The use of arecoline, in the form of areca nuts, dates back several thousand years, including inThailand,China, andPolynesia.[1] Arecoline was firstisolated in 1888 and itssynthesis was first proposed in 1891, with itschemical structure confirmed in 1907.[1] 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 usedpsychoactive drug in the world afteralcohol,nicotine, andcaffeine.[1][3] Despiteglobalization, arecoline is unusual amongrecreational drugs in that its use is still predominantly confined toAsia, though its use has been increasing and spreading in part due to theInternet.[1][3] Chewing areca nuts is said to be as familiar to various Asian peoples as chewing gum is to Americans.[1] The countries in which areca nut production are highest includeIndia,China,Myanmar,Malaysia,Indonesia, andBangladesh.[1] Arecoline and areca nut sale and consumption are not generallycontrolled throughout the world, with a few exceptions.[1]
TheLD50 of arecoline is 100 mg/kg, when administered subcutaneously in mice.[10] The minimum lethal dose (MLD) values of arecoline in mice, dogs, and horses is 100 mg/kg, 5 mg/kg and 1.4 mg/kg respectively.[9]
It causesoral submucous fibrosis by stimulating collagen, interleukin 6, keratinocyte growth factor-1, IGF-1, cystatin C, tissue inhibitor of matrix metalloproteinases in the mouth.[citation needed]
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 tonitrosamines that form in the mouth during chewing. Section 5.5 Evaluation on page 238 of IARC Monograph 85-6 states the following:[11]
[...]
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.
[...]
The toxicity of arecoline can be partially mitigated by vitamins C and E in mice.[12]
Arecoline is "obviously cytotoxic" to cultures of hepatocytes, bone marrow cells, lymphocytes, neuronal cell, myoblasts and endothelial cells.[9]
Arecoline generates excessivereactive 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.[9]
Arecoline is also genotoxic, being able to induce DNA damage and mutation in several cell cultures.[9] Mice chronically exposed to arecoline show relaxation of theirchromatin structure.[13]
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.[9] It increases the level of testosterone by stimulating Leydig's cells as well as levels of FSH and LH.[18][19] It also activates HPA axis and stimulates CRH release. It prevents the dysfunction of B cells of the pancreas from high fructose intake.[9] Arecoline has the ability to stimulate the digestive system through the activation ofmuscarinic 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.[9]
Arecoline is metabolized by both kidneys and liver.[20] Currently, 11 metabolites of arecoline are documented among whichN-methylnipecotic acid was found to be a major metabolite of both arecoline andarecaidine.[21] Lime, which is traditionally mixed to crushed areca nuts prior to consumption, is said to hydrolyse almost all arecoline toarecaidine, a GABA reuptake inhibitor.[22] Arecaidine is also formed during liver metabolism of arecoline in rats.[21]
Arecoline is very efficiently absorbed through oral musoca, with 85% bioavailbility. Maximum plasma concentration is reached within 3 minutes.[23]
Orally ingested arecoline is extensively metabolized in rats, with the vast majority of the dose being converted to arecaidine and arecolineN-oxide.[24]
Arecoline is a colorless odorless oily liquid.[1] It is abase, and its conjugate acid has a pKa ~ 6.8.[10]Arecoline is volatile in steam, miscible with most organic solvents and water, but extractable from water byether in presence of dissolved salts. Being basic, arecoline forms salts with acids. The salts are crystalline, but usuallydeliquescent: the hydrochloride, arecoline•HCl, forms needles, m.p. 158 °C;[10] the hydrobromide, arecoline•HBr, forms slender prisms, mp. 177–179 °C from hotmethanol; theaurichloride, arecoline•HAuCl4, is an oil, but theplatinichloride, arecoline2•H2PtCl6, mp. 176 °C, crystallizes from water in orange-red rhombohedrons. Themethiodide forms glancing prisms, mp. 173–174 °C.
Fischer esterification ofnicotinic acid (niacin) (1) givesmethyl nicotinate (2). Alkylation withmethyl 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 withHBr completes the synthesis (5).
A double Mannich reaction between methylamine (1), acetaldehyde (2) and formaldehyde (3) in the presence ofhydroxylamine 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.
Owing to itsmuscarinic and nicotinic agonist properties, arecoline has shown improvement in the learning ability of healthy volunteers. Since one of the hallmarks of Alzheimer's disease is a cognitive decline, arecoline was suggested as a treatment to slow down this process. Arecoline administered intravenously did indeed show modest verbal and spatialmemory improvement in Alzheimer's patients,[35] though due to arecoline's possible carcinogenic properties (see§ Toxicity), it is not the first drug of choice for this degenerative disease.[35]
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 ofxanomeline.[34] It enhances learning and memory in rodents.[9]
^Meltzer LT, Rosecrans JA (1981). "Discriminative stimulus properties of arecoline: a new approach for studying central muscarinic receptors".Psychopharmacology (Berl).75 (4):383–387.doi:10.1007/BF00435858.PMID6803285.
^Osborne PG, Ko YC, Wu MT, Lee CH (October 2017). "Intoxication and substance use disorder to Areca catechu nut containing betel quid: A review of epidemiological evidence, pharmacological basis and social factors influencing quitting strategies".Drug Alcohol Depend.179:187–197.doi:10.1016/j.drugalcdep.2017.06.039.PMID28787696.
^Yusuf H, Yong SL (July 2002). "Oral submucous fibrosis in a 12-year-old Bangladeshi boy: a case report and review of literature".International Journal of Paediatric Dentistry.12 (4):271–276.doi:10.1046/j.1365-263X.2002.00373.x.PMID12121538.
^abcWindholz M (1983).The Merck index: an encyclopedia of chemicals, drugs, and biologicals (10th ed.). Rahway, N.J., U.S.A.: Merck & Co. p. 113.ISBN978-0-911910-27-8.
^Saikia JR, Schneeweiss FH, Sharan RN (May 1999). "Arecoline-induced changes of poly-ADP-ribosylation of cellular proteins and its influence on chromatin organization".Cancer Letters.139 (1):59–65.doi:10.1016/S0304-3835(99)00008-7.PMID10408909.
^Fisher SK, Snider RM (July 1987). "Differential receptor occupancy requirements for muscarinic cholinergic stimulation of inositol lipid hydrolysis in brain and in neuroblastomas".Molecular Pharmacology.32 (1):81–90.doi:10.1016/S0026-895X(25)13765-6.PMID3600615.
^Mei L, Lai J, Yamamura HI, Roeske WR (February 1991). "Pharmacologic comparison of selected agonists for the M1 muscarinic receptor in transfected murine fibroblast cells (B82)".The Journal of Pharmacology and Experimental Therapeutics.256 (2):689–694.doi:10.1016/S0022-3565(25)22996-2.PMID1704434.
^Yen CY, Lin MH, Liu SY, Chiang WF, Hsieh WF, Cheng YC, et al. (May 2011). "Arecoline-mediated inhibition of AMP-activated protein kinase through reactive oxygen species is required for apoptosis induction".Oral Oncology.47 (5):345–351.doi:10.1016/j.oraloncology.2011.02.014.PMID21440488.
^Wang SW, Hwang GS, Chen TJ, Wang PS (August 2008). "Effects of arecoline on testosterone release in rats".American Journal of Physiology. Endocrinology and Metabolism.295 (2):E497 –E504.doi:10.1152/ajpendo.00045.2008.PMID18559981.
^Cox S, Ullah M, Zoellner H (January 2016). "Oral and systemic health effects of compulsive areca nut use.". In Preedy VR (ed.).Neuropathology of Drug Addictions and Substance Misuse; Volume 3: General Processes and Mechanisms, Prescription Medications, Caffeine and Areca, Polydrug Misuse, Emerging Addictions and Non-Drug Addictions. Academic Press. pp. 785–793.doi:10.1016/B978-0-12-800634-4.00078-0.ISBN978-0-12-800634-4.Animal models demonstrate that the primary sites for metabolism of arecoline are the liver (Giri et al., 2006; Nery, 1971) and kidneys (IARC, 2004).
^Cox S, Ullah M, Zoellner H (2016). "Oral and Systemic Health Effects of Compulsive Areca Nut Use". In Preedy VR (ed.).Neuropathology of Drug Addictions and Substance Misuse. pp. 785–793.doi:10.1016/B978-0-12-800634-4.00078-0.ISBN978-0-12-800634-4.
^Pan H, Li Y, Huang L, Zhou X, Lu Y, Shi F (May 2018). "Development and validation of a rapid LC-MS/MS method for simultaneous quantification of arecoline and its two active metabolites in rat plasma and its application to a pharmacokinetic study".Journal of Pharmaceutical and Biomedical Analysis.154:397–403.doi:10.1016/j.jpba.2018.03.033.PMID29573735.
^US 2506458, Howland KL, issued 2 May 1950, assigned to Nopco Chemical Co.
^Kozello IA, Gasheva AY, Khmelevskii VI (November 1976). "Improvement of the synthesis of arecoline from nicotinic acid".Pharmaceutical Chemistry Journal.10 (11):1515–1516.doi:10.1007/BF00760390.
^CN 105439941, Liu N, Li J, Liu C, published 30 March 2016, assigned to QINGDAO KANGYUAN PHARMACEUTICAL CO Ltd.
^Kozello IA, Khmelevskii VI, Gasheva AY, Birbaeva GN (November 1979). "An improved method of preparation of arecoline, starting from acetaldehyde (exchange of experience)".Pharmaceutical Chemistry Journal.13 (11):1158–1159.doi:10.1007/BF00778093.
^Ward Neal, process of the preparation of 3-substituted-4-aryl piperidine compounds, WO 0232870, 2002.
^Coffen, David L.; Hengartner, Urs; Katonak, David A.; Mulligan, Mary E.; Burdick, David C.; Olson, Gary L.; Todaro, Louis J. (1984). "Syntheses of an antipsychotic pyrrolo[2,3-g]isoquinoline from areca alkaloids". The Journal of Organic Chemistry 49 (26): 5109–5113. doi:10.1021/jo00200a019.
^Peter Moldt, Frank Watjen, & Jorgen Scheel-Kruger, WO1998051668 (to NTG Nordic Transport Group AS).
^Frank Wätjen, et al. WO2004039778 (to NTG Nordic Transport Group AS).
^abPaul SM, Yohn SE, Popiolek M, Miller AC, Felder CC (September 2022). "Muscarinic Acetylcholine Receptor Agonists as Novel Treatments for Schizophrenia".The American Journal of Psychiatry.179 (9):611–627.doi:10.1176/appi.ajp.21101083.PMID35758639.S2CID250070840.
^abChristie JE, Shering A, Ferguson J, Glen AI (January 1981). "Physostigmine and arecoline: effects of intravenous infusions in Alzheimer presenile dementia".The British Journal of Psychiatry.138 (1):46–50.doi:10.1192/bjp.138.1.46.PMID7023592.S2CID24009415.
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