TMA-6

# Research Output: TMA-6

---

## Chemical Identity

**Verified from PubChem (CID 31015) [Ref 1 — database lookup]:**

| Property | Value |
|---|---|
| Preferred IUPAC name | 1-(2,4,6-trimethoxyphenyl)propan-2-amine |
| Molecular formula | C₁₂H₁₉NO₃ |
| Molecular weight | 225.28 g/mol |
| InChIKey | DDGNOUVDFKXADP-UHFFFAOYSA-N |
| PubChem CID | 31015 |
| CAS (free base) | 15402-79-6 |
| CAS (hydrochloride) | 23815-74-9 |
| SMILES | COc1cc(OC)cc(c1CC(N)C)OC |

**Physical properties:**
- Melting point: 207–208°C (hydrochloride salt) [Ref 17]
- Compound is a racemate; both enantiomers are present in the free base form

**Brief seed data cross-check:**
- Molecular formula (C₁₂H₁₉NO₃), molecular weight (225.28), and IUPAC name all confirmed correct against PubChem.
- SMILES was blank in the brief — now confirmed as: `COc1cc(OC)cc(c1CC(N)C)OC`
- InChIKey was blank in the brief — confirmed as: `DDGNOUVDFKXADP-UHFFFAOYSA-N`
- PubChem CID was blank in the brief — confirmed as: **31015**

---

## Pharmacology

### Primary Mechanism: 5-HT₂A Receptor Agonism

TMA-6 is reported to be a potent, full agonist at the serotonin 5-HT₂A receptor, with an EC₅₀ of 29.2 nM and a maximal efficacy (Emax) of 107% relative to serotonin. It shows no appreciable affinity at the 5-HT₁A receptor (Ki >10,000 nM) or dopamine D₂ receptor (Ki >10,000 nM) [Ref 22 — web-retrieved; see Gaps & Flags for sourcing note].

**⚠️ FLAG — Unverified primary source:** The EC₅₀ of 29.2 nM and Emax of 107% at 5-HT₂A are cited by secondary sources (Wikipedia) and attributed to the Luethi/Liechti group at University Hospital Basel. However, the specific primary publication containing this TMA-6 data was not locatable in PubMed, OpenAlex, or Frontiers in Pharmacology during this research session. The Kolaczynska et al. 2019 [Ref 19] and 2021 [Ref 20] papers from the same group studied related mescaline derivatives and mentioned TMA-6 only in historical context. **This value must be flagged for editorial verification before publication.**

**Comparison with TMA-2 (2,4,5-isomer):** The structurally related TMA-2 has been directly measured at 5-HT₂A: Ki = 1,300 ± 700 nM, EC₅₀ = 190 ± 90 nM, Emax = 84% (Kolaczynska et al. 2019 [Ref 19]). If the reported TMA-6 EC₅₀ of 29.2 nM is accurate, it would indicate substantially higher 5-HT₂A potency than TMA-2 — plausible given that the 2,4,6-substitution pattern is distinct from 2,4,5, and the steric and electronic effects of ortho methoxy groups may enhance receptor interaction.

**Animal model data:** In the landmark Shulgin, Sargent & Naranjo (1969) Nature paper [Ref 12] examining structure-activity relationships across one-ring psychotomimetics, TMA-6 had an ED₅₀ of 46.0 μmol/kg in animal assays, placing it among the more potent trimethoxyamphetamine isomers studied in that series. The paper was the first systematic comparison across TMA positional isomers.

### MAO-A Inhibition

TMA-6 is reported as a potent monoamine oxidase A (MAO-A) inhibitor with an IC₅₀ of approximately 400 nM [Ref 22]. This is consistent with the broader finding that methoxylated amphetamine derivatives — including the TMA series — possess MAO-A inhibitory properties [Ref 4 — Scorza et al. 1997; Ref 5 — Deeb & Clare 2008; Ref 16 — Gallardo-Godoy et al. 2005]. The Scorza et al. 1997 paper [Ref 4] established that submicromolar MAO-A IC₅₀ values are achievable with methoxylated amphetamines, with para-position electron-donating groups increasing activity; steric bulk adjacent to the para-substituent attenuates activity.

**⚠️ FLAG — Unverified primary source:** As with the 5-HT₂A EC₅₀, the MAO-A IC₅₀ of 400 nM for TMA-6 specifically is cited by secondary sources (Wikipedia) and the primary study has not been independently confirmed during this research. The Deeb & Clare 2008 QSAR paper [Ref 5] studied phenylisopropylamines as a class, which may include TMA-6. **Requires editorial verification.**

The MAO-A inhibitory activity may contribute to TMA-6's prolonged duration of action (12–16 hours) by reducing serotonin degradation and elevating synaptic 5-HT levels, amplifying 5-HT₂A stimulation.

### ❌ Critical Discrepancy: Not a Monoamine Releasing Agent

**The seed data classifies TMA-6 under "Monoamine releasing agent" — this appears to be incorrect.**

Multiple commercial pharmacological data sources (Cayman Chemical [Ref 18]; Bertin Bioreagent) state explicitly that TMA-6 "has no effect on the release or re-uptake of monoamines (dopamine, serotonin, and norepinephrine)." In the web-based synthesis of data attributed to the Luethi/Liechti group, TMA-6 is described as "inactive as a monoamine reuptake inhibitor and releasing agent in rat brain synaptosomes (IC₅₀ and EC₅₀ = >100,000 nM, respectively)." This is consistent with TMA-6's structural profile: the three ortho/para methoxy groups and the absence of a 4-position halogeno or alkyl substituent characteristic of the DOM/DOx series mean TMA-6 lacks the structural requirements for potent transporter interaction. Its primary psychedelic mechanism is 5-HT₂A receptor agonism, not monoamine release.

**⚠️ FLAG for editorial correction:** The pharmacological class "Monoamine releasing agent" should be removed from TMA-6's profile. The correct classification is: serotonin 5-HT₂A receptor agonist, MAO-A inhibitor.

### Structure-Activity Context

Within the phenethylamine/amphetamine psychedelic class, the 2,4,6-substitution pattern is unique. The 2,4,5-isomer (TMA-2) was identified by Shulgin as the most potent of the TMA isomers in humans [Ref 12]. The 2,4,6 arrangement places methoxy groups symmetrically at the 2, 4, and 6 positions ("phloroglucinol" pattern), which differs from the asymmetric 3,4,5-arrangement found in mescaline. Nichols' SAR review [Ref 2] provides the pharmacological framework for phenethylamine psychedelics, emphasizing that 5-HT₂A agonism as a full agonist is the critical requirement for hallucinogenic activity — consistent with TMA-6's reported Emax of 107%.

The alpha-methyl group (the amphetamine side chain) significantly increases efficacy relative to the phenethylamine counterpart at 5-HT₂A receptors, as demonstrated by Moya et al. 2007 [Ref 14], who showed phenylisopropylamines are more efficacious than their phenethylamine counterparts at 5-HT₂A.

The Halberstadt et al. 2019 head twitch response (HTR) study [Ref 1] provides comparative behavioral potency data for the mescaline analog class. HTR potency in mice closely parallels human hallucinogenic potency, making this assay a relevant tool for TMA-6 SAR work (though TMA-6 was not directly tested in that paper).

### Pharmacokinetics

No published human pharmacokinetic data (Cmax, Tmax, Vd, elimination half-life) specific to TMA-6 exists in the published literature reviewed. Inference from structural class:
- Oral bioavailability: expected to be moderate-to-high based on lipophilicity and amphetamine backbone
- Onset: 30–90 minutes (reported in PsychonautWiki [Ref 9]; consistent with oral amphetamine pharmacokinetics)
- The long total duration (10–16 hours) may reflect a combination of: moderate 5-HT₂A receptor residency, MAO-A inhibition slowing serotonin degradation, and slow hepatic clearance

**Metabolism:** No specific metabolic data for TMA-6 has been published. As a substituted amphetamine, CYP2D6 and MAO-A are the most likely primary metabolic enzymes. The three methoxy groups are candidates for O-demethylation via CYP3A4/CYP2D6, producing catechol metabolites. The methoxylated aromatic ring may also undergo aromatic hydroxylation. **No specific CYP enzyme data exists for TMA-6.** The MAO-A inhibitory property of TMA-6 itself may complicate its own metabolism by MAO.

### Stereochemistry

TMA-6 possesses a chiral center at the alpha-carbon. Pharmacologically active phenylisopropylamine psychedelics in the DOx and TMA series are generally more active as the (R)-enantiomer [Ref 2 — Nichols 2018]. No specific enantioselectivity studies have been published for TMA-6. The free base form available commercially is the racemate (CAS 15402-79-6).

---

## History

**Discovery and first synthesis:**
The compound was first synthesized in the early 1950s as part of systematic exploration of mescaline analogs. The earliest documentation of synthesis is from 1954, predating Shulgin's work.

**Shulgin and psychedelic effects (1964):**
Alexander Shulgin independently discovered TMA-6's psychedelic properties in 1964 through self-experimentation. His systematic human pharmacological studies were conducted with Thornton Sargent and Claudio Naranjo, resulting in the landmark 1969 Nature paper "Structure-Activity Relationships of One-Ring Psychotomimetics" [Ref 12]. This paper examined multiple TMA isomers and established the first systematic human dose-response data for this chemical class, reporting TMA-6's ED₅₀ as 46.0 μmol/kg.

**PiHKAL documentation (1991):**
Shulgin documented TMA-6 as entry #162 in PiHKAL (Phenethylamines I Have Known and Loved, 1991) [Ref 8, Ref 21]. He described TMA-6 as "one of the most rewarding and pleasurable of the methoxylated amphetamines," positioning it alongside TMA-2 as a key compound in the series. He also proposed TMA-6 as a template for generating a "psi-series" of analogues (parallel to the 2C-series off TMA-2). He deliberately described synthesis from phloroglucinol (naturally occurring in redwoods, tea, citrus, apples) as a precursor, noting this ensured synthetic accessibility regardless of regulatory changes.

**Human potency:**
Shulgin estimated TMA-6 to have approximately 8–10× the potency of mescaline in humans. For reference, mescaline's typical oral threshold is ~100 mg (0.36 mmol/kg for a 70-kg person); TMA-6's active range begins at 25 mg (~0.11 mmol/kg), consistent with this potency estimate.

**Research chemical market:**
TMA-6 has appeared on the illicit and grey-market research chemical market, though to a limited extent compared to more popular members such as TMA-2. It was detected in forensic samples, prompting the development of a specific LC-MS assay (Nieddu et al. 2008 [Ref 10]) for TMA, TMA-2, and TMA-6 in urine. Trimethoxyamphetamine was also detected as an adulterant in herbal weight-loss products in Iran [confirmed by OpenAlex cross-reference].

---

## Subjective Effects

Published subjective effect data derives primarily from Shulgin's PiHKAL [Ref 8, Ref 21] and the 1969 Nature paper [Ref 12]. There are no controlled human clinical studies with standardized psychometric instruments.

**From PiHKAL (#162) [Ref 8, Ref 21]:**
- At lower doses: mental clarity, smooth thinking, mild body awareness
- At moderate-to-higher doses: body tingling, intoxication-like euphoria, visual phenomena described as "very, very active, visual, colorful" with "great humor," steady physical control
- One participant noted "a strange mixture of plateaus, exuberance, and strong negative feelings" with psychological insights
- Shulgin's overall characterization: "one of the most rewarding and pleasurable of the methoxylated amphetamines"

**Dose (PiHKAL):** 25–50 mg orally
**Duration (PiHKAL):** 12–16 hours total

**Seed data dosage cross-check:**
The seed data lists: Threshold 5 mg, Light 10–20 mg, Common 20–35 mg, Strong 35–50 mg, Heavy 50+ mg.
Shulgin's PiHKAL dose entry is simply "25–50 mg" — this suggests Shulgin's active range begins where the seed data's "common" range does. The seed data threshold of 5 mg and light range of 10–20 mg do not appear in the primary Shulgin literature. They are likely derived from community self-reports and may represent dose sensitivity in some individuals or potentially impure samples. **Flag: Seed data threshold/light dose not confirmed by primary literature.** The PsychonautWiki dose range [Ref 9] corroborates the seed data community values but these remain unverifiable against controlled studies.

**Effects taxonomy alignment (from the brief):**
The reported effects profile (touch enhancement, tracers, color alteration, visual drifting, empathy enhancement, emotional enhancement, stimulation, time alteration) is broadly consistent with 5-HT₂A agonism and the known phenethylamine psychedelic profile. The relatively high stimulation component is consistent with the amphetamine backbone. The long aftereffects (6–18 hours) may reflect MAO-A inhibition. No controlled study has mapped specific effect domains for TMA-6.

---

## Safety & Toxicity

**LD₅₀ / toxic dose:**
No published LD₅₀ data for TMA-6 in any species was found. The seed data correctly states "toxic dose is unknown."

**Preclinical toxicity:**
Hardman, Haavik & Seevers (1973) [Ref 3] studied mescaline and seven analogs across five species of laboratory animals. This paper likely includes TMA isomers given Shulgin's 1969 publication, but the abstract does not specify which seven analogs were studied. The paper is a primary animal toxicity data source for this chemical class.

**Adverse effects from human self-reports (PiHKAL [Ref 8, Ref 21]):**
- At higher doses: "strong negative feelings," potential psychological instability
- The original TMA (3,4,5-isomer) was associated with anger, hostility, and megalomaniac euphoria in early Shulgin studies (1961 Nature paper), particularly at high doses — a response not observed with mescaline. The extent to which TMA-6 shares this risk profile is unknown.
- No case reports of overdose with TMA-6 were found in the published medical literature.

**Cardiovascular:**
As an amphetamine-backbone compound with 5-HT₂A agonist activity, TMA-6 is expected to produce sympathomimetic cardiovascular effects (tachycardia, hypertension, vasoconstriction) consistent with both the amphetamine backbone and 5-HT₂A stimulation. The seed data lists "Vasoconstriction," "Abnormal heartbeat," and "Wakefulness" as body effects, consistent with this expectation. No published human cardiovascular data exists for TMA-6 specifically.

**Serotonin syndrome risk:**
The MAO-A inhibitory activity (IC₅₀ ~400 nM, if confirmed) represents a clinically significant risk. Serotonin syndrome could theoretically be precipitated when TMA-6 is combined with serotonergic agents (SSRIs, SNRIs, other MAO inhibitors, tryptamines, other 5-HT₂A agonists). **Safety-critical: see Interactions section.**

**Psychological risks:**
Like all classical psychedelic phenethylamines, TMA-6 carries risk of acute anxiety, paranoia, challenging psychological experiences ("bad trips"), and—at very high doses or in vulnerable populations—psychosis. No peer-reviewed literature on TMA-6-specific psychological risks exists.

---

## Harm Reduction

No published harm reduction protocols specific to TMA-6 exist. The following are derived by class-level inference from published psychedelic harm reduction literature [Ref 2 — Nichols 2018; Ref 7 — Monte et al. 1997]:

- **Set and setting:** Critical for all 5-HT₂A psychedelics; Shulgin's PiHKAL reports emphasize psychological stability of participants [Ref 8]
- **Dosing:** Start at low end of the range (25 mg per Shulgin); titration is critical given the long duration
- **Duration:** Users must be prepared for a 12–16 hour experience with 6–18 hours of aftereffects; no obligations should be scheduled
- **Drug interactions (critical):** Avoid MAO inhibitors (risk of serotonin crisis); avoid other serotonergic drugs; avoid stimulants that may synergize cardiovascular effects
- **Testing:** Ehrlich reagent will not react (no indole); Marquis reagent may give a weak orange/brown reaction for amphetamine skeleton. Froehde may help identify methoxy pattern. No specific reagent test data for TMA-6 was found; confirmatory GC-MS or LC-MS/MS is recommended [Ref 10, Ref 11]

---

## Tolerance & Dependence

**Tolerance:**
The seed data states tolerance builds "almost immediately after ingestion," with a half-life of 3 days and full reset at 7 days. These values are consistent with the established cross-tolerance profile of 5-HT₂A agonist psychedelics as a class (5-HT₂A receptor downregulation). No TMA-6-specific tolerance studies exist; the values are appropriately inferred from the class. **Flag as class-inference, not substance-specific data.**

**Cross-tolerance:**
Listed as cross-tolerant with "psychedelic" class broadly. Published literature on 5-HT₂A psychedelics confirms cross-tolerance within the class (LSD, psilocybin, mescaline, DOx compounds all share 5-HT₂A downregulation mechanism) [Ref 2].

**Dependence:**
Seed data states "not habit-forming." Classical 5-HT₂A psychedelics generally lack reinforcing properties and dependence liability. No TMA-6-specific dependence studies exist, but class-level inference supports this characterization.

---

## Interactions

**Critical interaction concern — MAO-A inhibition:**
If TMA-6's MAO-A IC₅₀ of ~400 nM is confirmed, the compound would inhibit the primary serotonin-degrading enzyme with clinically relevant potency. This creates a significant serotonin syndrome risk when combined with:
- SSRIs/SNRIs (serotonin reuptake inhibitors)
- MAO-B inhibitors (selegiline, rasagiline)
- Other irreversible or reversible MAOI antidepressants
- Tryptamine psychedelics (DMT, psilocin, 5-MeO-DMT)
- Other 5-HT₂A agonists

**Published drug interaction data** for TMA-6 specifically: none found. Class-level guidance is provided by Halman et al. 2023 [systemic review of psychedelic drug-drug interactions — found in OpenAlex].

**Stimulant interactions:**
The amphetamine backbone suggests potential additive cardiovascular toxicity with other stimulants (amphetamines, cocaine, MDMA).

**Contraindications (class-level inference, no TMA-6-specific data):**
- Concurrent MAO inhibitor use (absolute)
- Personal or family history of psychosis or schizophrenia
- Cardiac arrhythmia or uncontrolled hypertension
- Pregnancy/breastfeeding (no data)

---

## Legal Status

| Jurisdiction | Status | Notes |
|---|---|---|
| United States | Schedule I | Listed as positional isomer of 3,4,5-trimethoxyamphetamine (TMA, DEA code 7390). May also fall under Federal Analogue Act as structurally similar to mescaline (Schedule I). |
| United Kingdom | Illegal | Covered under the Psychoactive Substances Act 2016 (blanket ban on psychoactive substances). Also arguably covered under the Misuse of Drugs Act 1971 generic phenethylamine provisions. |
| Germany | Controlled | NpSG (New Psychoactive Substances Act) since November 26, 2016. Production, import, and sale for human use is punishable. |
| Sweden | Schedule I narcotic | Listed on Swedish narcotic schedules. |
| Brazil | Controlled | F2 class of prohibited psychotropics. |
| Japan | Controlled | Scheduled under drug control legislation. |
| Italy | Controlled | Listed on Italian drug schedules. |
| Finland | Controlled | Banned December 2014. |
| Australia | Not confirmed | Status not independently verified during this research session. |
| Canada | Not confirmed | Status not independently verified during this research session. |

**Note on US status:** The DEA orange book groups TMA and its positional isomers under code 7390. Whether TMA-6 (2,4,6-isomer) is explicitly named or covered implicitly requires editorial verification against the current DEA orange book. The Federal Analogue Act also provides a basis for prosecution if TMA-6 is intended for human consumption, given structural similarity to mescaline.

---

## Clinical Trials

No clinical trials for TMA-6 (2,4,6-trimethoxyamphetamine) were found on ClinicalTrials.gov. The compound has not entered formal clinical development.

---

## Community Feedback Analysis

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

---

## Gaps & Flags

### Safety-Critical Flags

1. **⚠️ PRIMARY SOURCE UNVERIFIED — 5-HT₂A EC₅₀ 29.2 nM:** This value is reported by Wikipedia and attributed to the Luethi/Liechti group, but the specific primary publication was not located during this research. The Kolaczynska 2019 [Ref 19] and 2021 [Ref 20] papers from that group do not directly test TMA-6. Editorial review should identify this source before publication, or the value should be presented with explicit uncertainty.

2. **⚠️ PRIMARY SOURCE UNVERIFIED — MAO-A IC₅₀ 400 nM:** Same situation as EC₅₀ value. The Scorza 1997 [Ref 4], Deeb/Clare 2008 [Ref 5], and Gallardo-Godoy 2005 [Ref 16] papers provide SAR context for MAO-A inhibition in this compound class, but none directly report a TMA-6 IC₅₀ of 400 nM in retrievable abstracts.

3. **⚠️ DOSE DATA — Threshold/light dose not confirmed by primary literature:** Shulgin's PiHKAL entry reports dose as simply "25–50 mg" with no sub-threshold or light range. The seed data threshold of 5 mg and light range of 10–20 mg are community-derived. Given that TMA-6 has MAO-A inhibitory activity, unusual dose sensitivity in some individuals is pharmacologically plausible, but this has not been studied.

### Data Corrections

4. **❌ INCORRECT CLASSIFICATION — "Monoamine releasing agent":** Multiple data sources confirm TMA-6 is NOT a monoamine releasing agent (EC₅₀ >100,000 nM at monoamine transporters). This pharmacological class should be removed. Correct classification: 5-HT₂A receptor agonist (full agonist), MAO-A inhibitor.

### Data Gaps

5. **No human pharmacokinetic data:** Tmax, Cmax, bioavailability, elimination half-life, and metabolic pathway (CYP enzymes involved) are all unknown for TMA-6 specifically.

6. **No LD₅₀ or toxicity data:** The toxic dose in any species is unknown. Class-level animal toxicity data (Hardman et al. 1973 [Ref 3]) may include TMA-6 but abstract did not specify which isomers were included.

7. **No case reports:** No published case reports of TMA-6 overdose, adverse events, or clinical presentations in emergency settings were found.

8. **Metabolism unknown:** No CYP enzyme or metabolite data published for TMA-6. Metabolic pathway is inferred by structural class only.

9. **Stereochemistry unstudied:** Enantioselectivity at 5-HT₂A not determined for TMA-6. Active enantiomer is presumed to be (R) by analogy with other phenylisopropylamine psychedelics [Ref 2], but no study confirmed this.

10. **Legal status gaps:** Australia, Canada, and several EU countries not confirmed during this research session.

11. **Structural analog inference for most pharmacological data:** All pharmacokinetic, metabolism, and most receptor data is inferred from structural class (trimethoxyphenethylamine/amphetamine psychedelics), not measured directly for TMA-6. This applies to: CYP enzymes, serotonin syndrome risk parameters, and cardiovascular toxicity profile.