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.
Studies have shown that other ingredients in inhaled tobacco smoke (as opposed to pure nicotine) inhibit the production of monoamine oxidase (MAO), 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.
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.
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, and beta-endorphin. This results in enhanced pleasure, decreased anxiety, and a state of alert relaxation. Nicotine appears to enhance concentration and learning 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. Most cigarettes (in the smoke inhaled) contain 0.1 to 2.8 milligrams of nicotine.
Research suggests that, when smokers wish to achieve a stimulating effect, they take short quick puffs, which produce a low level of blood nicotine. 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.
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.
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. 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. 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.
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.
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. 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, 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.
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, 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.
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". 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). 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. Smoking also appears to interfere with development of Kaposi's sarcoma, breast cancer among women carrying the very high risk BRCA gene, preeclampsia, and atopic disorders such as allergic asthma. 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.
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. Many such papers regarding Alzheimer's disease and Parkinson's Disease 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.
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.
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. More recent research has found the reverse, that it is a risk factor without long-term benefit, used only for its short term effects. 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.
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 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.