set]). Cardiac valvulopathy risk via 5-HT₂B is relevant to chronic use of 5-HT₂A agonists, though no specific data exists for 2C-P. The β-arrestin 2 assay (Pottie et al. 2020 [Ref 18]) suggests 2C-P has partial agonist character consistent with the broader 2C-X class.

---

## Pharmacokinetics

**Human data (single case estimate):** Stoller et al. 2017 [Ref 10] estimated the elimination half-life of 2C-P as approximately **19 hours** based on two blood sample concentrations in a single case. This is consistent with the prolonged duration of effects (10–20+ hours) reported by Shulgin and in clinical case series.

**Plasma concentrations:** In the five-case intoxication series [Ref 16], 2C-P was detected in urine in all five cases and in plasma in one case at a concentration of approximately **20 µg/L**. In the Stoller case, plasma concentrations were less than 10–20 µg/L.

**Metabolism** (Wink et al. 2015 [Ref 2]; Nieddu et al. 2023 [Ref 19]):
The following phase I and II metabolic pathways were identified in urine by GC-MS and LC-MS(n):
- **N-acetylation**
- **Deamination** followed by reduction to the corresponding alcohol and oxidation to carbonic acid
- **Mono- and bis-hydroxylation** at different ring and aliphatic positions
- **Mono- and bis-O-demethylation** at the 2- and/or 5-methoxy positions
- **Glucuronidation and/or sulfation** of hydroxylated/demethylated metabolites
- Combinations of the above steps

Proof of a common user's dose of 2C-P was confirmed detectable in urine by both standard GC-MS and LC-MS(n) screening (Wink et al. 2015 [Ref 2]).

**CYP enzyme involvement:** Not directly studied for 2C-P. For the broader 2C phenethylamine class, O-demethylation suggests involvement of CYP2D6 and CYP3A4, though this is class-level inference; no published 2C-P-specific CYP data was identified.

**FLAG (human review):** Half-life estimate of ~19 hours is derived from a single case with only two blood draws; this is a rough estimate and not a formal pharmacokinetic study. No population-level PK data exists for 2C-P.

---

## History

**Discovery and first documentation:**
2C-P was first synthesized by American chemist Alexander Shulgin and documented as entry #35 in *PiHKAL: A Chemical Love Story* (1991) [Ref 21], co-authored with Ann Shulgin. Shulgin named the compound **"Selene"** in his personal nomenclature, consistent with his practice of assigning feminine names to preferred compounds. This book represents the only contemporaneous documentation of first human trials.

**Shulgin's notes:**
- Oral dose: 6–10 mg
- Duration: 10–16 hours
- Described as among the most potent and long-lasting of the 2C psychedelics
- Characterized by a **steep dose–response curve**
- A dose of 16 mg was described as a "clear overdose" and "physical disaster" that was "not to be repeated" — this is a critically important safety observation documented in the primary source

**Emergence as a research chemical:**
After PiHKAL's publication, 2C-P began circulating on research chemical markets, particularly online. The Synthetic Drug Abuse Prevention Act (US, 2012) [Ref 22] and subsequent scheduling actions in Canada (2016) [Ref 23] and Germany (2014) suggest market presence through at least the early 2010s.

**First documented clinical cases:**
The earliest published case series of 2C-P intoxication was from France in 2015 [Ref 16], followed by the Stoller 2017 case in Switzerland [Ref 10] — both published after US scheduling in 2012.

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## Subjective Effects

Published subjective effect descriptions come primarily from Shulgin's self-experiments (PiHKAL, 1991) [Ref 21] and from clinical emergency case reports (five-case series [Ref 16]; Stoller 2017 [Ref 10]).

**From Shulgin (PiHKAL):**
- Open and closed-eye visuals
- Time distortion
- Conceptual thinking
- Euphoria
- Ego dissolution

**From clinical case reports** [Ref 10, 16]:
- Severe visual hallucinations
- Mydriasis (pupil dilation)
- Agitation and confusion
- Tachycardia (elevated heart rate)
- Hypertension

**Duration data:**
- Shulgin documented duration of 10–16 hours
- The seed database records total duration of 10–20 hours — this longer range likely reflects variability at the high end of the dose range
- The Stoller case (t₁/₂ ~19h) supports prolonged activity
- Onset 1–3 hours is consistent with the long come-up typical of phenethylamine 2C-class drugs taken orally

No controlled human studies of subjective effects exist. All human data comes from Shulgin's self-experiments (uncontrolled, n=small) and emergency case reports.

---

## Safety & Toxicity

### Dose Sensitivity

2C-P is notable within the 2C class for its **steep dose–response curve** (Shulgin 1991 [Ref 21]). The margin between a "strong" dose and an overwhelming/toxic dose appears narrow. Shulgin's explicit documentation of 16 mg as a "physical disaster" (only ~60% above his high-end common dose of 10 mg) is the most important primary safety signal in the literature.

### Acute Toxicity in Clinical Cases

**Five-case series (2015) [Ref 16]:** Five males aged 17–21 ingested 2C-P (powder or liquid) in a festive setting. Symptoms: mydriasis, severe agitation, confusion, visual hallucinations, sinus tachycardia, hypertension. All five patients recovered. 2C-P confirmed in urine (all 5) and plasma (1 case, 20 µg/L) by UPLC-MS/MS.

**Stoller 2017 [Ref 10]:** 19-year-old male presented to emergency department with severe hallucinations, mydriasis, tachycardia, agitation, and confusion after ingesting a substance sold as 2C-B. 2C-P confirmed by LC-MS. Patient recovered. Estimated t₁/₂ ~19 hours from two blood samples.

**Adulterant risk:** The Stoller 2017 case [Ref 10] is significant because the patient believed he was taking 2C-B (a better-characterized, shorter-acting substance). This represents a documented real-world harm from 2C-P being sold as 2C-B, with substantially different potency and duration.

### Neurotoxicity (Rodent Data)

Kim et al. 2021 [Ref 1] found that high doses of 2C-P induced:
- Microglial activation (neuroinflammation) in the striatum
- Decreased locomotor activity, rota-rod performance
- Impaired Y-maze, novel object recognition, and passive avoidance performance (memory impairment)
- Altered D1/D2 receptor expression and DAT phosphorylation in the nucleus accumbens and medial prefrontal cortex

These effects were observed at **high doses** in rodents. Whether these findings translate to human neurotoxicity at recreational doses is unknown. All rodent neurotoxicity data should be noted as animal-only.

### LD50 / Toxic Dose

No LD50 data has been published for 2C-P in any species. The toxic dose in humans is unknown. Shulgin's "physical disaster" at 16 mg (PiHKAL [Ref 21]) is the only direct human data point regarding dose-dependent toxicity.

**FLAG (human review):** The seed data notes "toxic dose is unknown" — this is confirmed. No LD50 or formal toxicity threshold data exists for 2C-P.

### Cardiovascular Risk

Clinical cases consistently document tachycardia and hypertension [Ref 10, 16]. These are class-level cardiovascular effects shared across serotonergic hallucinogens and reflect sympathomimetic activation. Severe cases may involve vasoconstriction and hyperthermia (reviewed in Luethi & Liechti 2020 [Ref 14]).

### Psychological Risk

2C-P's long duration (10–20+ hours), high potency, and steep dose-response curve create elevated risk for prolonged difficult experiences. The seed data's effects taxonomy includes "delusions," "thought loops," "cognitive dysphoria," and "ego dissolution"-adjacent states (non-dual awareness, entity contact) — all consistent with difficult or overwhelming experiences at high doses.

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## Harm Reduction

### Critical Risk Factors

1. **Steep dose–response curve** (Shulgin 1991 [Ref 21]): Small dose increases can produce dramatically more intense effects. Individual dose titration at 1–2 mg increments is essential.
2. **Long duration** (~10–20 hours): Users should plan for a full day of impairment; no responsibilities, safe setting required.
3. **Adulterant risk:** Documented cases of 2C-P sold as 2C-B [Ref 10]. Reagent testing and ideally mass spectrometric confirmation are strongly recommended.
4. **Onset delay:** 1–3 hour onset and 2–4 hour come-up means users risk re-dosing prematurely, leading to overdose.

### Drug Testing

2C-P is not reliably detected by standard immunoassay urine drug screens. Confirmation requires GC-MS, LC-MS(n), or UPLC-MS/MS (Wink et al. 2015 [Ref 2]; five-case series [Ref 16]). Healthcare providers should use targeted LC-MS methods in suspected 2C-P intoxications.

### Emergency Response

Emergency presentations follow the profile of serotonergic excess: mydriasis, tachycardia, hypertension, hyperthermia, agitation, hallucinations. Management is supportive. The 5-HT₂A antagonist M100907 blocks all behavioral effects in rodents (Elmore et al. 2018 [Ref 28]); cyproheptadine or atypical antipsychotics (e.g., quetiapine) may be considered in severe cases per clinical judgment.

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## Tolerance & Dependence

### Tolerance

Tolerance develops "almost immediately after ingestion" according to the seed data — this is consistent with the known mechanism: 5-HT₂A receptor downregulation following activation (Buckholtz et al. 1990 [Ref 24]; de la Fuente Revenga et al. 2022 [Ref 12]).

Mechanistically: repeated 5-HT₂A agonism leads to receptor downregulation in the frontal cortex, reducing responsiveness. Tolerance to the head-twitch response (animal model of hallucinogenic effects) develops progressively over 4 days of DOI administration in mice, with measurable 5-HT₂A density reduction. The mechanism is β-arrestin-2-independent (de la Fuente Revenga et al. 2022 [Ref 12]).

### Cross-Tolerance

Cross-tolerance between psychedelics occurs via shared 5-HT₂A receptor downregulation mechanism (de la Fuente Revenga et al. 2022 [Ref 12]; Buckholtz et al. 1990 [Ref 24]). 2C-P will produce cross-tolerance with other 5-HT₂A agonists (LSD, psilocybin, mescaline, other 2C drugs) and vice versa. The seed data's characterization of cross-tolerance class as "psychedelic" is confirmed by the literature.

### Dependence

**Abuse potential:** Kim et al. 2021 [Ref 1] demonstrated that 2C-P produced:
- Conditioned place preference (CPP) in mice in a dose-dependent manner
- Increased self-administration in rats

These findings suggest reinforcing properties. This is the only primary data on 2C-P abuse potential.

**Dependence formation:** The seed data rates this as "low potential for abuse and dependence." The rodent data somewhat challenges this characterization — CPP and self-administration are established preclinical models of abuse potential. The general consensus that classical psychedelics have low physical dependence liability is supported by the absence of withdrawal syndromes and the rapid tolerance development that limits self-escalation. However, the Kim 2021 rodent data should be flagged as evidence that 2C-P may have higher abuse potential than other classical psychedelics, possibly reflecting its dopaminergic effects at high doses.

**FLAG (human review):** The seed data's "low potential for abuse and dependence" claim is at least partially contradicted by Kim et al. 2021 [Ref 1] (CPP and self-administration in rodents). The generation agent should note this discrepancy and consider whether to revise characterization.

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## Interactions

### Tramadol (Seed data: "dangerous")

The seed database flags a dangerous interaction with tramadol. Tramadol is a serotonin-norepinephrine reuptake inhibitor and µ-opioid agonist. Combined with a 5-HT₂A agonist and potential MAO inhibitor (2C-P inhibits MAO at concentrations of 1.7–180 µM per Wagmann et al. 2019 [Ref 3]), the interaction risk is serotonin toxicity/syndrome. The combination could elevate synaptic serotonin via:
- 2C-P: 5-HT₂A agonism + MAO inhibition
- Tramadol: SERT inhibition + (norpethidine-mediated serotonin release)

**FLAG (human review):** No published primary source specifically documents 2C-P + tramadol causing serotonin syndrome. The "dangerous" classification in the seed data is mechanistically plausible but is derived from pharmacological reasoning, not a documented case. The interaction should be labeled as "theoretical/class-based" unless a case report is identified.

### Cannabis (Seed data: "unknown")

No published data on cannabis + 2C-P interactions found. The interaction is genuinely unknown. Cannabis may amplify or unpredictably modify psychedelic effects.

### Monoamine Oxidase Inhibitors (MAOIs)

2C-P shows in vitro MAO inhibition (IC₅₀ 1.7–180 µM range for MAO-B across the panel; Wagmann et al. 2019 [Ref 3]). Combining with exogenous MAOIs could potentiate serotonergic effects and increase risk of serotonin syndrome. Clinical significance is uncertain.

### Other Serotonergic Drugs

Combining with SSRIs, SNRIs, triptans, lithium, or other serotonergic agents increases serotonin syndrome risk. SSRIs may also blunt or block 2C-P's psychedelic effects via 5-HT₂A downregulation (class-level interaction).

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## Legal Status

| Jurisdiction | Status | Notes |
|---|---|---|
| United States | **Schedule I** | Synthetic Drug Abuse Prevention Act, signed July 9, 2012 [Ref 22]; DEA drug code 7524 |
| United Kingdom | **Class A** | Via phenethylamine catch-all clause in the Misuse of Drugs Act |
| Germany | **Anlage I** (BtMG) | Scheduled December 13, 2014 |
| Canada | **Schedule III** | Order Amending Schedule III to CDSA (2C-phenethylamines), effective May 2016 [Ref 23] |
| Netherlands | Status uncertain | Not clearly scheduled at time of web research; NPS legislation may apply |
| Australia | Likely **Schedule 9** (Prohibited Substance) | Not confirmed from primary regulatory source; likely captured by SUSMP catch-all or specific listing |
| European Union | No EU-wide scheduling found; individual member states have acted (e.g., Germany) | |

**FLAG (human review):** Australia's specific scheduling status and Netherlands current status should be confirmed against current TGA SUSMP and Dutch Opium Act listing before publication. EU status should be checked against EMCDDA database.

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## Clinical Trials

No clinical trials involving 2C-P were found on ClinicalTrials.gov. 2C-P has never been tested in a human clinical trial.

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## Community Feedback Analysis

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

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## Gaps & Flags

### Data Gaps

1. **No published Ki or EC50 values confirmed for 2C-P at any receptor from a primary source.** The web search produced an unconfirmed claim of 1–9 nM EC50 at 5-HT₂A for a "4-propyl analog" — this was not traced to a published paper. The Pottie 2020 β-arrestin 2 study [Ref 18] likely includes 2C-P but specific values were not confirmed from the abstract. Generation agent should use class-level SAR framing rather than specific values unless the Pottie full text is accessed.

2. **No human pharmacokinetic study exists.** The t₁/₂ ~19 hours estimate (Stoller 2017 [Ref 10]) is from a single case with two blood draws. All PK data should be labeled as preliminary case-based estimates.

3. **SMILES string not confirmed by API.** PubChem did not return SMILES for CID 44350080 in the API response. Derived structure (CCCc1cc(CCN)c(OC)cc1OC) is chemically consistent with the IUPAC name but requires verification.

4. **CAS number 207740-18-9 is web-retrieved only** — not confirmed by CAS Common Chemistry or PubChem API.

5. **MAO inhibition IC₅₀ for 2C-P specifically** not confirmed. Wagmann 2019 [Ref 3] reports ranges across 17 compounds; whether 2C-P falls within inhibitory or non-inhibitory subset for both MAO-A and MAO-B requires full-text access.

6. **CYP enzyme involvement** not characterized for 2C-P specifically.

7. **No LD50 or preclinical toxicity threshold** for 2C-P in any species.

8. **Australia legal status** not confirmed from a primary regulatory source.

9. **5-case intoxication series [Ref 16]** was not found on PubMed — it is web-retrieved from ResearchGate/ScienceDirect. The exact DOI could not be confirmed. Authors not confirmed. Citation requires verification before publication use.

### Safety-Critical Flags (Human Review Required)

- **⚠ Tramadol "dangerous" interaction:** Listed in seed data but no primary case report documenting this interaction. Classification is mechanistically plausible (serotonin syndrome risk) but is inference, not documented observation. Flag for editorial review.

- **⚠ Abuse potential characterization:** Seed data says "low potential for abuse and dependence." Kim et al. 2021 [Ref 1] demonstrates CPP and self-administration in rodents, suggesting the characterization warrants revision or nuanced framing (low physical dependence, but reinforcing properties present).

- **⚠ Dose range steep curve:** Shulgin's explicit documentation that 16 mg constitutes an overdose (vs. 10 mg as upper limit of "common" range) should be reflected in any dose table labeling. This is one of the most important harm reduction signals for this substance.

- **⚠ Adulterant risk:** Documented cases of 2C-P sold as 2C-B (Stoller 2017 [Ref 10]). Generation agent should ensure harm reduction section explicitly addresses this.