A neonatal withdrawal syndrome, sometimes severe, can occur when the mother had taken benzodiazepines, especially during the third trimester. Symptoms include hypotonia, apnoeic spells, cyanosis, and impaired metabolic responses to cold stress and seizures. The neonatal benzodiazepine withdrawal syndrome has been reported to persist from hours to months after birth.

A withdrawal syndrome is seen in about 20% of pediatric intensive care unit children after infusions with benzodiazepines or opioids. The likelihood of having the syndrome correlates with total infusion duration and dose, although duration is thought to be more important. Treatment for withdrawal usually involves weaning over a 3- to 21-day period if the infusion lasted for more than a week. Symptoms include tremors, agitation, sleeplessness, inconsolable crying, diarrhea and sweating. In total, over fifty withdrawal symptoms are listed in this review article. Environmental measures aimed at easing the symptoms of neonates with severe abstinence syndrome had little impact, but providing a quiet sleep environment helped in mild cases.

The severity and length of the withdrawal syndrome is likely determined by various factors, including rate of tapering, length of use and dosage size, and possible genetic factors. Those who have a prior history of withdrawing from benzodiazepines may have a sensitized or kindled central nervous system leading to worsening cognition and symptomatology, and making each subsequent withdrawal period worse.

Cross-tolerance is a phenomenon that occurs when tolerance to the effects of a certain drug produces tolerance to another drug. It often happens between two drugs with similar functions or effects – for example, acting on the same cell receptor or affecting the transmission of certain neurotransmitters. Cross-tolerance has been observed with pharmaceutical drugs such as anti-anxiety agents and illicit substances, and sometimes the two of them together. Often, a person who uses one drug can be tolerant to a drug that has a completely different function. This phenomenon allows one to become tolerant to a drug that they have never even used before.

Drug tolerance is a pharmacological concept describing subjects' reduced reaction to a drug following its repeated use. Increasing its dosage may re-amplify the drug's effects, however this may accelerate tolerance, further reducing the drug's effects. Drug tolerance is indicative of drug use but is not necessarily associated with drug dependence or addiction. The process of tolerance development is reversible (e.g., through a drug holiday) and can involve both physiological factors and psychological factors.

One may also develop drug tolerance to side effects, in which case tolerance is a desirable characteristic. A medical intervention that has for objective to increase tolerance (e.g., allergen immunotherapy, in which one is exposed to larger and larger amounts of allergen to decrease one's allergic reactions) is called drug desensitization.

The opposite concept to drug tolerance is drug reverse tolerance (or drug sensitization), in which case the subject's reaction or effect will increase following its repeated use. The two notions are not incompatible and tolerance may sometimes lead to reverse tolerance. For example, heavy drinkers initially develop tolerance to alcohol (requiring them to drink larger amounts to achieve a similar effect) but excessive drinking can cause liver damage, which then puts them at risk of intoxication when drinking even very small amounts of alcohol.

Drug tolerance should not be confused with drug tolerability, which refers to the degree to which overt adverse effects of a drug can be tolerated by a patient.

Tachyphylaxis is a subcategory of drug tolerance referring to cases of sudden, short-term onset of tolerance following the administration of a drug.

Research studies have come to different conclusions on the number of therapeutic dose users who develop a physical dependence and withdrawal syndrome. Estimates by researchers of the number of people affected range 20–100% of patients prescribed benzodiazepines at therapeutic dosages long term are physically dependent and will experience withdrawal symptoms.

Benzodiazepines can be addictive and induce dependence even at low doses, with 23% becoming addicted within 3 months of use. Benzodiazepine addiction is considered a public health problem. Approximately 68.5% of prescriptions of benzodiazepines originate from local health centers, with psychiatry and general hospitals accounting for 10% each. A survey of general practitioners reported that the reason for initiating benzodiazepines was due to an empathy for the patients suffering and a lack of other therapeutic options rather than patients demanding them. However, long-term use was more commonly at the insistence of the patient, it is presumed, because physical dependence or addiction had developed.

Approximately twice as many women as men are prescribed benzodiazepines. It is believed that this is largely because men typically turned to alcohol to cope with stress and women to prescription drugs. Biased perception of women by male doctors may also play a role in increased prescribing rates to women; however, increased anxiety features in women does not account for the wide gap alone between men and women.

A study published in the British Journal of General Practice in July 2017 found that in a sample taken from a survey conducted in 2014–2015 in Bradford a mean of 0.69% of registered patients had been prescribed benzodiazepines for more than a year. This would suggest that there were around 300,000 long-term users of diazepine in the UK.

Continued use of benzodiazepines may impair recovery from psychomotor and cognitive impairments from alcohol. Cigarette smoking may slow down or interfere with recovery of brain pathways in recovering alcoholics.

Sending a letter to patients warning of the adverse effects of long-term use of benzodiazepines and recommending dosage reduction has been found to be successful and a cost-effective strategy in reducing benzodiazepine consumption in general practice. Within a year of the letter's going out, there was found to be a 17% fall in the number of benzodiazepines being prescribed, with 5% of patients having totally discontinued benzodiazepines. A study in the Netherlands reported a higher success rate by sending a letter to patients who are benzodiazepine-dependent. The results of the Dutch study reported 11.3% of patients discontinuing benzodiazepines completely within a year.

Mild physical dependence can result from excessive caffeine intake. Caffeine addiction, or a pathological and compulsive form of use, has not been documented in humans.

Studies have demonstrated that people who take in a minimum of 100 mg of caffeine per day (about the amount in one cup of coffee) can acquire a physical dependence that would trigger withdrawal symptoms that include headaches, muscle pain and stiffness, lethargy, nausea, vomiting, depressed mood, and marked irritability. Professor Roland Griffiths, a professor of neurology at Johns Hopkins in Baltimore strongly believes that caffeine withdrawal should be classified as a psychological disorder. His research suggested that withdrawals began within 12–24 hours after stopping caffeine intake and could last as long as nine days. Continued exposure to caffeine will lead the body to create more adenosine receptors in the central nervous system which makes it more sensitive to the effects of adenosine in two ways. Firstly, it will reduce the stimulatory effects of caffeine by increasing tolerance. Secondly, it will increase the withdrawal symptoms of caffeine as the body will be more sensitive to the effects of adenosine once caffeine intake stops. Caffeine tolerance develops very quickly. Tolerance to the sleep disruption effects of caffeine were seen after consumption of 400 mg of caffeine 3 times a day for 7 days, whereas complete tolerance was observed after consumption of 300 mg taken 3 times a day for 18 days.

Treatment for physical dependence depends upon the drug being withdrawn and often includes administration of another drug, especially for substances that can be dangerous when abruptly discontinued or when previous attempts have failed. Physical dependence is usually managed by a slow dose reduction over a period of weeks, months or sometimes longer depending on the drug, dose and the individual. A physical dependence on alcohol is often managed with a cross tolerant drug, such as long acting benzodiazepines to manage the alcohol withdrawal symptoms.

Physical dependence is a physical condition caused by chronic use of a tolerance forming drug, in which abrupt or gradual drug withdrawal causes unpleasant physical symptoms. Physical dependence can develop from low-dose therapeutic use of certain medications such as benzodiazepines, opioids, antiepileptics and antidepressants, as well as the recreational misuse of drugs such as alcohol, opioids, and benzodiazepines. The higher the dose used, the greater the duration of use, and the earlier age use began are predictive of worsened physical dependence and thus more severe withdrawal syndromes. Acute withdrawal syndromes can last days, weeks or months. Protracted withdrawal syndrome, also known as post-acute-withdrawal syndrome or "PAWS", is a low-grade continuation of some of the symptoms of acute withdrawal, typically in a remitting-relapsing pattern, often resulting in relapse and prolonged disability of a degree to preclude the possibility of lawful employment. Protracted withdrawal syndrome can last for months, years, or depending on individual factors, indefinitely. Protracted withdrawal syndrome is noted to be most often caused by benzodiazepines. To dispel the popular misassociation with addiction, physical dependence to medications is sometimes compared to dependence on insulin by persons with diabetes.

Failure to manage the alcohol withdrawal syndrome appropriately can lead to permanent brain damage or death. It has been proposed that brain damage due to alcohol withdrawal may be prevented by the administration of NMDA antagonists, calcium antagonists, and glucocorticoid antagonists.

Excitation of the GABA receptor produces an influx of negatively charged chloride ions, which hyperpolarizes the neuron and makes it less likely to give rise to an action potential. In addition to gamma-Aminobutyric acid (GABA) itself, the GABA receptor can also bind barbiturates and benzodiazepines. Benzodiazepine binding increases the binding of GABA and barbiturates maximize the time the pore is open. Both of these mechanisms allow for influx of chloride ions. When these drugs are taken together, especially with ethanol (drinking alcohol), there is a disproportionate increase in toxicity because the effects of both occur simultaneously and add up since they act on the same receptor at different sites. Convergence upon the GABA receptor is why tolerance for one drug in the group will most likely cause cross-tolerance for the other drugs in the group. However, the barbiturates are also AMPA receptor blockers, and in addition interact with the nAChR and voltage-gated calcium channels. As a result, somebody who is tolerant to benzodiazepines is more sensitive to barbiturates than vice versa.

ADT tachyphylaxis specifically occurs in depressed patients using SSRIs and MAOIs. Currently, SSRIs are the preferred treatment for depression among clinicians, as MAOIs require the patient to avoid certain foods and other medications due to the potential for interactions capable of inducing dangerous side effects. Provided is a list of medications known to be subject to Poop-out.

A number of groups have been identified as being at greater risk of developing cannabis dependence and include adolescent populations, Aboriginal and Torres Strait Islanders (in Australia) and people suffering from mental health conditions.

Caffeine is a commonplace central nervous system stimulant drug which occurs in nature as part of the coffee, tea, yerba mate and other plants. It is also an additive in many consumer products, most notably beverages advertised as energy drinks. Caffeine is also added to sodas such as Coca-Cola and Pepsi, where, on the ingredients listing, it is designated as a flavoring agent, due to pure caffeine powder having a bitter flavour.

Caffeine's mechanism of action is somewhat different from that of cocaine and the substituted amphetamines; caffeine blocks adenosine receptors A and A2A. Adenosine is a by-product of cellular activity, and stimulation of adenosine receptors produces feelings of tiredness and the need to sleep. Caffeine's ability to block these receptors means the levels of the body's natural stimulants, dopamine and norepinephrine, continue at higher levels.

Patients affected by ADT tachyphylaxis experience a noticeably sudden progressive decrease in response to SSRIs. The reported rates of this condition vary from 9% to 33% of SSRI users, and the majority of those affected are less responsive to subsequent treatments. In most observational studies, these individuals suffer a recurrence or relapse of depression without changing the previously effective dose.

ADT tachyphylaxis incorporates drug sensitivity as a potential causal factor for the decreased response. However, tolerance provides a more accurate explanation. While the exact cause of ADT tachyphylaxis in individual cases is unknown, drug tolerance is a more comprehensive model, as it includes mechanisms of pharmacodynamic tolerance, metabolic tolerance, and others.

About 12% of American adults have had an alcohol dependence problem at some time in their life. In the UK the NHS estimates that around 9% of men and 4% of UK women show signs of alcohol dependence.

Barbiturate dependence develops with regular use of barbiturates. This in turn may lead to a need for increasing doses of the drug to get the original desired pharmacological or therapeutic effect. Barbiturate use can lead to both addiction and physical dependence, and as such they have a high potential for abuse. Management of barbiturate dependence involves considering the affected person's age, comorbidity and the pharmacological pathways of barbiturates. Psychological addiction to barbiturates can develop quickly. The GABA receptor, one of barbiturates' main sites of action, is thought to play a pivotal role in the development of tolerance to and dependence on barbiturates, as well as the euphoric "high" that results from their abuse. The mechanism by which barbiturate tolerance develops is believed to be different from that of ethanol or benzodiazepines, even though these drugs have been shown to exhibit cross-tolerance with each other. The management of a physical dependence on barbiturates is stabilisation on the long-acting barbiturate phenobarbital followed by a gradual titration down of dose. The slowly eliminated phenobarbital lessens the severity of the withdrawal syndrome and reduces the chances of serious barbiturate withdrawal effects such as seizures. Antipsychotics are not recommended for barbiturate withdrawal (or other CNS depressant withdrawal states) especially clozapine, olanzapine or low potency phenothiazines e.g. chlorpromazine as they lower the seizure threshold and can worsen withdrawal effects; if used extreme caution is required.

Young people are at greater risk of developing cannabis dependency because of the association between early initiation into substance use and subsequent problems such as dependence, and the risks associated with using cannabis at a developmentally vulnerable age. In addition there is evidence that cannabis use during adolescence, at a time when the brain is still developing, may have deleterious effects on neural development and later cognitive functioning.

There are approximately 976 million smokers in the world. Estimates are that half of smokers (and one-third of former smokers) are dependent based on DSM criteria, regardless of age, gender or country of origin, but this could be higher if different definitions of dependence were used. Recent data suggest that, in the United States, the rates of daily smoking and the number of cigarettes smoked per day are declining, suggesting a reduction in population-wide dependence among current smokers. However, there are different groups of people who are more likely to smoke than the average population, such as those with low education or low socio-economic status and those with mental illness. There is also evidence that among smokers, some subgroups may be more dependent than other groups. Men smoke at higher rates than do women and score higher on dependence indices; however, women may be less likely to be successful in quitting, suggesting that women may be more dependent by that criterion. Higher nicotine dependence has also been linked with mental illness, including anxiety and depression.

Nicotine binds with nicotinic receptors in the brain and releases a variety of neurotransmitters, including dopamine, which, in turn, produce the pleasurable effects associated with smoking. With repeated exposure to nicotine, the number of binding sites on nicotinic receptors in the brain increases. When these receptors are not occupied by nicotine, they are believed to produce withdrawal symptoms. This upregulation or increase in the number of nicotinic receptors also significantly alters the functioning of the brain reward system. There are genetic risk factors for developing dependence. For instance, genetic markers for a specific type of nicotinic receptor (the α5-α3-β4 nicotine receptors) have been linked to increased risk for dependence. In other words, for smokers with a specific genetic code, exposure to nicotine results in an increased risk for neuroadaptation and the development of nicotine dependence.

The tolerance to alcohol is not equally distributed throughout the world's population, and genetics of alcohol dehydrogenase indicate resistance has arisen independently in different cultures. In North America, Native Americans have the highest probability of developing alcoholism compared to Europeans and Asians.

Higher body masses and the prevalence of high levels of alcohol dehydrogenase in an individual increase alcohol tolerance.

Not all differences in tolerance can be traced to biochemistry. Differences in tolerance levels are also influenced by socio-economic and cultural difference including diet, average body weight and patterns of consumption.

An estimated one out of twenty people have an alcohol flush reaction. It is not in any way an indicator for the drunkenness of an individual. It is colloquially known as "face flush", a condition where the body metabolizes alcohol nearly 100-times less efficiently into acetaldehyde, a toxic metabolite. Flushing, or blushing, is associated with the erythema (reddening caused by dilation of capillaries) of the face, neck, and shoulder, after consumption of alcohol.

Inhalation of an agonist for the beta-2 adrenergic receptor, such as Salbutamol, Albuterol (US), is the most common treatment for asthma. Polymorphisms of the beta-2 receptor play a role in tachyphylaxis. Expression of the Gly-16 allele (glycine at position 16) results in greater receptor downregulation by endogenous catecholamines at baseline compared to Arg-16. This results in a greater single-use bronchodilator response in individuals homozygous for Arg-16 compared to Gly-16 homozygotes. However, with regular beta-2 agonist use, asthmatic Arg-16 individuals experience a significant decline in bronchodilator response. This decline does not occur in Gly-16 individuals. It has been proposed that the tachyphylactic effect of regular exposure to exogenous beta-2 agonists is more apparent in Arg-16 individuals because their receptors have not been downregulated prior to agonist administration.

Direct alcohol tolerance is largely dependent on body size. Large-bodied people will require more alcohol to reach insobriety than lightly built people. Thus men, being larger than women on average, will have a higher alcohol tolerance. The alcohol tolerance is also connected with activity of "alcohol dehydrogenases" (a group of enzymes responsible for the breakdown of alcohol) in the liver, and in the bloodstream.

High level of alcohol dehydrogenase activity results in fast transformation of ethanol to more toxic acetaldehyde. Such atypical alcohol dehydrogenase levels are less frequent in alcoholics than in nonalcoholics and, alongside other symptoms, can indicate various forms of liver disease. Furthermore, among alcoholics, the carriers of this atypical enzyme consume lower ethanol doses, compared to the individuals without the allele.