Opioids, because of their effect on the part of the brain that regulates breathing, can during overdoses lead to the person not breathing (respiratory depression) and therefore result in death. Opiate overdose symptoms and signs can be referred to as the "opioid overdose triad": decreased level of consciousness, pinpoint pupils and respiratory depression. Other symptoms include seizures and muscle spasms. Sometimes a person experiencing an opiate overdose can lead to such a decreased level of consciousness that he or she won't even wake up to their name being called or being shaken by another person.

Prolonged hypoxia from respiratory depression can also lead to detrimental damage to the brain and spinal cord and can leave the person unable to walk or function normally, even if treatment with naloxone is given.

Alcohol also causes respiratory depression and therefore when taken with opioids can increase the risk of respiratory depression and death.

Following an acute overdose of a benzodiazepine the onset of symptoms is typically rapid with most developing symptoms within 4 hours. Patients initially present with mild to moderate impairment of central nervous system function. Initial signs and symptoms include intoxication, somnolence, diplopia, impaired balance, impaired motor function, anterograde amnesia, ataxia, and slurred speech. Most patients with pure benzodiazepine overdose will usually only exhibit these mild CNS symptoms. Paradoxical reactions such as anxiety, delirium, combativeness, hallucinations, and aggression can also occur following benzodiazepine overdose. Gastrointestinal symptoms such as nausea and vomiting have also been occasionally reported.

Cases of severe overdose have been reported and symptoms displayed may include prolonged deep coma or deep cyclic coma, apnea, respiratory depression, hypoxemia, hypothermia, hypotension, bradycardia, cardiac arrest, and pulmonary aspiration, with the possibility of death. Severe consequences are rare following overdose of benzodiazepines alone but the severity of overdose is increased significantly if benzodiazepines are taken in overdose in combination with other medications. Significant toxicity may result following recreation drug misuse in conjunction with other CNS depressants such as opioids or ethanol. The duration of symptoms following overdose is usually between 12 and 36 hours in the majority of cases. The majority of drug-related deaths involve misuse of heroin or other opioids in combination with benzodiazepines or other CNS depressant drugs. In most cases of fatal overdose it is likely that lack of opioid tolerance combined with the depressant effects of benzodiazepines is the cause of death.

The symptoms of an overdose such as sleepiness, agitation and ataxia occur much more frequently and severely in children. Hypotonia may also occur in severe cases.

Signs and symptoms of an overdose vary depending on the drug or toxin exposure. The symptoms can often be divided into differing toxidromes. This can help one determine what class of drug or toxin is causing the difficulties.

Symptoms of opioid overdoses include slow breathing, heart rate and pulse. Opioid overdoses can also cause pinpoint pupils, and blue lips and nails due to low levels of oxygen in the blood. A person experiencing an opioid overdose might also have muscle spasms, seizures and decreased consciousness. A person experiencing an opiate overdose usually will not wake up even if their name is called or if they are shaken vigorously.

An opioid overdose is toxicity due to excessive opioids. Examples of opioids include morphine, heroin, fentanyl, tramadol, and methadone. Symptoms include insufficient breathing, small pupils, and unconsciousness. Onset of symptoms depends in part on the route opioids are taken. Among those who initially survive, complications can include rhabdomyolysis, pulmonary edema, compartment syndrome, and permanent brain damage.

Risk factors for opioid overdose include opioid dependence, injecting opioids, using high doses of opioids, mental disorders, 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. Diagnosis is generally based on symptoms.

Initial treatment involves supporting the person's breathing and providing oxygen. Naloxone is then recommended among those who are not breathing. Given naloxone into the nose or as an injection into a muscle appears to be equally effective. Among those who refuse to go to hospital following reversal, the risks of a poor outcome in the short term appear to be low. Efforts to prevent deaths from overdose include improving access to naloxone and treatment for opioid dependence.

Opioid use disorders resulted in 122,000 deaths globally in 2015, up from 18,000 deaths in 1990. In the United States over 33,000 deaths occurred from opioids in 2015, 20,100 from prescription opioids and 13,000 from heroin. Opioid deaths represent more than 60% of all drug overdose related deaths in the United States. The opioid epidemic is believed to be in part due to assurances in the 1990s by the pharmaceutical industry that prescription opioids were safe.

The word "overdose" implies that there is a common safe dosage and usage for the drug; therefore, the term is commonly only applied to drugs, not poisons, though even poisons are harmless at a low enough dosage. Drug overdoses are sometimes caused intentionally to commit suicide, parasuicide or as self-harm, but many drug overdoses are accidental, the result of intentional or unintentional misuse of medication. Intentional misuse leading to overdose can include using prescribed or unprescribed drugs in excessive quantities in an attempt to produce euphoria.

Usage of illicit drugs of unexpected purity, in large quantities, or after a period of drug abstinence can also induce overdose. Cocaine users who inject intravenously can easily overdose accidentally, as the margin between a pleasurable drug sensation and an overdose is small. Unintentional misuse can include errors in dosage caused by failure to read or understand product labels. Accidental overdoses may also be the result of over-prescription, failure to recognize a drug's active ingredient, or unwitting ingestion by children. A common unintentional overdose in young children involves multi-vitamins containing iron. Iron is a component of the hemoglobin molecule in blood, used to transport oxygen to living cells. When taken in small amounts, iron allows the body to replenish hemoglobin, but in large amounts it causes severe pH imbalances in the body. If this overdose is not treated with chelation therapy, it can lead to death or permanent coma. The term 'overdose' is often misused as a descriptor for adverse drug reactions or negative drug interactions due to mixing multiple drugs simultaneously.

Benzodiazepines have a wide therapeutic index and taken alone in overdose rarely cause severe complications or fatalities. More often than not, a patient who inadvertently takes more than the prescribed dose will simply feel drowsy and fall asleep for a few hours. Benzodiazepines taken in overdose in combination with alcohol, barbiturates, opioids, tricyclic antidepressants, or sedating antipsychotics, anticonvulsants, or antihistamines are particularly dangerous. In the case of alcohol and barbiturates, not only do they have an additive effect but they also increase the binding affinity of benzodiazepines to the benzodiazepine binding site, which results in a very significant potentiation of the CNS and respiratory depressant effects. In addition, the elderly and those with chronic illnesses are much more vulnerable to lethal overdose with benzodiazepines. Fatal overdoses can occur at relatively low doses in these individuals.

Include the following:

- Depression

- Shaking

- Feeling unreal

- Appetite loss

- Muscle twitching

- Memory loss

- Motor impairment

- Nausea

- Muscle pains

- Dizziness

- Apparent movement of still objects

- Feeling faint

- Noise sensitivity

- Light sensitivity

- Peculiar taste

- Pins and needles

- Touch sensitivity

- Sore eyes

- Hallucinations

- Smell sensitivity

All sedative-hypnotics, e.g. alcohol, barbiturates, benzodiazepines and the nonbenzodiazepine Z-drugs have a similar mechanism of action, working on the GABA receptor complex and are cross tolerant with each other and also have abuse potential. Use of prescription sedative-hypnotics; for example the nonbenzodiazepine Z-drugs often leads to a relapse back into substance misuse with one author stating this occurs in over a quarter of those who have achieved abstinence.

Signs and symptoms of opioid overdose include, but are not limited to:

- Pin-point pupils may occur. Patient presenting with dilated pupils may still be suffering an opioid overdose.

- Decreased heart rate

- Decreased body temperature

- Decreased breathing

- Altered level of consciousness. People may be unresponsive or unconscious.

- Pulmonary edema (fluid accumulation in the lungs)

- Shock

- Death

Combined drug intoxication (CDI), also known as multiple drug intake (MDI) or lethal polydrug/polypharmacy intoxication, is an unnatural cause of human death. CDI is often confused with drug overdose, but it is a completely different phenomenon. It is distinct in that it is due to the simultaneous use of multiple drugs, whether the drugs are prescription, over-the-counter, recreational, or some other combination. Alcohol can exacerbate the symptoms and may directly contribute to increased severity of symptoms. The reasons for toxicity vary depending on the mixture of drugs. Usually, most victims die after using two or more drugs in combination that suppress breathing, and the low blood oxygen level causes brain death.

The CDI/MDI phenomenon seems to be becoming more common in recent years. In December 2007, according to Dr. John Mendelson, a pharmacologist at the California Pacific Medical Center Research Institute, deaths by combined drug intoxication were relatively "rare" ("one in several million"), though they appeared then to be "on the rise". In July 2008, the Associated Press and CNN reported on a medical study showing that over two decades, from 1983 to 2004, such deaths have soared. It has also become a prevalent risk for older patients.

Cocaine increases alertness, feelings of well-being, euphoria, energy, competence, sociability, and sexuality. Common side effects include anxiety, increased temperature, paranoia, restlessness, and teeth grinding. With prolonged use, the drug can cause insomnia, anorexia, tachycardia, hallucinations, and paranoid delusions. Possible lethal side effects include rapid heartbeat, abnormal heart rhythms, tremors, convulsions, markedly increased core temperature, renal failure, heart attack, stroke and heart failure.

Depression with suicidal ideation may develop in heavy users. Finally, a loss of vesicular monoamine transporters, neurofilament proteins, and other morphological changes appear to indicate a long-term damage to dopamine neurons. Chronic intranasal usage can degrade the cartilage separating the nostrils (the septum nasi), which can eventually lead to its complete disappearance.

Studies have shown that cocaine usage during pregnancy triggers premature labor and may lead to abruptio placentae.

Signs and symptoms of opioid intoxication include:

- Decreased perception of pain

- Euphoria

- Confusion

- Desire to sleep

- Nausea

- Constipation

- Miosis

Sedative-hypnotics such as alcohol, benzodiazepines, and the barbiturates are known for the severe physical dependence that they are capable of inducing which can result in severe withdrawal effects. This severe neuroadaptation is even more profound in high dose drug users and misusers. A high degree of tolerance often occurs in chronic benzodiazepine abusers due to the typically high doses they consume which can lead to a severe benzodiazepine dependence. The benzodiazepine withdrawal syndrome seen in chronic high dose benzodiazepine abusers is similar to that seen in therapeutic low dose users but of a more severe nature. Extreme antisocial behaviors in obtaining continued supplies and severe drug-seeking behavior when withdrawals occur. The severity of the benzodiazepine withdrawal syndrome has been described by one benzodiazepine drug misuser who stated that I'd rather withdraw off heroin any day. If I was withdrawing from benzos you could offer me a gram of heroin or just 20mg of diazepam and I'd take the diazepam every time – I've never been so frightened in my life. Those who use benzodiazepines intermittently are less likely to develop a dependence and withdrawal symptoms upon dose reduction or cessation of benzodiazepines than those who use benzodiazepines on a daily basis.

Misuse of benzodiazepines is widespread amongst drug misusers; however, many of these people will not require withdrawal management as their use is often restricted to binges or occasional misuse. Benzodiazepine dependence when it occurs requires withdrawal treatment. There is little evidence of benefit from long-term substitution therapy of benzodiazepines, and conversely, there is growing evidence of the harm of long-term use of benzodiazepines, especially higher doses. Therefore, gradual reduction is recommended, titrated against withdrawal symptoms. For withdrawal purposes, stabilisation with a long-acting agent such as diazepam is recommended before commencing withdrawal. Chlordiazepoxide (Librium), a long-acting benzodiazepine, is gaining attention as an alternative to diazepam in substance abusers dependent on benzodiazepines due to its decreased abuse potential. In individuals dependent on benzodiazepines who have been using benzodiazepines long-term, taper regimens of 6–12 months have been recommended and found to be more successful. More rapid detoxifications e.g. of a month are not recommended as they lead to more severe withdrawal symptoms.

Tolerance leads to a reduction in GABA receptors and function; when benzodiazepines are reduced or stopped this leads to an unmasking of these compensatory changes in the nervous system with the appearance of physical and mental withdrawal effects such as anxiety, insomnia, autonomic hyperactivity and possibly seizures.

People who engage in polypharmacy and other hypochondriac behaviors are at an elevated risk of death from CDI. Elderly people are at the highest risk of CDI, because of having many age-related health problems requiring many medications combined with age-impaired judgment, leading to confusion in taking medications.

Examples (and ICD-10 code) include:

- F10.0 alcohol intoxication

- F11.0 opioid intoxication

- F12.0 cannabinoid intoxication

- F13.0 sedative and hypnotic intoxication (see benzodiazepine overdose and barbiturate overdose)

- F14.0 cocaine intoxication

- F15.0 caffeine intoxication

- F16.0 hallucinogen intoxication (See for example Lysergic acid diethylamide effects)

- F17.0 tobacco intoxication

The term contact high is sometimes used to describe intoxication without direct administration, either by second-hand smoke as with cannabis, or by placebo in the presence of others who are high.

Substance intoxication is a type of substance use disorder which is potentially maladaptive and impairing, but reversible, and associated with recent use.

If the symptoms are severe, the term "substance intoxication delirium" may be used.

Generic slang terms include: getting high or being stoned or blazed (all usually in reference to cannabis), with many more specific slang terms for each particular type of intoxicant. Alcohol intoxication is even graded in intensity, from buzzed, to tipsy, all the way up to hammered, smashed, wasted, destroyed, and a number of other similar terms.

A withdrawal syndrome, also called a discontinuation syndrome is a set of symptoms occurring in discontinuation or dosage reduction of some types of medications. The risk of a discontinuation syndrome occurring increases with dosage and length of use.

- Alcohol withdrawal syndrome, symptoms seen when an individual reduces or stops alcohol consumption after periods of excessive alcohol intake

- Antidepressant discontinuation syndrome, a syndrome that can occur following the interruption, dose reduction, or discontinuation of SSRI or SNRI medications

- Antipsychotic withdrawal syndrome or dopamine supersensitivity psychosis, symptoms seen when an individual reduces or suddenly stops antipsychotics

- Benzodiazepine withdrawal syndrome, symptoms that appear when a long term user stops taking benzodiazepines or reduces the dosage

- Cannabis withdrawal, a form of withdrawal associated with the substance cannabis

- Drug withdrawal

- Neonatal withdrawal, a withdrawal syndrome of infants, caused by administration of drugs or the prenatal exposure to a substance

- Nicotine withdrawal, the effects felt by a person who is nicotine dependent and suddenly stops or significantly reduces his or her nicotine intake

- Opioid withdrawal, symptoms seen cessation or rapid reduction of intake of opioid class drugs

Barbiturate overdose is poisoning due to excessive doses of barbiturates. Symptoms typically include difficulty thinking, poor coordination, decreased level of consciousness, and a decreased effort to breathe (respiratory depression). Complications of overdose can include noncardiogenic pulmonary edema. If death occurs this is typically due to a lack of breathing.

Barbiturate overdose may occur by accident or purposefully in an attempt to cause death. The toxic effects are additive to those of alcohol and benzodiazepines. The lethal dose varies with a person's tolerance and how the drug is taken. The effects of barbiturates occur via the GABA neurotransmitter. Exposure may be verified by testing the urine or blood.

Treatment involves supporting a person's breathing and blood pressure. While there is no antidote, activated charcoal may be useful. Multiple doses of charcoal may be required. Hemodialysis may occasionally be considered. Urine alkalinisation has not been found to be useful. While once a common cause of overdose, barbiturates are now a rare cause.

Cocaine intoxication refers to the immediate and deleterious effects of cocaine on the body. Although cocaine intoxication and cocaine dependence can be present in the same individual, these syndromes present with different symptoms.

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.

The peripheral autonomic nervous system, central nervous system and the heart are the main systems that are affected following overdose. Initial or mild symptoms typically develop within 2 hours and include tachycardia, drowsiness, a dry mouth, nausea and vomiting, urinary retention, confusion, agitation, and headache. More severe complications include hypotension, cardiac rhythm disturbances, hallucinations, and seizures. Electrocardiogram (ECG) abnormalities are frequent and a wide variety of cardiac dysrhythmias can occur, the most common being sinus tachycardia and intraventricular conduction delay resulting in prolongation of the QRS complex and the PR/QT intervals. Seizures, cardiac dysrhythmias, and apnea are the most important life-threatening complications.

Amphetamine dependence refers to a state of psychological dependence on a drug in the amphetamine class. In individuals with substance use disorder (problematic use or abuse with dependence), psychotherapy is currently the best treatment option as no pharmacological treatment has been approved. Tolerance is expected to develop with regular substituted amphetamine use. When substituted amphetamines are abused, drug tolerance develops rapidly.

Severe withdrawal associated with dependence from recreational substituted amphetamine use can be difficult for a user to cope with. Long-term use of certain substituted amphetamines, particularly methamphetamine, can reduce dopamine activity in the brain. Psychostimulants that increase dopamine and mimic the effects of substituted amphetamines, but with lower abuse liability, could theoretically be used as replacement therapy in amphetamine dependence. However, the few studies that used amphetamine, bupropion, methylphenidate and modafinil as a replacement therapy did not result in less methamphetamine use or craving.

In 2013, overdose on amphetamine, methamphetamine, and other compounds implicated in an "amphetamine use disorder" resulted in an estimated 3,788 deaths worldwide (3,425–4,145 deaths, 95% confidence).

Barbiturates increase the time that the chloride pore of the GABA receptor is opened for, thereby increasing the efficacy of GABA. This is as opposed to benzodiazepines which increase the frequency that the chloride pore is opened, thereby increasing GABA's potency.

Substance dependence also known as drug dependence is an adaptive state that develops from repeated drug administration, and which results in withdrawal upon cessation of drug use. A "drug addiction", a distinct concept from substance dependence, is defined as compulsive, out-of-control drug use, despite negative consequences. An "addictive drug" is a drug which is both rewarding and reinforcing. ΔFosB, a gene transcription factor, is now known to be a critical component and common factor in the development of virtually all forms of behavioral addiction and drug addictions, but not dependence.

Within the framework of the 4th edition of the "Diagnostic and Statistical Manual of Mental Disorders" ("DSM-IV"), substance dependence is redefined as a drug addiction, and can be diagnosed without the occurrence of a withdrawal syndrome. It is now described accordingly: "When an individual persists in use of alcohol or other drugs despite problems related to use of the substance, substance dependence may be diagnosed. Compulsive and repetitive use may result in tolerance to the effect of the drug and withdrawal symptoms when use is reduced or stopped. This, along with Substance Abuse are considered Substance Use Disorders."

Central nervous system depression or CNS depression refers to physiological depression of the central nervous system that can result in decreased rate of breathing, decreased heart rate, and loss of consciousness possibly leading to coma or death. CNS depression is specifically the result of inhibited brain activity.

Tricyclic antidepressant overdose is poisoning caused by excessive medication of the tricyclic antidepressant (TCA) type. Symptoms may include elevated body temperature, blurred vision, dilated pupils, sleepiness, confusion, seizures, rapid heart rate, and cardiac arrest. If symptoms have not occurred within six hours of exposure they are unlikely to occur.

TCA overdose may occur by accident or purposefully in an attempt to cause death. The toxic dose depends on the specific TCA. Most are non-toxic at less than 5 mg/kg except for desipramine, nortriptyline, and trimipramine which are generally non-toxic at less than 2.5 mg/kg. In small children one or two pills can be fatal. An electrocardiogram (ECG) should be included in the assessment when there is concern of an overdose.

In overdose activated charcoal is often recommended. People should not be forced to vomit. In those who have a wide QRS complex () sodium bicarbonate is recommended. If seizures occur benzodiazepines should be given. In those with low blood pressure intravenous fluids and norepinephrine may be used. The use of intravenous lipid emulsion may also be tried.

In the early 2000s TCAs were one of the most common cause of poisoning. In the United States in 2004 there was more than 12,000 cases. In the United Kingdom they resulted in about 270 deaths a year. An overdose from TCAs was first reported in 1959.