Complications of benzodiazepine abuse include drug-related deaths due to overdose especially in combination with other depressant drugs such as opioids. Other complications include: blackouts and memory loss, paranoia, violence and criminal behaviour, risk-taking sexual behaviour, foetal and neonatal risks if taken in pregnancy, dependence, withdrawal seizures and psychosis. Injection of the drug carries risk of: thrombophlebitis, deep vein thrombosis, deep and superficial abscesses, pulmonary microembolism, rhabdomyolysis, tissue necrosis, gangrene requiring amputation, hepatitis B and C, as well as blood borne infections such as HIV infection (caused by sharing injecting equipment). Long-term use of benzodiazepines can worsen pre-existing depression and anxiety and may potentially also cause dementia with impairments in recent and remote memory functions.

Use is widespread among amphetamine users, with those that use amphetamines and benzodiazepines having greater levels of mental health problems and social deterioration. Benzodiazepine injectors are almost four times more likely to inject using a shared needle than non-benzodiazepine-using injectors. It has been concluded in various studies that benzodiazepine use causes greater levels of risk and psycho-social dysfunction among drug misusers.

Poly-drug users who also use benzodiazepines appear to engage in more frequent high-risk behaviors. Those who use stimulant and depressant drugs are more likely to report adverse reactions from stimulant use, more likely to be injecting stimulants and more likely to have been treated for a drug problem than those using stimulant but not depressant drugs.

Individuals with a substance abuse history are at an increased risk of misusing benzodiazepines.

Several (primary research) studies, even into the last decade, claimed, that individuals with a history of familial abuse of alcohol or who are siblings or children of alcoholics appeared to respond differently to benzodiazepines than so called "genetically healthy" persons, with males experiencing increased euphoric effects and females having exaggerated responses to the adverse effects of benzodiazepines.

Whilst all benzodiazepines have abuse potential, certain characteristics increase the potential of particular benzodiazepines for abuse. These characteristics are chiefly practical ones—most especially, availability (often based on popular perception of 'dangerous' versus 'non-dangerous' drugs) through prescribing physicians or illicit distributors. Pharmacological and pharmacokinetic factors are also crucial in determining abuse potentials. A short elimination half-life, high potency and a rapid onset of action are characteristics which increase the abuse potential of benzodiazepines. The following table provides the elimination half-life, relevant potency to other benzodiazepines, speed of onset of action and duration of behavioural effects.

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.

A study consisting of 1,081 U.S. residents who had first used cocaine within the previous 24 months was conducted. It was found that the risk of becoming dependent on cocaine within two years of first use was 5–6%. The risk of becoming dependent within 10 years of first use increased to 15–16%. These were the aggregate rates for all types of use considered, such as smoking, snorting, and injecting. Among recent-onset users individual rates of dependency were higher for smoking (3.4 times) and much higher for injecting. Women were 3.3 times more likely to become dependent, compared with men. Users who started at ages 12 or 13 were four times as likely to become dependent compared to those who started between ages 18 and 20.

However, a study of non-deviant users in Amsterdam found a "relative absence of destructive and compulsive use patterns over a ten year period" and concluded that cocaine users can and do exercise control. "Our respondents applied two basic types of controls to themselves: 1) restricting use to certain situations and to emotional states in which cocaine's effects would be most positive, and 2) limiting mode of ingestion to snorting of modest amounts of cocaine, staying below 2.5 grams a week for some, and below 0.5 grams a week for most. Nevertheless, those whose use level exceeded 2.5 grams a week all returned to lower levels".

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.

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.

In the United States, cocaine use results in about 5,000–6,000 deaths annually.

Traditional cigarettes are the most common delivery device for nicotine. However, electronic cigarettes are becoming more popular. Nicotine can also be delivered via other tobacco products such as chewing tobacco, snus, pipe tobacco, hookah, all of which can produce nicotine dependence. The risk for developing dependence is related to how much nicotine is in a product and how fast it can get to the user’s brain. Smoke from products like cigarettes and hookah is absorbed in the lungs and then nicotine gets to the brain in about 6 seconds. Cigarettes and hookah also have large amounts of nicotine in them, and therefore people who use them have a higher risk of developing dependence. Products where nicotine is absorbed into the blood through the mouth (e.g., snus, chewing tobacco), and therefore takes longer to get to the brain, have lower dependence risk. Nicotine replacement medications like the nicotine patch, nicotine lozenges, and nicotine gum have minimal to no dependence risk because they do not contain nearly as much nicotine as tobacco products and they don’t get into the brain very quickly. This is why nicotine replacement medications are safe.

Withdrawal is the body's reaction to abstaining from a substance upon which a person has developed a dependence syndrome. When dependence has developed, cessation of substance use produces an unpleasant state, which promotes continued drug use through negative reinforcement; i.e., the drug is used to escape or avoid re-entering the associated withdrawal state. The withdrawal state may include physical-somatic symptoms (physical dependence), emotional-motivational symptoms (psychological dependence), or both. Chemical and hormonal imbalances may arise if the substance is not introduced. Psychological stress may also result if the substance is not re-introduced.

Infants also suffer from substance withdrawal, known as Neonnatal Abstinence Syndrome (NAS) which has severe and life-threatening effects on growing fetus. Addiction to drugs and alcohol in expecting mothers does not only cause NAS but also an array of other issues which can continually affect the infant throughout his/her lifetime. The type of drug which was abused during the months of pregnancy has many different effects on the child which can affect the infant in many ways throughout his/her life.

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 dependence potential of a drug varies from substance to substance, and from individual to individual. Dose, frequency, pharmacokinetics of a particular substance, route of administration, and time are critical factors for developing a drug dependence.

An article in "The Lancet" compared the harm and dependence liability of 20 drugs, using a scale from zero to three for physical dependence, psychological dependence, and pleasure to create a mean score for dependence. Selected results can be seen in the chart below.

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.

According to the CDC in 2017, in the US, "the age-adjusted drug poisoning death rate involving opioid analgesics increased from 1.4 to 5.4 deaths per 100,000 population between 1999 and 2010, decreased to 5.1 in 2012 and 2013, then increased to 5.9 in 2014, and to 7.0 in 2015. The age-adjusted drug poisoning death rate involving heroin doubled from 0.7 to 1.4 deaths per 100,000 resident population between 1999 and 2011 and then continued to increase to 4.1 in 2015."

In 2012 it was estimated that 9.2 percent of the population over the age of 12 years old had used an illicit drug in the previous month. In 2015, it was estimated the 20.5 million Americans had a substance use disorder. Of these 20.5 million, two million used prescribed pain medications (most of those being opioids) and one-half of a million were using heroin.

In 2015, in the US there were 33,000 deaths due to drug overdose that involved opioid use. Of these, about 15,000 were from prescribed opioids and 13,000 were from heroin use.

Non-medical consumption of opioids peaked around 2010 and then started to decrease between 2011 and 2013.

Among adults, the rate of inpatient hospital stays in the United States related to opioid overuse increased by an average of 5% annually from 1993–2012. The percentage of inpatient stays due to opioid overuse admitted from the emergency department increased from 43% in 1993 to 64% in 2005, but have remained relatively constant since 2005.

The prevalence of opioid use and opioid or opiate dependency varies by age and gender, among a myriad of other factors. Men are at higher risk for opioid use and dependency than women, and men also account for more opioid overdoses than women, although this gap is closing. Women are more likely to be prescribed pain relievers, be given higher doses, use them for longer durations, and may become dependent upon them faster.

Deaths due to opioid use also tend to skew at older ages than deaths from use of other illicit drugs. This does not reflect opioid use as a whole, which includes individuals in younger age demographics. Overdoses from opioids are highest among individuals who are between the ages of 40 and 50, in contrast to heroin overdoses, which are highest among individuals who are between the ages of 20 and 30. 21 to 35-year olds represent 77% of individuals who enter treatment for opioid use disorder, however, the average age of first-time use of prescription painkillers was 21.2 years of age in 2013.

As demonstrated by the chart below, numerous studies have examined factors which mediate substance abuse or dependence. In these examples, the predictor variables lead to the mediator which in turn leads to the outcome, which is always substance abuse or dependence. For example, research has found that being raised in a single-parent home can lead to increased exposure to stress and that increased exposure to stress, not being raised in a single-parent home, leads to substance abuse or dependence. The following are some, but by no means all, of the possible mediators of substance abuse.

As demonstrated by the chart below, numerous studies have examined factors which moderate substance abuse or dependence. In these examples, the moderator variable impacts the level to which the strength of the relationship varies between a given predictor variable and the outcome of substance abuse or dependence. For example, there is a significant relationship between psychobehavioral risk factors, such as tolerance of deviance, rebelliousness, achievement, perceived drug risk, familism, family church attendance and other factors, and substance abuse and dependence. That relationship is moderated by familism which means that the strength of the relationship is increased or decreased based on the level of familism present in a given individual.

Examples of mediators and moderators can be found in several empirical studies. For example, Pilgrim et al.’s hypothesized mediation model posited that school success and time spent with friends mediated the relationship between parental involvement and risk-taking behavior with substance use (2006). More specifically, the relationship between parental involvement and risk-taking behavior is explained via the interaction with third variables, school success and time spent with friends. In this example, increased parental involvement led to increased school success and decreased time with friends, both of which were associated with decreased drug use. Another example of mediation involved risk-taking behaviors. As risk-taking behaviors increased, school success decreased and time with friends increased, both of which were associated with increased drug use.

A second example of a mediating variable is depression. In a study by Lo and Cheng (2007), depression was found to mediate the relationship between childhood maltreatment and subsequent substance abuse in adulthood. In other words, childhood physical abuse is associated with increased depression, which in turn, in associated with increased drug and alcohol use in young adulthood. More specifically, depression helps to explain how childhood abuse is related to subsequent substance abuse in young adulthood.

A third example of a mediating variable is an increase of externalizing symptoms. King and Chassin (2008) conducted research examining the relationship between stressful life events and drug dependence in young adulthood. Their findings identified problematic externalizing behavior on subsequent substance dependency. In other words, stressful life events are associated with externalizing symptoms, such as aggression or hostility, which can lead to peer alienation or acceptance by socially deviant peers, which could lead to increased drug use. The relationship between stressful life events and subsequent drug dependence however exists via the presence of the mediation effects of externalizing behaviors.

An example of a moderating variable is level of cognitive distortion. An individual with high levels of cognitive distortion might react adversely to potentially innocuous events, and may have increased difficulty reacting to them in an adaptive manner (Shoal & Giancola, 2005). In their study, Shoal and Giancola investigated the moderating effects of cognitive distortion on adolescent substance use. Individuals with low levels of cognitive distortion may be more apt to choose more adaptive methods of coping with social problems, thereby potentially reducing the risk of drug use. Individuals with high levels of cognitive distortions, because of their increased misperceptions and misattributions, are at increased risk for social difficulties. Individuals may be more likely to react aggressively or inappropriately, potentially alienating themselves from their peers, thereby putting them at greater risk for delinquent behaviors, including substance use and abuse. In this study, social problems are a significant risk factor for drug use when moderated by high levels of cognitive distortions.

There are efforts to decrease the number of opioids prescribed in an effort to decrease opioid use disorder and deaths related to opioid use.

The initiation of drug and alcohol use is most likely to occur during adolescence, and some experimentation with substances by older adolescents is common. For example, results from 2010 Monitoring the Future survey, a nationwide study on rates of substance use in the United States, show that 48.2% of 12th graders report having used an illicit drug at some point in their lives. In the 30 days prior to the survey, 41.2% of 12th graders had consumed alcohol and 19.2% of 12th graders had smoked tobacco cigarettes. In 2009 in the United States about 21% of high school students have taken prescription drugs without a prescription. And earlier in 2002, the World Health Organization estimated that around 140 million people were alcohol dependent and another 400 million with alcohol-related problems.

Studies have shown that the large majority of adolescents will phase out of drug use before it becomes problematic. Thus, although rates of overall use are high, the percentage of adolescents who meet criteria for substance abuse is significantly lower (close to 5%). According to BBC, "Worldwide, the UN estimates there are more than 50 million regular users of morphine diacetate (heroin), cocaine and synthetic drugs."

Some medical systems, including those of at least 15 states of the United States, refer to an Addiction Severity Index to assess the severity of problems related to substance use. According to DARA Thailand, the index assesses potential problems in seven categories: medical, employment/support, alcohol, other drug use, legal, family/social, and psychiatric.

Street children in many developing countries are a high risk group for substance misuse, in particular solvent abuse. Drawing on research in Kenya, Cottrell-Boyce argues that "drug use amongst street children is primarily functional – dulling the senses against the hardships of life on the street – but can also provide a link to the support structure of the ‘street family’ peer group as a potent symbol of shared experience."

Risk factors for opioid overdose include opioid dependence, injecting opioids, using high doses of opioids, and use together with alcohol or benzodiazepines. The risk is particularly high following detoxification. Dependence on prescription opioids can occur from their use to treat chronic pain.

Opioid overdoses associated with a conjunction of benzodiazepines and/or alcohol use leads to a contraindicated condition. Other CNS depressants, or "downers", muscle relaxers, pain relievers, anti-convulsants, anxiolytics (anti-anxiety drugs), treatment drugs of a psychoactive or epileptic variety or any other such drug with its active function meant to calm or mitigate neuronal signaling (barbiturates, etc.) can additionally cause a worsened condition with less likelihood of recovery cumulative to each added drug. This includes drugs less immediately classed to a slowing of the metabolism such as with GABAergics like GHB or glutamatergic antagonists like PCP or ketamine.

The long-term abuse of stimulants ultimately causes very serious medical issues, including but not limited to, addiction. Addiction, which is a disease that causes high rates of relapse, can be defined as a chronic disease that is characterized as a compulsive drug seeking behavior in which the user will stop at nothing to obtain the drug. Long time users of stimulants have noted changes in the body such as brain function, chemistry and molecular or cellular adaptations.

The symptoms of stimulant use disorder include failure to control usage and frequency of use, an intense craving for the drug, increased use over time to obtain the same effects, known as a developed tolerance, and a continued use despite negative repercussions and interference in one’s everyday life and functioning. Furthermore, a disorder is noted when withdrawal symptoms occur because of a decrease in the drug amount and frequency, as well as stopping the use of the drug entirely. These withdrawal symptoms can last for days, weeks, months, and on rare occasions, years, depending on the frequency and dosages used by the individual. These symptoms include, but are not limited to, increased appetite, decreased energy, depression, loss of motivation and interest in once pleasurable activities, anxiety, insomnia, agitation and an intense craving for the drug. Unless intensive medical and psychological treatment is sought after, there is a very high likelihood of relapse among the user.

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.

The National Institute on Drug Abuse (NIDA) says that "even though anabolic steroids do not cause the same high as other drugs, steroids are reinforcing and can lead to addiction. Studies have shown that animals will self-administer steroids when given the opportunity, just as they do with other addictive drugs. People may persist in abusing steroids despite physical problems and negative effects on social relationships, reflecting these drugs’ addictive potential. Also, steroid abusers typically spend large amounts of time and money obtaining the drug; another indication of addiction. Individuals who abuse steroids can experience withdrawal symptoms when they stop taking them, including mood swings, fatigue, restlessness, loss of appetite, insomnia, reduced sex drive, and steroid cravings, all of which may contribute to continued abuse. One of the most dangerous withdrawal symptoms is depression. When depression is persistent, it can sometimes lead to suicidal thoughts. Research has found that some steroid abusers turn to other drugs such as opioids to counteract the negative effects of steroids."

Male anabolic-androgenic steroid abusers often have a troubled social background.