Gross formula

C 10 H 14 N 2

Pharmacological group of the substance Nicotine

Nosological classification (ICD-10)

CAS Code

54-11-5

Characteristics of the substance Nicotine

Alkaloid of tobacco leaves. It is a component of tobacco smoke, being in it mainly in an ionized form, insoluble in lipids.

Pharmacology

pharmachologic effect- n-cholinomimetic.

Interacts with peripheral (including those located in the sinocarotid zone, autonomic ganglia, adrenal medulla and neuromuscular plates) and central n-cholinergic receptors. In low concentrations it excites them, in high concentrations it blocks them. In the ganglia, the first phase (excitation) is associated with depolarization of the membranes of ganglionic neurons, the second (inhibition) is associated with competitive antagonism with acetylcholine. In the central nervous system, it influences the content and modulates the release of acetylcholine, norepinephrine, serotonin and other mediators in the terminals of neurons. Reduces the secretion of growth hormone and gonadotropins, increases the secretion of catecholamines and ADH. Promotes the release of endorphins. The effect on the central nervous system (excitation or depression) depends on the doses, the intervals between them and the psychological state of the person. Small doses excite the central nervous system, incl. vomiting center Nicotine can cause tremors and seizures. Stimulates the respiratory center (reflexively from the chemoreceptors of the sinocarotid zone and directly).

The effect on the cardiovascular system is due to the activation of sympathetic influences: tachycardia (ventricular extrasystole is possible), increased blood pressure, impaired blood supply to organs and tissues (vasoconstriction), hypernorepinephrine, increased glycogenolysis, etc. Nicotine increases cardiac output, enhances heart function and increases oxygen consumption myocardium. Activation of the parasympathetic ganglia leads to increased secretion (of bronchial glands and acidic gastric juice) and tone of smooth muscles of the bronchi and gastrointestinal tract. Facilitates neuromuscular transmission. Increases the content of fatty acids in the blood and the adhesive ability of platelets.

The effect on internal organs of small doses of nicotine entering the body during smoking is mainly due to the reflex effect (stimulation of chemoreceptors of the carotid sinus and aortic arch). Addiction to nicotine gradually develops.

Well absorbed from mucous membranes (bioavailability depends on pH). Ionized nicotine contained in cigarette smoke is poorly soluble in lipids, and its absorption in sufficient quantities is possible only in the lungs (large absorption surface). Non-ionized nicotine (pH 8.5) from pipe tobacco and cigar smoke is alkaline and is quickly absorbed in the mouth (not inhaled). The amount of nicotine absorbed by smokers varies from 90% (for those who inhale smoke) to 10% (for those who do not inhale it). T 1/2 from plasma - 2 hours. Most of it is converted to biologically inert substances in the liver, as well as in the kidneys and lungs. Metabolic products and a small amount of unchanged alkaloid are excreted in the urine in the first 10-15 hours.

Nicotine (smoking or chewing tobacco) contributes to the development of mental dependence, coronary artery disease, lung cancer, chronic bronchitis, emphysema and other diseases. People who sniff tobacco have an increased risk of developing nasal cancer, and those who chew tobacco are more likely to develop oral cancer. The increased risk of death (compared to nonsmokers) decreases after smoking cessation and after 10–15 years reaches approximately the same level as nonsmokers. In smokers, the degree of atherosclerotic narrowing of the smallest coronary arteries significantly increases, the ability of platelets to adhere to and the likelihood of developing thrombosis increases, and blood viscosity increases as a result of polycythemia. Chronic hypersecretion of mucus, accompanied by cough with sputum, contributes to the development of chronic bronchitis, obstructive pulmonary diseases and predisposes to lung cancer. Smoking slows down the healing of ulcers and increases the frequency of relapses of gastric ulcers, reduces immunity and increases susceptibility to infectious diseases. Women who smoke are less likely to become pregnant. During pregnancy, the risk of spontaneous abortion (as a result of oxygen deficiency in the blood) and disturbances in the development of the placenta associated with a large amount of abnormal DNA in it increases. Maternal smoking in the first three years of a child’s life increases the incidence of lung diseases and respiratory infections.

Use of the substance Nicotine

Treatment of tobacco/nicotine addiction:

Reducing withdrawal symptoms that occur with complete cessation of smoking in patients who decide to quit smoking;

With a temporary cessation of smoking;

To reduce the number of cigarettes smoked by those who cannot or do not want to completely quit smoking.

Contraindications

Hypersensitivity, erosive and ulcerative lesions of the gastrointestinal tract in the acute phase, unstable angina, severe arrhythmia, ischemic stroke or cerebrovascular accident (recently suffered), pregnancy, breastfeeding; for chewing gum - diseases of the temporomandibular joint (in active form), inflammatory diseases of the oral cavity and pharynx.

Restrictions on use

Uncontrolled arterial hypertension, impaired liver function, severe renal failure, uncontrolled hyperthyroidism, pheochromocytoma (due to the fact that nicotine causes the release of catecholamines from the adrenal medulla), diabetes mellitus, age under 18 years.

Use during pregnancy and breastfeeding

Nicotine penetrates into mother's milk and can create a high concentration in it, sufficient for the development of intoxication, incl. respiratory arrest in a child.

Side effects of the substance Nicotine

From the nervous system and sensory organs: dizziness, headache, anxiety.

From the gastrointestinal tract: gastrointestinal discomfort, nausea, vomiting, hiccups, irritation of the oral mucosa and upper respiratory tract, stomatitis, pain in the masticatory muscles, soreness or irritation of the tongue.

Others: pain in the throat or in the oral cavity, tachycardia, arrhythmia, allergic reactions, incl. skin

Overdose

Symptoms of acute nicotine poisoning: hypersalivation, nausea, vomiting, diarrhea, tachycardia, increased blood pressure, shortness of breath, respiratory depression, dilated pupils, visual impairment, hearing impairment, convulsions, possible death as a result of paralysis of the respiratory center.

Treatment: aimed at maintaining breathing (artificial respiration until nicotine detoxification).

Chronic poisoning is usually associated with tobacco smoking and is characterized by a variety of symptoms. Typical are inflammatory processes of the mucous membranes of the respiratory tract (including chronic bronchitis), hypersalivation, decreased acidity of gastric juice and increased motility of the large intestine.

Nicotine is the best known and one of many alkaloids found naturally in tobacco. Nicotine itself is present in many other nightshade plants, such as eggplants and peppers, but in minimal quantities. The effect of pure nicotine isolated from tobacco products or cigarettes is significantly different from the effect of tobacco itself, and in any case should be considered as the effect of a separate substance. Essentially, nicotine has multiple mechanisms of action. The first is that it mimics the action of the neurotransmitter acetylcholine and can directly activate acetylcholine receptors, which can then induce an increase in catecholamines such as adrenaline and dopamine. This mechanism underlies both the potential addiction to nicotine and the fat burning mechanism. Nicotine may also act as an anti-estrogen compound by directly inhibiting aromatase and one of the two estrogen receptors, which may underlie some of the side effects associated with chronic nicotine use, especially in women. Finally, nicotine by its nature causes oxidative stress, but at a level that is hormesis for the cell. This refers to the mimicking action of acetylcholine mentioned earlier and the anti-inflammatory effect. It is very likely that, due to its mechanisms of action on the body, nicotine is a fat burner, since as a result of its effects, the level of adrenaline increases, which then acts on beta-adrenergic receptors (the molecular target of ephedrine). Increased adrenaline levels mediate a significant but short-lived increase in metabolic rate in a moderate nicotine user. It is believed that the increase in the rate of lipolysis (breakdown of fatty acids) is not associated with adrenaline, but indirectly by other mechanisms, possibly causing oxidative stress. Increased levels of catecholamines also underlie many of the cognitive benefits of nicotine (mostly related to increased alertness and focus), while mimicking the effects of acetylcholine may contribute to the inherently nootropic effects. In relation to addiction, one can say that the risk of addiction is determined by the relationship between how much nicotine a person takes (the higher the amount, the greater the risk) and the speed at which nicotine reaches the brain (the faster the concentration of nicotine in the brain increases, the stronger the effects are felt and the higher risk of addiction). Dependence is not an inherent characteristic of nicotine, as evidenced by the results of nicotine therapy used to curb cigarette addiction. Gum and patches have less potential for addiction than cigarettes due to the speed at which nicotine reaches the brain. In the short term, due to the increase in catecholamine levels, the potential side effects of nicotine are similar to the acute side effects of other stimulants such as, or. In the long term, nicotine may rival ephedrine in its side effect profile, as they both suppress catecholamine secretion levels over time (yohimbe and caffeine lose their effectiveness within two weeks or less).

Nicotine: methods of use (recommended dosage, active quantities, other details)

Nicotine can be introduced into the body in several ways (excluding cigarettes, which are not recommended due to the risks that significantly outweigh the benefits of this method of taking nicotine):

An inhaler that allows you to quickly feel the effects of nicotine (and which inherently carries more risk than other methods due to the speed at which nicotine enters the body);

A nicotine patch that delays absorption for about an hour after application. The patch allows you to maintain a constant level of nicotine in the blood serum, but causes a smaller cognitive leap (minimal risk potential, minimal nootropic potential);

Chewing gum, the advantages and disadvantages of which are somewhere in between compared to the methods described above.

There is currently no evidence regarding the “optimal dose” of nicotine for a non-smoker. A non-smoker would be wise to follow the same directions as when taking stimulants, that is, start with small doses and increase gradually. This involves purchasing two-milligram gummies or a quarter of a 24-milligram patch to start and then increasing to what appears to be the minimum effective dose. At the moment there is no designated threshold level when the risk becomes too great, since this level is individual. When using nicotine in nicotine replacement therapy (to curb the craving for smoking), it is sufficient to follow the instructions for using the product. The amounts described in these instructions may be excessive for a non-smoker.

Sources and structure

Cigarettes and other sources

Nicotine is the main alkaloid in tobacco (minor alkaloids are nornicotine, anatabine, anabasine) and is present in tobacco leaves as a pesticide that kills insects that try to feed on them (the phytoalexins resveratrol and caffeine have a similar origin). Nicotine accounts for up to 1.5% of the total weight of commercial cigarette tobacco and 95% of its total alkaloid content. The average cigarette contains 10-14 mg of nicotine, but only 1-1.5 mg reaches the bloodstream after smoking. Most of the alkaloids found in tobacco are found only in tobacco and are structurally similar to nicotine, including myosmin, N"-methylmyosmin, cotinine, nicotirine, nornicotirine, nicotine N"-oxide, 2, 3"-bipyridyl, and metanicotine. Myosmin is not unique. alkaloid of tobacco and is quite widespread in the human diet, as is nicotine, which is present in small quantities in plants of the nightshade family (2-7 mcg/kg of vegetables).The average amount of nicotine that a person receives through vegetables from the nightshade family is at the level 1.4mcg per day, 95 percent of the population gets no more than 2.25mcg of nicotine from the vegetables they eat. This is about 444 times less than the amount of nicotine contained in one cigarette. Nicotine is the main alkaloid in tobacco. It is also present in plants of the nightshade family, such as eggplant, potatoes and tomatoes, but in such small quantities that it cannot cause the neurological effects that smoking does.

Pharmacology of nicotine

Absorption when smoking

Under normal conditions, nicotine is a weak base with a pKa = 8.0 and in acidic environments, where nicotine is usually in an ionized state, it cannot easily penetrate membranes. Smoke from warm air-dried cigarettes (pH 5.5-6.0) is in most cases acidic, so nicotine cannot easily pass through the oral mucosa. Some amount of nicotine can still pass through the mucous membrane, because Nicotine tar drops may have a higher pH level, but the majority of absorption in the case of tobacco smoking occurs in the respiratory tract. Nicotine can pass through the oral mucosa at elevated pH levels. This refers to air-cured tobacco, which is commonly used in pipes and cigars (different from the already mentioned warm air-cured tobacco of North American cigarettes). The nicotine in such tobacco is usually non-ionizing and can pass through the oral mucosa. In the mouth, nicotine can pass through the oral mucosa if the environment (tobacco smoke) is alkaline. This environment is typical for pipe tobacco, cigars and nicotine gum. In the lungs, nicotine is absorbed when it comes into contact with the alveoli. The rate of absorption is believed to be high due to the large area of ​​the alveoli and because the pH in the lungs is 7.4, which facilitates the transport of nicotine across the membrane. Nicotine is rapidly absorbed in the lung tissues.

Suction (other types)

Chewing tobacco, nicotine gum, and snuff have special pH-increasing substances added to help facilitate the passage of nicotine through the oral mucosa. The same substances are added to the nicotine patch to improve the absorption of nicotine by the skin. The overall bioavailability of nicotine in nicotine gum is less than with inhalation and is approximately 50-80%. Less bioavailability is due to the absorption of nicotine in the intestine, which enters there along with swallowed saliva under conditions of first-pass metabolism. Nicotine patches vary in absorption depending on the brand, although any patch usually delivers nicotine into the bloodstream within an hour of being applied. Residues of nicotine (10% of the patch content) still enter the bloodstream after the patch has been peeled off. This nicotine enters the bloodstream from the skin soaked in nicotine.

Pharmacokinetics in the bloodstream

Some studies of cigarette smoking show that Tmax (the time to reach the maximum concentration of nicotine in the blood) coincides with the end of smoking the cigarette, while for chewing tobacco and snuff the corresponding time is slightly longer (difficult to titrate), and chewing nicotine gum does not achieve this The same maximum concentration of nicotine in the blood as an equivalent dose of nicotine obtained from smoking cigarettes or using chewing tobacco. The first maximum effect of cigarette nicotine on the nervous system occurs within 10-20 seconds after a puff, however, the exact amount of nicotine a person receives during this time may vary, since the puffs themselves can be different (they can be large or small, their speed can be different , may be affected by how much air is diluted in the puff), although the average amount of nicotine reaching the systemic circulation for a typical smoker who prefers average North American cigarettes is 1-1.5 milligrams. Smoking cigarettes leads to a very rapid increase in the concentration of nicotine in the bloodstream. It is estimated that chewing gum containing 6 milligrams of nicotine increases blood nicotine levels by 15 to 20 nanograms/milliliter, while smoking a cigarette can increase blood levels by 15 to 30 nanograms/milliliter.

Distribution

A pH level of 7.4 in the blood indicates that nicotine is in a state where the ratio of its ionized to non-ionized part is 69:31, and its binding to blood plasma proteins is less than 5%. The average steady-state volume of distribution of nicotine is 2.6 liters/kg. Nicotine is widely distributed throughout the body. Organs with the greatest affinity for nicotine are the liver, kidneys, spleen and lungs; the smallest is adipose tissue. This was determined through autopsies of smokers. The concentration of nicotine in skeletal muscles and in the blood is the same. In smokers, compared to non-smokers, nicotine may bind to brain tissue with greater affinity and have an increased ability to bind to the receptor. Nicotine accumulates in body fluids, especially saliva and gastric juice, due to ion scavenging, and can also accumulate in breast milk at a ratio of 2.9:1 (milk:plasma). In addition, it readily crosses the placental barrier and can accumulate in the amniotic fluid in concentrations slightly higher than serum concentrations and can penetrate the fetus.

Neurokinetics

Due to the rapid passage of smoke into the lungs, as well as rapid absorption into them, nicotine can be contained in the brain tissue 10-20 seconds after a cigarette puff, which is faster than with an intravenous injection. The rapid delivery of nicotine to the brain, as well as the potential for nicotine to cause addiction (context of reward), and, in addition, the ability of the smoker to control the smoking process in accordance with their own preferences, make cigarettes the most dangerous method of nicotine consumption in terms of addiction. The volume of distribution of nicotine in plasma (100% is taken as the volume of distribution in non-brain plasma) is about 20% for the whole brain (negligible, as shown by the primate study in which this value was obtained) with a predominant distribution in the previsual field ( 29%) and amygdala (39%) and less widespread in the white matter (10%). However, the study that produced these findings used an aromatase inhibitor for the assessment, whereas in primates the distribution of aromatase rivals that reported above (although in humans large amounts of aromatase are found in the thalamus). Nicotine intake by smoking cigarettes is, from a neurological point of view, the most effective method of introducing nicotine into the body due to its pharmacokinetics and the ability of the smoker to control the nicotine entering the body according to individual needs.

Metabolism

Nicotine undergoes extensive metabolism through various pathways, but the main route of nicotine metabolism is through cotinine (70-80%). Despite the fact that 10-15% of all nicotine metabolic products excreted in urine is cotinine, the main metabolism occurs through cotinine, and cotinine itself undergoes further metabolization. The direct conversion of nicotine to cotinine occurs through the participation of an intermediary. This mediator is ionized nicotine-Δ1"(5")-iminium, the conversion of nicotine into which occurs due to the P450 enzyme CYP2A6. Further conversion to cotinine occurs due to cytoplasmic aldehyde oxidase. Cotinine can subsequently be glucuronidated and excreted in the urine as cotinine glucuronide, or can be transformed into cotinine-N-oxide or trans 3-hydroxycotinine (which can then also be glucuronidated and excreted in the urine). It should also be noted that nicotine itself can be glucuronidated and excreted in urine as nicotine glucuronide. This process occurs with 3-5% of the total amount of nicotine that enters the human body. It is believed that in addition to 10-15% of nicotine metabolized through cotinine and 3-5% of nicotine metabolized by glucuronidation, the remaining metabolic products are trans-3-hydroxycotinine (the most significant metabolite, 33-40% of metabolism), cotinine glucuronide (12-17 %) and trans 3-hydroxycotinine glucuronide (7-9%). The main route of nicotine metabolism is through cotinine. Cotinine is then either excreted unchanged in detectable amounts or it is further metabolized. Both nicotine or cotinine and cotinine metabolites can undergo glucuronidation (attachment of glucose to a molecule). Another phenomenon responsible for 4-7% of metabolism is nicotine N-oxide, which results from the reaction of nicotine with flavin monooxidase 3 (FMO3), and produces the primarily trans isomer nicotine N-oxide. It is a product of the urinary tract and can be found in urine or reduced back to nicotine in the intestines. This metabolite, together with the alkaline nicotine glucuronide (3-5% of all nicotine entering the body), is responsible for the bulk of what remains from metabolism through cotinine.

Enzyme interactions

It appears that the aromatase enzyme (CYP1A1/2) is inhibited by nicotine, with an IC50 value of 223+/-10µM, and since nicotine is twice as potent as its metabolite cotinine, the two together may inhibit aromatase more potently. High doses of androstenedione can reverse the aromatase inhibition of nicotine and cotinine. Other aromatase inhibitors found in tobacco include myosamine (IC50 33+/-2µM; 7 times more potent inhibitor than nicotine), anabasine, N-n-octanoylnornicotine (comparable to aminoglutethimide), and N-(4-hydroxyanedecanoyl)anabasine. Nicotine inhibits aromatase. However, it is a relatively weak inhibitor when considering the concentrations required to inhibit 50% of enzyme activity. Other substances found in tobacco are more potent aromatase inhibitors. In one study using intravenous injections of nicotine in baboons (at levels similar to the nicotine content of a cigarette; 0.015-0.3 mg/kg), inhibition of aromatase in the brain was observed.

Neurology

Neurophysiology

Injections of nicotine (in smokers) increase neural activity in the frontal and cingulate regions of the brain, as well as in the nucleus accumbens and amygdala, areas of the brain involved in processes associated with addiction.

Attention and reaction time

A meta-analysis of nicotine and its effects on the brain in humans showed that there is ample evidence that nicotine enhances attention (both the ability to respond instantly and to various external stimuli). This meta-analysis was more focused on studying nicotine per se, since previous studies had focused more on smokers and examined the effects of nicotine on the brain only after cessation of use. Another meta-analysis focused only on laboratory studies of healthy people and excluded smokers who quit nicotine or those who were not included in the double-blind study compared with placebo. This meta-analysis pooled data from 41 studies and analyzed measures of immediate response (accuracy and reaction time) as well as response to stimuli (accuracy and reaction time), 76% of trials, and the meta-analysis itself were not associated with the tobacco industry (were independent ). Nine of these studies examined the accuracy of immediate reactions, and 8 of these studies plus 5 others examined reaction time. Only 5 (unique) studies examined stimulus response accuracy as well as stimulus reaction time, in addition to the other six studies. A significant and positive effect was observed for instantaneous response accuracy (g=0.34, z=4.19, p less than 0.001), instantaneous reaction time (g=0.34, z=3.85, p less than 0.001) and stimulus reaction time (g=0.30, z= 3.93, p less than 0.001). Non-significant improvements were observed for stimulus response accuracy (g=0.13, z=0.47, p less than 0.6). A strict linear dependence was observed regarding these parameters. Relative improvements in attention scores were observed with varying doses of nicotine in a dose-dependent paradigm. Improvements were observed in directing and maintaining attention to stimuli, accuracy, and when switching attention between stimuli, but improvements in accuracy of attention switching may not be as significant.

Anxiety and depression

In a study of patients with mild cognitive decline (non-smokers), use of nicotine patches at a dose of 15 mg daily for 6 months was associated with improvements in subjective anxiety scores, a measure of the anxiolytic effects of nicotine. The same study did not demonstrate significant improvement in subjective depression scores. One study using nicotine in non-smokers noted that a 2mg dose of nicotine (nicotine gum) caused increased activity in areas of the brain associated with negative perception compared to placebo. Thus, it is hypothesized that nicotine may increase anxiety.

Aphrodisiac

One study comparing regular and non-nicotine cigarettes found that cigarettes containing nicotine had a negative effect on sexual effects as measured through the bloodstream (penis diameter measurements were taken). Thus, it is hypothesized that nicotine may act as an anaphrodisiac. Two more recent studies in nonsmoking men and women found that nicotine may reduce sexual stimulation (induced by watching pornographic films or self-stimulating) without significantly affecting other mood parameters; men have also reported decreased erections after taking nicotine.

Nootropic effects

A meta-analysis of nicotine found that nicotine causes improvements in memory, especially short-term memory. A 6-month study of patients with mild cognitive impairment (over 55 years of age reporting memory lapses) found that daily use of 15 mg nicotine patches (release over 16 hours) was associated with improvements in memory, attention and psychomotor speed. reactions.

Fatigue

Nicotine has been shown to reduce brain fatigue in individuals with increased impulsivity (and decreased self-control), with little effect in individuals with decreased impulsivity.

Reward mechanism

In a study of non-smokers, 14 mg nicotine patches (two 7 mg patches) increased reward response to non-drug stimuli. The study used a sophisticated computer imaging test. Users given nicotine responded better to reward-related stimuli, and their reward mechanism lasted longer than the control group. The same conclusion was reached by researchers who gave smokers money after the test. Similar results were found in animal studies where nicotine administration was associated with an increase in reward response to non-drug stimuli. Nicotine cessation was associated with decreased reward responding.

Impulsiveness

In a study of smokers with problem gambling, it was noted that although taking 4 mg of nicotine (via an inhaler) suppressed cravings for cigarettes, there was no effect on problem gambling compared to placebo. When examining nicotinic acetylcholine receptors (which nicotine activates), using transdermal nicotine patches (7mg) and assessing impulsivity using three different tests, nicotine was found to improve measures related to impulsivity in a group with increased baseline levels of impulsivity (lower self-control). with no significant effect on individuals low in impulsivity. At the same time, different indicators of reaction time were observed, the best indicators were recorded in the group with reduced impulsivity.

Neuroscience (Addiction)

Mechanisms

The current prevailing theory of the mechanisms of nicotine dependence is the activation of nicotinic acetylcholine receptors (nAChRs) on mesocorticolimbic dopaminergic neurons, which serve to enhance the response to rewards and motivation, as well as to non-pharmacological stimuli. The nootropic effect of nicotine also manifests itself through these mechanisms. Secondary to the activation of α4ß2 and ß2 nicotinic acetylcholine receptors on dopaminergic neurons, they depolarize, causing an increase in neuronal firing. Direct activation of α4ß2 nicotinic acetylcholine receptors directly excites these dopaminergic neurons. All of these mechanisms result in the influx of dopamine into the nucleus accumbens, which is also associated with the addictive mechanism underlying the action of substances such as heroin and cocaine. Inhibition of this dopaminergic process results in a reduction in nicotine-related cravings. Activation of a7 nicotinic acetylcholine receptors increases excitation through the nucleus accumbens from the ventral tegmental area (VTA), as well as in two other regions known as the pedunculopontine tegmental nucleus (PPT) and laterodorsal tegmental nucleus (LDT), as binding to presynaptic a7 nicotinic acetylcholine receptors increases glutaminergic activity and provides long-term potentiation. Unlike α4ß2 and ß2 receptors, which desensitize quite quickly after activation, α7 nicotinic acetylcholine receptors desensitize slowly, which ensures their long-term potentiation through an increase in glutaminergic signaling. In many cases, the inhibitory potential of GABAergic neurons is reduced. GABAergic neurons, which are expressed primarily in the ventral tegmental area and under normal conditions oppose the excitation of glutaminergic neurons, express primarily α4ß2 receptors. When smokers chronically ingest nicotine and maintain elevated levels of nicotine in their bodies, these receptors are desensitized and their effects are reduced due to decreased α4ß2 activation, leading to a dramatic increase in α7 nicotinic acetylcholine receptors and glutaminergic neuron activation. Activation of dopaminergic neurons is directly related to many of the short-term effects of nicotine in this brain region, and activation of a7 nicotinic acetylcholine receptors on neurons other than this brain region strengthens the neuronal network and is a mechanism of long-term addiction. Dependent smokers exhibit increased dopamine release, which was absent in non-smokers in this study. When comparing nicotine per se and tobacco from cigarettes in dependent smokers who were pre-given a 4 mg nicotine lozenge versus placebo, and then when comparing smoking a cigarette without nicotine in both groups, it was shown that smoking cigarettes, regardless of their nicotine content, was associated with feelings of pleasure and decreased cravings, and that pre-administration of nicotine reduced the number of puffs and subsequently reduced cravings. Other studies have also confirmed these findings for nicotine-containing cigarettes.

Kinetics

One aspect of the reward mechanism of nicotine use is the speed at which nicotine reaches the brain and is associated with perceived reward. When smoked, nicotine can reach neural tissue within 10-20 seconds, faster than intravenous injections, which is comparable to intranasal nicotine. A rapid increase in neural nicotine concentrations is one of the factors of addiction. Other nicotine administrations that avoid such a rapid and precipitous Cmax in neural tissue (gum, patches, sublingual tablets, and lozenges) are associated with lower rates of addiction, but the lower rate of addiction with these products is also related to the amount of nicotine dose absorbed. The rate at which nicotine reaches the brain and the total concentration of nicotine reaching the brain are predictors of addictive potential. High doses and rapid absorption (from cigarette smoking) are associated with greater addiction than sustained-release forms of nicotine (gum, patches). One study of nicotine in smokers who wanted to quit noted that in a group that used nicotine gum (2mg or 4mg; n=127), 15mg transdermal patch (15mg; n=124), nasal spray (n=126) ) or nicorette inhaler (n=127) with ad libitum use of the products noted that among users who had not smoked for at least 3 weeks and completed a 12-week study, all methods were equally effective, relative to the number of smokers who continued their cessation smoking and average enjoyment or satisfaction over that time period. Dependence rates during nicotine replacement therapy were assessed by how many people continued to use nicotine 3 weeks after the end of the study (37% in the spray group, 28% in the gum group, 19% in the inhaler group, and 8% in the patch group), and on subjective dependence indications during this time period (33% inhaler, 22% gum, 20% nasal spray, 0% patch). When considering these study endpoints, nicotine gum was associated with lower rates of subjective dependence than the inhaler and nasal spray combined. The patch was associated with the lowest rates of dependence. Nicotine replacement therapy itself is associated with the development of addiction, which is related to the rate and total amount of nicotine consumed. The level of addiction is lower than that of smoking cigarettes.

Effect of nicotine on men and women

Nicotine cravings are associated with sexual dimorphism, since women require a smaller dose of nicotine to develop addiction, and smoking cessation is more difficult for women than for men. These differences have a biological basis, as studies of laboratory animals also show such differences. Low doses of nicotine (bordering the level at which rats may not self-administer nicotine, which is an indicator of addiction) have a greater effect on females than males. It was shown that females were willing to travel longer distances to obtain a dose of nicotine, compared to males. It is believed that hormones circulating in the body may play a role in these differences, since exogenous progesterone is associated with reduced cravings and the enjoyment of smoking. Additionally, there has been some correlation of nicotine with the estrous cycle as it relates to the development of nicotine addiction, as women report increased cigarette use during menstruation. This phenomenon is independent of menstrual symptoms (eg, smoking to relieve menstrual symptoms). However, some studies have failed to demonstrate this association. Particular sensitivity to smoking cessation develops during menstruation and some time after its end. These interactions may underlie the ability of nicotine to interfere with estrogen signaling in neural tissue by directly inhibiting the beta subunit of the estrogen receptor and inhibiting aromatase.

Nicotine and the development of addiction

19.8% of the American population smoke cigarettes (not nicotine per se) (2007 data), and although 45% of smokers tried to quit (2008), only 4-7% succeeded. During smoking cessation, one of the common side effects reported by respondents was difficulty concentrating. One of the most common reasons for smoking resumption was the subjective nootropic effects of nicotine. For these reasons, nicotine has long been studied in relation to the development of dependence on tobacco cigarettes.

The cardiovascular system

Heart rate

When a 21-year-old man took 6 mg of nicotine gum, there was an increase in heart rate, as well as an increase in diastolic and systolic blood pressure 30 minutes after use. The same study in women also showed an increase in heart rate but no significant increase in blood pressure. A 6-month study using nicotine patches at a dose of 15 mg showed a significant reduction in blood pressure, with a mean increase of 9.6 mmHg in the placebo group. in 6 months. In the group using nicotine patches, a decrease in systolic pressure of 4 mm Hg was observed.

Interactions with glucose metabolism

Inflammation and glucose metabolism

Secondary to the anti-inflammatory effects of nicotine, nicotine may enhance insulin sensitivity if the mechanism of insulin resistance is related to inflammation, and in rats nicotine affects insulin without affecting body weight.

Research

Cigarette smoking per se may have a negative effect on glucose metabolism. Long-term use of nicotine gum correlates with insulin resistance. In this regard, the effect of nicotine per se is very interesting in terms of research. When looking at the effects of nicotine in isolation in healthy smokers, it was noted that use of a 14mg nicotine transdermal patch increased insulin resistance and blood glucose levels. Nicotine infusions in non-smokers had no effect on baseline glucose uptake levels in healthy individuals (10.9+/-0.3mg/kg LBM), and in type II diabetics uptake was impaired by approximately 32+/-6%. Thus, nicotine has been shown to have different effects on healthy individuals and diabetic patients. These data support previous research that suggests that nicotine use in diabetics worsens insulin resistance, while a study using snuff noted that in healthy individuals, tobacco per se was not associated with the development of insulin resistance, as opposed to smoking; thus, a compound found in cigarettes rather than snuff may be associated with the development of insulin resistance, and this compound is not nicotine per se. In this study, where smokers were divided into “healthy” and “diabetic” groups, the division was based on circulating levels of glucose, insulin and HbA1c (elevated in diabetics); The nicotine dose was 0.3 µg/kg/min, and simulated cigarette smoking. 6.3. Insulin sensitivity after smoking cessation It is known that weight gain, usually fat, is common after smoking cessation; this is due to both decreased metabolism and increased caloric intake, although it may also be due in part to increased insulin sensitivity after smoking cessation. Nicotine patches have no effect on increasing insulin sensitivity after smoking cessation.

Obesity

It is known that cigarettes can stimulate lipolysis (fat burning). This effect can also be reproduced by intravenous administration of the same doses of nicotine; When comparing monozygotic twins, the weight of smoking brothers/sisters was 2.5-5.0 kg less than the weight of non-smoking brothers/sisters. Although weight can be influenced by a variety of factors, stimulation of lipolysis and excitation of the cholinergic neuron in adipose tissue are direct fat-burning effects that occur through nicotinic acetylcholine receptors.

Mechanisms

Nicotine may enhance AMP-dependent kinase activity in adipocytes, which is associated with increased lipolysis in a time- and concentration-dependent manner. Since the increase in AMP-dependent kinase and lipolysis were inhibited by N-acetylcysteine, they were mediated by pro-oxidative effects. Oxidative stress is known to regulate AMP-dependent kinase, particularly peroxynitrate (a pro-oxidative derivative of nitric oxide), and these effects were observed at circulating nicotine levels achieved through smoking a single cigarette (6nM, increasing to 600nM). However, activation of AMP-dependent kinase does not induce lipolysis upon nicotine administration (as the inhibitor, compound C, successfully inhibited AMP-dependent kinase but did not abolish lipolysis). The increase in lipolysis with nicotine is due to nicotine inhibiting fatty acid synthase (by 30% at 100 nM), which may be secondary to peroxynitrate, and a possible increase in catecholamines, such as epinephrine, that are released in response to nicotine stimulation ( which was shown after intravenous use). The study notes that 7.2ng/ml nicotine (levels achieved after smoking a cigarette) increased epinephrine and norepinephrine levels by 213+/-30% and 118+/-5%, respectively. Glycerol release (144-148%) was inhibited by a cholinergic agonist (acting at the acetylcholine receptor) and was reduced by 60% by propanolol (a beta-adrenergic antagonist involved in the release of catecholamines). A reduction in nicotine-induced lipolysis has also been observed in other studies with concomitant beta-adrenergic receptor blockade. Nicotine acts on acetylcholine receptors, releasing epinephrine and norepinephrine, which then act on beta-adrenergic receptors (the molecular target of adrenaline and ephedrine), affecting fat burning processes. This is not the only, but the most important mechanism of action of nicotine. Activation of nicotinic acetylcholine receptors on fat cells is associated with decreased secretion of pro-inflammatory TNF-a, and this receptor (namely a7nAChR) is negatively correlated with body fat mass; People with a body mass index (BMI) of 40 or higher have up to 75% less mRNA and protein content than people of normal weight. Activation of nicotinic acetylcholine receptors on fat cells mediates anti-inflammatory effects in the fat cell, and decreases the secretion of pro-inflammatory cytokines.

Metabolism

In healthy people, nicotine gum containing 1-2 mg of nicotine increases the metabolic rate by 3.7-4.9%. These figures increase even more with the simultaneous use of 50-100 mg of caffeine in chewing gum, without the dose dependence observed with caffeine addiction. The rate of fat oxidation does not change when taking nicotine compared to the control group. The measurements were carried out for 180 minutes, during the first 25 minutes the subjects chewed gum.

Research

In rodents, nicotine can reduce fat weight when fed either a high-fat diet or a regular diet. In both cases, blocking of this effect was observed when taking the acetylcholine receptor antagonist mecamylamine; One study showed that selective inhibition of the α4ß2 receptor (using varenicline) could only partially inhibit fat loss. In experiments on rats, it was shown that the fat burning effect is observed with controlled food intake, without reducing calories. These studies, however, use very high doses of nicotine (2-4mg/kg, one study used doses up to 4.5mg/kg, equivalent to 2.5 packs of cigarettes). These changes were observed at doses of 0.5 mg/kg orally and were dose-dependent, but their statistical significance may decrease over time (as effectiveness decreases). In one study of male smokers (unresponsive to the effects of nicotine) who were given 4mg nicotine gum or an equivalent dose via cigarette or inhaler, there was no increase in lipolysis over 180 minutes, nor was there an increase in epinephrine levels. Regarding metabolic rate, several studies have observed increased metabolism in rats when given isolated nicotine. People who smoked cigarettes experienced an increase in metabolic rate of approximately 210 kcal per 24 hours compared to non-smokers. This increase in metabolic rate may be mediated by simply increasing the amount of epinephrine and norepinephrine, with a half-life of 3.5 minutes (similar to the active half-life of adrenaline receptors). The increase in lipolysis does not show an obvious half-life. Animal studies show a significant increase in lipolysis and metabolic rate, which decreases over time (at low doses, nicotine is not very different from placebo, and only at high doses is lipolysis observed). The increase in metabolism may simply be due to an increase in the amount of catecholamines (adrenaline and norepinephrine). One study using nicotine patches in 55-year-old men and women found that after 91 days of nicotine use there was a 1.3kg weight loss (0.13kg in the placebo group). However, when measured again after 6 months, the difference disappeared. Human studies show that using nicotine in isolation for long periods of time is not effective for weight loss.

Weight gain

Quitting the habit of smoking cigarettes is often accompanied by weight gain, mainly fat mass, which is associated with a slower metabolism and increased food consumption. Nicotine itself (to a small extent) may help reduce weight gain after quitting smoking, but results have been mixed and this cannot be proven with certainty. Nicotine gum, for example, may not counteract weight gain after quitting smoking (2 mg gum; no dose limit). One study demonstrated benefits when using 2-4 mg gum in a specific regimen. A dose-dependent effect is possible (which was not confirmed later in experiments with nicotine patches). Compounds that may help prevent weight gain after quitting smoking include naltrexone, dexfenfluramine and phenylpropanolamide, as well as fluoxetine.

Skeletal muscles

Mechanisms

Nicotine has been shown to be able to activate mTOR when incubated in skeletal muscle culture, possibly mediating the decrease in insulin sensitivity associated with smoking (as mTOR activation induces IRS-1 and suppresses insulin signaling).

Effect of nicotine on inflammatory processes

Mechanisms

Nicotine exhibits anti-inflammatory properties by acting as a cholinergic agonist by activating the a7 nicotinic acetylcholine receptor (a7nAChR) on immune cells, particularly dendritic cells and macrophages. This pathway is naturally regulated by the neurotransmitter acetylcholine released from the vagus nerve, which inhibits the ability of immune cells to respond to TNF-a and reduces its release from immune cells. It was also later demonstrated that nicotine can inhibit NF-κB activation in LPS-activated macrophages and also affect splenocytes. It appears that activation of the nicotinic receptor by either nicotine itself or the neurotransmitter acetylcholine can suppress inflammatory responses on immune cells and reduce the secretion of pro-inflammatory cytokines. Activation of a7nAChR by nicotine increases the release of JAK2 and STAT3, which in turn causes the release of tristetraproline (TTP), which destabilizes TNF-a and interferes with its action. TTP is a low-efficiency cytoplasmic regulator of inflammation, and its absence causes arthritis in rats. Another possible mechanism of action of nicotine is the inhibition of high mobility group 1 proteins, which may be a possible mechanism for reducing the clinical signs of sepsis.

Ulcerative colitis

Epidemiological studies have shown that smokers have a reduced risk of developing ulcerative colitis. The relative risk is 0.6 (0.4-1.0) when compared with non-smokers. People who quit smoking have a twofold increased risk of developing UC compared to smokers (1.1-3.7). Similar findings have been found in other studies, however, these rates do not extend to other gastrointestinal diseases such as Crohn's disease (sometimes associated with an increased risk) and inflammatory bowel disease. It has been noted that ulcerative colitis is more likely to develop in people who have quit smoking than in current smokers. These paradoxical effects are secondary to the fact that nicotine acts as an anti-inflammatory alkaloid. Even when consuming nicotine through cigarettes, there is an inverse relationship with the development of ulcerative colitis.

Nicotine and cancer

Metabolites

N′-nitrosonornicotine (NNN), a nitrosamine found in tobacco, a metabolite of nornicotine, may have carcinogenic potential. NNN was found in the urine of people who quit smoking and used nicotine patches or gum. It has been suggested that some individuals may produce NNN ecdogenously from nicotine. One study using 21mg nicotine patches for 24 weeks after smoking cessation noted that urinary NNN levels dropped to levels close to the detection limit (0.005pmol/ml-0.021pmol/ml). The study also noted that 40% of passive smokers (out of 10) had urinary NNN levels of 0.002 pmol/ml, and although these two studies (the latter of which was well-designed) noted a significant increase in urinary NNN levels, at least , one study showed no increase with nicotine replacement therapy (using patches).

Lungs

Activation of the α7 acetylcholine receptor promotes anabolic effects such as Akt phosphorylation and Src activation. Activation of the nicotinic receptor increases cytoplasmic markers of pro-inflammation (5-LOX, COX-2 and NF-kB translocations). Nicotine at a concentration of 100 nM cannot induce proliferation, but may exhibit anti-apoptotic effects. Cholinergic receptors act as a cell survival signaling pathway in lung cancer, which also applies to acetylcholine.

Interaction with hormones

Testosterone

Nicotine and its metabolite cotinine negatively affect testicular structure and circulating testosterone levels, and may reduce the number of androgen receptors expressed (rat study, prostate measurements). Some of these mechanisms are secondary to testicular oxidation (including damage and enzyme depletion), but some suppression may be secondary to cholinergic agonism in the testes. Similar mechanisms operate for nicotine and cotinine. One study using doses of 0.5 mg/kg and 1 mg/kg via gavage (into the stomach) for 30 days noted a decrease in testicular weight associated with nicotine use. There was no clear effect on prostate hypertrophy. A decrease in circulating testosterone levels was observed in a dose-dependent paradigm, but returned to normal after 30 days of nicotine withdrawal. In a study using a lower dose, 0.6 mg/100 g, for 12 weeks, there was also a decrease in testicular weight and suppression of circulating and testicular testosterone levels. The amino acid taurine was able to halve the decline in testosterone levels at a dose of 50 mg/kg body weight. A greater effect was observed with the use of human chorionic gonadotropin. Nikitin can reduce the release of 17ß-HSD and 3ß-HSD and StAR expression to 60% of the control group. These effects may be reduced by taking taurine and normalized by taking human chorionic gonadotropin. Finally, another study using mice at 20 weeks of age (average age), when given nicotine at low doses (0.0625mg/kg body weight) after a short initial phase, noted that, after 90 days, there was a suppression of testosterone levels from 898.4ng /ml in the control group to 364ng/ml (59.5% reduction) in the nicotine group, which was associated with abnormal cell organization in the prostate. Similar results have already been obtained previously. This is thought to be due to decreased androgen levels, although the exact cause is still unknown. In a rat study, suppression of testosterone levels was observed with nicotine at psychologically relevant doses, which is partly due to receptor activation (muscarinic cholinergic) and, in chronic situations, testicular damage due to oxidation; the damage was partially reduced by the use of antioxidants. One study included men who were considered nicotine dependent by smoking 15. 48 mg nicotine (equivalent to serum levels of 20 ng/ml or higher) showed no change in circulating testosterone levels when measured over two hours, although a decreasing trend was observed. Another study in Medline was a cohort study of men aged 35-59 years (n=221) who were daily smokers before the study. Circulating testosterone levels were assessed in these men after a year of abstinence. Measurements of baseline testosterone levels were shown to be similar one year after smoking cessation. A larger study in older men (n=375, age 59.9+/-9.2 years) shows that smoking is associated with increased testosterone levels. Other studies show no significant difference between groups, or even a trend towards higher testosterone levels in smokers (4.33+/-0.53ng/ml in non-smokers, 4.84+/-0.37ng/ml in smokers).

Estrogen

In experiments with baboons, nicotine was shown to be an aromatase inhibitor in vivo after injections of nicotine into baboons at concentrations of 0.015-0.03 mg/kg (plasma levels reached 15.6-65 ng/ml), as after smoking a cigarette. These data contradict previous studies showing that nicotine is a potent aromatase inhibitor in vitro. This may explain why women who smoke heavily are often susceptible to estrogen deficiency disorders (osteoporosis, menstrual disorders, early menopause) and explain the increased levels of circulating testosterone in smokers of both sexes (which has not been demonstrated in short-term studies). The ability of nicotine (and related nicotine alkaloids) to inhibit the aromatase enzyme may cause a shift toward androgens rather than estrogens over time. The degree of change observed in these studies may be greater than with nicotine alone due to the presence of other alkaloids in tobacco. In a study of estrogen levels in rat serum, it was shown that circulating estradiol levels decreased over an average of 4 estrous cycles compared with controls 4 days later. Some differences were observed in the degree of reduction. Estrogen partially protects against damage resulting from ischemia (lack of oxygen) and reperfusion (reintroduction of oxygen), and this protection is suppressed by long-term nicotine use. A later study identifying the mechanisms underlying this noted that rats given nicotine hydrogen tartrate at a dose of 4.5 mg/kg (to produce effects identical to chronic cigarette smoking) for 16 days before cerebral ischemia experienced increased damage caused by ischemia when consuming nicotine (oral contraceptives, harmless individually, acted in synergy with nicotine, increasing the damage). These effects were thought to be mediated by estrogen inhibition of intracellular estrogen signaling, and since these effects were also seen with 1 µM ICI 182780, it was argued that nicotine inhibits estrogen receptors and CREB phosphorylation, which mediates the neuroprotective effects of estrogen (by inhibiting NADPH oxidase and reducing pro-oxidation in cage); Nicotine reduces the amount of ER-ß protein but not ER-a, and this inhibition of ER-ß has also been implicated in reducing neuronal plasticity and mitochondrial loss in neurons.

Luteinizing hormone

In rats, when given nicotine at a dose of 0.6 mg/100 g body weight for 12 weeks, levels of luteinizing hormone and follicle-stimulating hormone are reduced by 40% and 28%, respectively. In one human study, when assessing LH levels for two hours after administration of 15.48 mg nicotine (via smoking in dependent smokers), it was noted that LH levels increased within 14 minutes of cigarette smoking and were highly correlated (r=0.642) with serum levels nicotine

Prolactin

Cigarette smoking in dependent smokers is associated with an increase in prolactin levels within 6 minutes of cigarette smoking. Levels remain elevated for another 42 minutes and then return to normal within 120 minutes.

Interaction with other substances

Nicotine and caffeine

The combined use of caffeine and nicotine (coffee and cigarettes) is very popular; Smokers are also much bigger coffee drinkers than non-smokers. When used together in large doses, nicotine and caffeine exhibit a thermogenic effect (440 mg of caffeine and 18.6-19.6 cigarettes per day). This thermogenic effect is further enhanced by exercise, but one study indicates that this phenomenon is only observed in men. One study noted that using 50-100mg coffee and 1-2mg nicotine gum produced greater appetite suppression than nicotine alone. Use of this combination in high doses (100 mg caffeine and 2 mg nicotine) may be associated with nausea. One study showed that caffeine (250 gm) administered to 4-week caffeine-naïve smokers with nicotine infusions resulted in a decrease in the perceived stimulant effects of nicotine compared to placebo. In people who do not smoke but consume caffeine, there is no significant interaction between caffeine and nicotine. One study (self-reported) noted that caffeine did not increase nicotine addiction potential when both were used in adequate doses. These results, however, contradict another study in which participants were asked to decide how much money they were willing to spend on caffeine or nicotine injections. This study showed that caffeine's ability to reduce the "negative" effects of nicotine stimulated increased addiction. Nicotine replacement therapy (to reduce nicotine cravings) has no effect on caffeine withdrawal or caffeine dependence.

Nicotine and alcohol

Alcohol (ethanol) is a popular drink in society. Alcohol is popular among people who smoke, and vice versa. In addition, the use of nicotine stimulates alcohol consumption, especially in men. In a study assessing the combined use of alcohol and nicotine, it was noted that nicotine (10 mcg/kg) significantly suppresses the subjective perception of alcohol intoxication (exhaled breath alcohol level - 40-80 mg%), but increases alcohol-related memory deficits. The sedative effect of alcohol may be reduced by nicotine consumption. Nicotine can increase the euphoria of drinking alcohol. This decrease in short-term memory has been reported previously, with the group taking the combination of alcohol and nicotine performing worse than both the placebo group and the group taking alcohol alone. Alcohol, nicotine, or a combination of these substances do not have a significant effect on attention scores.

Nicotine and N-acetylcysteine

N-acetylcysteine ​​(NAC) is a bioactive form of the amino acid cysteine ​​(found in large quantities in whey protein) that has been studied as a substance that may reduce nicotine addiction. The theory about the role of NAC in addiction is based on glutamate transmission. Relapse during withdrawal of addictive drugs is associated with a decrease in basal concentrations of extracellular glutamate. This results in decreased activation of presynaptic mGluR2/3 receptors, which normally suppress glutamate signaling, and an increase in glutamate signaling; Although most studies have been conducted in cocaine models, these receptors are also activated in nicotine addiction. Stimulating these receptors reduces the “positive” effect of nicotine. Increasing extracellular glutamate levels reduces withdrawal symptoms. NAC may reduce withdrawal symptoms, increase extracellular glutamate levels, and to some extent suppress addiction to cocaine and heroin in rats. One double-blind study of smokers (15 or more cigarettes per day) who quit smoking abruptly and then took either placebo or NAC twice daily for a total dose of 3,600 mg did not show a reduction in nicotine cravings when taking NAC. The reduction in side effects was small and did not reach statistical significance. However, when the subjects were invited back to the laboratory and asked to smoke (which signaled the end of the trial), the subjects who were given NAC reported a significant decrease in the enjoyment of smoking compared to the control group. On a scale of 1 to 100, the placebo group rated the enjoyment of smoking a cigarette as 65.58+/-24.7 and NAC as 42.6+/-29.02 (35.1% less). This reduction in positive effects may apply more to people who smoke than to those who quit. One study (double-blind) noted that NAC at a dose of 2,400mg per day for 4 weeks in smokers did not reduce the number of cigarettes smoked per week per se, but in social situations (smoking combined with drinking) there was a significant reduction in the number of cigarettes smoked ; these effects were more pronounced when using NAC for 4 weeks or more.

Nicotine and St. John's wort

St. John's wort is a dopamine antidepressant being investigated as an anti-nicotine addiction compound due to its positive effects in mice and mechanically reducing addiction through modulation of catecholamines (dopamine, norepinephrine, epinephrine). Buproprion (an antidepressant) is an effective smoking cessation aid. The first open-label (non-blind) trial of St. John's wort for nicotine addiction found that St. John's wort at a dose of 900 mg daily for three months was associated with a 24% abstinence rate at the end of the study. This was followed by another double-blind study of St. John's wort 300 mg and 600 mg three times daily (total dose 900 mg or 1800 mg; 0.3% hypericin) for 12 weeks against placebo, in which St. John's wort showed no significant difference from placebo.

Nicotine and modafinil

Modafinil is a prescription drug for narcolepsy with nootropic effects that is being studied as a treatment for reducing nicotine dependence. In one blinded study, modafinil not only failed to reduce withdrawal symptoms, but actually increased negative nicotine withdrawal symptoms. When modafinil was taken for 8 weeks at a dose of 200 mg in the morning, the dropout rate was 44.2% in the placebo group and 32% in the modafinil group (not significant). Modafinil was also associated with a significant increase in depressive symptoms and negative mood, without an effect on positive mood or desire to smoke.

Nicotine and taurine

Taurine is a nonessential amino acid that contains a sulfur group. Taurine reduces (but not completely) the decrease in testosterone and other hormones (luteinizing hormone, follicle-stimulating hormone) observed with nicotine use in rats. Taurine has been studied for this purpose because it is the most abundant free ß-amino acid in the male reproductive system and exhibits protective effects against the effects of nicotine on cardiac tissue, as well as the bladder and urinary tract, due to its antioxidant properties.

Nicotine and ephedrine

In one study using nicotine (0.2 mg/kg) in rats, where no adverse effects on cardiac tissue were found when nicotine was taken in isolation, minor toxic signs were found when a combination of caffeine and ephedrine was taken in the presence of nicotine; This study used fairly large doses of ephedrine (30 mg/kg) but adequate doses of caffeine (24 mg/kg) and nicotine. A dose of 0.2 mg/kg in mice is approximately equivalent to a dose of 3 mg in a 90 kg human.

Safety and toxicity

A study using nicotine patches at a dose of 15 mg for 6 months in otherwise healthy people aged 55 years with slight memory impairment found that the total number of negative effects was significantly greater with nicotine (82) than with placebo (52), however none of these effects were characterized as "severe". The study also reported a decrease in blood pressure and an increase in cognitive performance when taking nicotine.

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List of used literature:

Benowitz NL, Jacob P 3rd. Daily intake of nicotine during cigarette smoking. Clin Pharmacol Ther. (1984)

Siegmund B, Leitner E, Pfannhauser W. Determination of the nicotine content of various edible nightshades (Solanaceae) and their products and estimation of the associated dietary nicotine intake. J Agric Food Chem. (1999)

Benowitz NL, et al. Nicotine absorption and cardiovascular effects with smokeless tobacco use: comparison with cigarettes and nicotine gum. Clin Pharmacol Ther. (1988)

Benowitz NL, Jacob P 3rd, Savanapridi C. Determinants of nicotine intake while chewing nicotine polacrilex gum. Clin Pharmacol Ther. (1987)

Benowitz NL, et al. Interindividual variability in the metabolism and cardiovascular effects of nicotine in man. J Pharmacol Exp Ther. (1982)

Lindell G, Lunell E, Graffner H. Transdermally administered nicotine accumulates in gastric juice. Eur J Clin Pharmacol. (1996)

Benowitz NL, Jacob P 3rd. Metabolism of nicotine to cotinine studied by a dual stable isotope method. Clin Pharmacol Ther. (1994)

Barbieri RL, Gochberg J, Ryan KJ. Nicotine, cotinine, and anabasine inhibit aromatase in human trophoblast in vitro. J Clin Invest. (1986)

Kadohama N, Shintani K, Osawa Y. Tobacco alkaloid derivatives as inhibitors of breast cancer aromatase. Cancer Lett. (1993)

Stein EA, et al. Nicotine-induced limbic cortical activation in the human brain: a functional MRI study. Am J Psychiatry. (1998)

Heishman SJ, Kleykamp BA, Singleton EG. Meta-analysis of the acute effects of nicotine and smoking on human performance. Psychopharmacology (Berl). (2010)

Poltavski DV, Petros T. Effects of transdermal nicotine on attention in adult non-smokers with and without attentional deficits. Physiol Behav. (2006)

Rusted JM, Alvares T. Nicotine effects on retrieval-induced forgetting are not attributable to changes in arousal. Psychopharmacology (Berl). (2008)

Vossel S, Thiel CM, Fink GR. Behavioral and neural effects of nicotine on visuospatial attentional reorienting in non-smoking subjects. Neuropsychopharmacology. (2008)

Colzato LS, et al. Caffeine, but not nicotine, enhances visual feature binding. Eur J Neurosci. (2005)

Kobiella A, et al. Nicotine increases neural response to unpleasant stimuli and anxiety in non-smokers. Addict Biol. (2011)

Gilbert DG, Hagen RL, D"Agostino JA. The effects of cigarette smoking on human sexual potency. Addict Behav. (1986)

Harte CB, Meston CM. Acute effects of nicotine on physiological and subjective sexual arousal in nonsmoking men: a randomized, double-blind, placebo-controlled trial. J Sex Med. (2008)

Harte CB, Meston CM. The inhibitory effects of nicotine on physiological sexual arousal in nonsmoking women: results from a randomized, double-blind, placebo-controlled, cross-over trial. J Sex Med. (2008)

Newhouse P, et al. Nicotine treatment of mild cognitive impairment: a 6-month double-blind pilot clinical trial. Neurology. (2012)

Potter AS, Bucci DJ, Newhouse PA. Manipulation of nicotinic acetylcholine receptors differentially affects behavioral inhibition in human subjects with and without disordered baseline impulsivity. Psychopharmacology (Berl). (2012)

Dawkins L, et al. A double-blind placebo controlled experimental study of nicotine: I–effects on incentive motivation. Psychopharmacology (Berl). (2006)

Nicotine -(S)-3-(1-methyl-2-pyrrolidinyl)pyridine, an alkaloid found in plants of the nightshade family (Solanaceae). The maximum amount of nicotine is found in tobacco, but there are 66 other plant species that contain nicotine. In small quantities, for example, it is present in eggplants, potatoes, tomatoes, and bell peppers. Nicotine makes up from 0.3 to 5% of the mass of tobacco in dry form, nicotine biosynthesis occurs in the roots, nicotine accumulation occurs in the leaves.
Nicotine is a colorless oily liquid (boiling point 247.6 °C), which quickly darkens in air. At temperatures below 60 °C and above 210 °C, nicotine mixes with water, and in the temperature range from 60 °C to 210 °C it has limited solubility in water. Chemical formula of nicotine C10H14N2

The name nicotine was coined in honor of Zhana Nikota- French ambassador to the Portuguese court, who in 1560 sent some tobacco to Queen Catherine de Medici as a remedy for migraines. They were also used to treat wounds, rheumatism, asthma and toothache.

Ways to use nicotine-, inhalation, chewing tobacco.

Nicotine is quickly absorbed through the mucous membranes of the mouth, alimentary canal, and also through the lungs. It can also enter the body through intact skin. Once nicotine enters the body, it quickly spreads through the blood. Average 7 seconds after inhaling tobacco smoke are enough for nicotine to reach the brain. The half-life of nicotine from the body is about two hours. The nicotine inhaled through tobacco smoke when smoking is a small fraction of the nicotine contained in tobacco leaves (most of the substance is burned). The amount of nicotine absorbed by the body when smoking depends on many factors, including the type of tobacco, whether all the smoke is inhaled, and whether a filter is used. With chewing tobacco and snuff, which are placed in the mouth and chewed or inhaled through the nose, the amount of nicotine entering the body is much greater than with smoking tobacco.

Consequences of nicotine use:
Nicotine acts on nicotinic acetylcholine receptors. At low concentrations, it increases the activity of these receptors, which, among other things, leads to an increase in the amount of the stimulating hormone adrenaline (epinephrine). The release of adrenaline leads to an increased heart rate, increased blood pressure and increased breathing, as well as higher blood glucose levels.

Nicotine is a toxic substance. It affects the central and peripheral nervous system. Particularly characteristic is the effect of nicotine on the ganglia of the autonomic nervous system. In this regard, nicotine is classified as a “ganglionic poison”. After large doses of nicotine enter the body, depression and paralysis of the nervous system occurs, respiratory arrest followed by cessation of cardiac activity. The average lethal dose for humans is 0.5–1 mg/kg.

Despite its strong toxicity, when used in small doses, for example through smoking, nicotine acts as a psychostimulant. Nicotine's effects on mood vary. By causing the release of glucose from the liver and adrenaline (epinephrine) from the adrenal medulla, it causes excitement. From a subjective point of view, this is manifested by feelings of relaxation, calmness and liveliness, as well as a moderately euphoric state. For some smokers, a decrease in appetite and increased metabolism may result in weight loss.

Repeated use of nicotine causes physical and mental dependence. Long-term use can cause diseases and dysfunctions such as visual impairment, gastric damage and intestinal damage, hyperglycemia, arterial hypertension, atherosclerosis, tachycardia, arrhythmia, angina pectoris, coronary heart disease, heart failure and myocardial infarction. When combined with tar, nicotine contributes to the development of lung cancer. In addition, if you use nicotine for several decades, impotence can develop.

Signs of nicotine use:
When first used, nicotine may cause nausea and vomiting. Then, as adaptation progresses, these protective phenomena disappear. Possible slight agitation. In any case, relaxation of the skeletal muscles and tremors of the hands are observed. A smoker experiences: increased excitability, improved short-term memory, decreased reaction time, improved attention, decreased anxiety, decreased appetite, and general relaxation. However, all the positive aspects are quickly replaced by the opposite, after the concentration of nicotine in the brain drops.

Nicotine poisoning is characterized by:
development of nausea and vomiting;
drooling;
stomach ache;
rapid pulse and high blood pressure at the beginning of smoking;
weak pulse and low blood pressure 30 minutes after smoking;
confusion;
general weakness;
decreased vitality.
Nicotine poisoning is usually a fairly rare occurrence and mainly occurs in children who follow adults in trying to smoke an adult dose. Help in case of poisoning: access to fresh air, protection of the respiratory tract from vomit, irrigation of the facial skin with cold water. If convulsions occur, it is necessary to ensure airway patency and prevent tongue biting before the ambulance arrives.

External signs of smoking are the smell of tobacco from the mouth, from the hands, the index and middle fingers yellowed from the filter.

From the history of nicotine:
600-1000 AD - Uaxactun, Guatemala. The first graphic image of a smoker. A clay vessel was found, depicting a Mayan Indian smoking rolled tobacco leaves tied with thread. The Mayans called smoking sikar.
October 12, 1492 - Christopher Columbus sails to the shores of San Salvador and sees tobacco leaves dried by the natives.
1530 - Franciscan monk Bernardino de Shahagun distinguishes two types of tobacco: “pleasant” - Nicotiana tabacum and “rough” Nicotiana rustica.
1531 - Santo Domingo. European tobacco cultivation begins.
1556 - Andre Thevet first brings tobacco (Nicotiana tabacum) to France from Brazil, claiming that tobacco was created for a comfortable pastime.
1559 - The main component of tobacco, nicotine, is named after Jean Nicot de Villemain (Jean Nicot) - the French ambassador to Portugal, who describes its medicinal properties and sends it as a panacea to the French court.
1571 - The issue of smoking “for pleasure” is still unresolved, since tobacco is considered primarily a medicine. Nicolas Monardes devotes the second part of his book New World Plants to tobacco, recommending it as a surefire remedy for 36 different diseases. Monardes calls tobacco the "holy herb" and his work becomes the fundamental source for all subsequent pro-tobacco literature.
1586 - Germany. "De plantis epitome utilissima" prints one of the first tobacco warnings, calling tobacco a "dangerous plant."
623 - Italy. The Church prohibits smoking in holy places. Pope Urban VIII threatens excommunication for anyone who smokes or snuffs tobacco in holy places.
1634 - Russia. Tsar Alexei introduces penalties for smoking. The first violation is flogging, tearing out the nostrils and exile to Siberia, the second is the death penalty.
1795 - Samuel Thomas Van Semmering of Maine claims that pipe smoking causes cancer.
1828 - Germany. Heidelberg University students Ludwig Reimann and Wilhelm Heinrich Posselt write a comprehensive dissertation on the pharmacology of nicotine, where they confidently claim that it is a “dangerous poison.”
1883 - Oscar Hammerstein receives a patent for a cigar rolling machine.
1905 - Tobacco is removed from the official list of drugs. This is done in exchange for votes from the tobacco lobby on the Food and Drug Act of 1906. Tobacco automatically falls out of the jurisdiction of the Food and Drug Administration (FDA).
1965 - The US Congress approves legislation to label cigarette packages with Department of Health warnings.
1980s The global offensive against tobacco begins. Tobacco taxes in the United States and Western Europe increased by 85% during this period.
In the 1990s, litigation dominated the news about the tobacco industry.
2003 - The World Health Organization Framework Convention on Tobacco Control was adopted. In four years, 146 countries around the world have joined the Convention. This document has become one of the most rapidly implemented UN treaties throughout the world (WHO is part of the UN).

Lastly, watch a video that talks about nicotine.

Even a short period of smoking causes chronic nicotine intoxication. Harmful compounds and toxic resins accumulate in the human body. Under their negative influence, the functional activity of all vital systems decreases. Carcinogens contained in tobacco are especially dangerous. These substances provoke cellular mutation, which results in the formation of benign and malignant tumors. The negative effects of nicotine on the human body have long been known and well studied. But people continue to smoke because of a well-established mental and physical addiction.

How nicotine works

Nicotine is an alkaloid of organic origin, which is synthesized in small quantities in the roots of plants of the nightshade family and accumulates in their leaves and stems. Pharmacologists know the compound as a powerful toxin that damages the tissue of the heart muscle, blood vessels and brain. Smoking tobacco not only destroys healthy cells and causes their mutation - under the influence of nicotine, many chronic diseases worsen and new pathologies arise.

Eggplants, green peppers, potatoes and tomatoes contain small doses of the toxic compound. Therefore, narcologists advise all people who decide to break a bad habit to reconsider their diet. The number of cigarettes smoked will be significantly reduced with constant consumption of salads and stews made from these vegetables.

After entering the human body, nicotine is absorbed into the blood and within a few seconds ends up in the central nervous system. It easily overcomes all biological barriers, including the blood-brain barrier. The toxic substance accumulates in the internal organs, brain, and bone tissue. With each cigarette smoked, the concentration increases, and the poisoning of the body by nicotine intensifies. Under the influence of carcinogens, cells change at the genetic level, and their number also increases:

• The division of healthy cells leads to the formation of benign tumors - polyps and cysts:
• the division of damaged and deformed cells provokes the formation of cancerous tumors.

Experts say that a smoked cigarette contains fewer toxic compounds than its smoke. There is such a term - “passive smoking”. Nicotine is especially dangerous for children and adolescents. A person addicted to cigarettes puts not only himself, but also the people around him at risk. Family members under the influence of nicotine also form tumors or develop pathologies, just like the smoker himself.

Trying to quit a bad habit, some people begin to use snuff and chewing tobacco. This not only does not help to quit smoking, but also strengthens the addiction. The concentration of nicotine and toxic tars in these types of tobacco far exceeds the amount of toxic compounds in cigarettes.

Nicotine in the human body begins to affect specific acetylcholine receptors. An increase in their activity provokes increased production of stress and joy hormones - epinephrine and adrenaline. They are released into the blood and transferred to the central nervous system, causing a person to:

• feeling of slight excitement;
• feeling of cheerfulness, a surge of strength;
• euphoric state;
• relaxation.

When smoking a cigarette, a person feels pleasure and even happiness. This occurs under the influence of the pleasure hormone dopamine. This is how psychological and physical dependence on nicotine is formed. The person tries to experience euphoria again and reaches for a cigarette. Scientists have isolated and synthesized enzymatic compounds that can reduce the harm of nicotine by breaking it down into harmless (usually beneficial) nicotinic acid. But there are no such enzymes in the human body.

Heart and blood vessels

The harm of nicotine on the heart and blood vessels has been well studied. Penetration of cigarette smoke increases the load on the myocardium, veins, arteries and capillaries. The production of biologically active substances decreases, nervous and humoral regulation is disrupted. The heart rate increases and peripheral vessels constrict. If nicotine enters the body regularly, then the cardiovascular system has virtually no relaxation stage. This leads to rapid wear of the blood vessels, their damage, and in especially severe cases, loss of integrity. Various complications develop:

• blood viscosity increases;
• the risk of blood clots increases;
• blood supply to tissues is disrupted.

Smoking affects the heart, but developing arterial hypertension is also dangerous. High blood pressure causes arrhythmias, strokes and heart attacks. A person often begins to feel dizzy, blood rushes to the upper part of the body, and lethargy and apathy appear. Arterial hypertension can provoke an increase in pressure in the renal vessels, which leads to a decrease in the functional activity of the urinary system.

Gastrointestinal tract

Even a minimal amount of nicotine has a negative effect on the mucous membrane of the digestive system. The following are subject to destruction:

• teeth and gums;
• stomach;
• intestines;
• liver and gall bladder.

The main reason for the development of gastric pathologies is slow digestion. Products remain in the hollow organ for a long time, which leads to increased production of aggressive hydrochloric acid and pepsin. Digestive enzymes and caustic juice damage epithelial cells. In a person with a long history of smoking, the negative process affects the deeper layers of the gastric walls. Their inner surface is deformed and growths form on it.

Smokers are rarely diagnosed with acute gastritis; it immediately takes on a chronic form, which is a precancerous condition. The body loses its ability to neutralize pathogenic microorganisms. Viruses and bacteria enter the ulcerated mucous membrane, forming infectious foci. They gradually enlarge and become the cause of a dangerous inflammatory process - peptic ulcer of the stomach and duodenum. All smokers develop:

• slow digestion;
• death of beneficial microflora in the intestines;
• chronic constipation or diarrhea.

The beneficial bacteria inhabiting the intestines are replaced by pathogenic microorganisms. The absorption of vitamins and microelements decreases, which has a bad effect on a person’s appearance. His nails begin to peel, his hair falls out, and his skin loses its elasticity and firmness. Many women who resort to smoking as an effective method of losing excess weight do not think about this.

Nicotine can reduce appetite, but only for a short time. The metabolic processes of fats, proteins and carbohydrates are gradually distorted - body weight begins to increase. As a result, the person gains weight, but is no longer able to quit smoking due to the developed psychological and physical dependence.

The liver is located in close proximity to the gastrointestinal tract and over time begins to feel the negative effects of nicotine addiction. She experiences increased stress due to indigestion, so her tissues are damaged. The liver is one of the most important biological filters of the body - a decrease in its functional activity under the influence of nicotine affects other vital systems.

Airways

Tobacco smoke is the main cause of the development of nonspecific respiratory diseases. Constant intake of nicotine damages the mucous membranes of the trachea, pharynx, bronchi, bronchioles. The alveolar walls lose their elasticity, become rough and swell. Why is nicotine harmful? A person who smokes is more likely to develop:

• Chronical bronchitis;
• bronchial asthma;
• laryngitis, pharyngitis, tracheitis.

Separately, it is worth highlighting the chronic cough of a smoker. A significant amount of toxic compounds and toxic resins accumulate in the human body per day.

As soon as he gets out of bed, the smoker begins to cough violently. In this way, the respiratory tract is cleansed of harmful substances. The cough subsides only by noon and starts again in the morning. If a person decides to get rid of a bad habit, his lungs will clear only after a few months.

The effect of nicotine on the lungs is extremely negative. Under its influence, emphysema can develop, a pathological condition characterized by unnatural expansion of the lungs. Each cigarette smoked reduces their functional activity, and this seriously increases the likelihood of tuberculosis. Nicotine damages the vocal cords, leading to hoarseness and hoarseness.

Reproductive organs

Nicotine affects the human body regardless of gender. According to statistics, many women and men start smoking at an early age, before having children. Poisonous resins act directly on the organs that are responsible for reproduction. The genitals of the stronger sex are especially vulnerable to toxic compounds from cigarettes.

Smoking causes distortion of spermatogenesis, reduces potency, and predisposes to the development of prostate cancer. This is facilitated by impaired blood supply to the pelvic organs due to the accumulation of harmful substances in the vessels.

Despite the fact that the harm of nicotine is confirmed by scientific research, many women continue to smoke even while pregnant. The tars contained in tobacco reduce the production of prolactin-like protein. Protein is responsible for the cyclicity of menstruation and maintains a woman’s hormonal levels in a normal state. Its disorder can lead to infertility, which is not always treatable.

Toxic compounds easily penetrate through all barriers, so a smoking mother seriously endangers not only her health, but also her unborn child. The negative effect of nicotine on the body of a person who was not born is difficult to overestimate:

• the risk of sudden death and congenital anomalies increases;
• the brain is exposed to oxygen starvation;
• the lungs do not receive enough oxygen;
• the possibility of asphyxia increases;
• the risk of mental and physical development lag increases;
• Premature birth is possible.

After the baby is born, he receives nicotine through breast milk. Studies have shown that, despite excellent heredity, smoking can cause a malfunction at the genetic level. The molecular structure of DNA is disrupted and children are born with disorders of the nervous system. Undoubtedly, this will negatively affect brain activity and will guarantee poor learning. According to statistics, a child of a smoking mother has a significantly higher craving for cigarettes than his peers.

Brain and nicotine

The effect of nicotine on the nervous system is only negative, because all the substances included in its composition are neurotoxins. From the lungs, toxic compounds enter the blood, causing reflexive compression of blood vessels. The brain begins to lack molecular oxygen. Blood circulation in the central nervous system is disrupted, which, despite its complex organization, is not stable. Small doses of nicotine lead to its excitation, and large doses inhibit the activity of neurons.

The activity of not only the central but also the peripheral nervous system is disrupted. An inflammatory process develops in the nerve trunks, and a person develops:

• irritability;
• apathy, lethargy, fatigue;
• drowsiness;
• headaches and migraines.

Doctors strongly recommend that people with neurological disorders quit smoking. Even inhaling tobacco smoke aggravates the disease and delays recovery for a long time. The effects of nicotine on the brain are not limited to a decrease in physical activity. A person has memory problems, which negatively affects his professional activities. This is based on distorted transmission of nerve impulses and dysregulation.

About the benefits of nicotine

Like most alkaloids, nicotine also has some positive effects on the human body. For example, scientists have proven that the frequency of attacks in schizophrenics who smoke is lower than in those leading a healthy lifestyle. This disease occurs against the background of insufficient production of proteins that are responsible for connections between neurons. A person with schizophrenia experiences anxiety, visual and auditory hallucinations, and emotional instability. The benefit of nicotine for the body of such people is to normalize protein production and reduce the severity of the disease.

Nicotine is useful because it can suppress cravings for drugs. Based on it, tools may soon be developed to help get rid of drug addiction. Nicotine is also used medically as an antidote for ricin poisoning and to treat Parkinson's disease.