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Nicotine

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This article is about the chemical compound. For other uses, see Nicotine (disambiguation).
Nicotine
Clinical data
Dependence
liability		Medium to high
Routes of
administration		Smoked (as tobacco), Insufflated (as snuff), Chewed
ATC code
Legal status
Legal status
  • AU: Unscheduled
  • UK: Unscheduled
  • US: Unscheduled, but age restricted.
Pharmacokinetic data
Elimination half-life2 hours
Identifiers
  • (S)-3-(1-Methyl-2-pyrrolidinyl)pyridine
CAS Number
PubChem CID
ChemSpider
CompTox Dashboard (EPA)
ECHA InfoCard100.000.177 Edit this at Wikidata
Chemical and physical data
FormulaC10H14N2
Molar mass162.26 g/mol g·mol−1
3D model (JSmol)
Density1.01 g/cm3
Melting point−79 °C (−110 °F)
Boiling point247 °C (477 °F)
  • C1=CC=NC=C1[C@@H]2CCCN2C

Nicotine is an alkaloid found in the nightshade family of plants (Solanaceae) which constitutes approximately 0.6–3.0% of dry weight of tobacco,[1][2] with biosynthesis taking place in the roots, and accumulating in the leaves. It functions as an antiherbivore chemical with particular specificity to insects; therefore nicotine was widely used as an insecticide in the past, and currently nicotine analogs such as imidacloprid continue to be widely used.

In low concentrations (an average cigarette yields about 1 mg of absorbed nicotine), the substance acts as a stimulant in mammals and is one of the main factors responsible for the dependence-forming properties of tobacco smoking. According to the American Heart Association, "Nicotine addiction has historically been one of the hardest addictions to break." The pharmacological and behavioral characteristics that determine tobacco addiction are similar to those that determine addiction to drugs such as heroin and cocaine.[3]

History and name

Nicotine is named after the tobacco plant Nicotiana tabacum, which in turn is named after Jean Nicot de Villemain, French ambassador in Portugal, who sent tobacco and seeds from Brazil to Paris in 1560 and promoted their medicinal use. Nicotine was first isolated from the tobacco plant in 1828 by German chemists Posselt & Reimann.[citation needed] Its chemical empirical formula was described by Melsens in 1843,[4] its structure was discovered by Adolf Pinner in 1893, and it was first synthesized by A. Pictet and Crepieux in 1904.[citation needed]

Chemistry

Nicotine is a hygroscopic, oily liquid that is miscible with water in its base form. As a nitrogenous base, nicotine forms salts with acids that are usually solid and water soluble. Nicotine easily penetrates the skin. As shown by the physical data, free base nicotine will burn at a temperature below its boiling point, and its vapors will combust at 308K (35°C or 95°F) in air despite a low vapor pressure. Because of this, most of the nicotine is burned when a cigarette is smoked; however, enough is inhaled to provide the desired effects.

Optical activity

Nicotine is optically active. Natural nicotine is levorotatory, ([α]d = -166.4o). The salts of (-) nicotine are dextrorotatory. The dextrorotatory (+) nicotine has only one-half the physiological activity of natural (-) nicotine and is weaker only in the sense that a higher dose is required to attain the same effects as the other enantiomer.[5]

Pharmacology

Pharmacokinetics

As nicotine enters the body, it is distributed quickly through the bloodstream and can cross the blood-brain barrier. On average it takes about seven seconds for the substance to reach the brain when inhaled. The half life of nicotine in the body is around two hours.[6] The amount of nicotine inhaled with tobacco smoke is a fraction of the amount contained in the tobacco leaves. The amount of nicotine absorbed by the body from smoking depends on many factors, including the type of tobacco, whether the smoke is inhaled, and whether a filter is used. For chewing tobacco, dipping tobacco and snuff, which are held in the mouth between the lip and gum, or taken in the nose, the amount released into the body tends to be much greater than smoked tobacco. Nicotine is metabolized in the liver by cytochrome P450 enzymes (mostly CYP2A6, and also by CYP2B6). A major metabolite is cotinine.

Pharmacodynamics

Nicotine acts on the nicotinic acetylcholine receptors, specifically the ganglion type nicotinic receptor and one CNS nicotinic receptor. The former is present in the adrenal medulla and elsewhere, while the latter is present in the central nervous system (CNS). In small concentrations, nicotine increases the activity of these receptors. Nicotine also has effects on a variety of other neurotransmitters through less direct mechanisms.

In CNS

By binding to nicotinic acetylcholine receptors, nicotine increases the levels of several neurotransmitters - acting as a sort of "volume control". It is thought that the increased levels of dopamine in the reward circuits of the brain is what is responsible for the euphoria/pleasure, relaxation and eventual addiction caused by nicotine consumption.

Studies have shown that other ingredients in inhaled tobacco smoke (as opposed to pure nicotine) inhibit the production of monoamine oxidase (MAO),[7] an enzyme responsible for breaking down monoaminergic neurotransmitters in the brain (e.g. dopamine, norepinephrine, serotonin, etc.). The compounds responsible for this effect are beta-carboline alkaloids such as harmine and norharmine.

In PNS

Nicotine also activates the sympathetic nervous system,[8] acting via splanchnic nerves to the adrenal medulla, stimulates the release of epinephrine. Acetylcholine released by preganglionic sympathetic fibers of these nerves acts on nicotinic acetylcholine receptors, causing the release of epinephrine (and norepinephrine) into the bloodstream.

In adrenal medulla

By binding to ganglion type nicotinic receptors in the adrenal medulla nicotine increases flow of adrenaline (epinephrine), a stimulating hormone. By binding to the receptors, it causes cell depolarization and an influx of calcium through voltage-gated calcium channels. Calcium triggers the exocytosis of chromaffin granules and thus the release of epinephrine (and norepinephrine) into the bloodstream. The release of epinephrine (adrenaline) causes an increase in heart rate, blood pressure and respiration, as well as higher blood glucose levels[9]

Cotinine is a byproduct of the metabolism of nicotine which remains in the blood for up to 48 hours. It can therefore be used as an indicator of a person's exposure to smoke.[citation needed]

Psychoactive effects

Nicotine's mood-altering effects are different by report. First causing a release of glucose from the liver and epinephrine (adrenaline) from the adrenal medulla, it causes stimulation. Users report feelings of relaxation, sharpness, calmness, and alertness.[10] By reducing the appetite and raising the metabolism, some smokers may lose weight as a consequence.[11][12]

When a cigarette is smoked, nicotine-rich blood passes from the lungs to the brain within seven seconds and immediately stimulates the release of many chemical messengers including acetylcholine, norepinephrine, epinephrine, vasopressin, arginine, dopamine, autocrine agents, and beta-endorphin[citation needed]. This results in enhanced pleasure[citation needed], decreased anxiety[citation needed], and a state of alert relaxation[citation needed]. Nicotine appears to enhance concentration[13] and learning[citation needed] due to the increase of acetylcholine. It also appears to enhance alertness due to the increases of acetylcholine and norepinephrine. Arousal is increased by the increase of norepinephrine. Pain is reduced by the increases of acetylcholine and beta-endorphin. Anxiety is reduced by the increase of beta-endorphin. Nicotine also sensitises brain reward systems.[14] Most cigarettes (in the smoke inhaled) contain 0.1 to 2.8 milligrams of nicotine.[15]

Research suggests that, when smokers wish to achieve a stimulating effect, they take short quick puffs, which produce a low level of blood nicotine.[16] This stimulates nerve transmission. When they wish to relax, they take deep puffs, which produce a high level of blood nicotine, which depresses the passage of nerve impulses, producing a mild sedative effect. At low doses, nicotine potently enhances the actions of norepinephrine and dopamine in the brain, causing a drug effect typical of those of psychostimulants. At higher doses, nicotine enhances the effect of serotonin and opiate activity, producing a calming, pain-killing effect. Nicotine is unique in comparison to most drugs, as its profile changes from stimulant to sedative/pain killer in increasing dosages and use.

A 21 mg patch applied to the left arm

Nicotine gum, usually in 2-mg or 4-mg doses, and nicotine patches are available, that do not have all the other ingredients in smoked tobacco.

Dependence

See also: Smoking cessation

Modern research shows that nicotine acts on the brain to produce a number of effects. Specifically, its addictive nature has been found to show that nicotine activates reward pathways—the circuitry within the brain that regulates feelings of pleasure and euphoria.[17]

To reduce the health effects of cigarette smoking, the best thing to do is to quit. Public health authorities do not endorse either smoking fewer cigarettes or switching to lower tar and nicotine brands as a satisfactory way of reducing risk.[18]

Dopamine is one of the key neurotransmitters actively involved in the brain. Research shows that by increasing the levels of dopamine within the reward circuits in the brain, nicotine acts as a chemical with intense addictive qualities. In many studies it has been shown to be more addictive than cocaine and heroin, though chronic treatment has an opposite effect on reward thresholds. Like other physically addictive drugs, nicotine causes down-regulation of the production of dopamine and other stimulatory neurotransmitters as the brain attempts to compensate for artificial stimulation. In addition, the sensitivity of nicotinic acetylcholine receptors decreases. To compensate for this compensatory mechanism, the brain in turn upregulates the number of receptors, convoluting its regulatory effects with compensatory mechanisms meant to counteract other compensatory mechanisms. The net effect is an increase in reward pathway sensitivity, opposite of other drugs of abuse such as cocaine and heroin, which reduce reward pathway sensitivity.[19] This neuronal brain alteration persists for months after administration ceases. Due to an increase in reward pathway sensitivity, nicotine withdrawal is relatively mild compared to ethanol or heroin withdrawal.[citation needed] Nicotine also has the potential to cause dependence in many animals other than humans. Mice have been administered nicotine and exhibit withdrawal reactions when its administration is stopped.[citation needed]

A study found that nicotine exposure in adolescent mice retards the growth of the dopamine system, thus increasing the risk of substance abuse during adolescence.[20]

Toxicology

The LD50 of nicotine is 50 mg/kg for rats and 3 mg/kg for mice. 40–60 mg (0.5-1.0 mg/kg) can be a lethal dosage for adult humans.[21][22] This designates nicotine as an extremely deadly poison. It is more toxic than many other alkaloids such as cocaine, which has an LD50 of 95.1 mg/kg when administered to mice. Spilling a sufficient concentration of nicotine onto the skin can result in poisoning or even death since Nicotine readily passes into the bloodstream from dermal contact.[23]

The carcinogenic properties of nicotine in standalone form, separate from tobacco smoke, have not been evaluated by the IARC, and it has not been assigned to an official carcinogen group. The currently available literature indicates that nicotine, on its own, does not promote the development of cancer in healthy tissue and has no mutagenic properties, but does speed growth and migration of existing cancerous cells, as well as turning some precancerous cells cancerous.[24] Its teratogenic properties have not yet been adequately researched, and while the likelihood of birth defects caused by nicotine is believed to be very small or nonexistent, nicotine replacement product manufacturers recommend consultation with a physician before using a nicotine patch or nicotine gum while pregnant or nursing. However, nicotine and the increased cholinergic activity it causes have been shown to impede apoptosis,[citation needed][25] which is one of the methods by which the body destroys unwanted cells (programmed cell death). Since apoptosis helps to remove mutated or damaged cells that may eventually become cancerous, the inhibitory actions of nicotine may create a more favourable environment for cancer to develop, though this also remains to be proven.[citation needed]

Nicotine and oxidative stress

Nicotine is detoxified by the cytochrome p450 in the liver.

Nicotine has very powerful effects on arteries throughout the body. Nicotine is a stimulant, speeding up the heart by about 20 beats per minute with every cigarette; it raises blood pressure, and is a vasoconstrictor, making it harder for the heart to pump through the constricted arteries. It causes the body to release its stores of fat and cholesterol into the blood.

Nicotine has been speculated to increase the risk of blood clots by increasing plasminogen activator inhibitor-1, though this has not been proven. Plasma fibrinogen levels are elevated in smokers and are further elevated during acute COPD exacerbation. Also, Factor XIII, which stabilizes fibrin clots, is increased in smokers. But neither of the two previous effects have been shown yet to be caused by nicotine, [4] If blood clots in an artery, blood flow is reduced or halted, and tissue loses its source of oxygen and nutrients and dies in minutes.

Peripheral circulation, arteries going to the extremities, are also highly susceptible to the vasoconstrictor effects of nicotine as well as the increased risk of clots and clogging.[citation needed]

Therapeutic uses

The primary therapeutic use of nicotine is in treating nicotine dependence in order to eliminate smoking with its risks to health. Controlled levels of nicotine are given to patients through gums, dermal patches, lozenges, electronic/substitute cigarettes or nasal sprays in an effort to wean them off their dependence.

However, in a few situations, smoking has been observed to apparently be of therapeutic value to patients. These are often referred to as "Smoker’s Paradoxes".[26] Although in most cases the actual mechanism is understood only poorly or not at all, it is generally believed that the principal beneficial action is due to the nicotine administered, and that administration of nicotine without smoking may be as beneficial as smoking, without the higher risk to health due to tar and other ingredients found in tobacco.

For instance, recent studies suggest that smokers require less frequent repeated revascularization after percutaneous coronary intervention (PCI).[26] Risk of ulcerative colitis has been frequently shown to be reduced by smokers on a dose-dependent basis; the effect is eliminated if the individual stops smoking.[27][28] Smoking also appears to interfere with development of Kaposi's sarcoma,[29] breast cancer among women carrying the very high risk BRCA gene,[30] preeclampsia,[31] and atopic disorders such as allergic asthma.[32] A plausible mechanism of action in these cases may be nicotine acting as an anti-inflammatory agent, and interfering with the inflammation-related disease process, as nicotine has vasoconstrictive effects.[33]

With regard to neurological diseases, a large body of evidence suggests that the risks of Parkinson's disease or Alzheimer's disease might be twice as high for non-smokers than for smokers.[34] Many such papers regarding Alzheimer's disease[35] and Parkinson's Disease[36] have been published. More recent studies find that there's no beneficial link between smoking and Alzheimer's, and in some cases suggest that it actually results in an earlier onset of the disease.[37][38][39][40]

Recent studies have indicated that nicotine can be used to help adults suffering from Autosomal dominant nocturnal frontal lobe epilepsy. The same areas that cause seizures in that form of epilepsy are also responsible for processing nicotine in the brain.[41]

It has been noted that the majority of people diagnosed with schizophrenia smoke tobacco. Estimates for the number of schizophrenics that smoke range from 75% to 90%. It was recently argued that the increased level of smoking in schizophrenia may be due to a desire to self-medicate with nicotine.[42][43] More recent research has found the reverse, that it is a risk factor without long-term benefit, used only for its short term effects.[44] All of these studies are based only on observation, and no interventional (randomized) studies have been done. Research on nicotine as administered through a patch or gum is ongoing.

Research as a potential basis for an antipsychotic agent

However, when the metabolites of nicotine were isolated and their effect on first the animal brain and then the human brain in people with schizophrenia were studied, it was shown that the effects helped with cognitive and negative symptoms of schizophrenia. Therefore, the nicotinergic agents, as antipsychotics which do not contain nicotine but act on the same receptors in the brain are showing promise as adjunct antipsychotics in early stages of FDA studies on schizophrenia. "The prepulse inhibition (PPI) is a phenomenon in which a weak prepulse attenuates the response to a subsequent startling stimulus. Therefore, PPI is believed to have face, construct, and predictive validity for the PPI disruption in schizophrenia, and it is widely used as a model to study the neurobiology of this disorder and for screening antipsychotics. The prepulse inhibition (PPI) is a phenomenon in which a weak prepulse attenuates the response to a subsequent startling stimulus. Alpha7 nicotinic receptor agonists have reported to reverse the PPI disruption." Department of Clinical Pharmacology and Pharmacy, Neuroscience, Ehime University Graduate School of Medicine, Shitsukawa, Toon 791-0295, Japan. [email protected]

Additionally, studies have shown that there are genes predisposing people with schizophrenia to nicotine. "Evidence of association between smoking and alpha7 nicotinic receptor subunit gene in schizophrenia patients" .De Luca V, Wong AH, Muller DJ, Wong GW, Tyndale RF, Kennedy JL. Neurogenetics Section, Clarke Site, Centre for Addiction and Mental Health, Department of Psychiatry, Toronto, Ontario, Canada.

Therefore with these factors taken together the heavy usage of cigarettes and other nicotine related products among people with schizophrenia may be explained and novel antipsychotic agents developed that have these effects in a manner that is not harmful and controlled and is a promising arena of research for schizophrenia.

Nicotine and its metabolites are being researched for the treatment of a number of disorders, including ADHD, Schizophrenia and Parkinson's Disease.[45]

The therapeutic use of nicotine as a means of appetite-control and to promote weight loss is anecdotally supported by many ex-smokers who claim to put on weight after quitting. Studies of nicotine in mice[46] suggest it may play a role in weight-loss that is independent of appetite and studies involving the elderly suggest that nicotine affects not only weight loss, but also prevents some weight gain.[47]

See also

References

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  2. ^ "Smoking and Tobacco Control Monograph No. 9" (PDF).
  3. ^ American Heart Association and Nicotine addiction.
  4. ^ Melsens (1844). "Ueber das Nicotin". Journal für Praktische Chemie. 32 (1): 372–377. doi:10.1002/prac.18440320155.
  5. ^ "Optical activity and living matter".
  6. ^ "Interindividual variability in the metabolism and cardiovascular effects of nicotine in man".
  7. ^ Fowler JS, Volkow ND, Wang GJ, Pappas N, Logan J, MacGregor R, Alexoff D, Wolf AP, Warner D, Cilento R, Zezulkova I (1998). "Neuropharmacological actions of cigarette smoke: brain monoamine oxidase B (MAO B) inhibition". Journal of addictive diseases. PMID 9549600.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  8. ^ Paper published on PubMed
  9. ^ Elaine N. Marieb and Katja Hoehn (2007). Human Anatomy & Physiology (7th Ed.). Pearson. pp. ?. ISBN 0-805-35909-5.
  10. ^ Gilbert Lagrue, François Lebargy, Anne Cormier, "From nicotinic receptors to smoking dependence: therapeutic prospects" Alcoologie et Addictologie Vol. : 23, N° : 2S, juin 2001, pages 39S - 42
  11. ^ Jean-Claude Orsini, "Dependence on tobacco smoking and brain systems controlling glycemia and appetite" Alcoologie et Addictologie Vol. : 23, N° : 2S, juin 2001, pages 28S - 36S
  12. ^ Smokers lose their appetite : Media Releases : News : The University of Melbourne
  13. ^ Rusted, J (1994-5-5). "Does nicotine improve cognitive function?". Psychopharmacology (115). Springer-Verlag: 547–549. Retrieved 2008-11-15. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  14. ^ Kenny PJ, Markou A. "Nicotine self-administration acutely activates brain reward systems and induces a long-lasting increase in reward sensitivity". However, these effects are an illusion brought about by Nicotine addiction. What appears to be relaxation, is merely the effect of ending the craving for Nicotine. The longer the periods between Nicotine intake, the greater the illusion of pleasure will be. Neuropsychopharmacology (2006) 31, 1203–1211.
  15. ^ Erowid Nicotine Vault : Dosage
  16. ^ Einstein, Stanley (1989). Drug and Alcohol Use: Issues and Factors. Springer. pp. 101–118. ISBN 0306413787.
  17. ^ NIDA - Research Report Series - Tobacco Addiction - Extent, Impact, Delivery, and Addictiveness
  18. ^ Smoking & Health Issues - Philip Morris USA
  19. ^ [1]
  20. ^ Nolley E.P. & Kelley B.M. "Adolescent reward system perseveration due to nicotine: Studies with methylphenidate.," Neurotoxicol Teratol., 2006 Oct 4
  21. ^ Okamoto M., Kita T., Okuda H., Tanaka T., Nakashima T. (1994). "Effects of aging on acute toxicity of nicotine in rats". Pharmacol Toxicol. 75 (1): 1–6.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  22. ^ IPCS INCHEM
  23. ^ Lockhart LP (1933). Nicotine poisoning (letter). Br Med J 1:246-247
  24. ^ http://www.nlm.nih.gov/medlineplus/news/fullstory_70531.html
  25. ^ "Toxicology". Retrieved 2008-10-05. {{cite web}}: Text "eBasedTreatment" ignored (help)
  26. ^ a b Cohen, David J. (2001). "Impact of Smoking on Clinical and Angiographic Restenosis After Percutaneous Coronary Intervention". Circulation. 104: 773. Retrieved 2006-11-06. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  27. ^ Longmore, M., Wilkinson, I., Torok, E. Oxford Handbook of Clinical Medicine (Fifth Edition) p. 232
  28. ^ Green, JT (November, 2000). "Nitric oxide mediates a therapeutic effect of nicotine in ulcerative colitis". Aliment Pharmacol Ther. 14 (11): 1429–1434. PMID 11069313 : 11069313. Retrieved 2006-11-06. {{cite journal}}: Check |pmid= value (help); Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  29. ^ "Smoking Cuts Risk of Rare Cancer". UPI. March 29, 2001. Retrieved 2006-11-06. {{cite news}}: Cite has empty unknown parameter: |coauthors= (help)
  30. ^ Recer, Paul (May 19, 1998). "Cigarettes May Have an Up Side". AP. Retrieved 2006-11-06. {{cite news}}: Cite has empty unknown parameter: |coauthors= (help)
  31. ^ Lain, Kristine Y. (November 1991). "Urinary cotinine concentration confirms the reduced risk of preeclampsia with tobacco exposure". American Journal of Obstetrics and Gynecology. 181 (5): 908–14. PMID 11422156 : 11422156. Retrieved 2006-11-06. {{cite journal}}: Check |pmid= value (help); Unknown parameter |coauthors= ignored (|author= suggested) (help); line feed character in |coauthors= at position 79 (help)
  32. ^ Hjern, A (June 2001). "Does tobacco smoke prevent atopic disorders? A study of two generations of Swedish residents". Clin Exp Allergy. 31 (6): 908–914. PMID 11422156 : 11422156. Retrieved 2006-11-06. {{cite journal}}: Check |pmid= value (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  33. ^ Lisa Melton (June 2006). "Body Blazes". Scientific American: p.24. {{cite journal}}: |pages= has extra text (help)
  34. ^ Fratiglioni, L (August 2000). "Smoking and Parkinson's and Alzheimer's disease: review of the epidemiological studies". Behav Brain Res. 113 (1–2): 117–120. PMID 10942038 : 10942038. Retrieved 2006-11-06. {{cite journal}}: Check |pmid= value (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  35. ^ Thompson, Carol. "Alzheimer's disease is associated with non-smoking". Retrieved 2006-11-06. {{cite web}}: Cite has empty unknown parameter: |coauthors= (help)
  36. ^ Thompson, Carol. "Parkinson's disease is associated with non-smoking". Retrieved 2006-11-06. {{cite web}}: Cite has empty unknown parameter: |coauthors= (help)
  37. ^ "Alzheimer's Starts Earlier for Heavy Drinkers, Smokers". Reuters. 2008-17-04. Retrieved 2008-27-06. {{cite web}}: Check date values in: |accessdate= and |date= (help); Cite has empty unknown parameter: |coauthors= (help)
  38. ^ Peck, Peggy (2002-25-07). "Smoking Significantly Increases Risk of Alzheimer's Disease Among Those Who Have No Genetic Predisposition". Retrieved 2008-27-06. {{cite web}}: Check date values in: |accessdate= and |date= (help); Cite has empty unknown parameter: |coauthors= (help)
  39. ^ Aggarwal, Neelum, "The Relation of Cigarette Smoking to Incident Alzheimer's Disease in a Biracial Urban Community Population", Neuroepidemiology, 26 (3): 140–146, doi:2006, retrieved 2008-27-06 {{citation}}: Check |doi= value (help); Check date values in: |accessdate= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  40. ^ Lerche Davis,, Jeanie (2004-22-03). "Smoking Speeds Dementia, Alzheimer's Disease". Retrieved 2008-27-06. {{cite web}}: Check date values in: |accessdate= and |date= (help)CS1 maint: extra punctuation (link)
  41. ^ "Nicotine as an antiepileptic agent in ADNFLE: An n-of-one study".
  42. ^ Schizophr. Res. 2002
  43. ^ Am. J. Psychiatry 1995
  44. ^ Br. J. Psychiatry 2005
  45. ^ "Attention-Deficit Hyperactivity Disorder". Reuters Health. Reuters. 2001. Archived from the original on 2006-04-26. Nicotine improves ADHD symptoms. Although such findings should certainly not encourage anyone to smoke, some studies are focusing on benefits of nicotine therapy in adults with ADHD. {{cite web}}: Unknown parameter |month= ignored (help)
  46. ^ NIH, online at [2]
  47. ^ Cigarette Smoking and Weight Loss in Nursing Home Residents [3]


45. Nihon Shinkei Seishin Yakurigaku Zasshi. 2008 Jun;28(3):121-6

46. Neuropsychopharmacology. 2004 Aug;29(8):1522-6.

Further reading

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