Nicotine and Caffeine

 

Nicotine

Background and History

Basic Pharmacology of Nicotine and Its Relationship to Smoking

Mechanisms of Action

• Nicotine is an alkaloid found in tobacco leaves. Tobacco plants are native to North and South America, and these plants were domesticated several thousand years ago by Native Americans.
• When tobacco was first brought back to Europe from the New World, use of this substance was primarily by means of pipe smoking, cigar smoking, and chewing. Snorting finely powdered tobacco leaves (snuff) later became popular.
• Tobacco cigarettes were first introduced in the mid-nineteenth century, and cigarette smoking subsequently increased as the result of improved methods of curing the tobacco leaves, as well as the advent of modern cigarette manufacturing machines.
• The contemporary e-cigarette was introduced in 2003 by a Chinese pharmacist. Since that time, e-cigarettes and other electronic nicotine delivery systems (ENDS) have greatly increased in popularity.
• A typical tobacco cigarette contains 6 to 11 mg of nicotine, of which only about 1 to 3 mg actually reaches the smoker’s bloodstream. Nicotine is vaporized by the high temperature at the tip of the burning cigarette and enters the smoker’s lungs on tiny particles called tar.
• Once in the lungs, the nicotine is readily absorbed into the blood and quickly reaches the brain. The rapid delivery of nicotine to the brain is believed to be a powerful reinforcer of smoking behavior.
• A typical e-cigarette consists of a plastic cartridge containing nicotine dissolved in propylene glycol or glycerin, a battery-powered heating element, a microprocessor control system, and an LED that simulates the glow of a burning cigarette tip. Flavorings are often added to the nicotine solution to enhance its taste. Manufacturers’ stated nicotine concentrations vary from low (3–6 mg/ml), to medium (9–12 mg/ml), to high (16–24 mg/ml) levels, although the actual nicotine concentration is often lower than the stated concentration. The rapidity of nicotine delivery from an e-cigarette is similar to that from tobacco cigarettes.
• Nicotine is metabolized primarily to cotinine by the liver enzyme CYP2A6. The cotinine and other nicotine metabolites are then excreted mainly in the urine. People who metabolize nicotine inefficiently because of genetically determined low CYP2A6 activity seem to be less vulnerable to cigarette smoking than efficient metabolizers.
• The elimination half-life of nicotine is typically about 2 hours. Nicotine clearance from the body is an important reason why most smokers and vapers smoke or vape throughout the day. Tolerance to at least some of nicotine’s effects occurs during this period, but during sleep this tolerance partially dissipates and the smoker awakens in a state of mild withdrawal.
• The principal mechanism of nicotine action is to stimulate nAChRs in the brain and the autonomic nervous system. In particular, there are high-affinity nAChRs that most commonly are composed of two α4 or α3 subunits, along with three β2 subunits. Some nicotinic receptors, typically composed of α7 subunits, are located presynaptically on nerve terminals where they function to enhance the release of neurotransmitters such as glutamate.
• The opening of nAChR channels permits Na⁺ to flow across the cell membrane, thereby causing membrane depolarization and a fast excitatory response. High-affinity nAChRs desensitize rapidly in the presence of nicotine, thereby leading to reduced transmission by ACh. Very high doses of nicotine can cause persistent activation of nAChRs, leading to a temporary depolarization block of the postsynaptic cell.

Behavioral and Physiological Effects

• The mood-altering effects of nicotine depend on whether the individual is an abstinent smoker or a nonsmoker. In temporarily abstinent smokers, administration of pure nicotine usually increases calmness and relaxation. This effect is due, in part, to relief from nicotine withdrawal symptoms, because nicotine given to nonsmokers more often elicits feelings of tension, arousal, lightheadedness or dizziness, and sometimes nausea.
• Administration of nicotine to abstinent smokers also leads to enhanced performance on various cognitive tasks, particularly those involving attentional demands. In this case, however, some nicotine-related functional enhancement has also been reported for nonsmokers. Some research has found that nicotine enhancement is most clearly evident in people with a low baseline level of attention.
• Animal studies have found that nicotine improves performance on tasks requiring sustained attention and working memory. Certain hippocampal-dependent tasks, such as contextual fear conditioning and spatial learning, are also sensitive to nicotine. Research with nAChR subunit knockout mice as well as the antagonists DhβE (selective for α4β2-containing high-affinity nAChRs) and MLA (selective for α7-containing low-affinity nAChRs) revealed that high-affinity nAChRs play a greater role in the nicotine enhancement of hippocampal-dependent tasks. Other neurotransmitter receptors involved in the positive effects of nicotine on sustained attention include β-adrenergic and NMDA receptors, but not D₁ or D₁ receptors for DA.
• Within a certain dose range, pure nicotine is reinforcing to both humans and experimental animals, as shown by IV self-administration. Females are more sensitive than males to nicotine reward/reinforcement in both humans and rodents. Rodent studies have additionally found greater nicotine reward/reinforcement in adolescent than in adult animals.
• The reinforcing properties of nicotine involve activation of high-affinity receptors located in the VTA, which stimulates burst firing of the dopaminergic neurons and increases DA release in the NAcc. This hypothesis is supported by the finding that nicotinic receptors in the VTA containing β2 subunits in combination with α4 and/or α6 subunits are necessary for nicotine self-administration. Polymorphisms in the genes coding for these subunits have been associated with the subjective effects of smoking, smoking rates, and the risk for developing nicotine dependence in humans.
• Nicotine can also exert aversive effects, which seem susceptible to chronic tolerance with continued nicotine exposure. Nonsmokers injected with a high dose of nicotine experienced a number of symptoms such as nausea, dizziness, sweating, headache, palpitations, and stomachache. Nicotine aversion in both humans and experimental animals involves the stimulation of nAChRs containing α5, α3, and β4 subunits. These receptors are expressed at high levels in the medial habenula–interpeduncular nucleus pathway, and the genes for the subunits are clustered together on human chromosome 15.
• Nicotine additionally produces a variety of peripheral physiological effects. These include release of epinephrine and norepinephrine from the adrenal glands, tachycardia, and elevated blood pressure, all of which contribute to the arousing effects of the drug. Nicotine also increases hydrochloric acid secretion in the stomach and muscle contraction in the bowel, both of which can adversely affect the gastrointestinal tract. Finally, nicotine modestly increases metabolic rate and suppresses appetite, which accounts for why smokers typically gain weight after quitting.
• Nicotine is a toxic substance that can cause potentially dangerous symptoms such as nausea, salivation, abdominal pain, vomiting and diarrhea, confusion, and weakness. If a sufficient dose has been ingested, death may occur from respiratory failure. Treatment involves an attempt to remove the nicotine from the victim’s stomach (if the nicotine has been swallowed), administration of artificial respiration, and dealing with drug-induced shock.
• Repeated exposure to nicotine can lead to tolerance and, in some cases, sensitization. Single doses of nicotine cause a rapid but transient form of acute tolerance that depends on desensitization of nicotinic receptors. Long-term nicotine exposure is associated with chronic tolerance, as a consequence of which smokers do not exhibit the adverse reactions to high doses of nicotine that are observed in nonsmokers. Smokers show an up-regulation of nAChR levels in many brain areas, seemingly as a compensatory response to the chronic receptor desensitization associated with repeated nicotine exposure.
• Chronic nicotine can also cause dependence, thereby leading to withdrawal symptoms upon abstinence. The DSM-5 contains the category tobacco use disorder, which is diagnosed by finding at least two out three listed criteria. Compulsive cigarette use is characterized by successive stages of wanting, craving, and finally needing a cigarette. A number of questionnaires have additionally been developed to identify and quantify nicotine dependence. Prolonged abstinence in nicotine-dependent people evokes a complex syndrome of affective, somatic, and cognitive symptoms. Initial studies suggest that e-cigarette users are generally less dependent than tobacco cigarette users, but additional research is needed to confirm this finding.
• Animal models of nicotine dependence are important for studying the mechanisms of dependence and for testing new drug treatments. When rats are made dependent on nicotine by giving them continuous exposure to the drug (e.g., with osmotic minipumps), withdrawal symptoms can be observed if the dependent animals are administered a nicotinic receptor antagonist such as mecamylamine. This withdrawal syndrome has been related to resensitization of desensitized and up-regulated nAChRs, reduced activity of the mesolimbic dopaminergic pathway, increased CRF signaling in the central nucleus of the amygdala, and activation of the nicotine aversion pathway involving the medial habenula and interpeduncular nucleus.

Cigarette Smoking and Vaping

• Approximately 24% of the population of this country (corresponding to 64 million people) were current users of tobacco products at the time of the 2015 National Survey on Drug Use and Health. Less than 4% of adults age 18 or older were current users of e-cigarettes according to the 2014 National Health Interview Survey. Overall, cigarette smoking is declining across the population, whereas the use of e-cigarettes is growing.
• Smokers typically begin during adolescence, and many different reasons have been given for teenage smoking. Longitudinal surveys found that poor academic performance, rebelliousness, sensation seeking, receptivity to cigarette advertising/marketing, and smoking by family and/or friends are significant predictors of smoking onset. nnIndividuals go through several stages on the way from nonsmoking through occasional smoking and then eventually to established smoking. Several different kinds of trajectories have been reported for people progressing through these stages. DiFranza and coworkers have proposed a model of adolescent nicotine dependence in which smokers pass through successive stages of “wanting,” “craving,” and finally “needing” a cigarette. Once nicotine dependence has developed, cigarettes become compulsory (i.e., smoked in order to alleviate withdrawal symptoms) instead of elective.
• Although first exposure to a cigarette is aversive in most cases, a subset of individuals experience relaxation at their first smoking experience. This response is likely related to the rewarding effects of nicotine.
• Various hypotheses have been offered to explain why young people are more attracted to e-cigarettes than tobacco cigarettes. These hypotheses are related to flavor, health, price, concealment, role models, and acceptance of e-cigarettes compared with tobacco cigarettes. Because e-cigarettes are now the most common route of nicotine exposure among young people, concerns have been raised that e-cigarettes are becoming a gateway to nicotine dependence and, in some cases, use of combustible tobacco products.
• Several factors contribute to the development and maintenance of a smoking habit. Delivery of nicotine and, for many, the development of nicotine dependence are obviously key factors in smoking and vaping. Repeated cigarette smoking during the day leads to nicotinic receptor desensitization, which is partially reversed by overnight abstinence. Because smokers commonly report that smoking causes relaxation, a reduction in stress, and increased concentration, some researchers have proposed a nicotine resource model hypothesizing that the nicotine obtained through smoking has the beneficial effects of increasing mood control (in relation to stress reduction) and enhancing concentration. An alternative model, the deprivation reversal model, argues that the positive effects experienced during smoking actually constitute the alleviation of withdrawal effects such as irritability, anxiety, and poor concentration. Both models are supported by certain evidence, with mood regulation (i.e., alleviation of anxiety) perhaps being more important in female than male smokers. In addition, stimuli associated with cigarette smoke, such as the taste and smell of cigarette smoke, are thought to function as secondary reinforcers after being repeatedly paired with the primary reinforcing effects of nicotine.
• Other constituents of cigarette smoke or ecigarette vapor may also influence smoking or vaping behavior. Certain non-nicotine constituents of tobacco inhibit MAO-A, an enzyme important for DA metabolism. Researchers have hypothesized that this effect is likely to be most important for enhancing the reinforcement of low-nicotine cigarettes. Menthol, a well-known flavorant used in both tobacco cigarettes and e-cigarettes, acts as a negative allosteric modulator of nAChRs. The net effects of this interaction may be to increase the frequency and/or intensity of smoking or vaping by the user.
• Chippers are long-term smokers who smoke a few cigarettes daily on a regular basis but do not become dependent. However, chippers do develop nicotine tolerance, which suggests that tolerance and dependence are produced by different physiological mechanisms.
• Although withdrawal symptoms undoubtedly play an important role in maintaining the smoking habit in dependent smokers, other factors also contribute to this habit, including the taste and smell of cigarette smoke.
• Chronic use of tobacco results in many adverse health consequences, including cancer, cardiovascular disease, and respiratory diseases such as emphysema and bronchitis. The deleterious effects of inhaling cigarette smoke have been related not only to nicotine but also to tar and carbon monoxide gas that is produced by the burning of tobacco.
• Smoking by a pregnant woman has adverse consequences for her fetus due to a combination of nicotine exposure, exposure to other components of cigarette smoke, and disruption of the woman’s endocrine system. Infants born to smokers are at elevated risk for intrauterine growth restriction and later susceptibility to developing cardiovascular disease, type 2 diabetes, or stroke. The longterm consequences of smoking during pregnancy are consistent with the developmental origins of health and disease hypothesis.
• The brain is still developing during adolescence, and animal studies have found that exposure of the adolescent brain to nicotine can have deleterious effects on dendritic branching and on neurotransmitter development. Behavioral processes such as attention, impulse control, and vulnerability to drug self-administration are also influenced by adolescent nicotine exposure.
• Many different treatment strategies have been developed to assist smokers in quitting. Individuals who are trying to quit can take advantage of various behavioral and psychosocial interventions, some of which are web based and available at no cost. Pharmacological interventions take three forms: nicotine replacement therapy (NRT), non-nicotine drugs aimed at reducing craving and withdrawal symptoms, and antinicotine vaccines. Nicotine replacement can be accomplished by means of nicotine gum, lozenges, patches, nasal spray, or an inhaler. For some, e-cigarettes may represent yet another potential kind of NRT. Currently available non-nicotine drugs for smoking cessation are bupropion (Zyban), which is a mixed DA and NE reuptake inhibitor and weak nAChR antagonist, and varenicline (Chantix), which is a partial agonist at high-affinity α4β2 nAChRs. Both NRT and these alternative pharmacological approaches are more effective when paired with some type of behavioral or psychosocial intervention. Finally, a nicotine vaccine that reduces nicotine availability to the brain has been under development for a number of years; however, clinical testing has not yet demonstrated significant therapeutic efficacy of this approach. Because breaking the smoking habit is almost always a difficult proposition, it is much better never to become dependent in the first place.

Caffeine

Background

Basic Pharmacology of Caffeine

Behavioral and Physiological Effects

Mechanisms of Action

• Caffeine and theophylline are members of a class of plant-derived substances called methylxanthines. Caffeine, especially, is contained in a number of foods such as coffee and tea. When consumed orally, it is readily absorbed from the gastrointestinal tract and is gradually metabolized and excreted with a typical half-life of approximately 4 hours.
• Caffeine and other ingredients (e.g., sugar, amino acids, and sometimes alcohol) are constituents of so-called energy drinks. These beverages are consumed for the same stimulating effects as other caffeine-containing foods and beverages. While energy drinks can serve a useful function by combating fatigue and inattention, they can also contribute to excessive caffeine consumption and may be dangerous when the caffeine is combined with significant amounts of alcohol in an effort to counteract alcohol’s intoxicating effects. nnIn rodents, caffeine has locomotor stimulant effects at low doses but actually reduces activity at high doses.
• Humans generally experience heightened attention and arousal, reduced fatigue, and reduced sleep in response to normal amounts of caffeine. Higher doses, typically greater than 400 mg, can lead to feelings of tension and anxiety. nnLaboratory studies have demonstrated enhanced mood, improved psychomotor performance, and increased memory consolidation following caffeine administration. When used by athletes, caffeine also enhances performance in both endurance sports and short-term high-intensity activities.
• Regular caffeine use leads to tolerance and physical dependence. Symptoms of caffeine withdrawal include headache, drowsiness, fatigue, impaired concentration, and reduced psychomotor performance.
• Caffeine acutely produces various physiological effects, such as increased blood pressure and respiration rate, diuresis, and increased catecholamine release.
• Daily caffeine use up to 400 mg is generally considered to be safe, except perhaps in pregnant women. Consumption of high doses, however, has been associated with two psychiatric disorders: caffeine intoxication, and caffeine dependence syndrome or caffeine use disorder. Caffeine intoxication, caused by recent excessive caffeine consumption, is characterized by symptoms of restlessness, nervousness, insomnia, and physiological disturbances such as tachycardia, muscle twitching, and gastrointestinal upset. Caffeine dependence syndrome is a syndrome of substance dependence (see Chapter 9) associated with chronic, maladaptive caffeine use. This syndrome is currently accepted by the ICD-10 but needs further confirmation according to the DSM-5.
• Caffeine has several clinical uses, including pain relief and the treatment of newborn infants with apnea.
• Epidemiological studies indicate that regular coffee consumption of three to four cups per day reduces the risk of developing type 2 diabetes. This protective effect may be due to the presence of chlorogenic acids in coffee, rather than its caffeine content. Additional research is ongoing to determine whether coffee/caffeine consumption reduces the risk of developing Parkinson’s disease as well as age-related cognitive decline.
• Although caffeine has a number of biochemical effects on the brain, its psychological and behavioral properties are mediated primarily by its ability to block A₁ and A_2A receptors for the neurotransmitter/neuromodulator adenosine. Extracellular adenosine is derived largely from the breakdown of ATP that has been released into the extracellular space. The behavioral stimulant properties of caffeine have been linked especially to antagonism of A_2A receptors, which form heteromeric complexes with DA D₂ receptors in the striatum. Under drug-free conditions, adenosine activation of striatal A_2A receptors exerts a negative allosteric effect on the D₂ receptors, thereby weakening cellular signaling through those receptors. Caffeine blockade of the adenosine receptors releases the D₂ receptors from this negative effect, thereby enhancing dopaminergic transmission in the striatum.