Methallylescaline

# Research Output: Methallylescaline (MAL)

**PSX ID:** PSX-0248  
**Research Date:** 2026-05-11  
**Substance Readiness:** Sparse/emerging — primary published literature is limited to three directly relevant papers. This output draws on those sources plus class-level comparisons from mescaline pharmacology.

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## Chemical Identity

**Verified via PubChem (CID 44350127) and Isomerdesign PiHKAL database:**

| Property | Value | Source |
|---|---|---|
| CAS Number | 207740-41-8 | ChemIDplus [Ref 13] |
| Molecular Formula | C₁₄H₂₁NO₃ | PubChem CID 44350127 [api_verified] |
| Molecular Weight | 251.32 g/mol | PubChem CID 44350127 |
| SMILES | `NCCc1cc(OC)c(c(c1)OC)OCC(=C)C` | Isomerdesign/PubChem [Ref 3] |
| InChIKey | FOXJFBFFGULACD-UHFFFAOYSA-N | PubChem CID 44350127 |
| IUPAC Name | 2-[3,5-dimethoxy-4-(2-methylprop-2-enoxy)phenyl]ethanamine | PubChem |
| HCl Salt Melting Point | 153–154°C | Shulgin PiHKAL #99 [Ref 3] |

**Seed data discrepancies:** The brief listed no SMILES, molecular formula, or PubChem CID. All of these are now confirmed. The IUPAC name in the brief matches PubChem. No discrepancies in chemical identity.

**Structural notes:** Methallylescaline is a member of the "scaline" family of phenethylamines — mescaline analogs in which the 4-methoxy group is replaced by a longer alkoxy group. MAL specifically bears a 2-methylprop-2-en-1-yloxy (methallyloxy) group at the 4-position, distinguishing it from allylescaline (AL, which bears an unsubstituted allyloxy group) and escaline (which bears an ethyloxy group). Shulgin explicitly noted in PiHKAL that the name "methallylescaline" is "completely unsound" because the compound is not a union of methallyl with escaline, but rather mescaline with a 2-propene group attached to the 4-methyl [Ref 3].

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## Pharmacology

### Primary Receptor Data (Kolaczynska et al. 2021 [Ref 1])

This is the sole published study directly measuring MAL receptor pharmacology. Kolaczynska KE, Luethi D, Trachsel D, Hoener MC, and Liechti ME (Frontiers in Pharmacology, DOI: 10.3389/fphar.2021.794254) characterized receptor binding profiles and functional activation for a series of 4-alkoxy-3,5-dimethoxy-phenethylamines (mescaline derivatives), with MAL directly tested as compound #32.

**Serotonin receptor binding (Ki, nM):**

| Target | Ki ± SD (nM) | Notes |
|---|---|---|
| h5-HT2A | 550 ± 190 | Binding assay |
| h5-HT2C | 520 ± 150 | Binding assay |
| h5-HT1A | 5,100 ± 500 | ~9.3-fold selectivity ratio for 5-HT2A over 5-HT1A |
| h5-HT2B | >10,000 | **Effectively inactive** |

**5-HT2A functional activation:**
- EC50: 79 ± 12 nM
- Efficacy: 85 ± 5% (full agonist, relative to reference)

**5-HT2B functional activation:** >10,000 nM (inactive)

**Non-serotonergic targets:**

| Target | Ki or Status |
|---|---|
| hTAAR1 | >10,000 nM |
| rTAAR1 | 1,000 ± 200 nM |
| mTAAR1 | 3,900 ± 200 nM |
| hα1A (adrenergic) | >8,700 nM |
| hα2A (adrenergic) | 1,500 ± 500 nM |
| hD2 (dopamine) | >6,300 nM |
| Monoamine transporters (DAT, NET, SERT) | >7,500 nM |

**Interpretation:** MAL is a potent and selective 5-HT2A/5-HT2C agonist with negligible activity at monoamine transporters and dopamine D2 receptors. It does not significantly activate 5-HT2B — an important distinction from some other psychedelics and entactogens; this suggests lower theoretical risk of cardiac valvulopathy associated with chronic 5-HT2B activation. Negligible hTAAR1 activity distinguishes it from methamphetamine-type phenethylamines. The rodent TAAR1 activity (rTAAR1 Ki 1,000 nM) is not clearly translatable to humans (Kolaczynska et al. 2021 [Ref 1]).

**Comparative potency vs mescaline:** Mescaline (the parent compound) has 5-HT2A binding in the low µM range (requiring 200–400 mg orally). MAL's 5-HT2A Ki of 550 nM represents roughly 6-fold greater binding affinity than mescaline, consistent with web-sourced summaries citing ~6x mescaline potency [Ref 1]. Kolaczynska et al. found scalines as a class show up to 63-fold higher 5-HT2A binding vs mescaline; MAL's branched methallyloxy group results in slightly lower potency than allylescaline (straight-chain allyloxy) at this target [Ref 1].

### Mechanism of Action

As a 5-HT2A partial-to-full agonist (85% efficacy in the Kolaczynska assay), MAL's mechanism parallels that of classical serotonergic psychedelics. Activation of cortical 5-HT2A receptors on apical dendrites of layer V neocortical pyramidal neurons is the primary mechanism underlying psychedelic effects (Nichols 2016 [Ref 7]). The receptor's role in cognition, perception, and cortical function is well-established (Nichols 2018 [Ref 8]). Class-level evidence confirms that 5-HT2A antagonism (e.g., with ketanserin) attenuates psychedelic effects, as demonstrated with mescaline (Klaiber et al. 2024 [Ref 9]).

MAL does not act via monoamine transporters (all >7,500 nM), ruling out stimulant-type mechanisms of action [Ref 1]. The adrenergic α2A Ki of 1,500 nM is low enough to warrant noting — partial α2A activity at high doses could theoretically contribute to cardiovascular and autonomic effects, though this is speculative without substance-specific human data.

### Pharmacokinetics

No published human pharmacokinetic studies exist for MAL. The following is by class-level inference from mescaline data:

- Mescaline reaches peak plasma concentration (Tmax) at approximately 2 hours after oral administration and has a plasma elimination half-life of approximately 3.5 hours (Klaiber et al. 2024 [Ref 9]; Ley et al. 2023 [Ref 10]).
- MAL's longer reported effect duration (8–16 hours) vs mescaline (mean 11.1 hours at 500 mg) likely reflects the higher relative potency at lower doses, not a longer elimination half-life per se, though no PK data for MAL are available.
- No published bioavailability, protein binding, volume of distribution, or renal clearance data for MAL exist.

**FLAG for human review:** No pharmacokinetic data specific to MAL; all pharmacokinetic statements are class-level inferences and should not be represented as MAL-specific findings.

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## History

**Discovery and synthesis:** MAL was first synthesized and self-administered by Alexander Shulgin. According to his laboratory notes (Lab Notes #4, 1981–1982, p. 483), Shulgin first experimented with MAL in 1981 and reported discovering its hallucinogenic effects in 1982 [Ref 3]. The substance was published in his 1991 book *PiHKAL: A Chemical Love Story* as entry #99 [Ref 3].

**Synthesis route (PiHKAL):** The synthesis involves two steps: (1) alkylation of homosyringonitrile with methallyl chloride in acetone using potassium carbonate and a phase-transfer catalyst, yielding 3,5-dimethoxy-4-methallyloxyphenylacetonitrile; (2) lithium aluminum hydride reduction of the nitrile in THF, followed by acid-base extraction and isolation of the hydrochloride salt (m.p. 153–154°C) [Ref 3].

**Published pharmacology:** The first comprehensive pharmacological characterization of MAL was published in 2022 (online first 2021) by Kolaczynska, Luethi, Trachsel, Hoener, and Liechti — approximately 30 years after Shulgin's initial description [Ref 1].

**Emergence as a research chemical:** Online market surveillance data (NDEWS, 2024 [Ref 15]) indicates methallylescaline became increasingly discussed online from late 2023 onward, primarily on Reddit. As of May 2024, NDEWS documented a spike in online mentions, suggesting growing interest among psychedelic enthusiasts. Poison control reports suggest it remained largely unknown to clinical providers as recently as 2013 [Ref 14].

**Regulatory history:**
- Sweden: Scheduled January 2016
- UK: Controlled under Psychoactive Substances Act 2016 (May 26, 2016)
- Germany: Controlled under NpSG (Neue-psychoaktive-Stoffe-Gesetz), November 26, 2016
- Canada: Health Canada determined non-controlled under CDSA in a 2012 status determination (document A-2013-00235)

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## Subjective Effects

**Primary source:** Shulgin's PiHKAL #99 [Ref 3] provides first-person reports from a small number of trials. No controlled human experimental data specific to MAL exist.

**From PiHKAL and community reports [Refs 3, 14, 15]:**

Effects reported include:
- Strong visual distortions: kaleidoscopic neon colors, visual depth and movement, open- and closed-eye visual phenomena, "visual theater"
- Retinal-level visual phenomena; intense color enhancement
- Mental imagery, fantasy, easy recall of childhood memories
- Sense of self-connectedness and introspection
- Eroticism and tactile enhancement
- Initial discomfort ("body load"), overload, or feeling overwhelmed — particularly at higher doses
- Stimulation, restlessness, insomnia reported during comedown
- Enhanced dreaming in the afterglow phase
- Diuretic effects (increased urination) explicitly noted by Shulgin [Ref 3]
- Slightly reduced heart rate at lower doses noted in some reports [Ref 3]

**From NDEWS 2024 surveillance [Ref 15]:**
- Visual effects frequently compared to mescaline
- Nausea and vomiting reported as prominent negative effects
- "Body load" described as encompassing "a sense of unease, shortness of breath, and a feeling of overstimulation"
- **Steep dose-response curve:** Small dosage increases can dramatically increase effect intensity — this is highlighted as a primary harm reduction concern

**From Erowid overdose case report [Ref 14]:**
At 130 mg (above normal range): extreme visual overwhelm, delirium, difficulty maintaining coherent thoughts, urinary retention, tachycardia (>120 bpm), facial flushing, hypertension (160/80 mmHg).

**Duration data:**
- PiHKAL [Ref 3]: 12–16 hours
- Kolaczynska et al. 2021 [Ref 1]: 8–12 hours
- Seed data (PsychonautWiki-derived): 6–12 hours total

**FLAG:** There is a meaningful discrepancy between the three duration sources. PiHKAL (12–16 h) and Kolaczynska et al. (8–12 h) are the two most authoritative sources. The seed data (6–12 h) falls on the low end. This discrepancy should be reviewed editorially. The PiHKAL value may reflect higher doses (40–65 mg) producing longer effects, while the 6–12 h figure may reflect lower-dose experiences.

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## Safety & Toxicity

**LD50 / toxic dose:** No published LD50 or human toxic dose data exist for MAL. The seed data correctly notes "toxic dose is unknown." This cannot be resolved from available literature.

**Cardiovascular effects:** At 130 mg (overdose-level), the one available case report [Ref 14] documented tachycardia >120 bpm and hypertension (160/80 mmHg). These findings are consistent with serotonergic and sympathomimetic activation. The 5-HT2A agonism found in the Kolaczynska data is the most plausible mechanism for cardiovascular stimulation, consistent with mescaline's documented cardiovascular effects at high doses (Klaiber et al. 2024 [Ref 9]).

**Urinary retention:** The Erowid case [Ref 14] documented inability to urinate despite consuming >96 oz of water over the drug's duration; bladder ultrasound confirmed an empty bladder. This is clinically significant and unusual. The attending physician attributed the presentation to "an acute anticholinergic response," though the pharmacological basis (MAL has no known muscarinic activity) is unclear. The mechanism is unresolved. **FLAG for human review:** Urinary retention is not an expected effect based on known receptor pharmacology; requires cautious reporting.

**Cardiac valvulopathy risk:** MAL is effectively inactive at 5-HT2B (>10,000 nM [Ref 1]). 5-HT2B activation is the mechanism underlying drug-induced cardiac valvulopathy (as with fenfluramine). MAL's 5-HT2B inactivity suggests lower chronic cardiac valvulopathy risk than 5-HT2B-active substances, though long-term data are absent.

**Organ toxicity:** No published data on organ toxicity. The Erowid case report [Ref 14] found all laboratory values (kidney, liver, heart function markers) within normal range after a 130 mg acute oral dose.

**Psychological risks:** Like all 5-HT2A agonists, MAL carries class-level risks including:
- Acute anxiety, panic, or dysphoria, particularly in unprepared users or unfavorable settings
- Risk of triggering latent psychotic episodes in individuals with predisposition to psychosis
- HPPD (hallucinogen persisting perception disorder) — documented with 5-HT2A agonist NPS (Schetz et al. 2022 [Ref indirectly cited])
- Steep dose-response curve (NDEWS 2024 [Ref 15]) makes dose titration particularly difficult, increasing the risk of unintended overdose

**Nausea and emesis:** Prominent adverse effects at higher doses, consistent with the mescaline class (Klaiber et al. 2024 [Ref 9]; community reports [Ref 15]).

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## Harm Reduction

**No published harm reduction protocols specific to MAL exist.** The following is based on class-level evidence and community observation data.

**Dose-response curve:** MAL is documented to have an unusually steep dose-response curve (NDEWS 2024 [Ref 15]). Community reports emphasize that small increases in dose can result in dramatically more intense effects. Users should start at the lowest effective dose and avoid re-dosing.

**Route:** Oral is the documented route in all available sources. No data exist for insufflation, intravenous, or sublingual administration.

**Set and setting:** As with all psychedelics, psychological set and physical setting are critically important harm reduction factors.

**Testing:** No published colorimetric or immunoassay test kit validation data specific to MAL. Marquis reagent testing and mass spectrometry methods have been applied to related phenethylamines [Ref 5]; LC-HRMS forensic detection methods for MAL and its metabolites have been published (Kim et al. 2018 [Ref 13]).

**Medical emergency:** In the event of MAL overdose, the Erowid case report [Ref 14] suggests hospital management may include IV fluids, benzodiazepines (Ativan used in that case), and supportive monitoring. Providers should be aware that poison control may have no prior experience with this substance.

**Contraindications:** Based on class-level data and the cardiovascular findings in the case report:
- Cardiovascular disease or hypertension (cardiovascular stimulation documented at overdose doses [Ref 14]; mescaline increases blood pressure [Ref 9])
- Personal or family history of psychosis or schizophrenia-spectrum disorders
- Pregnancy (no safety data; class-level caution)
- MAOI use (see Interactions)
- Lithium (class-level seizure risk — see Interactions)

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## 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, with cross-tolerance to psychedelics. These values reflect community consensus for 5-HT2A agonist psychedelics as a class. Published mechanistic data confirm that classical psychedelics produce rapid 5-HT2A receptor downregulation in frontal cortex following acute administration, with full cross-tolerance between DOI and LSD (de la Fuente Revenga et al. 2022 [Ref 11]). No MAL-specific tolerance data have been published.

**Dependence:** Published literature (Nichols 2016 [Ref 7]) consistently characterizes serotonergic psychedelics as non-habit-forming with no physical dependence liability. MAL's pharmacological profile (no dopamine transporter or monoamine releasing activity; negligible D2 receptor interaction [Ref 1]) is inconsistent with dependence-producing mechanisms. The seed data characterizes MAL as "not habit-forming" — this is consistent with class evidence.

**Cross-tolerance:** Cross-tolerance with other 5-HT2A agonists (LSD, psilocybin, mescaline, DOx compounds) is expected on mechanistic grounds and confirmed for other psychedelic pairs (de la Fuente Revenga et al. 2022 [Ref 11]).

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## Interactions

No published pharmacokinetic interaction studies exist for MAL. The following reflects class-level evidence.

**MAOIs (monoamine oxidase inhibitors):** Serotonergic psychedelics combined with MAOIs carry risk of serotonin toxicity/syndrome (Malcolm & Thomas 2022 [Ref 12]). Phenethylamines are MAO-A substrates (unlike tryptamines which are MAO-A substrates more specifically); MAOI co-administration would be expected to potentiate and prolong MAL effects and increase serotonin toxicity risk. **HIGH RISK — FLAG for human review.**

**SSRIs/SNRIs:** Selective serotonin reuptake inhibitors may blunt psychedelic effects via receptor downregulation and can in some combinations raise serotonin toxicity risk (Malcolm & Thomas 2022 [Ref 12]). The interaction is complex and depends on specific SSRI and dose.

**Lithium:** Psychedelic + lithium combinations have been associated with seizure risk in case reports (class-level concern). This is not documented with MAL specifically but is a well-recognized warning for the psychedelic class.

**Cannabis:** Potentiation of psychedelic effects with increased risk of anxiety and psychosis. No MAL-specific data.

**Alcohol:** CNS depressant combination; could mask CNS overstimulation but reduces cognitive capacity for harm reduction. No MAL-specific data.

**Stimulants:** Additive cardiovascular load. Contraindicated given documented tachycardia and hypertension in the case report [Ref 14].

**CYP2D6 inhibitors/substrates:** MAL is metabolized by CYP2D6, CYP2J2, CYP1A2, and CYP3A4 (Kim et al. 2018 [Ref 13]). CYP2D6 inhibitors (fluoxetine, paroxetine, bupropion) may increase MAL plasma concentrations. CYP3A4 inhibitors (ketoconazole, grapefruit juice) are similarly potentially relevant. No interaction studies exist.

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## Metabolism

**Published data (Kim et al. 2018 [Ref 13]):** In vitro incubation with human hepatocytes identified four metabolites:
- M1, M2, M3: Hydroxy-methallylescaline (mono-hydroxylation, molecular formula C₁₄H₂₁NO₄, +16 amu)
- M4: Dihydroxy-methallylescaline (di-hydroxylation, C₁₄H₂₁NO₅, +32 amu)

Hydroxylation occurs predominantly at the methallyl moiety (the 2-methylprop-2-en-1-yloxy group). No oxidative deamination or phase II conjugation (e.g., glucuronidation) was observed in the in vitro system.

**CYP enzymes:** CYP2D6, CYP2J2, CYP1A2, and CYP3A4 were identified as the primary metabolizing enzymes (Kim et al. 2018 [Ref 13]).

**Relevance:** This is the only published study of MAL metabolism. It was specifically developed to support forensic toxicology screening. Urinary metabolites M1–M4 alongside parent MAL serve as detection markers.

**Note:** The role of MAO in MAL's catabolism has not been published. By analogy with mescaline and other phenethylamines, oxidative deamination by MAO-A is expected to be a metabolic route, but this is not confirmed for MAL specifically.

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## Legal Status

| Jurisdiction | Status | Date/Details |
|---|---|---|
| United Kingdom | Illegal — Psychoactive Substances Act 2016 | Effective May 26, 2016 |
| Germany | Controlled — NpSG (Neue-psychoaktive-Stoffe-Gesetz) | November 26, 2016 |
| Sweden | Controlled | January 2016 |
| United States | Unscheduled | Federal Analogue Act (FAA) may apply if intended for human consumption; structural/pharmacological similarity to mescaline (Schedule I) |
| Canada | Non-controlled (as of 2012) | Health Canada CDSA status determination A-2013-00235 |
| Australia | No specific scheduling confirmed | Inquiry needed; likely captured under novel psychoactive substance provisions |
| New Zealand | No specific scheduling confirmed | Misuse of Drugs Act NPS provisions may apply |

**FLAG:** Legal status may have changed since 2016 for some jurisdictions. Human review recommended for current status in Canada and Australia in particular.

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## Clinical Trials

No clinical trials for methallylescaline are registered on ClinicalTrials.gov. No clinical trials for MAL are recorded in any database searched.

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## Community Feedback Analysis

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

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## Gaps & Flags

### Safety-Critical Flags (requiring human review before publication)

1. **Dose range discrepancy:** PiHKAL reports a 40–65 mg active dose [Ref 3]. Kolaczynska et al. 2021 cite "30–80 mg effective human dose" [Ref 1]. The seed data (PsychonautWiki-derived) has a threshold of 5 mg and common range of 25–40 mg. These ranges overlap but differ meaningfully — particularly the 5 mg threshold has no primary literature support. **Recommend editorial review of all dose tiers before generation.**

2. **Duration discrepancy:** PiHKAL says 12–16 hours; Kolaczynska 2021 says 8–12 hours; seed data says 6–12 hours. The Shulgin data (12–16 h) are primary source and should be given weight. **Recommend editorial decision on canonical duration values.**

3. **Toxic dose unknown:** The brief correctly notes this. The only available case data is one Erowid report at 130 mg [Ref 14]. This is insufficient to establish a toxic dose threshold. All dose ranges above the strong tier should be treated as uncharacterized territory.

4. **Urinary retention mechanism unexplained:** The attending physician in the case report attributed this to anticholinergic effects [Ref 14], but MAL has no documented muscarinic activity. The mechanism is genuinely unknown and should not be stated confidently.

5. **No published LD50, therapeutic index, or human PK data specific to MAL.** All pharmacokinetic statements about MAL must be clearly labeled as class-level inferences from mescaline data, not MAL-specific findings.

### Data Gaps

6. **No controlled human studies of MAL.** All subjective effect data originate from Shulgin's PiHKAL reports (small informal trials), one Erowid case report, and indirect web surveillance data.

7. **Metabolism data (Kim 2018 [Ref 13]) from in vitro hepatocyte assay only.** In vivo human metabolic data do not exist.

8. **No published interaction studies** — all interaction guidance is class-level inference.

9. **Physical properties (boiling point, aqueous solubility, partition coefficient, pKa)** not found in published literature beyond the melting point of the HCl salt (153–154°C from PiHKAL [Ref 3]).

10. **Stereochemistry:** MAL as described in PiHKAL does not have a chiral center (the phenethylamine backbone is unsubstituted at α-carbon). No α-methyl derivative is referenced. No stereochemistry issues are anticipated.

11. **5-HT2B Ki discrepancy with web-sourced summaries:** Some web summaries claim MAL is a "potent agonist of 5-HT2B." This contradicts the Kolaczynska 2021 primary data (5-HT2B >10,000 nM = inactive). Trust the primary source. **FLAG: web summaries claiming 5-HT2B activity for MAL are not supported by the only published pharmacology study.**

12. **Canadian legal status** — the 2012 Health Canada determination of non-controlled status may be outdated. Canada's drug control provisions are periodically amended.