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Arecoline is a cholinergic agent, stimulant, and natural product alkaloid found in areca nut of the areca palm ( Areca catechu) found in South Asia and Southeast Asia. Its effects, depending on the dose, include stimulation, alertness, increased concentration, nootropic, mood lift, euphoriant, aphrodisiac effects, relaxation, anxiolytic, and sedation, as well as drug addiction and drug withdrawal upon discontinuation. Its effects are described as subtle and it has been likened to a strong cup of coffee. There are also active constituents of areca nuts, but arecoline is the key active component, with a percentage of ~0.3 to 0.6%. Areca nuts are administered by chewing for 5 to 20minutes without swallowing.
of arecoline include hypersalivation, hypotension, vertigo, miosis, tremor, and bradycardia, among others. Other adverse effects can include extrapyramidal syndrome and . Addiction and drug dependence can occur, with withdrawal symptoms including , anxiety, irritability, and insomnia. Rarely, psychosis can occur during withdrawal in heavy users. Areca nut use, the primary method of consuming arecoline, is highly associated with oral disease and oral cancer. Overdose of arecoline can be treated with antimuscarinic drugs like atropine or scopolamine.
The drug acts as a non-selective partial agonist of muscarinic and nicotinic acetylcholine receptors. The major metabolite of arecoline, arecaidine, is a GABA reuptake inhibitor. The subjective effects of arecoline appear to be mediated by muscarinic acetylcholine receptors and not by nicotinic acetylcholine receptors based on animal study. However, its mechanism of action is still yet to be fully understood and other activities have also been described. The stimulant and addictive effects of arecoline are thought to be due to increased dopaminergic neurotransmission in the mesolimbic pathway of the brain. In terms of chemical structure, arecoline is closely related to nicotinic acid.
The use of arecoline, in the form of areca nuts, dates back several thousand years, including in Thailand, China, and Polynesia. Arecoline was first isolated in 1888 and its synthesis was first proposed in 1891, with its chemical structure confirmed in 1907. Arecoline, in the form of areca nuts, is used by more than 600million people worldwide (~10–20% of the global population), and is the fourth most commonly used psychoactive drug in the world after alcohol, nicotine, and caffeine. Despite globalization, arecoline is unusual among recreational drugs in that its use is still predominantly confined to Asia, though its use has been increasing and spreading in part due to the Internet. Chewing areca nuts is said to be as familiar to various Asian peoples as chewing gum is to Americans. The countries in which areca nut production are highest include India, China, Myanmar, Malaysia, Indonesia, and Bangladesh. Arecoline and areca nut sale and consumption are not generally controlled throughout the world, with a few exceptions.
It causes oral submucous fibrosis by stimulating collagen, interleukin 6, keratinocyte growth factor-1, IGF-1, cystatin C, tissue inhibitor of matrix metalloproteinases in the mouth.
Current science is confident that areca nut chewing is carcinogenic. Research suggests this is probably at least partly because of arecoline itself, although it could also be from the other constituents of the nut as well, some of which are precursors to that form in the mouth during chewing. Section 5.5 Evaluation on page 238 of IARC Monograph 85-6 states the following:
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- There is sufficient evidence in humans for the carcinogenicity of betel quid without tobacco. Betel quid without tobacco causes oral cancer.
- There is sufficient evidence in experimental animals for the carcinogenicity of betel quid without tobacco.
- There is sufficient evidence in experimental animals for the carcinogenicity of betel quid with tobacco.
- There is sufficient evidence in experimental animals for the carcinogenicity of areca nut.
- There is sufficient evidence in experimental animals for the carcinogenicity of areca nut with tobacco.
- There is limited evidence in experimental animals for the carcinogenicity of arecoline.
- There is inadequate evidence in experimental animals for the carcinogenicity of arecaidine.
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The toxicity of arecoline can be partially mitigated by vitamins C and E in mice.
Arecoline generates excessive reactive oxygen species (ROS) in a number of cell types, including oral epithelial cells and neuronal cells. In adult mice, arecoline is toxic to the testes and liver via ROS generation.
Arecoline is also genotoxic, being able to induce DNA damage and mutation in several cell cultures. Mice chronically exposed to arecoline show relaxation of their chromatin structure.
AN (Areca Nut) is a vasodilator mainly due to the presence of arecoline. It also has anti-thrombosis and anti-atherogenic effects by increasing plasma nitric oxide, eNos, and mRNA expression and decreasing IL-8 along with other downregulations. It increases the level of testosterone by stimulating Leydig's cells as well as levels of FSH and LH. It also activates HPA axis and stimulates CRH release. It prevents the dysfunction of B cells of the pancreas from high fructose intake. Arecoline has the ability to stimulate the digestive system through the activation of muscarinic receptors. Areca nut water extract could increase the contractions of gastric smooth muscle and muscle strips of the duodenum, ileum, and colon significantly. This activity could be caused by arecoline.
Arecoline is very efficiently absorbed through oral musoca, with 85% bioavailbility. Maximum plasma concentration is reached within 3 minutes. (2025). 9780128006344 ISBN 9780128006344
Orally ingested arecoline is extensively metabolized in rats, with the vast majority of the dose being converted to arecaidine and arecoline N-oxide.
Fischer esterification of nicotinic acid (niacin) ( 1) gives methyl nicotinate ( 2). Alkylation with methyl iodide then gives 3-methoxycarbonyl-1-methylpyridinium iodide ( 3). Hydride reduction with an agent such as potassium borohydride thus gives the tetrahydropyridine ( 4). Salt formation with hydrogen bromide completes the synthesis ( 5).
A double Mannich reaction between methylamine ( 1), acetaldehyde ( 2) and formaldehyde ( 3) in the presence of hydroxylamine hydrochloride is supposed to have delivered 1-methyl-1,2,5,6-tetrahydropyridine-3-carbaldehyde oxime hydrochloride ( 4) as the product. Dehydration of the aldoxime to the nitrile occurs upon treatment with acetic anhydride giving 3-cyano-1-methyl-1,2,5,6-tetrahydropyridine ( 5). Functional group interconversion of the nitrile to the methyl carboxylate ester then occurs upon acid-catalyzed treatment in methanol, and then conversion to the HBr salt completes the synthesis.
Anecdotal reports indicate that it has a short-lived effect against schizophrenia. Among male schizophrenia patients, higher areca nut consumption is associated with weaker symptoms. It inspired the development of xanomeline. It enhances learning and memory in rodents.
Veterinary use
In 2012, Chinese Ministry of Agriculture listed arecoline hydrobromide as an abolished veterinary drug and stopped its production and use.
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