Arecoline

methyl 1-methyl-3,6-dihydro-2H-pyridine-5-carboxylate

Overview

Arecoline belongs to Stimulants.

Key safety note: Areca-nut chewing, the usual source of arecoline exposure, is classified by IARC as carcinogenic to humans (Group 1) and causes oral cancer, oral submucous fibrosis and leukoplakia, with raised risk of pharyngeal, oesophageal, stomach and liver cancers.[5][3][4]
Effects
Subjective effects vary. What a substance feels like depends on dose, individual physiology, mindset, and setting. The points below describe commonly reported effects, not guaranteed, uniform, or desirable outcomes.
  • The psychoactive effect is a mild, subtle stimulation, alertness, improved concentration, a sense of well-being and warmth, often likened to a strong cup of coffee rather than to a classic psychedelic or a strong stimulant.
  • Higher doses can add mild euphoria or elation, relaxation and reduced anxiety, and pro-sexual effects, typically with a flushed, warm sensation.
  • Cholinergic side effects accompany the wanted effects: profuse salivation (and the characteristic red betel spit), sweating, miosis, dizziness or vertigo, tremor and a slowed heart rate.
  • Onset is rapid (within a few minutes of chewing) and the effect is short-lived, which encourages repeated use through the day. Chronic use is addictive.
Dosing & duration
Harm-reduction note: These are commonly cited reference ranges, not a recommendation or a “safe” dose. Potency, purity, body chemistry, tolerance, and drug combinations vary widely. Start low, go slow, wait for full effects before redosing, and never assume an unknown product matches these figures. Missing data is not evidence of safety.

Oral (buccal: chewed as areca nut / betel quid). Arecoline is almost always taken as areca nut or betel quid held and chewed against the cheek for 5–20 minutes, not as an isolated compound, so these figures are descriptive, not a recommendation. Arecoline is only ~0.3–0.6% of the nut, its content varies widely between nuts and preparations, and added slaked lime converts much of it to arecaidine, so the delivered dose is variable and imprecise. There is no safe level of areca-nut use. It is a Group 1 human carcinogen.

Dose ranges

Arecoline in areca nut

≈0.3–0.6% by weight

Per areca nut (approx.)

≈a few to tens of mg arecoline (highly variable)

Duration

onset

≈1–5 min (buccal)

total

Short (minutes-order)

Chemical & Physical Properties
FormulaC8H13NO2
Molar mass155.19 g/mol
StateNot reported
Melting point27 °C
Boiling point209 °C
Density≈1.05 g/cm³
Vapor pressureNot reported
pKa≈6.8 (conjugate acid)
LogP0.3 (predicted, XLogP3)
SolubilityVery high: miscible with water (~1,000,000 mg/L at 25 °C)
Refractive indexNot reported
Identifiers & Synonyms
CASNot reported
CAS (enantiomer)
PubChem CID2230
InChIKeyHJJPJSXJAXAIPN-UHFFFAOYSA-N
InChIInChI=1S/C8H13NO2/c1-9-5-3-4-7(6-9)8(10)11-2/h4H,3,5-6H2,1-2H3
SMILESCN1CCC=C(C1)C(=O)OC

Synonyms

    Pharmacodynamics & Biochemistry

    Arecoline is the principal psychoactive alkaloid of the areca ('betel') nut and the agent responsible for its mild stimulant effect. Its pharmacology is broadly cholinergic (parasympathomimetic) rather than serotonergic: it is a non-selective agonist of muscarinic acetylcholine receptors and also acts at nicotinic acetylcholine receptors. In receptor assays it behaves as an agonist across the M1–M4 muscarinic subtypes (see the binding table). Overall it is usually described as a non-selective partial agonist of muscarinic and nicotinic receptors. Its central stimulant, alerting and mildly rewarding effects are attributed mainly to muscarinic activation, with a contribution from increased dopaminergic neurotransmission in the mesolimbic pathway thought to underlie its addictive potential. Its nicotinic actions are mixed and subtype-dependent, including antagonism at some neuronal nicotinic subtypes, which may account for reported anti-inflammatory effects. As a small, lipophilic tertiary amine it crosses the blood–brain barrier readily, and as a direct muscarinic agonist it produces the classic peripheral cholinergic picture: salivation, lacrimation, miosis, bronchial secretion and bradycardia. This muscarinic action is also why arecoline has served as a pharmacological probe and was trialled as a cognition-enhancing agent in Alzheimer's disease. The best-characterised quantitative targets are the human M1–M4 muscarinic receptors, at which arecoline binds in the low-micromolar range (pKi ≈ 5.2–5.7, see the binding table). Its major metabolite arecaidine is largely inactive at muscarinic receptors but acts as a GABA-uptake inhibitor, so areca-nut effects reflect a mixture of parent drug and metabolites.

    Biological targets

    • mAChR
    • nAChR

    Binding & functional measurements

    TargetMeasurementSpecies
    M1 receptorpKi 5.7Human
    M4 receptorpKi 5.5Human
    M3 receptorpKi 5.4Human
    M1 receptorpKi 5.3Rat
    M2 receptorpKi 5.2Human
    Pharmacokinetics
    BioavailabilityHigh buccal bioavailability (~85%) through the oral mucosa, peak plasma concentration within ~3 minutes of chewing
    TmaxNot reported
    Half-lifeShort (rapid metabolism, minutes-order)
    VdNot reported
    Protein bindingNot reported
    MetabolismHepatic and renal: hydrolysis by carboxylesterase to arecaidine (accelerated by added lime), N-oxidation to arecoline N-oxide, CYP450 N-demethylation, hydrogenation and mercapturic-acid conjugation
    ExcretionRenal, largely as metabolites (arecaidine, arecoline N-oxide, N-methylnipecotic acid)
    Toxicology & Safety
    Harm-reduction note: Toxicity and risk depend on dose, route, purity, combinations, setting, and individual health factors. Missing harms should never be interpreted as evidence of safety.

    Not reported

    Areca-nut chewing, the usual source of arecoline exposure, is classified by IARC as carcinogenic to humans (Group 1) and causes oral cancer, oral submucous fibrosis and leukoplakia, with raised risk of pharyngeal, oesophageal, stomach and liver cancers. Arecoline itself is rated a possible human carcinogen (Group 2B) and drives oral submucous fibrosis by promoting collagen accumulation in the oral mucosa. Arecoline is genotoxic and cytotoxic in many cell types, generates reactive oxygen species, and is toxic to the testes and liver in animals. As a direct cholinergic agonist, acute overdose produces a muscarinic toxidrome: hypersalivation, sweating, miosis, bradycardia, hypotension, bronchoconstriction, vomiting and tremor, with seizures and extrapyramidal effects at high doses: managed with antimuscarinics such as atropine. Regular use is addictive and has a withdrawal syndrome (mood swings, anxiety, irritability, insomnia), and use in pregnancy is linked to adverse birth outcomes. Long traditional use and a 'natural' origin are not evidence of safety: this is one of the most harmful widely-used psychoactive substances.[5][3][4]

    Legal Status
    Legal note: Legal status can change over time and may vary by country, region, formulation, analogue status, prescription context, and enforcement practice. Always confirm with current official sources before relying on this section.
    Interactions & Contraindications

    Drug interactions

    Cholinesterase inhibitors (physostigmine, donepezil, pyridostigmine, organophosphates) Additive muscarinic toxicity with donepezil, pilocarpine, pyridostigmine or organophosphates: bradycardia, bronchoconstriction, hypersalivation.[3]
    Anticholinergic drugs Antimuscarinics (atropine, scopolamine, many antihistamines and tricyclics) antagonise arecoline's effects. Atropine is the antidote to cholinergic overdose.[3]
    Non-selective beta-blockers, Antihypertensive drugs Additive bradycardia and hypotension with beta-blockers and other rate-slowing or hypotensive drugs.[3]

    Contraindications

    Respiratory disease or sleep apnoea asthma, COPD or other bronchospastic disease (muscarinic bronchoconstriction).[3]
    Cardiovascular disease, hypertension or arrhythmia bradycardia, heart block or other conduction disorders (cholinergic slowing).[3]
    Paralytic ileus or gastrointestinal obstruction peptic ulcer disease (increased gastric and salivary secretion).[2]
    Pregnancy or breastfeeding adverse birth outcomes with areca-nut use.[4]
    Usage & Context
    • Chewing areca nut / betel quid is one of the most widespread psychoactive habits in the world: used by an estimated 600 million people and reckoned the fourth most-used psychoactive substance after alcohol, nicotine and caffeine, and is deeply embedded in South and Southeast Asian and Pacific cultures.
    • Historically used in veterinary and traditional medicine as an anthelmintic (deworming agent) and, because of its muscarinic action, investigated as a cholinergic/cognition-enhancing probe in Alzheimer's disease research.
    • Sold as areca nut and commercial areca/betel products (e.g. pan masala, gutka). Isolated arecoline is also offered as a research chemical.
    Sources & Evidence
    1. PubChem: Arecoline (CID 2230) — identifiers & computed properties
    2. Wikipedia: Arecoline (pharmacology, effects, metabolism & legal status) CC BY-SA 4.0
    3. Volgin AD, Bashirzade A, Amstislavskaya TG, et al. (2019). DARK Classics in Chemical Neuroscience: Arecoline. ACS Chem Neurosci 10:2176-2185.

      PMID 30664352 · doi:10.1021/acschemneuro.8b00711

    4. Stokes C, Pino JA, Hagan DW, et al. (2022). Betel quid: New insights into an ancient addiction. Addict Biol 27:e13223.

      PMID 36001424 · doi:10.1111/adb.13223

    5. IARC (2004). Betel-quid and Areca-nut Chewing and Some Areca-nut-derived Nitrosamines. IARC Monographs Vol 85 (areca nut Group 1, arecoline Group 2B)
    6. IUPHAR/BPS Guide to PHARMACOLOGY: arecoline (ligand 296) — muscarinic binding data CC BY-SA 4.0
    7. Richards MH, van Giersbergen PL (1995). Human muscarinic receptors expressed in A9L and CHO cells: activation by full and partial agonists. Br J Pharmacol 114:1241-9.

      PMID 7620715 · doi:10.1111/j.1476-5381.1995.tb13339.x

    8. Mei L, Lai J, Roeske WR, et al. (1989). Pharmacological characterization of the M1 muscarinic receptors expressed in murine fibroblast B82 cells. J Pharmacol Exp Ther 248:661-70.

      PMID 2537406

    9. Jakubík J, Bacáková L, El-Fakahany EE, et al. (1997). Positive cooperativity of acetylcholine and other agonists with allosteric ligands on muscarinic acetylcholine receptors. Mol Pharmacol 52:172-9.

      PMID 9224827 · doi:10.1124/mol.52.1.172

    10. Ozenil M, Pacher K, Balber T, et al. (2020). Enhanced arecoline derivatives as muscarinic acetylcholine receptor M1 ligands for potential application as PET radiotracers. Eur J Med Chem 204:112623.

      PMID 32717485 · doi:10.1016/j.ejmech.2020.112623

    Further Information