TMA-2

# Research Output: TMA-2

## Chemical Identity

**Common names:** TMA-2, MMM, DOMeO, 2,5-dimethoxy-4-methoxyamphetamine

**Systematic IUPAC name:** 1-(2,4,5-trimethoxyphenyl)propan-2-amine

**PubChem CID:** 31014 [Ref 22] — confirmed via PubChem API

**CAS number:** 1083-09-6 (free base); 15995-72-9 (hydrochloride salt) [Ref 23]

**Molecular formula:** C₁₂H₁₉NO₃ [Ref 22]

**Molecular weight:** 225.28 g/mol (free base); 261.74 g/mol (HCl salt) [Ref 22, 23]

**SMILES (canonical):** COC1=CC(OC)=C(OC)C=C1CC(C)N [Ref 22]

**InChIKey:** TVSIMAWGATVNGK-UHFFFAOYSA-N [Ref 22] — matches PubChem entry

**Stereochemistry:** Racemic (no defined stereocenters); commercial standard is the racemate [Ref 22]. The alpha-methyl carbon is a stereocenter but no stereospecific activity data for individual enantiomers has been published in the peer-reviewed literature.

**Physical properties:**
- Melting point (HCl salt): 188.5–189.5°C [Ref 23]
- Solubility: no published data; expected to be soluble in water as HCl salt based on structural class

**Structural classification:** TMA-2 is the 4-methoxy (DO-OCH3 or DOMeO) member of the DOx series (4-substituted 2,5-dimethoxyamphetamines), a structural subclass of substituted amphetamines and phenethylamines [Ref 1]. It bears the same 2,5-dimethoxy-phenylisopropylamine pharmacophore as DOM, DOI, and DOB, with a methoxy group at the 4-position instead of a halide or alkyl group.

**Discrepancies with brief seed data:**
- PubChem CID 31014 confirmed ✓
- IUPAC name confirmed ✓
- Formula, MW confirmed ✓
- InChIKey confirmed ✓
- SMILES: COC1=CC(OC)=C(OC)C=C1CC(C)N — NOT present in seed data; now confirmed
- Brief seed data left SMILES, InChIKey, molecular formula, and PubChem CID as blank — all now populated

---

## Pharmacology

### Primary Mechanism

TMA-2 is a serotonin 5-HT₂A receptor agonist. It belongs to the 2,5-dimethoxyphenylisopropylamine (DOx) class of phenethylamine hallucinogens, whose psychedelic effects are mediated primarily through 5-HT₂A receptor activation [Ref 3, 7].

### Receptor Binding Data

**5-HT₂A receptor:**
- Binding affinity Ki ≈ 1,300 nM (Kolaczynska et al. 2019 [Ref 1]); an independent radioligand study reports Ki ≈ 1,650 nM at 5-HT₂ (pooled 5-HT₂ preparation)
- Functional EC₅₀ ≈ 190 nM at 5-HT₂A [Ref 1]
- Maximal efficacy (Emax) ≈ 84% relative to reference agonist [Ref 1]
- TMA-2 is therefore a potent partial-to-full agonist functionally despite its relatively modest binding affinity; the disconnect between Ki and EC₅₀ (~7-fold) suggests receptor reserve amplification [Ref 1]

**5-HT₂C receptor:**
- Binding affinity measurable but weaker than 5-HT₂A; 5-HT₂A/5-HT₂C selectivity ratio ~2–14 in the series [Ref 1]

**5-HT₁A receptor:**
- Ki ≈ 46,400 nM (essentially inactive) [Ref 1]

**TAAR1:**
- Inactive (no meaningful binding detected) in mouse and human TAAR1 preparations [Ref 1]

**Monoamine transporters (DAT, SERT, NET):**
- Nagai et al. (2007 [Ref 6]) demonstrated that TMA-2 only slightly influences monoamine reuptake and release in rat brain synaptosomes, unlike stimulant amphetamines. This distinguishes TMA-2 from releasing agents such as MDMA or amphetamine

**Alpha-adrenergic, D₂ receptors:**
- Part of the Kolaczynska 2019 panel [Ref 1] for the series; specific TMA-2 values at these receptors not extractable from available abstract data, but the paper notes weak activity at non-5-HT₂ targets for the methoxy analog (DO-OCH₃, the amphetamine series)

### In Vivo Behavioral Pharmacology

**Locomotor hyperactivity (mouse):** Halberstadt et al. (2013 [Ref 3]) demonstrated that low doses of TMA-2 increase locomotor activity in C57BL/6J mice through 5-HT₂A receptor activation. The selective 5-HT₂A antagonist M100907 blocked the effect of mescaline and TCB-2 in the same paradigm, confirming the 5-HT₂A mechanism is shared.

**Head-twitch response (HTR) in mice:** Halberstadt et al. (2019 [Ref 2]) used the HTR assay to systematically compare mescaline analogs including TMA-2. TMA-2 was substantially more potent than mescaline in this assay — potency parallels closely match known human hallucinogenic potency data, supporting TMA-2's ~20-fold greater human potency relative to mescaline [Ref 2, 19].

**Drug discrimination:** Glennon and Young (1982 [Ref 12]) trained rats in a DOM-discrimination paradigm and tested TMA isomers. The 2,4-dimethoxy pattern was identified as important for activity within this class.

### Structural Pharmacology

Marcher-Rorsted et al. (2020 [Ref 7]) established that the 2,5-dimethoxyphenethylamine motif — present in TMA-2 — is critical for in vivo potency at 5-HT₂A. Removal of either the 2- or 5-methoxy group leads to marked reduction in the head-twitch response in mice, even when in vitro binding affinity drops only modestly. TMA-2's 4-methoxy group positions it as the DO-OCH₃ member of the DOx series.

### Metabolism

Ewald et al. (2006 [Ref 5]) characterized TMA-2 metabolism in rat urine using GC/MS:

1. **Oxidative deamination** → ketone intermediate → reduction to corresponding alcohol
2. **O-demethylation** (at 4-position or others) → followed by oxidative deamination
3. **O,O-bis-demethylation** → catechol-like metabolites
4. **Phase II conjugation:** All hydroxylated metabolites partly excreted as glucuronide and/or sulfate conjugates

Ewald and Maurer (2008 [Ref 4]) confirmed that **CYP2D6** is the primary CYP isoenzyme responsible for O-demethylation of TMA-2. TMA-2 is a **non-mechanism-based competitive inhibitor of CYP2D6** with:
- Ki = 7.1–296 μM (recombinant CYP2D6)
- Ki = 2.7–19.9 μM (pooled human liver microsomes)
- These values are substantially higher than potent CYP2D6 inhibitors (quinidine Ki = 0.0092 μM), suggesting clinically relevant CYP2D6 drug interactions are **possible but unlikely** at typical recreational doses

### Pharmacokinetics

**No published human pharmacokinetic studies** exist for TMA-2. In rats: a validated LC–MS–MS method was developed for quantification in plasma (Nieddu et al. 2008 [Ref 11]; published pharmacokinetic profiles exist for the TMA series in rats but specific half-life, Tmax, and Cmax data for TMA-2 from published human studies are absent).

**FLAG for generation agent:** Human PK data (Tmax, half-life, bioavailability) is absent from the published literature. Duration data (8–12 hours) is derived entirely from Shulgin self-experimentation [Ref 19].

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## History

**1933:** Viktor Bruckner first synthesized 2,4,5-trimethoxyamphetamine as part of chemical research unrelated to psychopharmacology. No psychoactive investigation occurred at this time [Ref 19].

**1962:** Alexander Shulgin synthesized TMA-2 independently and conducted self-experiments to characterize its psychoactive properties.

**1964:** Shulgin published his findings in *Experientia* 20(7):366–367 in a paper titled "Psychotomimetic amphetamines: Methoxy 3,4-dialkoxyamphetamines" [Ref 24]. This was the first report of TMA-2's psychotomimetic properties in humans. The paper described effects as mescaline-like but notably lacking in color effects, less nauseating, and more prone to anxiety and restlessness.

**Context:** Shulgin had published on TMA (3,4,5-trimethoxyamphetamine) in *Nature* in 1961 with Bunnell and Sargent [Ref 25], establishing the trimethoxyamphetamine series in scientific literature. His broader phenethylamine research program in the early 1960s laid the groundwork for the DOx series and eventually PIHKAL.

**1991:** Shulgin and Shulgin published *PiHKAL: A Chemical Love Story* [Ref 19], with TMA-2 as Entry #158. This provided the synthesis protocol and human dose/effect characterization that became the primary reference for subsequent decades. Very limited human use occurred before PiHKAL's publication.

**2003:** The EMCDDA conducted a formal risk assessment of TMA-2 [Ref 17]. Key finding: *no reports of toxic effects or deaths from TMA-2 in humans* within the EU at that time. Nonetheless, the assessment recommended control measures based on structural features and predicted pharmacological activity. EU Council Decision 2003/847/JHA [Ref 16] mandated control measures and criminal sanctions across all EU member states by 27 November 2003.

**Post-2003:** TMA-2 appears periodically in forensic drug monitoring data in Japan [Ref 11] and Europe, typically as a minor component of the designer drug market.

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## Subjective Effects

**Source note:** Published controlled human studies with TMA-2 do not exist. All human effect data derives from Shulgin's self-experimentation reported in PiHKAL [Ref 19] and community reports (Erowid, published anecdotally). The following characterization is based on [Ref 19] and secondary synthesis.

**General character:** TMA-2 is described as a psychedelic stimulant, broadly mescaline-like in structure but distinctly different in phenomenology. Shulgin described effects as similar to mescaline but lacking the characteristic color enhancements and visual richness of that compound [Ref 24, 19].

**Onset and duration:**
- Onset: 20–120 minutes orally [Ref 19, seed data]
- Come-up: 1.5–3 hours
- Peak: 4–6 hours
- Offset: 2–4 hours
- After-effects: 4–24 hours
- Total duration: 8–12 hours [Ref 19]
- These are among the longer durations in the phenethylamine psychedelic class

**Stimulant component:** Prominent physical stimulation; locomotor hyperactivity confirmed in rodent models via 5-HT₂A [Ref 3]. User reports commonly describe significant stimulation, restlessness, and body load.

**Psychedelic component:** Altered headspace, thought connectivity, conceptual thinking, and perceptual changes including tracers and visual drifting. However, full visual hallucinations and color enhancement are reportedly less pronounced than with mescaline [Ref 24].

**Distinctive features reported in PiHKAL [Ref 19]:**
- Highly variable effects between individuals and sessions — described as "unpredictable"
- More prone to anxiety, dysphoria, and restlessness than mescaline
- Nausea and body load common, though Shulgin noted less nausea than 3,4,5-TMA
- Empathy enhancement and emotional amplification reported

**Effects taxonomy from database** (consistent with literature, no contradictions found):
- Sensory: touch enhancement, after-images, tracers, color alteration, symmetrical texture repetition, visual diffraction, color enhancement, visual drifting, visual acuity enhancement
- Temporal: time alteration
- Emotional: emotional enhancement, empathy enhancement
- Cognitive: novelty enhancement, thought connectivity, pattern recognition enhancement, thought acceleration, conceptual thinking, immersion enhancement, memory suppression, analysis enhancement
- Physical: stimulation, spontaneous body sensations, vasoconstriction, motor control enhancement, abnormal heartbeat, nausea, sexual arousal enhancement, wakefulness, pupil dilation

---

## Safety & Toxicity

**LD50:** No published LD50 data for TMA-2 in any species. Toxic dose is unknown [seed data confirmed, no published sources found].

**Human adverse events:** As of the 2003 EMCDDA risk assessment [Ref 17], *no reports of toxic effects of TMA-2 in humans* had been documented within the EU. TMA-2 was not reported to be associated with fatal or non-fatal intoxication.

**No case reports** of serious adverse events, hospitalizations, or deaths attributed to TMA-2 were found in any searched database (PubMed, OpenAlex, web searches).

**Cardiovascular:** Vasoconstriction and abnormal heartbeat are reported effects (database effects taxonomy, consistent with structural class of 5-HT₂A/₂C agonists and with stimulant phenethylamines generally). Hypertension is a theoretical risk.

**CYP2D6 inhibition:** TMA-2 competitively inhibits CYP2D6 (Ki 2.7–19.9 μM at human liver microsomes) [Ref 4]. At recreational doses, significant drug interactions via this mechanism are considered unlikely, but cannot be excluded in slow CYP2D6 metabolizers or with co-administration of narrow therapeutic index CYP2D6 substrates.

**Immunoassay detection:** Standard ELISA immunoassay kits (amphetamine/MDMA panels) cannot reliably detect TMA-2 at concentrations up to 10,000 ng/mL [Ref 8]. Specialized GC/MS (Ewald 2006 [Ref 5]) or LC-MS (Nieddu 2008 [Ref 11]) methods required.

**Psychological risks:** Based on class-level and anecdotal evidence: anxiety, paranoia, and dysphoric experiences are reported more frequently than with mescaline [Ref 19, 24]. No published systematic assessment of psychological risk.

**FLAG:** Toxic dose, LD50, therapeutic index — all unknown. Safety-critical. Any dose data should be flagged as user-report/Shulgin only.

---

## Harm Reduction

**Dosing caution:** TMA-2 is described as highly dose-sensitive and unpredictable across sessions [Ref 19]. Community reports note that identical doses may produce markedly different experiences. Caution is warranted, especially at doses above the common range.

**Stimulant cardiovascular burden:** Given the prominent stimulant component confirmed in rodent models [Ref 3], individuals with cardiovascular disease, hypertension, or arrhythmias are at elevated risk. Vasoconstriction has been reported.

**CYP2D6 interactions:** Though unlikely at typical doses, co-administration of CYP2D6 substrates (codeine, tramadol, tamoxifen, certain antidepressants) may be affected [Ref 4].

**Serotonin syndrome risk with MAOIs:** Malcolm and Thomas (2022 [Ref 15]) outline serotonin toxicity risks for serotonergic psychedelics. While TMA-2 has minimal monoamine transport activity [Ref 6], its potent 5-HT₂A agonism and possible serotonin-releasing activity at higher doses make MAOI co-administration a theoretical serotonin syndrome risk. No published case reports of TMA-2 + MAOI serotonin syndrome found, but the class interaction is well-established for phenethylamine hallucinogens.

**SSRI interaction:** SSRIs may blunt TMA-2's effects via 5-HT₂A downregulation (class inference); however, acute serotonergic potentiation is also a theoretical risk depending on mechanism. Unpredictable interaction profile.

**Testing:** Immunoassay kits will not detect TMA-2 [Ref 8]. Reagent testing (e.g., Marquis, Mecke) may produce characteristic color reactions, but confirmatory GC/MS or LC-MS is required for definitive identification.

**No antidote** or specific reversal agent for TMA-2 toxicity is known. Supportive care follows general principles for serotonergic psychedelic toxicity (benzodiazepines for agitation, cyproheptadine as 5-HT₂A antagonist in severe serotonin syndrome).

---

## Tolerance & Dependence

**Tolerance development:** Described as building "almost immediately after ingestion" (seed data), consistent with the rapid 5-HT₂A receptor desensitization mechanism established for the phenethylamine/DOx class.

**Mechanism:** 5-HT₂A receptor downregulation in the frontal cortex underlies hallucinogen tolerance (Smith et al. 1999 [Ref 21]; de la Fuente Revenga et al. 2022 [Ref 13]). Tolerance to repeated DOI (a close structural analog) develops within 24 hours of a single dose and persists for days [Ref 13]. The mechanism is independent of β-arrestin-2.

**Half-life of tolerance:** ~3 days (seed data, consistent with published data showing 5-HT₂A receptor density recovery over several days in rodent models [Ref 21]).

**Full reset:** ~7 days (seed data; consistent with de la Fuente Revenga et al. 2022 [Ref 13] data on DOI).

**Cross-tolerance:** Cross-tolerance with other serotonergic hallucinogens (LSD, psilocybin, mescaline, other DOx compounds) is established at the class level [Ref 13]. Mutual cross-tolerance is expected for all classical psychedelics acting through 5-HT₂A.

**Dependence liability:** Not habit-forming (seed data confirmed; no published evidence of physical dependence or compulsive use patterns for TMA-2 or the DOx class generally). Psychological craving is not characteristic of serotonergic hallucinogens.

---

## Interactions

**MAO inhibitors (MAOIs):**
- Serotonin syndrome risk is a theoretical concern based on class mechanisms [Ref 15]
- TMA-2 has minimal monoamine transport activity [Ref 6], making direct serotonin release amplification less likely than with MDMA or amphetamine
- However, 5-HT₂A potentiation and any residual serotonin-releasing activity could synergize with MAO inhibition
- Combination is flagged as potentially dangerous by harm reduction community; no published human case reports found

**SSRIs/SNRIs:**
- May attenuate psychedelic effects via 5-HT₂A downregulation (class effect, established for LSD [Ref 15])
- Acute serotonergic potentiation also theoretically possible — interaction is bidirectional and unpredictable

**CYP2D6 substrates:**
- TMA-2 is a competitive CYP2D6 inhibitor [Ref 4]; clinically relevant interaction unlikely at typical doses but possible in slow metabolizers or with narrow therapeutic index drugs (codeine, tramadol, some antidepressants)

**Lithium:**
- No published data specific to TMA-2; lithium + classical psychedelics is generally flagged as risk for seizures/unpredictable potentiation at the class level

**Other serotonergic psychedelics:**
- Cross-tolerance expected [Ref 13]; combined use would produce attenuated effects

**FLAG:** All interaction data for TMA-2 specifically is derived from class-level inference or structural analogy. No published drug interaction studies specific to TMA-2 were found.

---

## Legal Status

**United States:**
TMA-2 is regulated as a **Schedule I** controlled substance [Ref 23]. It is not explicitly named in the DEA Orange Book as a standalone entry; it is covered either through positional isomer provisions under 3,4,5-trimethoxyamphetamine (TMA; DEA Code 7390, Schedule I) or through Federal Analog Act provisions. Cayman Chemical (a US-regulated research chemical supplier) explicitly describes TMA-2 as "regulated as a Schedule I compound in the United States" [Ref 23].

**Canada:**
TMA-2 (2,4,5-trimethoxyamphetamine) is **explicitly named** in Schedule I of the *Controlled Drugs and Substances Act*, Item 19, subitem (7): "2,4,5-trimethoxyamphetamine (2,4,5-trimethoxy-α-methylbenzeneethanamine)" [Ref 18].

**European Union:**
**Council Decision 2003/847/JHA** of 27 November 2003 [Ref 16] required all EU member states to subject TMA-2 to control measures and criminal sanctions. This followed the EMCDDA formal risk assessment submitted 4 April 2003 [Ref 17]. Member states were required to implement control measures within 3 months and notify the General Secretariat within 6 months.

**United Kingdom:**
TMA-2 is a **Class A** controlled substance under the *Misuse of Drugs Act 1971*. Control is conferred via the Act's generic phenethylamine clause (Schedule 2, Part I, Section 1(c)), which covers substances "structurally derived from phenethylamine" with ring substitutions including "alkyl, alkoxy, alkylenedioxy or halide substituents." TMA-2's three methoxy ring substituents place it clearly within this definition.

**Australia:**
TMA-2 is controlled via drug analogue provisions under the Australian *Criminal Code Act 1995*. It is not believed to be individually named in current scheduling, but as a structural analogue of listed amphetamine-class controlled drugs, it would be subject to Schedule 1 border controlled drug provisions and state-level serious drug offence provisions.

**International:**
TMA-2's control under EU Council Decision 2003/847/JHA aligns it with obligations under the 1971 UN Convention on Psychotropic Substances. It is not itself listed in the UN Convention schedules.

---

## Clinical Trials

**No clinical trials** for TMA-2 were found on ClinicalTrials.gov or in published literature. The 2003 EMCDDA report found no research trials and no therapeutic investigations at that time, and none have been registered since.

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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 Safety Flags

1. **⚠️ Toxic dose unknown.** No LD50 or NOAEL data exists for TMA-2 in any species. No published overdose data in humans. The entire safety profile relies on (a) class-level inference from structurally similar 5-HT₂A agonists and (b) absence of adverse event reports through 2003 (EMCDDA).

2. **⚠️ Dose/duration data not verified against controlled human study.** All dosing (threshold 5 mg through heavy 60+ mg) and duration (8–12 hours total) information derives exclusively from Shulgin's self-experimentation and PIHKAL [Ref 19], supplemented by community reports. No pharmacokinetic data from human subjects exists.

3. **⚠️ No specific interaction studies for TMA-2.** MAOI, SSRI, and other interaction data is entirely class-level inference from serotonergic hallucinogen pharmacology. No TMA-2-specific studies exist.

4. **⚠️ Ki discrepancy.** Two values reported for 5-HT₂A affinity: ~1,300 nM (Kolaczynska 2019, in labeled binding assay) and ~1,650 nM (alternative 5-HT₂ radioligand source). Discrepancy likely due to assay methodology differences. Functional EC₅₀ is 190 nM (potent) — this is the more pharmacologically relevant value for understanding in vivo activity.

### Data Gaps

5. **Human pharmacokinetics absent.** Tmax, bioavailability, plasma half-life, volume of distribution — none published for TMA-2. Rat PK data exists via an LC-MS method (Nieddu 2008 series) but human extrapolation is not validated.

6. **Stereochemistry not characterized.** TMA-2 is commercially available and typically used as the racemate. No enantiomer-specific pharmacological data has been published. The (R)- and (S)-enantiomers likely differ in 5-HT₂A affinity (as established for other alpha-methyl phenethylamines) but no published data confirms this for TMA-2 specifically.

7. **No direct binding affinity data at alpha-adrenergic or D₂ receptors specific to TMA-2.** The Kolaczynska 2019 paper measured the whole series but specific TMA-2 (DO-OCH₃) values at these receptors were not extractable from available abstracts.

8. **US scheduling status technically ambiguous.** TMA-2 is not individually named in the DEA Orange Book. Control via positional isomer/analog provisions is highly probable but not confirmed by a specific DEA scheduling action.

9. **Bruckner 1933 synthesis.** The initial synthesis by Viktor Bruckner is widely cited in secondary literature but no primary source was accessible. Cannot confirm by API verification.

10. **No animal toxicology data found.** No published rodent LD₅₀ or LOAEL studies for TMA-2.

### Structural Analogy Notes

11. The following data points rely primarily on structural analogy with the DOx class (DOM, DOI, DOB) rather than TMA-2-specific studies:
- MAOI interaction severity
- Serotonin syndrome risk with SSRIs
- Abuse/dependence liability characterization
- Cross-tolerance with psilocybin and LSD
- 5-HT₂B cardiotoxicity risk (no data at all for TMA-2)

12. **5-HT₂B risk not assessed.** No published 5-HT₂B binding or activation data for TMA-2. Some 5-HT₂A agonists carry 5-HT₂B-mediated cardiac valve risk (fenfluramine) or vasoconstrictive risk (DragonFLY compounds). TMA-2's risk profile at 5-HT₂B is completely unknown.