The distribution of naloxone to injection drug users and other opioid drug users decreases the risk of death from overdose. The Centers for Disease Control and Prevention (CDC) estimates that U.S. programs for drug users and their caregivers prescribing take-home doses of naloxone and training on its utilization are estimated to have prevented 10,000 opioid overdose deaths. Healthcare institution-based naloxone prescription programs have also helped reduce rates of opioid overdose in the U.S. state of North Carolina, and have been replicated in the U.S. military. Nevertheless, scale-up of healthcare-based opioid overdose interventions is limited by providers' insufficient knowledge and negative attitudes towards prescribing take-home naloxone to prevent opioid overdose. Programs training police and fire personnel in opioid overdose response using naloxone have also shown promise in the US.

Death can be prevented in individuals who have overdosed on opioids if they receive basic life support and naloxone is administered soon after the overdose occurs. Naloxone is effective at reversing the cause, rather than just the symptoms, of an opioid overdose. A longer-acting variant of naloxone is naltrexone. Naltrexone is primarily used to treat opioid and alcohol dependence.

Programs to provide drug users and their caregivers with naloxone are recommended. In the United States its use is estimated to have prevented 10,000 opioid overdose deaths. Healthcare institution-based naloxone prescription programs have also helped reduce rates of opioid overdose in the US state of North Carolina, and have been replicated in the US military. Nevertheless, scale-up of healthcare-based opioid overdose interventions are limited by providers’ insufficient knowledge and negative attitudes towards prescribing take-home naloxone to prevent opioid overdose. Programs training police and fire personnel in opioid overdose response using naloxone have also shown promise.

Stabilization of the victim's airway, breathing, and circulation (ABCs) is the initial treatment of an overdose. Ventilation is considered when there is a low respiratory rate or when blood gases show the person to be hypoxic. Monitoring of the patient should continue before and throughout the treatment process, with particular attention to temperature, pulse, respiratory rate, blood pressure, urine output, electrocardiography (ECG) and O saturation. Poison control centers and medical toxicologists are available in many areas to provide guidance in overdoses to both physicians and the general public.

Although opioid overdose accounts for the leading cause of accidental death, it can be prevented in primary care settings. Clear protocols for staff at emergency departments and urgent care centers can reduce opioid prescriptions for individuals presenting in these settings who engage in drug seeking behaviors or who have a history of substance abuse. Providers should routinely screen patients using tools such as the CAGE-AID and the Drug Abuse Screening Test (DAST-10) to screen adults and the CRAFFT to screen adolescents aged 14–18 years. Other “drug seeking” behaviors and physical indications of drug use should be used as clues to perform formal screenings.

Individuals diagnosed with opioid dependence should be prescribed naloxone to prevent overdose and/or should be directed to one of the many intervention/treatment options available, such as needle exchange programs and treatment centers. Brief motivational interviewing can also be performed by the clinician during patient visits and has been shown to improve patient motivation to change their behavior. Despite these opportunities, the dissemination of prevention interventions in the US has been hampered by the lack of coordination and sluggish federal government response.

Prescription monitoring program allow physicians to view individuals' history of prescribed opioids and other controlled substances to prevent risky behaviors, such as doctor shopping and drug diversion. These programs are operational in 49 states and the District of Columbia, and have generally been found to decrease prescribing of opioids.

Regulative policies, such as Florida’s pill mill law, have also been found to decrease opioid prescribing and use, which are both correlated with opioid overdoses. Florida's pill mill law addressed pill mills, or rogue pain management clinics where prescription drugs are inappropriately prescribed and dispensed, and required these clinics to register with the state, have a physician-owner, created inspection requirements, and established prescribing and dispensing requirements and prohibitions for physicians at these clinics.

Flumazenil (Romazicon) is a competitive benzodiazepine receptor antagonist that can be used as an antidote for benzodiazepine overdose. Its use, however, is controversial as it has numerous contraindications. It is contraindicated in patients who are on long-term benzodiazepines, those who have ingested a substance that lowers the seizure threshold, or in patients who have tachycardia, widened QRS complex on ECG, anticholinergic signs, or a history of seizures. Due to these contraindications and the possibility of it causing severe adverse effects including seizures, adverse cardiac effects, and death, in the majority of cases there is no indication for the use of flumazenil in the management of benzodiazepine overdose as the risks in general outweigh any potential benefit of administration. It also has no role in the management of unknown overdoses. In addition, if full airway protection has been achieved, a good outcome is expected, and therefore flumazenil administration is unlikely to be required.

Flumazenil is very effective at reversing the CNS depression associated with benzodiazepines but is less effective at reversing respiratory depression. One study found that only 10% of the patient population presenting with a benzodiazepine overdose are suitable candidates for flumazenil. In this select population who are naive to and overdose solely on a benzodiazepine, it can be considered. Due to its short half life, the duration of action of flumazenil is usually less than 1 hour, and multiple doses may be needed. When flumazenil is indicated the risks can be reduced or avoided by slow dose titration of flumazenil. Due to risks and its many contraindications, flumazenil should be administered only after discussion with a medical toxicologist.

Medical observation and supportive care are the mainstay of treatment of benzodiazepine overdose. Although benzodiazepines are absorbed by activated charcoal, gastric decontamination with activated charcoal is not beneficial in pure benzodiazepine overdose as the risk of adverse effects would outweigh any potential benefit from the procedure. It is recommended only if benzodiazepines have been taken in combination with other drugs that may benefit from decontamination. Gastric lavage (stomach pumping) or whole bowel irrigation are also not recommended. Enhancing elimination of the drug with hemodialysis, hemoperfusion, or forced diuresis is unlikely to be beneficial as these procedures have little effect on the clearance of benzodiazepines due to their large volume of distribution and lipid solubility.

In general, the simultaneous use of multiple drugs should be carefully monitored by a qualified individual such as board certified and licensed medical doctor, either an MD or DO Close association between prescribing physicians and pharmacies, along with the computerization of prescriptions and patients' medical histories, aim to avoid the occurrence of dangerous drug interactions. Lists of contraindications for a drug are usually provided with it, either in monographs, package inserts (accompanying prescribed medications), or in warning labels (for OTC drugs). CDI/MDI might also be avoided by physicians requiring their patients to return any unused prescriptions. Patients should ask their doctors and pharmacists if there are any interactions between the drugs they are taking.

On June 30, 2009, an FDA advisory panel recommended that Vicodin and another painkiller, Percocet, be removed from the market because they have allegedly caused over 400 deaths a year. The problem is with paracetamol (acetaminophen/Tylenol for example ) overdose and liver damage. These two drugs, in combination with other drugs like Nyquil and Theraflu, can cause death by multiple drug intake and/or drug overdose. Another solution would be to not include paracetamol with Vicodin or Percocet.

Little attention has focused on the degree that benzodiazepines are abused as a primary drug of choice, but they are frequently abused alongside other drugs of abuse, especially alcohol, stimulants and opiates. The benzodiazepine most commonly abused can vary from country to country and depends on factors including local popularity as well as which benzodiazepines are available. Nitrazepam for example is commonly abused in Nepal and the United Kingdom, whereas in the United States of America where nitrazepam is not available on prescription other benzodiazepines are more commonly abused. In the United Kingdom and Australia there have been epidemics of temazepam abuse. Particular problems with abuse of temazepam are often related to gel capsules being melted and injected and drug-related deaths. Injecting most benzodiazepines is dangerous because of their relative insolubility in water (with the exception of midazolam), leading to potentially serious adverse health consequences for users.

Benzodiazepines are a commonly misused class of drug. A study in Sweden found that benzodiazepines are the most common drug class of forged prescriptions in Sweden. Concentrations of benzodiazepines detected in impaired motor vehicle drivers often exceeding therapeutic doses have been reported in Sweden and in Northern Ireland. One of the hallmarks of problematic benzodiazepine drug misuse is escalation of dose. Most licit prescribed users of benzodiazepines do not escalate their dose of benzodiazepines.

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.

The treatment of barbiturate abuse or overdose is generally supportive. The amount of support required depends on the person's symptoms. If the patient is drowsy but awake and can swallow and breathe without difficulty, the treatment can be as simple as monitoring the person closely. If the person is not breathing, it may involve mechanical ventilation until the drug has worn off.

Supportive treatment often includes the following:

- Activated charcoal may be given via nasogastric tube.

- Intravenous administration of saline, naloxone, thiamine, and/or glucose.

- Intubation and bemegride, or a hand-breather where these are not available until the patient can breathe under their own power.

- Observation in the Emergency Department for a number of hours or admission to the hospital for several days of observation if symptoms are severe.

- Advise the patient about drug misuse or refer for psychiatric consult.

Emergency treatment of cocaine-associated hyperthermia consists of administering a benzodiazepine sedation agent, such as diazepam (Valium) or lorazepam (Ativan) to enhance muscle relaxation and decrease sympathetic outflow from the central nervous system. Physical cooling is best accomplished with tepid water misting and cooling with a fan (convection and evaporation), which can be carried out easily in the field or hospital. There is no specific pharmacological antidote for cocaine overdose. The chest pain, high blood pressure, and increased heart rate caused by cocaine may be also treated with a benzodiazepine. Multiple and escalating dose of benzodiazepines may be necessary to achieve effect, which increases risk of over-sedation and respiratory depression. A comprehensive systematic review of all pharmacological treatments of cocaine cardiovascular toxicity revealed benzodiazepines may not always reliably lower heart rate and blood pressure.

Nitric-oxide mediated vasodilators, such as nitroglycerin and nitroprusside, are effective at lowering blood pressure and reversing coronary arterial vasoconstriction, but not heart rate. Nitroglycerin is useful for cocaine-induced chest pain, but the possibility of reflex tachycardia must be considered. Alpha-blockers such as phentolamine have been recommended and may be used to treat cocaine-induced hypertension and coronary arterial vasoconstriction, but these agents do not reduce heart rate. Furthermore, phentolamine is rarely used, not readily available in many emergency departments, and many present-day clinicians are unfamiliar with its use and titratability. Calcium channel blockers may also be used to treat hypertension and coronary arterial vasoconstriction, but fail to lower tachycardia based on all cocaine-related studies. Non-dihydropyridine calcium channels blockers such as diltiazem and verapamil are preferable, as dihydropyridine agents such as nifedipine have much higher risk of reflex tachycardia.

Agitated patients are best treated with benzodiazepines, but antipsychotics such as haloperidol and olanzapine may also be useful. The alpha-2 agonist dexmedetomidine may also be useful for treatment of agitation, but effects on heart rate and blood pressure are variable based on several studies and case reports. Lidocaine and intravenous lipid emulsion have been successfully used for serious ventricular tachyarrhythmias in several case reports.

The use of beta-blockers for cocaine cardiovascular toxicity has been subject to a relative contraindication by many clinicians for several years despite extremely limited evidence. The phenomenon of “unopposed alpha-stimulation,” in which blood pressure increases or coronary artery vasoconstriction worsens after blockade of beta-2 vasodilation in cocaine-abusing patients, is controversial. This rarely-encountered and unpredictable adverse effect has resulted in some clinicians advocating for an absolute contraindication of the use of all beta-blockers, including specific, non-specific, and mixed. Many clinicians have disregarded this dogma and administer beta-blockers for cocaine-related chest pain and acute coronary syndrome, especially when there is demand ischemia from uncontrolled tachycardia. Of the 1,744 total patients identified in the aforementioned systematic review, only 7 adverse events were from putative cases of “unopposed alpha-stimulation” due to propranolol (n=3), esmolol (n=3), and metoprolol (n=1). Some detractors of beta-blockers for cocaine-induced chest pain have cited minimal acute mortality and the short half-life of the drug, making it unnecessary to aggressively treat any associated tachycardia and hypertension. However, the long-term effect of cocaine use and development of heart failure, with early mortality, high morbidity, and tremendous demand on hospital utilization should be taken under consideration.

The mixed beta/alpha blocker labetalol has been shown to be safe and effective for treating concomitant cocaine-induced hypertension and tachycardia, without any “unopposed alpha-stimulation” adverse events recorded. The use of labetalol is approved by a recent AHA/ACC guideline for cocaine and methamphetamine patients with unstable angina/non-STEMI.

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

Heroin-assisted treatment (HAT, the medical prescription of heroin) has been available in Switzerland since 1994. A 2001 study found a high rate of treatment retention and significant improvement in health, social situation and likelihood to leave the illegal drug scene in enrolled participants. The study found that the most common reason for discharge was the start of abstinence treatment or methadone treatment. The study also found that heroin-assisted treatment is cost-beneficial on a society level due to reduced criminality and improved overall health of participants.

The heroin-assisted treatment program was introduced in Switzerland to combat the increase in heroin use in the 1980s and 1990s and written into law 2010 as one pillar of a four-pillar strategy using repression, prevention, treatment and risk reduction. Usually, only a small percentage of patients receives heroin and have to fulfil a number of criteria. Since then, HAT programs have been adopted in the Netherlands, United Kingdom, Germany, Spain, Denmark, Belgium, Canada, and Luxembourg.

Cocaine can be snorted, swallowed, injected, or smoked. Most deaths due to cocaine are accidental but may also be the result of body packing or stuffing with rupture in the gastrointestinal tract. Use of cocaine causes tachyarrhythmias and a marked elevation of blood pressure (hypertension), which can be life-threatening. This can lead to death from acute myocardial infarction, respiratory failure, stroke, cerebral hemorrhage, or heart failure. Cocaine overdose may result in hyperthermia as stimulation and increased muscular activity cause greater heat production. Heat loss is also inhibited by the cocaine-induced vasoconstriction. Cocaine and/or associated hyperthermia may cause muscle cell destruction (rhabdomyolysis) and myoglobinuria resulting in renal failure. Individuals with cocaine overdose should be transported immediately to the nearest emergency department, preferably by ambulance in case cardiac arrest occurs en route. According to the National Institute on Drug Abuse, approximately 5000 deaths occur annually in the US due to cocaine overdose.

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.

These drugs block dopamine receptors and some also block serotonin receptors (such as chlorpromazine, the first antipsychotic used clinically). Having been on one or more antipsychotics for any appreciable amount of time results in dramatically reduced sensitivity to others with similar mechanisms of action. However, an antipsychotic with a substantial disparity in pharmacology (e.g. haloperidol and quetiapine) may retain significant efficacy.

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.

MAO inhibitor drugs block an enzyme system resulting in increased stores of monoamine neurotransmitters. More common antidepressants such as tricyclic antidepressants and SSRIs block reuptake transporters causing increased levels of norepinephrine or serotonin in synapses. Mood stabilizers include lithium and many anticonvulsants, such as carbamazepine and lamotrigine are also used for mood disorders. This would demonstrate little to zero cross-tolerance with serotonergic or lithium treatment.

In a study comparing the central nervous depression due to supra-therapeutic doses of Triazolam (Benzodiazepine), Pentobarbital (Barbiturate) and GHB it appeared as if GHB had the strongest dose-effect function. Since, GHB had a high correlation between its dose and its central nervous system depression it has a high risk of accidental overdose. In the case of accidental overdose of GHB, patients could become drowsy, fall asleep and may enter a coma. Although GHB had higher sedative effects at high doses as compared to Triazolam and Pentobarbital, it had less amnestic effects as compared to Triazolam and Pentobarbital. Arousal of subjects in the GHB group sometimes even required a painful stimulus; this was not seen in the Triazolam or the Pentobarbital group. Fortunately, during this heavy sedation with GHB the subjects maintained normal respiration and blood pressure. This is often not the case with opioids as they will cause respiratory depression.

Tricyclic antidepressants are highly protein bound and have a large volume of distribution; therefore removal of these compounds from the blood with hemodialysis, hemoperfusion or other techniques are unlikely to be of any significant benefit.

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.

Initial treatment of an acute overdose includes gastric decontamination. This is achieved by giving activated charcoal which adsorbs the drug in the gastrointestinal tract either by mouth or via a nasogastric tube. Activated charcoal is most useful if given within 1 to 2 hours of ingestion. Other decontamination methods such as stomach pumps, ipecac induced emesis, or whole bowel irrigation are generally not recommended in TCA poisoning. Stomach pumps may be considered within an hour of ingestion but evidence to support the practice is poor.

Addiction is a complex but treatable condition. It is characterized by compulsive drug craving, seeking, and use that persists even if the user is aware of severe adverse consequences. For some people, addiction becomes chronic, with periodic relapses even after long periods of abstinence. As a chronic, relapsing disease, addiction may require continued treatments to increase the intervals between relapses and diminish their intensity. While some with substance issues recover and lead fulfilling lives, others require ongoing additional support. The ultimate goal of addiction treatment is to enable an individual to manage their substance misuse; for some this may mean abstinence. Immediate goals are often to reduce substance abuse, improve the patient's ability to function, and minimize the medical and social complications of substance abuse and their addiction; this is called "harm reduction".

Treatments for addiction vary widely according to the types of drugs involved, amount of drugs used, duration of the drug addiction, medical complications and the social needs of the individual. Determining the best type of recovery program for an addicted person depends on a number of factors, including: personality, drugs of choice, concept of spirituality or religion, mental or physical illness, and local availability and affordability of programs.

Many different ideas circulate regarding what is considered a successful outcome in the recovery from addiction. Programs that emphasize controlled drinking exist for alcohol addiction. Opiate replacement therapy has been a medical standard of treatment for opioid addiction for many years.

Treatments and attitudes toward addiction vary widely among different countries. In the US and developing countries, the goal of commissioners of treatment for drug dependence is generally total abstinence from all drugs. Other countries, particularly in Europe, argue the aims of treatment for drug dependence are more complex, with treatment aims including reduction in use to the point that drug use no longer interferes with normal activities such as work and family commitments; shifting the addict away from more dangerous routes of drug administration such as injecting to safer routes such as oral administration; reduction in crime committed by drug addicts; and treatment of other comorbid conditions such as AIDS, hepatitis and mental health disorders. These kinds of outcomes can be achieved without eliminating drug use completely. Drug treatment programs in Europe often report more favorable outcomes than those in the US because the criteria for measuring success are functional rather than abstinence-based. The supporters of programs with total abstinence from drugs as a goal believe that enabling further drug use means prolonged drug use and risks an increase in addiction and complications from addiction.

CNS depression is generally caused by the use of depressant drugs such as ethanol, opioids, barbiturates, benzodiazepines, general anesthetics, and anticonvulsants such as pregabalin used to treat epilepsy.

Drug overdose is often caused by combining two or more depressant drugs, although overdose is certainly possible by consuming a large dose of one depressant drug. CNS depression can also be caused by the accidental or intentional inhalation or ingestion of certain volatile chemicals such as Butanone (contained in Plastic Cement) or Isopropyl Alcohol. Other causes of CNS depression are metabolic disturbances such as hypoglycaemia.