Nicotine is an extremely addictive drug that produces both neurological stimulation and relaxation when used. The way nicotine produces these effects is quite complex and involves many brain regions and while it primarily affects one neurotransmitter, it can produce downstream effects in several different neurotransmitters. Firstly, when smoking a cigarette, nicotine is absorbed into the blood through the lungs and quickly diffuses into the brain. Once in the brain, it binds strongly with specific neurotransmitter receptors known as nicotinic acetylcholine receptors (NARs) that normally respond to the neurotransmitter acetylcholine. The potency with which nicotine binds to these receptors produces very strong direct and indirect effects including a release of dopamine, serotonin, norepinephrine, glutamate, GABA, acetylcholine, and endorphins. This lively downstream effect of neurotransmitter release is responsible for the “buzz” or high produced by nicotine use. 1, 2, 3
As far as the addictive potential of nicotine use, the neurotransmitter dopamine is mostly responsible. This is an excitatory neurotransmitter that produces feelings of reward and pleasure. Dopamine is released in many brain regions and its specific effect depends on where in the brain it is released. The immediate effects of nicotine use are produced by dopamine in the locus coeruleus and nucleus accumbens, among other areas. In certain regions of the brain, such as the nucleus accumbens, increased dopamine signaling is a known contributor to addictive behaviors as we will explore more in-depth a little later. A complementary effect of cigarette smoking, although not due to nicotine itself, is that chronic smoking will lead to reduced levels of the enzymes monoamine oxidase A and B. These enzymes break down certain neurotransmitters such as dopamine and norepinephrine after they have been released. With reduced levels of these enzymes, there is more available dopamine in the brain and this could lead to an accelerated addiction process. 3, 4
Through chronic use of nicotine, the brain will begin to adapt to the increased levels of the neurotransmitters that are released through using the drug. This initially takes the form of downregulation, which is the process of the brain reducing the sensitivity of the overstimulated neurotransmitter receptors in an attempt to maintain balance. This initially produces tolerance and continued use will result in a physiological dependence. A further process known as neurological remodeling will begin after downregulation has started, and this process is much slower to perform and, subsequently, to reverse once someone stops smoking. Remodeling is the act of structural changes occurring in the brain to prioritize and encourage nicotine use, and the nucleus accumbens is a major player in this regard. Long-term nicotine use can also, paradoxically, lead to the upregulation of nicotinic acetylcholine receptors, which increases the brain’s sensitivity to nicotine. This can increase the desire for nicotine as well as the psychological effects of nicotine use. In the short term, once downregulation has begun, someone will begin to experience nicotine withdrawal symptoms when they go too long without using the drug. 5
Nicotine withdrawal symptoms are mostly psychological, although there are physical symptoms as well. The symptoms are quite intense in the first few days after the last nicotine use, and the physical symptoms usually resolve within days.
Some of the most common symptoms of nicotine withdrawal include:
The psychological symptoms are usually the most intense and longest-lasting out of these and may remain at a high level for several weeks. There are medications and behavioral therapies that may help treat the symptoms of nicotine withdrawal, but the only way for these symptoms to permanently resolve is through continued abstinence from nicotine. 6
While the acute phase of nicotine withdrawal may last several days or a week, the post-acute symptoms may last much, much longer. These are often much less intense than the acute symptoms, but their persistence can be very challenging.
The post-acute symptoms of nicotine withdrawal include:
These symptoms may persist for many months and are often the reason someone will return to nicotine use. The long duration of these symptoms seems to wear people down, with strong and sometimes constant cravings driving someone back to nicotine use. These symptoms also may benefit from medications or behavioral therapy, but the only permanent solution is to stay away from nicotine use.
The symptoms of nicotine withdrawal usually begin fairly soon after the last time someone used the drug. The half-life of nicotine is fairly short at between 1 to 3 hours. Because of this, symptoms will begin within 6 hours of the last use. Below, we will take a look at the symptom progression of nicotine withdrawal over the first 4 weeks of abstinence. 7
Within hours of the last drug use, the symptoms of nicotine withdrawal will begin to appear. The first symptoms to emerge are usually anxiety, restlessness, and cravings. These will increase over the first day and will usually be joined by increased appetite and irritability. Insomnia may emerge during the first night and thinking may become disorganized or clouded. The second day may be marked by headaches and constipation and irritability may increase. These symptoms will worsen over the second day and, oftentimes, into the third day since the last nicotine use. The symptoms will usually peak during the third day before starting a slow resolution that will take place over the following weeks.
The second week usually starts off much better than the first, as most of the physical symptoms are well on their way to resolution. The psychological symptoms, however, are usually still at a fairly high level. Anxiety, depression, fatigue, and strong cravings should still be expected, although they are usually improved compared to the first week. Bowel movements may still be somewhat infrequent, but this usually improves as the week progresses. Insomnia may still be present, although it should see some improvement. Once sleep becomes more regular, it is often characterized by vivid dreams or nightmares, and these may persist for the rest of the week, at least.
The beginning of the third week often sees the total resolution of physical symptoms of nicotine withdrawal. The psychological symptoms, while often still present, should be much improved by this time. Anxiety, depression, and minor fatigue may be expected, although cravings can still be quite intense. Restlessness and difficulty concentrating may be present as well, but they are usually on their way towards resolution.
By four weeks after the last nicotine use, most of the symptoms should either be completely resolved or show substantial improvement. While cravings may be present, they usually come and go and may not necessarily be constant./Strong cravings may be triggered by specific things, such as second-hand smoke. Depression and anxiety are frequently still present but are usually much improved. Even though the worst of the nicotine withdrawal symptoms may be passed, there is still work to do. Relapse is still a very real risk, and continued care is often needed to prevent a return to nicotine addiction.
Even though the effects of nicotine withdrawal are mostly psychological, the physical effects can nevertheless be uncomfortable. The part of the body that is hardest hit in the short-term is the gastrointestinal tract. For those who smoked or vaped nicotine, after a brief period of abstinence, the lungs may begin to be affected as well and commonly manifest a cough in the first few weeks or months after quitting.
Let’s take a look at the effects of nicotine withdrawal on these two physical systems:
The gastrointestinal effects of nicotine detox are usually noticeable within the first few days of nicotine withdrawal. These effects are not usually dangerous or severe and often manifest as increased appetite, constipation, and possibly mild stomach aches. The specific receptors that notice binds to, nicotinic acetylcholine receptors (NARs), are found not only in the brain but all throughout the body. They have a large presence in the gastrointestinal tract, and specifically in the enteric nervous system. In the GI tract, these receptors are responsible for activating a variety of digestive functions, including gastric fluid secretion and intestinal muscle contractions.
The way the body responds to nicotine is somewhat unique among addictive drugs. The process of upregulation is fairly common, and this process increases the numbers of NARs. The unique aspect of nicotine addiction is that a desensitization process also occurs which blunts the sensitivity of these receptors. Nicotine can stimulate these receptors very strongly; more so than the natural neurotransmitter acetylcholine that is produced by the body. When nicotine is suddenly removed, this desensitization creates a situation where the receptors are unable to reach their stimulation threshold since the body’s natural neurotransmitters have a reduced impact. Due to this, the gastrointestinal tract will have depressed and sluggish function until the body can restore neurotransmitter function to pre-nicotine use levels. 8, 9, 10, 11
Another very common effect of nicotine withdrawal, although specific to smoking, is the development of cough, wheezing, shortness of breath, and increased phlegm. These are not due to nicotine itself, but rather smoking cigarettes and possibly vaping nicotine. These symptoms may begin days after someone stops smoking and often begin to improve around a month or two after smoking ceases. They may persist for many more months but are usually fully resolved by 12 to 18 months after the last time someone smoked. The one exception is increased phlegm, which seems to persist longer and may even be permanent in some cases due to smoking- or vaping-induced permanent damage to the mucociliary elevator. 12, 13, 14
The psychological effects of nicotine withdrawal are usually the most challenging and sometimes difficult effects to overcome. These may start out quite intense, and while they improve wit time, they can persist for months or years after quitting nicotine use. The profound effects that nicotine use can produce in the brain are very comprehensive, and it takes time for the brain to undo these changes once use ceases.
Some of the most common psychological effects of nicotine detox include:
Cravings for nicotine may be the most common and challenging effect of nicotine withdrawal and is often the main reason someone returns to nicotine use. Chronic nicotine use can produce extensive changes in the brain, both short-term and long-term. Initially, the up- or downregulation that occurs to certain neurotransmitter systems can cause someone to feel unhappy, unsatisfied, and result in a reduced ability to experience pleasure. Further changes in the form of neurological remodeling can prime the brain to seek out and use nicotine, especially in times of stress or discomfort. Finally, there are psychological mechanisms at play as well, and these causes can conspire to produce some very strong and long-lasting cravings for nicotine.
From a neurological perspective, nicotine cravings are somewhat similar to cravings for other drugs of abuse during detox and withdrawal. Downregulation to dopamine and serotonin neurotransmitter systems can cause the normal levels of these neurotransmitters to be unable to effectively stimulate their receptors. Dopamine is a major excitatory neurotransmitter in the brain and is responsible for feelings of reward and pleasure while serotonin is a mood elevator and regulator. When these systems are disrupted, mood will be depressed and it is very difficult or even impossible to experience any sense of pleasure for a time. The neurological remodeling that begins after downregulation occurs can deepen this reliance on nicotine by creating strong associations between nicotine and feeling good. Due to the psychological unpleasantness of nicotine withdrawal, a desire for relief will naturally elicit strong cravings for nicotine.
From a psychological standpoint, the reliance on nicotine as a coping mechanism is to blame. Nicotine use can begin as a fun thing done with friends or at parties, but it often becomes more of a requirement over time and continued use. Even though nicotine is a stimulant, it can produce a sensation of relaxation or stress relief, and this often results in it being associated with comfort and peace. As use continues, this perception can increase to the point that nicotine is “needed” in any stressful situation to help someone cope with whatever they may be going through. When nicotine is suddenly removed, someone may suddenly feel exposed and vulnerable. Because of the heavy reliance on nicotine as a way to cope with stress or life in general, when this coping mechanism is lost it is not uncommon for someone to feel stressed, overwhelmed, and unable to manage their problems. This will improve with time, but behavioral therapy may be able to speed up the process and reduce symptoms in the meantime. 2, 3, 15, 16, 17
Two very common effects of nicotine detox are increased anxiety and depression. These issues are caused by similar, although distinct neurological changes in the brain and may also have a behavioral cause somewhat similar to that of nicotine cravings. Neurologically, downregulation to dopamine and serotonin is involved and could be a major cause of both of these effects. Dopamine and serotonin dysregulation can have a profound and negative impact on mood and outlook, resulting in lowered motivation, reduced ability to experience pleasure, and a general sense of dissatisfaction with life. Serotonin dysregulation can contribute to depressed mood, increased anxiety, and may instill a bleak or hopeless outlook on life. From a behavioral standpoint, similar to cravings the loss of a coping mechanism can lead to increased levels of anxiety and a depressed mood. All of these issues, both neurological and behavioral, can benefit from medications and clinical therapies but the only way to permanently reduce these psychological effects is to maintain abstinence from nicotine use. 18, 19, 20, 21, 22
As we have mentioned throughout the article, medications and therapy can provide massive benefits to someone’s subjective experience of nicotine withdrawal symptoms and their objective chances of a successful recovery and long-term abstinence from nicotine use. While nicotine replacement therapy can be useful in helping someone quit smoking, there are still risks associated with nicotine use, regardless of the route it is used. 8, 9, 11, 24 The safest option is to quit using nicotine entirely. There are multiple effective medications that can reduce the symptoms of nicotine withdrawal and behavioral therapies can help reduce cravings. Quitting nicotine use can seem like an impossible challenge at times, but with help, it can be done. Don’t wait, recovery can start today.
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