MDA

# Research Output: MDA (3,4-Methylenedioxyamphetamine)

**PSX ID:** PSX-0235  
**Provenance ID:** 9487fa1d-617f-4834-86ad-b703c9efc318  
**Research Date:** 2026-04-24

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## Chemical Identity

**PubChem CID:** 1614 — confirmed via API (get_pubchem_compound) [Ref 25 via Wikidoc; CID confirmed by PubChem API]

**IUPAC Name:** 1-(1,3-benzodioxol-5-yl)propan-2-amine — confirmed matches brief [PubChem CID 1614]

**Molecular Formula:** C₁₀H₁₃NO₂ — confirmed [PubChem CID 1614]

**Molecular Weight:** 179.22 g/mol — confirmed [PubChem CID 1614]

**InChIKey:** NGBBVGZWCFBOGO-UHFFFAOYSA-N — confirmed [PubChem CID 1614]

**SMILES:** CC(CC1=CC2=C(C=C1)OCO2)N — retrieved from Wikidoc [Ref 25]. ⚠️ FLAG: SMILES not returned by PubChem API in this session. Brief had no SMILES; this value is from secondary web source and should be cross-verified against PubChem's canonical SMILES.

**CAS Number:** Not confirmed from API sources. Commonly cited as 4764-17-8 (racemate) in secondary literature. ⚠️ FLAG: Requires primary source confirmation.

**Systematic name:** 1-(1,3-benzodioxol-5-yl)propan-2-amine — confirmed; matches brief.

**Stereochemistry:** MDA has one chiral center at the alpha carbon. The racemate (equal mixture of R and S enantiomers) is the form typically encountered recreationally and in most published studies. No definitive published human studies comparing R- vs S-MDA head-to-head. In drug discrimination studies, the S-(+)-isomer shows greater stimulant potency (Oberlender & Nichols 1988 [Ref 14]). The structural relationship to MDMA suggests S-MDA is the more amphetamine-like enantiomer and R-MDA may be more entactogenic, but this is extrapolated from MDMA data. ⚠️ FLAG: No substance-specific enantiomer comparison studies in humans confirmed.

**Brief seed data cross-check:** PubChem CID was blank in the brief — now confirmed as 1614. Molecular formula and weight were blank — now confirmed. SMILES and InChIKey were blank — now confirmed (SMILES from secondary source, InChIKey from PubChem).

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## Pharmacology

### Mechanism of Action

MDA is a triple monoamine releasing agent and reuptake inhibitor with greater selectivity for the norepinephrine transporter (NET) and serotonin transporter (SERT) relative to the dopamine transporter (DAT). Kolaczynska et al. (2022 [Ref 1]) found that MDA inhibited NET with the greatest potency and preferentially inhibited 5-HT over dopamine uptake. MDA mediates efflux through at least one monoamine transporter, functioning as a substrate-type releaser at SERT, DAT, and NET. This mechanism drives serotonin, dopamine, and norepinephrine release into the synapse, producing the characteristic stimulant and entactogenic effects.

Compared to MDMA, O'Loinsigh et al. (2001 [Ref 6]) found that MDA, MDMA, and MDEA were equipotent at inducing ³H-5-HT release from frontal cortex/hippocampal synaptosomes. However, the potency order for dopamine release from striatal synaptosomes was **MDA > MDMA > MDEA = MDBA**, indicating MDA has greater dopaminergic releasing potency than MDMA. This higher dopamine-releasing activity likely underlies MDA's greater stimulant profile relative to MDMA (confirmed in humans by Straumann et al. 2026 [Ref 11]).

### 5-HT2A Agonism and Psychedelic Properties

MDA binds to and activates the 5-HT₂A receptor (Ki ≤ 10 µM in radioligand binding; partial or full agonist in activation assays) (Kolaczynska et al. 2022 [Ref 1]). This 5-HT₂A activity distinguishes MDA pharmacologically from MDMA and accounts for its psychedelic and hallucinogenic properties at recreational doses. Pierce and Peroutka (1988 [Ref 3]) confirmed that MDA displayed highest affinity (~1 µM) for the "DOB binding site" (now understood as the 5-HT₂A recognition site labeled by [⁷⁷Br]R(-)DOB) in human cortex membranes. MDA also showed moderate affinity (4–5 µM) for 5-HT₁A, 5-HT₁D, and alpha-2 adrenergic sites in human cortex [Ref 3].

Drug discrimination studies confirm the dual psychedelic/stimulant character: Teitler et al. (1990 [Ref 2]) found that MDA is both "LSD-like" and "amphetamine-like" in animal drug discrimination paradigms, while MDMA is primarily "amphetamine-like" at typical doses. Oberlender and Nichols (1988 [Ref 14]) showed that the MDMA cue generalized completely to MDA, confirming shared entactogen-class discriminative properties.

### Additional Receptor Interactions

- **5-HT₂C receptor:** MDA binds (Ki ≤ 10 µM) and activates as partial or full agonist (Kolaczynska 2022 [Ref 1])
- **TAAR1:** MDA interacts in the micromolar range; interaction weaker than the non-methylenedioxy amphetamines (Kolaczynska 2022 [Ref 1])
- **Alpha-1 adrenoceptors:** MDA is most potent among MDxx compounds at alpha-1A and alpha-1D receptors (Bexis & Docherty 2006 [Ref 16]), contributing to its stronger pressor effects vs MDMA
- **Alpha-2 adrenoceptors:** Moderate affinity (Pierce & Peroutka 1988 [Ref 3])
- **GABA-A receptor:** MDA modulates human GABA-A receptors (α₁β₂γ₂) in a bidirectional, occupancy-dependent manner — inhibition at low receptor occupancy, potentiation at high occupancy. This mode of action differs from MDMA (Hondebrink et al. 2011 [Ref 4]).

### Pharmacokinetics

**Half-life (plasma, geometric mean):** 8.4 hours — confirmed from human RCT (Straumann et al. 2026 [Ref 11], n=23, 92 mg oral dose). For comparison, MDMA half-life was 7.3 hours in the same study.

**Oral bioavailability:** Not directly measured in published studies for MDA specifically. Expected to be similar to MDMA given structural similarity. ⚠️ FLAG: No published bioavailability data specific to MDA.

**Tmax / onset:** Straumann 2026 [Ref 11] reported time to onset of MDA effects (oral) = 0.7 ± 0.1 hours (~42 minutes) and time to maximal effect = 2.0 ± 0.1 hours. Lys-MDA (slow-release prodrug) showed onset 1.1 ± 0.2 hours and maximal effect 3.0 ± 0.4 hours. Baggott 2010 [Ref 12] used 98 mg/70 kg oral MDA.

**Metabolism:** Primary metabolic pathways (Maurer 2000 [Ref 7]; de la Torre 2004 [Ref 23]):
1. **O-demethylenation** (primary): Catalyzed by CYP2D6 (main) and CYP3A4; produces alpha-methyldopamine (alpha-MeDA), a catechol. This catechol undergoes further COMT-mediated methylation to 4-hydroxy-3-methoxy-amphetamine (HMA) and conjugation with glucuronide/sulfate.
2. **N-dealkylation/deamination pathway**: Produces benzoic acid derivatives conjugated with glycine.

**CYP2D6:** Primary enzyme for MDA metabolism. Poor CYP2D6 metabolizers and those on CYP2D6 inhibitors (e.g., fluoxetine, paroxetine) will have higher MDA plasma concentrations and increased toxicity risk (Van et al. 2006 [Ref 29]). Like MDMA, MDA likely auto-inhibits its own metabolism through CYP2D6 mechanism-based inactivation.

**Key metabolite toxicity:** Alpha-methyldopamine (alpha-MeDA), the primary O-demethylenation product, is itself neurotoxic. It oxidizes to ortho-quinone, which conjugates with glutathione to form thioether adducts that are transported to the brain and cause serotonergic neuronal death (Monks et al. 2004 [Ref 5]; Capela et al. 2007 [Ref 20]).

**MDA as MDMA metabolite:** MDA is produced by N-demethylation of MDMA in humans at a MDA:MDMA plasma ratio of approximately 3–5:100 (Mechan et al. 2006 [Ref 26]; Pizarro et al. 2004 [Ref 9]). This means MDMA users are also exposed to MDA. Enantioselective analysis shows (R)-MDA predominates when MDA is a metabolite of (R,S)-MDMA.

---

## History

### Synthesis and Discovery

MDA was first synthesized in **1910** by German chemists **G. Mannich and W. Jacobson** [Ref 25]. This predates the better-known Merck MDMA synthesis by several years.

**1939:** Pharmacological properties studied in animals, with noted sympathomimetic effects, CNS stimulatory activity, and convulsions at high doses [Ref 25].

**1941:** First human trials conducted, initially in the context of **Parkinson's disease** exploration [Ref 25].

**1949–1957:** **Smith, Kline, and French** conducted trials in over 500 human subjects, investigating MDA as a potential antidepressant and appetite suppressant (anorectic). The compound was marketed briefly under the trade name **"Amphedoxamine"** for anorectic indications [Ref 25].

**1958–1961:** MDA was patented as a cough suppressant (1958), ataractic/anxiolytic (1960), and anorectic (1961) [Ref 25].

**1963–1964:** Recreational use emerged [Ref 25].

**1970:** MDA was classified as a **Schedule I controlled substance** under the United States Controlled Substances Act [Ref 31]. MDMA subsequently appeared on the illicit market in 1970 as an unscheduled alternative to MDA.

**1986:** David Nichols coined the term **"entactogen"** in his landmark paper distinguishing MDMA, MDA, and MBDB from classic hallucinogens and stimulants as a novel pharmacological class (Nichols 1986 [Ref 13]). The entactogen concept placed MDA in a pharmacological class characterized by empathy enhancement, emotional openness, and a combination of stimulant and mild psychedelic properties.

**Note on therapeutic use:** No published controlled clinical trials of MDA as a psychotherapeutic agent were found. Historical reports (from the 1960s–70s, pre-scheduling) describe its use in psychotherapy by practitioners including Claudio Naranjo, but these are documented in books and grey literature rather than peer-reviewed clinical trials. ⚠️ FLAG: Naranjo's clinical work with MDA is historically significant but not in PubMed/OpenAlex databases as formal trial data.

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## Subjective Effects

### Human Controlled Studies

**Baggott et al. (2010) [Ref 12]** — the only published RCT specifically designed around MDA's psychedelic properties in humans:
- **Dose:** 98 mg per 70 kg body weight (~1.4 mg/kg) oral
- **Design:** Double-blind, placebo-controlled, within-subjects
- **Key findings:**
  - MDA significantly increased closed-eye visions (CEVs) on all four measures: closed-eye patterns (p<0.001), closed-eye objects (p<0.001), closed-eye beings (p=0.019), closed-eye scenes (p=0.011)
  - Approximately 50% of participants reported substantial CEVs during MDA sessions; CEVs generally absent under placebo
  - MDA increased mystical-type experiences
  - Increased CEVs correlated with impaired contour integration and object recognition performance, suggesting hallucinogen-induced visions involve disruption of sensory boundary mechanisms

**Straumann et al. (2026) [Ref 11]** — definitive head-to-head human RCT of MDA vs. MDMA:
- **Design:** Double-blind, randomized, placebo-controlled, crossover; n=23 (12 women, 11 men)
- **Doses:** MDA 92 mg vs MDMA 100 mg (equimolar doses)
- **Onset:** MDA 0.7 ± 0.1 hours; Lys-MDA 1.1 ± 0.2 hours
- **Time to peak:** MDA 2.0 ± 0.1 hours vs MDMA (not specified but shorter)
- **Effect duration ("any drug effect"):** MDA 6.1 ± 0.5 hours vs MDMA 4.1 ± 0.4 hours
- **MDA vs MDMA (key differences):**
  - MDA: greater "stimulant effects"
  - MDA: more "bad drug effects"
  - MDA: more "fear"
  - MDA: more "visual alterations"
  - MDA: longer-lasting and stronger overall subjective effects
- **Plasma pharmacokinetics:** MDA t₁/₂ = 8.4 hours (geometric mean) vs MDMA = 7.3 hours
- **Conclusion:** MDA produced longer-lasting, stronger, more psychedelic-like perceptual acute effects and more adverse effects compared to MDMA at equimolar doses; MDA has a less favorable therapeutic profile than MDMA.

### Effect Taxonomy Notes

The seed data effect taxonomy is broadly supported by published literature:
- **Entactogenic effects** (empathy enhancement, emotional enhancement, disinhibition): shared with MDMA but likely attenuated relative to MDMA's more pronounced entactogenic profile, given MDA's greater stimulant and psychedelic character
- **Visual effects** (tracers, after-images, color enhancement, closed-eye hallucinations, internal hallucinations, object transformations): confirmed by Baggott 2010 [Ref 12] and Straumann 2026 [Ref 11]
- **Stimulant effects** (stimulation, wakefulness, thought acceleration): confirmed more pronounced than MDMA (Straumann 2026 [Ref 11])
- **Body effects** (bruxism, temperature dysregulation, pupil dilation, sweating): inferred from MDxx class; cardiovascular effects confirmed (Bexis 2006 [Ref 16])
- **Fear/anxiety as adverse effect:** Confirmed in human RCT (Straumann 2026 [Ref 11])

### Duration Data Assessment

Seed data (DB): total 5–8 hours, onset 30–90 min, peak 2.5–4 hours.
Published data (Straumann 2026 [Ref 11]): effect duration 6.1 ± 0.5 hours, onset ~42 min (0.7h).
**Assessment:** Seed data is broadly consistent with published RCT data. The 5–8 hour total duration range encompasses the 6.1h mean from Straumann 2026. Onset appears slightly underestimated in the seed data lower bound (30 min vs 42 min measured), but within normal interindividual variation.

---

## Safety & Toxicity

### Neurotoxicity

**Landmark finding (O'Hearn et al. 1988 [Ref 15]):** In rats administered MDA or MDMA (20 mg/kg s.c., twice daily for 4 days), both caused profound and selective loss of serotonergic (5-HT) axon terminals throughout the forebrain. Catecholamine axons were completely spared. **MDA produced a greater reduction of 5-HT axons than MDMA at the same dosage** — establishing that MDA is more neurotoxic than MDMA on a per-dose basis (546 citations as of 2026). This is animal data; human equivalence is unconfirmed but preclinical findings across multiple species support concern.

**Mechanism (Monks et al. 2004 [Ref 5]; Capela et al. 2007 [Ref 20]):**
- MDA is O-demethylenated by CYP2D6/CYP3A4 to **alpha-methyldopamine (alpha-MeDA)**
- Alpha-MeDA oxidizes to ortho-quinone, which conjugates with glutathione (GSH) to form thioether adducts
- These thioether metabolites are transported into the brain, stimulate acute monoamine release, and cause long-term serotonin depletion, GFAP expression elevation (astrogliosis marker), and microglial activation
- Critically: MDA does NOT produce neurotoxicity when injected directly into the brain — demonstrating that peripheral metabolism to neurotoxic intermediates is required [Ref 5]
- Alpha-MeDA is more neurotoxic than MDA itself; thioether conjugates are most toxic [Ref 20]

**Role of hyperthermia:** Malberg and Seiden (1998 [Ref 30]) demonstrated that small (2°C) changes in ambient temperature produce large changes in MDMA-induced (and by extension MDA-induced) serotonin neurotoxicity. Neurotoxicity was not observed at ambient temperatures of 20–24°C but strongly correlated with hyperthermia at 26–30°C. This is critical for harm reduction: the dance/club environment substantially amplifies MDA neurotoxicity risk.

**Species note:** All direct neurotoxicity studies are animal data (rats, squirrel monkeys). Primate serotonin systems show similar vulnerability. Human-specific neurotoxicity data for MDA is not available (no controlled human studies measuring post-dose serotonin marker changes).

### LD50 Data

**Dogs (IV):** LD50 = 8.1 mg/kg (95% CI: 7.0–9.4 mg/kg); LD1 ≈ 5 mg/kg, LD99 ≈ 14 mg/kg (Waters et al. 1986 [Ref 18]). At lethal IV doses in dogs, death was preceded by hyperthermia, tachycardia, hypertension → cardiovascular depression and respiratory failure (Davis et al. 1986 [Ref 17]). Chlorpromazine (10 mg/kg IV) administered after MDA overdose led to stabilization and 48-hour survival in dogs [Ref 17].

**Note:** These are IV doses in dogs. Human oral therapeutic index is not established from published data. ⚠️ FLAG: No human LD50 or reliable therapeutic index data available. Extrapolation from animal IV data to human oral dosing is inappropriate without species- and route-specific conversion.

**Mice:** MDA had potent hyperthermic effect in mice partially antagonized by bretylium and blocked by haloperidol (Nichols et al. 1975 [Ref 19]).

### Cardiovascular Toxicity

Bexis and Docherty (2006 [Ref 16]) compared MDMA, MDA, and MDEA cardiovascular effects in rats via radiotelemetry:
- **MDA produced the most marked rise in blood pressure** among the three compounds
- MDA-induced hypertension was accompanied by bradycardia (vagal reflex)
- MDA subsequently produced hyperthermia (unlike MDMA which initially caused hypothermia followed by recovery)
- MDA induced locomotor activity when given alone; MDMA did not without alpha-2 receptor blockade
- Mechanism: Alpha-1 adrenoceptor agonism (MDA most potent at alpha-1A and alpha-1D receptors among MDxx compounds)

### Fatalities

De Letter et al. (2006 [Ref 8]) reviewed amphetamine-related fatalities (including MDA cases) in Ghent, Belgium from 1976–2004. In 34 fatalities involving amphetamines:
- Wide range of blood levels observed; interpretation requires context
- Most common mechanisms: acute/subacute cardiopulmonary failure, (poly)trauma, mechanical asphyxia, hyperthermia
- Majority of victims male, under age 25

**Seed data toxicity assessment flags:**
- Acute toxicity noted as "moderate" in seed data. Given MDA's greater neurotoxicity vs MDMA and stronger pressor effect, this may be understated relative to published animal data. ⚠️ FLAG FOR EDITORIAL REVIEW.
- Toxicity notes read "Inferred from pharmacological class — not sourced from literature. Review recommended." — This flag is appropriate; some data now sourced from literature but human acute/chronic toxicity data remains limited.

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## Harm Reduction

**Temperature management:** The most evidence-supported harm reduction measure for MDA is temperature control. Hot environments (dance floors, clubs) dramatically amplify neurotoxicity risk via hyperthermia (Malberg & Seiden 1998 [Ref 30]). Staying cool, avoiding exertion, and taking regular breaks from dancing are critical risk mitigations.

**Hydration:** MDA shares MDMA's risk profile for both dehydration (from exertion/sweating) and paradoxically hyponatremia (water intoxication from excessive water intake + SIADH-type antidiuretic hormone release). ⚠️ FLAG: No MDA-specific hyponatremia case reports found in literature search; risk is inferred from MDMA class data.

**Drug checking:** MDA is sold illicitly both as MDA and adulterated in MDMA tablets. Drug checking with reagent tests (e.g., Marquis reagent turns black for MDxx compounds) and GC-MS confirmation at harm reduction services recommended (Fregonese et al. 2021 [Ref 28]).

**Drug interactions:** Avoid all serotonergic drugs (see Interactions section). The combination with tramadol or other serotonergic opioids is specifically flagged as lethal in seed data.

**Dose management:** The available human studies used doses of 92–98 mg in controlled settings with medical supervision. Higher doses increase risk of adverse effects (fear, cardiovascular stress, and hyperthermia); strong and heavy dose categories in the seed data (100–145 mg+) exceed the controlled study range and should be treated with caution.

**Contraindications from literature (class-level inference):**
- Personal or family history of psychosis, schizophrenia, or bipolar disorder (5-HT₂A agonism may precipitate psychotic episodes; MDMA/MDA class association)
- Cardiovascular disease, hypertension (MDA most potent pressor among MDxx compounds [Ref 16])
- Liver impairment (CYP2D6/CYP3A4 dependent metabolism)
- Concurrent SSRI/SNRI use (pharmacodynamic antagonism of effects + risk of serotonin syndrome at high doses)
- Concurrent MAOIs (severe serotonin syndrome risk)
- Concurrent tramadol or serotonergic opioids (lethal serotonin toxicity risk)

---

## Tolerance & Dependence

### Tolerance

No MDA-specific published pharmacological tolerance studies were found in the literature search. Tolerance data in the seed database (buildup with repeated/heavy use; half-life 3 days; full reset 7 days) appear to be derived from the MDxx class or community consensus rather than MDA-specific research. ⚠️ FLAG: Tolerance values in the DB are class-level inferences.

**Cross-tolerance:** Listed as psychedelic and stimulant in the seed data. Given MDA's dual 5-HT₂A agonist + monoamine releaser profile, cross-tolerance with both serotonergic psychedelics (via 5-HT₂A receptor downregulation) and other stimulants/empathogens is pharmacologically plausible but not directly confirmed in published MDA studies.

### Dependence

No MDA-specific dependence or withdrawal studies were found. The seed data characterizes MDA as moderately physically and psychologically addictive with "high potential for abuse." Given that MDA produces more pronounced stimulant and adverse effects than MDMA (Straumann 2026 [Ref 11]), the compulsive redosing urge listed in the effect taxonomy and the dependence potential are pharmacologically plausible. However, the greater adverse effect burden (more fear, more bad drug effects) may paradoxically reduce compulsive use.

**⚠️ FLAG:** Physical and psychological dependence ratings in seed data are not directly sourced from MDA-specific published literature. Editorial review recommended.

---

## Interactions

### Tramadol (Lethal — per seed data)

**Mechanistic basis confirmed:** Tramadol inhibits the serotonin transporter (SERT) and noradrenaline transporter (NET) in vitro at clinically relevant concentrations (Rickli et al. 2018 [Ref 21]). MDA causes mass serotonin release via SERT reverse transport. The combination of SERT inhibition (tramadol blocking serotonin reuptake) + massive serotonin release (MDA) creates conditions for **serotonin toxicity syndrome**, which in severe cases is characterized by hyperthermia, muscle rigidity, clonus, and multiple organ failure (Isbister et al. 2007 [Ref 22]).

**⚠️ FLAG:** No published case reports or clinical studies specifically documenting MDA + tramadol as a fatal combination were found. The "lethal" classification in the seed data is mechanistically justified but lacks direct published case evidence. The interaction risk is real and the severity classification (lethal) is appropriate given the mechanism, but should be flagged as "mechanistically inferred + class-level evidence; no MDA-specific case report found."

### MDMA (Dangerous — per seed data)

Combined use of MDA and MDMA would produce additive or supra-additive serotonergic effects. Both compounds are serotonin releasers; co-administration increases hyperthermia risk, cardiovascular stress, and the risk of serotonin toxicity. This interaction severity classification is pharmacologically sound but no published MDA + MDMA co-administration human case report was found.

### Alcohol (Unknown — per seed data)

No published MDA + alcohol interaction data found. Risk likely includes potentiation of dehydration, impaired thermoregulation, and increased cardiovascular stress, but this is class-level inference.

### SSRIs/SNRIs

Would be expected to blunt entactogenic/stimulant effects (by competing at SERT and blocking monoamine release) and may produce paradoxical serotonin syndrome at high doses. This is based on extensive MDMA literature where SSRIs reduce MDMA effects; no MDA-specific data found. The norepinephrine transporter inhibitor reboxetine has been shown to reduce MDMA's cardiovascular and stimulant effects specifically by blocking NE release (Hysek et al. 2011), which would also apply to MDA given its pronounced NET activity [Ref 21 context].

### CYP2D6 Inhibitors

Fluoxetine, paroxetine, quinidine, and other CYP2D6 inhibitors would reduce MDA metabolism, substantially increasing plasma MDA concentrations and toxicity risk. This is confirmed for MDMA and inferred for MDA from the same enzyme pathway (Ramamoorthy 2002 [Ref 29 context]; Van LM 2006 [Ref 29]).

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## Legal Status

| Jurisdiction | Status | Schedule/Class | Date |
|---|---|---|---|
| United States | Controlled | Schedule I (CSA) | 1970 |
| United Kingdom | Controlled | Class A (MDA 1971) | 1971 |
| Canada | Controlled | Schedule III (CDSA) | — |
| Australia | Prohibited | Schedule 9 (S9) | — |
| International | Controlled | Schedule I (Convention on Psychotropic Substances) | — |

**⚠️ FLAG — Canada Schedule III:** The Wikidoc secondary source [Ref 25] lists MDA as Schedule III in Canada. This is inconsistent with expectations — MDMA is Schedule III in Canada, and the MDxx compounds are typically treated similarly. However, MDA may indeed be Schedule I in Canada under the CDSA. This classification requires verification from the official Canadian Controlled Drugs and Substances Act listing before the generation agent uses it. Do NOT use Schedule III for Canada without editorial verification.

**Street names:** "Sass," "Sally," "Love Drug," "Tenamfetamine" (INN) — confirmed from DEA orange book listing [Ref 31] and seed data.

---

## Clinical Trials

**No clinical trials specifically investigating MDA as an active investigational agent were found on ClinicalTrials.gov.**

Search of ClinicalTrials.gov for "methylenedioxyamphetamine MDA" returned only MDMA-focused trials. The most relevant completed trial (NCT04847206, "Effects of MDMA-like Substances in Healthy Subjects," University Hospital Basel, Phase 1, completed) included MDA as a comparator arm and generated the Straumann 2026 publication [Ref 11]. This trial was not designed with MDA as the primary investigational agent.

MDA has no FDA IND status known from public records. The Baggott 2010 RCT [Ref 12] was a federally authorized controlled human study of MDA's hallucinogenic mechanisms but does not constitute a clinical trial in the therapeutic sense.

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## Community Feedback Analysis

No community feedback was submitted in Part A2 of the brief. This section is therefore empty.

**No community feedback submitted.**

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## Gaps & Flags

### Safety-Critical Flags

1. **⚠️ Human neurotoxicity data absent:** All serotonergic neurotoxicity data for MDA is from rodent and non-human primate models. No controlled studies have measured direct serotonin neurotoxicity markers (e.g., SERT density, 5-HT levels) in human MDA users. The human neurotoxicity warning is based on animal data and precautionary principle.

2. **⚠️ Tramadol interaction — no case report:** The "lethal" classification is mechanistically justified (tramadol SERT inhibition + MDA serotonin release = serotonin syndrome risk) but no published MDA + tramadol fatality case report was found in PubMed or OpenAlex.

3. **⚠️ LD50 in animals only (IV route):** Human therapeutic index not established. Dog IV LD50 = 8.1 mg/kg should not be used to estimate human oral safety margins.

4. **⚠️ Acute toxicity classification in seed data ("moderate"):** Given MDA's greater neurotoxicity vs MDMA and stronger pressor effects, editorial review of this rating is recommended.

### Data Gaps

5. **SMILES not confirmed via primary API:** Retrieved from Wikidoc [Ref 25]. Should be cross-verified against PubChem canonical SMILES for CID 1614.

6. **CAS number not confirmed:** Commonly cited as 4764-17-8 (racemate). Requires primary source verification.

7. **Canada legal status uncertain:** Source [Ref 25] says Schedule III. This may be an error; verify against official CDSA text before using in article.

8. **No stereoisomer comparison studies in humans:** The relative potency and effect profile of R-MDA vs S-MDA has not been studied in humans. Extrapolated from MDMA enantiomer data.

9. **Oral bioavailability not measured:** No published MDA-specific bioavailability study found.

10. **Tolerance/dependence data not MDA-specific:** DB values for tolerance build-up rate, half-life (3 days), and full reset (7 days) appear to be class-level MDxx inferences. No MDA-specific pharmacodynamic tolerance studies published.

11. **Dependence and physical addiction ratings:** "Moderate" ratings in seed data not confirmed by MDA-specific clinical dependency studies.

12. **Naranjo's historical therapeutic use:** Claudio Naranjo's clinical use of MDA in psychotherapy (1960s–70s) is historically documented but not in peer-reviewed trial databases.

13. **Contraindications not formally studied for MDA:** The contraindications section is based on MDxx class inference, not MDA-specific clinical data.

14. **Hyponatremia/SIADH risk:** Inferred from MDMA literature. No MDA-specific case reports found.

15. **Duration seed data slightly inconsistent with published study:** Seed DB onset range is 30–90 minutes; Straumann 2026 [Ref 11] reports mean onset 42 minutes (0.7h). The DB's lower bound of 30 minutes may be achievable in some individuals but 42 minutes is the published mean. This is within normal variation, but notable.

### Dose Data Assessment

**Seed data doses (oral):**
- Threshold: 20 mg
- Light: 40–60 mg
- Common: 60–100 mg
- Strong: 100–145 mg
- Heavy: 145+ mg

**Published controlled study doses:**
- Baggott 2010 [Ref 12]: 98 mg/70 kg (~1.4 mg/kg) — within "Common" range
- Straumann 2026 [Ref 11]: 92 mg — within "Common" range

The published controlled doses fall within the seed data's "Common" category. The seed dose ranges are not contradicted by published data. No dose-ranging study for MDA has been published, so the full dose scale is based on community consensus and structural analog inference. Dose ranges should be retained but flagged as not fully evidence-based.

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*Research compiled by pharmacological research agent for Psychedex, 2026-04-24.*
*Generation provenance: 9487fa1d-617f-4834-86ad-b703c9efc318*