3,4-CTMP

# Research Output: 3,4-CTMP

## Chemical Identity

**Confirmed via PubChem CID 44296390** [Ref 17]:

| Property | Value |
|---|---|
| Molecular Formula | C₁₄H₁₇Cl₂NO₂ |
| Molecular Weight | 302.2 g/mol |
| IUPAC Name | methyl (2R)-2-(3,4-dichlorophenyl)-2-[(2R)-piperidin-2-yl]acetate |
| InChIKey | JUKMAYKVHWKRKY-CHWSQXEVSA-N |
| PubChem CID | 44296390 |
| CAS Number (racemic HCl) | 214149-42-5 |
| CAS Number (RR enantiomer) | 1364331-88-3 |

**Nomenclature note:** The abbreviation "3,4-CTMP" is technically imprecise. The compound is more correctly designated 3,4-DCMP (3,4-dichloromethylphenidate). "3,4-CTMP" refers specifically to the d,l-threo diastereomer — the form sold on the research chemical market — while 3,4-DCMP encompasses all diastereomers. Both terms appear in the literature and both refer to the same racemic threo compound in practice.

**Seed data verification:** The brief's systematic name (methyl (2R)-2-(3,4-dichlorophenyl)-2-[(2R)-piperidin-2-yl]acetate) matches PubChem exactly. Molecular formula, weight, and InChIKey are confirmed. No SMILES or PubChem CID were in the seed data — these are now populated above. No contradictions with seed data found.

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## Pharmacology

### Mechanism of Action

3,4-CTMP is a potent monoamine reuptake inhibitor acting primarily at the dopamine transporter (DAT) and norepinephrine transporter (NET), with additional affinity at the serotonin transporter (SERT) — a profile that distinguishes it from the parent compound methylphenidate, which has negligible SERT affinity (Luethi et al. 2018 [Ref 2]).

Unlike amphetamine-class stimulants, 3,4-CTMP does not elicit transporter-mediated monoamine efflux. It is a pure reuptake inhibitor that blocks dopamine and norepinephrine clearance, increasing their synaptic availability (Luethi et al. 2018 [Ref 2]).

### Transporter Binding Affinities

From Luethi et al. 2018 [Ref 2] (in vitro, HEK293 cells transfected with human monoamine transporters):

- **DAT:** 3,4-CTMP inhibits the dopamine transporter ~12-fold more potently than methylphenidate. A DAT IC₅₀ of approximately 65 nM has been reported in rat striatal tissue.
- **NET:** 3,4-CTMP inhibits the norepinephrine transporter ~76-fold more potently than methylphenidate. This represents a striking increase in NET selectivity not seen with simple ester-chain modifications.
- **SERT:** Unlike methylphenidate, 3,4-CTMP has meaningful affinity for SERT. The 3,4-dichlorination is specifically responsible for this increased serotonin transporter selectivity; however, all phenidate-based compounds in the Luethi series inhibited NET and DAT 4- to >1000-fold more potently than SERT.

**⚠️ Flag:** Specific Ki values (in nM) for DAT, NET, and SERT were identified in the Luethi 2018 Neuropharmacology paper but are behind a paywall. The data summarized above derives from secondary reporting of that paper's findings. The generation agent should note uncertainty on exact numerical Ki values.

### 5-HT2B Receptor Agonism

3,4-CTMP has been identified as a relatively potent agonist at 5-HT2B serotonin receptors (Luethi et al. 2018 [Ref 2]). 5-HT2B agonism is clinically significant because it is associated with cardiac valvulopathy and pulmonary arterial hypertension in the setting of chronic use — a well-characterized mechanism seen previously with fenfluramine and ergot alkaloids. The specific EC₅₀ value for 5-HT2B agonism is not available from secondary sources; the primary data is in Luethi et al. 2018 [Ref 2].

**⚠️ Flag:** The 5-HT2B agonist finding is safety-critical and should be presented prominently. No human data on cardiac or pulmonary consequences of 3,4-CTMP use exists. This is a theoretical risk based on receptor pharmacology.

### Functional Neurochemistry

Davidson et al. 2018 [Ref 1] measured evoked dopamine and noradrenaline efflux in adolescent male rat brain slices using fast cyclic voltammetry:

- **Nucleus accumbens (dopamine):** 3,4-CTMP at 0.1 and 1 µM increased evoked dopamine efflux ~6-fold.
- **Ventral BNST (noradrenaline):** 3,4-CTMP at 0.1 and 1 µM increased evoked noradrenaline efflux ~2-fold.
- **Comparison:** Methylphenidate at 10 µM (100× higher concentration) produced only 4-fold dopamine and 2-fold noradrenaline efflux — demonstrating 3,4-CTMP's substantially greater potency.
- Ethylphenidate at 1 µM doubled both dopamine and noradrenaline efflux (weaker than 3,4-CTMP).

**Authors conclude:** "All three psychostimulant drugs, through their effects on dopamine efflux, may have addictive liability although the effect of 3,4-CTMP on dopamine suggests that it might be most addictive and ethylphenidate least addictive" (Davidson et al. 2018 [Ref 1]).

**Important mechanism note:** The DAT inhibitor GBR12909 and NET inhibitor desipramine confirmed that Davidson et al. were measuring true DAT-mediated dopamine release in the accumbens and NET-mediated noradrenaline release in BNST — ruling out artifact.

### Potency vs. Reinforcing Effects

3,4-CTMP is approximately 7-fold more potent than methylphenidate overall in animal studies (per secondary sources citing Deutsch et al. 1996 [Ref 8]). Note: The Deutsch 1996 paper specifically reports the m,p-dichloro analog as 32-fold more potent than methylphenidate at [³H]dopamine uptake inhibition in rat striatal tissue — this may reflect a specific isomer or measurement. The "7-fold" figure is the commonly cited general comparison.

Despite its high potency, 3,4-CTMP has weaker reinforcing effects than its potency would suggest, attributable to its slow onset of action — consistent with pharmacokinetic theories of abuse potential (Deutsch et al. 1996 [Ref 8]; Froimowitz et al. 2023 [Ref 10]). H.M. Deutsch's discrimination ratio implies it to be more reinforcing than cocaine in rodents despite the slow onset.

### Pharmacokinetics

**Metabolism (Manier et al. 2020 [Ref 7]):**
- UHPLC-HRMS/MS analysis of rat urine identified **7 phase I metabolites** and **no phase II metabolites** for 3,4-CTMP.
- Pooled human S9 fraction (pS9) incubations indicated primary hydrolysis to the corresponding carboxy metabolite — the main route of biotransformation.
- The carboxy metabolite is recommended as an additional analytical screening target alongside the parent compound.
- Study used: in vivo rat urine + pooled human S9 fraction (microsomal + cytosolic liver homogenate).

**⚠️ Flag:** No human clinical pharmacokinetics data exists for 3,4-CTMP. No Tmax, Cmax, bioavailability, plasma half-life, or human CYP enzyme involvement studies have been published.

**Metabolic resistance:** The 3,4-dichloro substitution increases resistance to aromatic ring oxidation, a primary metabolic pathway for methylphenidate. This accounts for 3,4-CTMP's substantially prolonged duration of action — 6–18 hours vs. 4–6 hours for methylphenidate.

**CYP involvement:** Not published for 3,4-CTMP specifically. Methylphenidate is not appreciably CYP-metabolized (hydrolysis-dominant). By analogy, 3,4-CTMP likely depends primarily on carboxylesterases for hydrolysis, though this is an inference — not confirmed data.

---

## History

### Synthesis and Research Origins

3,4-CTMP was first synthesized and pharmacologically characterized as part of a medicinal chemistry program at Georgia Tech aimed at developing potential cocaine antagonists/cocaine abuse treatments. The foundational paper is:

**Deutsch HM, Shi Q, Gruszecka-Kowalik E, Schweri MM (1996).** "Synthesis and Pharmacology of Potential Cocaine Antagonists. 2. Structure−Activity Relationship Studies of Aromatic Ring-Substituted Methylphenidate Analogs." *Journal of Medicinal Chemistry* 39(6):1201–1209. DOI: 10.1021/jm950697c [Ref 8].

This paper synthesized a series of ring-substituted methylphenidate analogs and evaluated them for [³H]WIN 35,428 binding (DAT) and [³H]dopamine uptake inhibition in rat striatal tissue. The m,p-dichloro analog (i.e., 3,4-DCMP/3,4-CTMP) was identified as among the most potent compounds — 32-fold more potent than methylphenidate at dopamine uptake inhibition.

The research was framed around cocaine abuse treatment, based on the hypothesis that a long-acting DAT inhibitor with slow onset might attenuate cocaine craving without the rapid reinforcing effects of cocaine itself (Froimowitz et al. 2023 [Ref 10]).

### Research Chemical Market Emergence

3,4-CTMP appeared on the UK research chemical market in **2013** (Davidson et al. 2018 [Ref 1]). It was marketed as a "designer drug" or "research chemical" and sold in powder and pellet form via online vendors. The substance had been on Bluelight and similar online drug user communities since approximately 2013–2014.

### Regulatory History

| Date | Jurisdiction | Action |
|---|---|---|
| 10 November 2014 | Sweden | Classified as hazardous substance |
| 10 April 2015 | UK | Temporary Class Drug Order (TCDO) under Misuse of Drugs Act 1971 s.2A(1) [Ref 14] |
| October 2015 | China | Scheduled as controlled substance |
| November 2016 | Canada | CDSA Schedule III |
| 26 November 2016 | Germany | Controlled under NpSG (New Psychoactive Substances Act) |
| 31 May 2017 | UK | Permanent Class B scheduling under Misuse of Drugs Act 1971 Amendment Order 2017 [Ref 15] |

The UK TCDO covered 5 methylphenidate-related NPS simultaneously: ethylphenidate, 3,4-dichloromethylphenidate, methylnaphthidate (HDMP-28), isopropylphenidate, and propylphenidate. The ACMD recommendation was dated March 31, 2015.

**⚠️ Flag for review:** The Misuse of Drugs Act 1971 (Amendment) Order 2017 (SI 2017/634) schedules 3,4-CTMP as Class B in the UK — legal citations should confirm the exact Schedule (most likely Schedule 1, no medicinal use). This should be verified.

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## Subjective Effects

**Note:** No controlled human studies of 3,4-CTMP have been published. All subjective effects data derives from self-reported user accounts (Erowid, Bluelight, Drugs-Forum) and community consensus. These are user-report-only data, labeled accordingly.

### Effects Profile (User Reports)

Based on community reporting:

**Stimulant effects:** Moderate-to-high stimulation, described as stronger than caffeine and comparable to (or slightly stronger than) methylphenidate at equivalent doses, but weaker than amphetamine or cocaine. Effects include increased focus, task-specific motivation, reduced appetite, and wakefulness.

**Dopamine-mediated effects:** Euphoria, mood elevation, motivation enhancement, cognitive acceleration, increased sociability. Users report effects described as "functional" at lower doses and more intensely stimulating at higher doses.

**Noradrenergic effects:** Vasoconstriction (frequently reported as prominent), increased heart rate and blood pressure, dry mouth, pupil dilation.

**Duration note:** At least one detailed user report (Erowid, 2014 [Ref 16]) documents oral onset of **3–4 hours** — significantly longer than the DB seed data of 1–2 hours. Nasal administration produced onset within 30–90 minutes. Total duration was approximately 10–12 hours in that report.

**⚠️ Discrepancy flag:** The seed database onset value of 1–2 hours (oral) appears inconsistent with available user reports documenting 3–4 hour oral onset. The long onset delay is also documented in secondary sources noting the risk of premature redosing. This value should be reviewed. The seed total duration of 6–18 hours is consistent with user reports and the metabolic resistance explanation. Aftereffects of 2–24 hours is plausible given reports of prolonged insomnia.

**Dose-response:** At ~2 mg oral, users report smooth, productive stimulation comparable to 60 mg oral Adderall without "jitter." At higher doses (6–8+ mg), effects become more intense. A single dose exceeding 10 mg is strongly cautioned against by experienced users due to severe cardiovascular effects.

**Adverse subjective effects:** Vasoconstriction (prominent), insomnia (major concern given duration), elevated heart rate, anxiety at higher doses, compulsive redosing urge, cognitive dysphoria on comedown.

---

## Safety & Toxicity

### Acute Toxicity

**No published LD₅₀ data exists for 3,4-CTMP** in any species. No human acute toxicity studies have been conducted. The exact toxic dosage is unknown.

The seed data toxicity characterization ("Acute: moderate; Chronic: moderate — Inferred from pharmacological class, not sourced from literature") is consistent with this finding. These values are class-inferred, not substance-specific, and should be labeled accordingly in the article.

### Case Reports

**No published case reports of 3,4-CTMP fatalities or hospitalizations were found** in PubMed, OpenAlex, or the Mohr et al. 2022 adverse events review (2017–2020) [Ref 13]. The substance does not appear prominently in the forensic toxicology literature as a cause of death or serious adverse event.

The closest available fatality data is for the structurally related ethylphenidate: Maskell et al. 2016 [Ref 12] documented 7 fatalities involving ethylphenidate in the UK (February 2013–January 2015), with blood concentrations of 0.026–2.18 mg/L, 1 sole EPH toxicity death, and 4 mixed-drug toxicity deaths. This provides a cautionary analogy but cannot be directly extrapolated to 3,4-CTMP.

**⚠️ Flag:** The known interaction listing "Tramadol: lethal" in the DB seed data was not confirmed by a published case report involving 3,4-CTMP specifically. The tramadol interaction risk is pharmacologically plausible (both lower seizure threshold; stimulant + opioid cardiovascular interactions), but no published case has been found. This should be labeled as theoretical/plausible risk, not documented fatality.

### 5-HT2B Cardiac Risk

As noted under pharmacology, 3,4-CTMP's 5-HT2B agonism raises theoretical concern about cardiac valvulopathy and pulmonary arterial hypertension with chronic use, by analogy with fenfluramine and ergot-based drugs. This has not been documented in human users of 3,4-CTMP.

### Overdose Risk

Key overdose risks based on pharmacological profile:
- **Cardiovascular:** Hypertension, tachycardia, arrhythmia (noradrenergic + dopaminergic stimulation)
- **Hyperthermia:** Sympathomimetic hyperthermia
- **Seizures:** Stimulant-induced seizure threshold reduction
- **Serotonin toxicity:** Theoretical risk given SERT inhibition + 5-HT2B agonism, especially with MDMA or serotonergic drugs

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## Harm Reduction

**No published harm reduction guidelines specific to 3,4-CTMP exist.** The following is inferred from pharmacological profile and user reporting:

1. **Onset delay:** The 3–4 hour oral onset window is the primary acute harm vector — users frequently redose before the first dose takes effect, resulting in dangerous dose stacking. Users should wait ≥4 hours before redosing.

2. **Dose starting point:** Start at 2 mg or below for oral use given potency differential vs. methylphenidate.

3. **Cardiac contraindications:** Contraindicated with pre-existing cardiovascular disease, hypertension, arrhythmias, or structural heart defects.

4. **Drug interactions:**
   - **Tramadol** (listed as "lethal" in DB): Seizure risk (both lower seizure threshold) + cardiovascular interaction. Avoid combination.
   - **MDMA** (listed as "dangerous"): Serotonin toxicity risk (both act on SERT/serotonin system); cardiovascular strain from combined stimulant effects.
   - **MAOIs:** Hypertensive crisis risk — standard stimulant contraindication.
   - **Alcohol** (listed as "unknown"): Likely masks intoxication from both; cardiovascular burden.
   
5. **Duration management:** The 6–18 hour duration creates significant insomnia risk. Use should be timed well before expected sleep.

6. **Testing:** No immunoassay drug test routinely detects 3,4-CTMP; LC-MS/MS testing can confirm presence. Carboxy metabolite is the recommended additional analytical target (Manier et al. 2020 [Ref 7]).

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## Tolerance & Dependence

**No published tolerance or dependence studies for 3,4-CTMP in humans or animals exist.**

By structural analogy and pharmacological class (DAT inhibitor), tolerance is expected to develop with repeated use via dopamine receptor downregulation and DAT upregulation mechanisms — consistent with all DAT inhibitor stimulants.

The Davidson et al. 2018 [Ref 1] assessment that 3,4-CTMP may have the highest addictive liability among the phenidate NPS studied (vs. ethylphenidate and methylphenidate) is based on its greater dopamine efflux potency. However, the slower onset tempers this prediction relative to cocaine.

Cross-tolerance with methylphenidate, cocaine, and other DAT inhibitors is expected based on shared mechanism.

**⚠️ Flag:** Tolerance and dependence values in the DB are missing. These should be labeled as "class-inferred, not substance-specific" in the article.

---

## Interactions

### Known Interactions

| Interaction | Severity | Mechanism | Evidence Level |
|---|---|---|---|
| Tramadol | Listed as "lethal" in DB | Lowered seizure threshold; opioid + stimulant cardiovascular stress | **Theoretical/not confirmed by case report** |
| MDMA | Listed as "dangerous" | Serotonin toxicity potential; SERT inhibition from both; cardiovascular strain | **Pharmacological inference** |
| Alcohol | Listed as "unknown" | Masking of CNS effects; cardiovascular burden | **Unknown** |
| MAOIs | Not listed; assumed contraindicated | Hypertensive crisis (stimulant class effect) | **Class inference** |

**⚠️ Flag:** None of the interaction severity ratings in the DB seed data were confirmed by published literature specific to 3,4-CTMP. The tramadol "lethal" designation is a safety-critical value without a cited case report. The generation agent should flag this for editorial review and label appropriately.

### Serotonin Toxicity Risk

3,4-CTMP's dual action at SERT (reuptake inhibition) and 5-HT2B (agonism) creates a theoretical serotonin toxicity risk when combined with other serotonergic compounds. Combinations with SSRIs, SNRIs, MAOIs, serotonin releasers (MDMA, methamphetamine), or other 5-HT2B agonists should be avoided.

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## Legal Status

| Jurisdiction | Status | Date | Notes |
|---|---|---|---|
| United Kingdom | Class B, Schedule 1 | 31 May 2017 | Permanent scheduling under MDA 1971 Amendment Order 2017 [Ref 15]; preceded by TCDO from 10 April 2015 [Ref 14] |
| Sweden | Controlled | 10 November 2014 | Classified as hazardous substance |
| China | Controlled | October 2015 | — |
| Germany | Controlled (NpSG) | 26 November 2016 | Punishable to produce, import with intent to sell, supply |
| Canada | CDSA Schedule III | November 2016 | — |
| United States | Not explicitly scheduled | — | Likely subject to Federal Analog Act (21 U.S.C. § 813) as structurally similar to Schedule II methylphenidate; no explicit DEA scheduling found |
| Australia | Not confirmed | — | Possibly subject to analog legislation; no explicit scheduling confirmed in search |
| European Union | Not uniformly scheduled | — | Varies by member state |

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## Clinical Trials

**No clinical trials involving 3,4-CTMP were found** on ClinicalTrials.gov or in any published literature. This substance has no approved medical use in any jurisdiction.

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## Community Feedback Analysis

No community feedback was submitted in Part A2 of the brief for 3,4-CTMP.

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## Gaps & Flags

### Safety-Critical Values Needing Editorial Review

1. **Tramadol "lethal" interaction**: Listed in DB seed data but no published case report was found confirming a fatality or even a documented adverse event from 3,4-CTMP + tramadol combination. This is pharmacologically plausible but unconfirmed. **Must be reviewed before publication.**

2. **Dose range (oral onset 1–2 hours)**: Inconsistent with user-reported onset of 3–4 hours and with secondary source characterizations. The DB value may be inaccurate. Onset is more likely 2–4 hours (oral). **Recommend editorial review of onset data.**

3. **"7× more potent than methylphenidate"**: The commonly cited figure; the Deutsch 1996 source reports 32-fold potency at dopamine uptake inhibition. The discrepancy may reflect different isomers, different assays, or different species. Both figures appear in the literature. **Flag for clarification.**

4. **5-HT2B agonism cardiac risk**: Pharmacologically significant but not documented in human users. Should be prominently noted as a theoretical risk, not a confirmed adverse effect.

5. **Toxicity ratings ("Acute: moderate, Chronic: moderate")**: Explicitly noted in seed data as inferred from pharmacological class, not sourced. **Must be labeled as class-inferred in the article.**

### Data Absence Notes

- No human pharmacokinetic studies (Tmax, half-life, bioavailability, CYP enzymes)
- No controlled human pharmacodynamic studies
- No published LD₅₀ in any species
- No published case reports of 3,4-CTMP-specific fatalities or hospitalizations
- No dependence/withdrawal studies
- Australia and EU member-state-by-state legal status is unconfirmed
- US DEA scheduling status is not explicit (Federal Analog Act applicability is an inference)
- Specific Ki/Kd values (in nM) from Luethi et al. 2018 were not accessible — paper is behind paywall; secondary sources confirm relative potency ratios

### Structural Inference Areas

- CYP enzyme involvement in metabolism: inferred from methylphenidate class (carboxylesterase dominant), not confirmed for 3,4-CTMP
- Dependence liability: inferred from DAT inhibitor class pharmacology
- Withdrawal characterization: no published data; expected to mirror stimulant class
- Cardiovascular risk at therapeutic doses: inferred from pharmacological targets

### Dose/Duration Assessment

**Proposed DB values vs. findings:**
- Onset (oral): DB has 1–2 hours; user reports and secondary sources suggest 2–4 hours (some say 3–4 hours). Recommend revising to 2–4 hours.
- Total duration (6–18 hours): Consistent with available data. Retain.
- Aftereffects (2–24 hours): Plausible; insomnia reports support upper end. Retain with note.
- Dose ranges (Threshold 2 mg; Light 2–4 mg; Common 4–6 mg; Strong 6–8 mg; Heavy 8+ mg): Consistent with community consensus and user reports. No clinical data to confirm.