Effects of electronic cigarettes on the developing human brain
Exposure to nicotine, from conventional or electronic cigarettes during adolescence can impair the developing human brain. E-cigarette use is recognized as a substantial threat to adolescent behavioral health. The use of tobacco products, no matter what type, is almost always started and established during adolescence when the developing brain is most vulnerable to nicotine addiction. Young people's brains build synapses faster than adult brains. Because addiction is a form of learning, adolescents can get addicted more easily than adults. The nicotine in e-cigarettes can also prime the adolescent brain for addiction to other drugs such as cocaine. Exposure to nicotine and its great risk of developing an addiction, are areas of significant concern.
Nicotine is a parasympathomimetic stimulant that binds to and activates nicotinic acetylcholine receptors in the brain, which subsequently causes the release of dopamine and other neurotransmitters, such as norepinephrine, acetylcholine, serotonin, gamma-aminobutyric acid, glutamate and endorphins. Nicotine interferes with the blood–brain barrier function, and as a consequence raises the risk of brain edema and neuroinflammation. When nicotine enters the brain it stimulates, among other activities, the midbrain dopaminergic neurons situated in the ventral tegmental area and pars compacta.
Nicotine negatively affects the prefrontal cortex of the developing brain. Prenatal nicotine exposure can result in long-term adverse effects to the developing brain. Prenatal nicotine exposure has been associated with dysregulation of catecholaminergic, serotonergic, and other neurotransmitter systems. E-liquid exposure whether intentional or unintentional from ingestion, eye contact, or skin contact can cause adverse effects such as seizures and anoxic brain trauma. A study on the offspring of the pregnant mice, which were exposed to nicotine-containing e-liquid, showed significant behavioral alterations. This indicated that exposure to e-cigarette components in a susceptible time period of brain development could induce persistent behavioral changes.
Effects of nicotine.
The health effects of long-term nicotine use is unknown. It may be decades before the long-term health effects of nicotine e-cigarette aerosol (vapor) inhalation is known. Short-term nicotine use excites the autonomic ganglia nerves and autonomic nerves, but chronic use seems to induce negative effects on endothelial cells. Nicotine may result in neuroplasticity modifications in the brain. Nicotine has been demonstrated to alter the amounts of brain-derived neurotrophic factor in humans. Side effects of nicotine include mild headache, headache, dysphoria, depressed mood, irritability, aggression, frustration, impatience, anxiety, sleep disturbances, abnormal dreams, irritability, and dizziness. 
The neuroregulation and structural interactions in the brain and lungs from nicotine may interfere with an array of reflexes and responses. These alterations may raise the risk of hypoxia. Continued use of nicotine may result in harmful effects to women's brains because it restricts estrogen signaling. This could lead to making the brain more vulnerable to ischemia. A 2015 review concluded that "Nicotine acts as a gateway drug on the brain, and this effect is likely to occur whether the exposure is from smoking tobacco, passive tobacco smoke or e-cigarettes."
Nicotine may have a profound impact on sleep. The effects on sleep vary after being intoxicated, during withdrawal, and from long-term use. Nicotine may result in arousal and wakefulness, mainly via incitement in the basal forebrain. Nicotine withdrawal, after abstaining from nicotine use in non-smokers, was linked with longer overall length of sleep and REM rebound. A 2016 review states that "Although smokers say they smoke to control stress, studies show a significant increase in cortisol concentrations in daily smokers compared with occasional smokers or nonsmokers. These findings suggest that, despite the subjective effects, smoking may actually worsen the negative emotional states. The effects of nicotine on the sleep-wake cycle through nicotine receptors may have a functional significance. Nicotine receptor stimulation promotes wake time and reduces both total sleep time and rapid eye movement sleep."
Addiction and dependence.
Psychological and physical dependence.
Nicotine, a key ingredient in most e-liquids, is well-recognized as one of the most addictive substances, as addictive as heroin and cocaine. Addiction is believed to be a disorder of experience-dependent brain plasticity. The reinforcing effects of nicotine play a significant role in the beginning and continuing use of the drug. First-time nicotine users develop a dependence about 32% of the time. Chronic nicotine use involves both psychological and physical dependence. Nicotine-containing e-cigarette aerosol induces addiction-related neurochemical, physiological and behavioral changes. 
Nicotine affects neurological, neuromuscular, cardiovascular, respiratory, immunological and gastrointestinal systems. Neuroplasticity within the brain's reward system occurs as a result of long-term nicotine use, leading to nicotine dependence. The neurophysiological activities that are the basis of nicotine dependence are intricate. It includes genetic components, age, gender, and the environment. Pre-existing cognitive and mood disorders may influence the development and maintenance of nicotine dependence. 
Nicotine addiction is a disorder which alters different neural systems such as dopaminergic, glutamatergic, GABAergic, serotoninergic, that take part in reacting to nicotine. In 2015 the psychological and behavioral effects of e-cigarettes were studied using whole-body exposure to e-cigarette aerosol, followed by a series of biochemical and behavioral studies. The results showed that nicotine-containing e-cigarette aerosol induces addiction-related neurochemical, physiological and behavioral changes.
Long-term nicotine use affects a broad range of genes associated with neurotransmission, signal transduction, and synaptic architecture. The most well-known hereditary influence related to nicotine dependence is a mutation at rs16969968 in the nicotinic acetylcholine receptor "CHRNA5", resulting in an amino acid alteration from aspartic acid to asparagine. The single-nucleotide polymorphisms (SNPs) rs6474413 and rs10958726 in "CHRNB3" are highly correlated with nicotine dependence. Many other known variants within the "CHRNB3–CHRNA6" nicotinic acetylcholine receptors are also correlated with nicotine dependence in certain ethnic groups. There is a relationship between "CHRNA5"-"CHRNA3"-"CHRNB4" nicotinic acetylcholine receptors and complete smoking cessation. 
Increasing evidence indicates that the genetic variant "CHRNA5" predicts the response to smoking cessation medicine. The ability to quitting smoking is affected by genetic factors, including genetically based differences in the way nicotine is metabolized. In the "CYP450" system there are 173 genetic variants, which impacts how quickly nicotine is metabolizes by each individual. The speed of metabolism impacts the regularity and quantity of nicotine used. For instance, in people who metabolize nicotine gradually their central nervous system effects of nicotine lasts longer, increasing their probability of dependence, but also increasing ability with quitting smoking.
Stimulation of the brain.
Nicotine is a parasympathomimetic stimulant that binds to and activates nicotinic acetylcholine receptors in the brain, which subsequently causes the release of dopamine and other neurotransmitters, such as norepinephrine, acetylcholine, serotonin, gamma-aminobutyric acid, glutamate, endorphins, and several neuropeptides, including proopiomelanocortin-derived α-MSH and adrenocorticotropic hormone. Corticotropin-releasing factor, Neuropeptide Y, orexins, and norepinephrine are involved in nicotine addiction. 
Continuous exposure to nicotine can cause an increase in the number of nicotinic receptors, which is believed to be a result of receptor desensitization and subsequent receptor upregulation. Long-term exposure to nicotine can also result in downregulation of glutamate transporter 1. Long-term nicotine exposure upregulates cortical nicotinic receptors, but it also lowers the activity of the nicotinic receptors in the cortical vasodilation region. These effects are not easily understood.
With constant use of nicotine, tolerance occurs at least partially as a result of the development of new nicotinic acetylcholine receptors in the brain. After several months of nicotine abstinence, the number of receptors go back to normal. The extent to which alterations in the brain caused by nicotine use are reversible is not fully understood. Nicotine also stimulates nicotinic acetylcholine receptors in the adrenal medulla, resulting in increased levels of epinephrine and beta-endorphin. Its physiological effects stem from the stimulation of nicotinic acetylcholine receptors, which are located throughout the central and peripheral nervous systems. 
The α4β2 nicotinic receptor subtype is the main nicotinic receptor subtype. Nicotine activates brain receptors which produce sedative as well as pleasurable effects. Chronic nicotinic acetylcholine receptor activation from repeated nicotine exposure can induce strong effects on the brain, including changes in the brain's physiology, that result from the stimulation of regions of the brain associated with reward, pleasure, and anxiety. These complex effects of nicotine on the brain are still not well understood.
Nicotine interferes with the blood–brain barrier function, and as a consequence raises the risk of brain edema and neuroinflammation. When nicotine enters the brain it stimulates, among other activities, the midbrain dopaminergic neurons situated in the ventral tegmental area and pars compacta. It induces the release of dopamine in different parts of the brain, such as the nucleus accumbens, amygdala, and hippocampus. Ghrelin-induced dopamine release occurs as a result of the activation of the cholinergic–dopaminergic reward link in the ventral tegmental area, a critical part of the reward areas in the brain related with reinforcement. Ghrelin signaling may affect the reinforcing effects of drug dependence.
Discontinuing nicotine use.
When nicotine intake stops, the upregulated nicotinic acetylcholine receptors induce withdrawal symptoms. These symptoms can include cravings for nicotine, anger, irritability, anxiety, depression, impatience, trouble sleeping, restlessness, hunger, weight gain, and difficulty concentrating. When trying to quit smoking with vaping a base containing nicotine, symptoms of withdrawal can include irritability, restlessness, poor concentration, anxiety, depression, and hunger. The changes in the brain cause a nicotine user to feel abnormal when not using nicotine. In order to feel normal, the user has to keep his or her body supplied with nicotine. E-cigarettes may reduce cigarette craving and withdrawal symptoms.
Limiting tobacco consumption with the use of campaigns that portray cigarette smoking as unacceptable and harmful have been enacted; though, advocating for the use of e-cigarettes jeopardizes this because of the possibility of escalating nicotine addiction. It is not clear whether e-cigarette use will decrease or increase overall nicotine addiction, but the nicotine content in e-cigarettes is adequate to sustain nicotine dependence. Chronic nicotine use causes a broad range of neuroplastic adaptations, making quitting hard to accomplish. 
A 2015 study found that users vaping non-nicotine e-liquid exhibited signs of dependence. Experienced users tend to take longer puffs which may result in higher nicotine intake. It is difficult to assess the impact of nicotine dependence from e-cigarette use because of the wide range of e-cigarette products. The addiction potential of e-cigarettes may have risen because as they have progressed, they delivery nicotine better. A 2016 review states that "The highly addictive nature of nicotine is responsible for its widespread use and difficulty with quitting."
Young adults and youth.
Addiction and dependence.
E-cigarettes use by children and adolescents may result in nicotine addiction. Following the possibility of nicotine addiction via e-cigarettes, there is concern that children may start smoking cigarettes. Adolescents are likely to underestimate nicotine's addictiveness. Vulnerability to the brain-modifying effects of nicotine, along with youthful experimentation with e-cigarettes, could lead to a lifelong addiction. A long-term nicotine addiction from using a vape may result in using other tobacco products. 
The majority of addiction to nicotine starts during youth and young adulthood. Adolescents are more likely to become nicotine dependent than adults. The adolescent brain seems to be particularly sensitive to neuroplasticity as a result of nicotine. Minimal exposure could be enough to produce neuroplastic alterations in the very sensitive adolescent brain. Exposure to nicotine during adolescence may increase vulnerability to getting addicted to cocaine and other drugs. 
The ability of e-cigarettes to deliver comparable or higher amounts of nicotine compared to traditional cigarettes raises concerns about e-cigarette use generating nicotine dependence among young people. Youth who believe they are vaping without nicotine could still be inhaling nicotine because there are significant differences between declared and true nicotine content.
A 2016 US Surgeon General report concluded that e-cigarette use among young adults and youths is of public health concern. Various organizations, including the International Union Against Tuberculosis and Lung Disease, the American Academy of Pediatrics, the American Cancer Society, the Centers for Disease Control and Prevention, and the US Food and Drug Administration (US FDA), have expressed concern that e-cigarette use could increase the prevalence of nicotine addiction in youth. 
Flavored tobacco is especially enticing to youth, and certain flavored tobacco products increase addiction. There is concern that flavored e-cigarettes could have a similar impact on youth. The extent to which teens are using e-cigarettes may lead to addiction or substance dependence in youth, is unknown. A 2017 review noted that "adolescents experience symptoms of dependence at lower levels of nicotine exposure than adults. Consequently, it is harder to reverse addiction originating in this stage compared with later in life."
Adolescents are particularly susceptible to nicotine addiction: the majority (90%) of smokers start before the age of 18, a fact that has been utilized by tobacco companies for decades