Specific antidotes are available for certain overdoses. For example, Naloxone is the antidote for opiates such as heroin or morphine. Similarly, benzodiazepine overdoses may be effectively reversed with flumazenil. As a nonspecific antidote, activated charcoal is frequently recommended if available within one hour of the ingestion and the ingestion is significant. Gastric lavage, syrup of ipecac, and whole bowel irrigation are rarely used.

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.

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.

Supportive measures include observation of vital signs, especially Glasgow Coma Scale and airway patency. IV access with fluid administration and maintenance of the airway with intubation and artificial ventilation may be required if respiratory depression or pulmonary aspiration occurs. Supportive measures should be put in place prior to administration of any benzodiazepine antagonist in order to protect the patient from both the withdrawal effects and possible complications arising from the benzodiazepine. A determination of possible deliberate overdose should be considered with appropriate scrutiny, and precautions taken to prevent any attempt by the patient to commit further bodily harm. Hypotension is corrected with fluid replacement, although catecholamines such as norepinephrine or dopamine may be required to increase blood pressure. Bradycardia is treated with atropine or an infusion of norepinephrine to increase coronary blood flow and heart rate.

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.

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.

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.

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.

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.

Administration of intravenous sodium bicarbonate as an antidote has been shown to be an effective treatment for resolving the metabolic acidosis and cardiovascular complications of TCA poisoning. If sodium bicarbonate therapy fails to improve cardiac symptoms, conventional antidysrhythmic drugs or magnesium can be used to reverse any cardiac abnormalities. However, no benefit has been shown from Class 1 antiarrhythmic drugs; it appears they worsen the sodium channel blockade, slow conduction velocity, and depress contractility and should be avoided in TCA poisoning. Low blood pressure is initially treated with fluids along with bicarbonate to reverse metabolic acidosis (if present), if the blood pressure remains low despite fluids then further measures such as the administration of epinephrine, norepinephrine, or dopamine can be used to increase blood pressure.

Another potentially severe symptom is seizures: Seizures often resolve without treatment but administration of a benzodiazepine or other anticonvulsive may be required for persistent muscular overactivity. There is no role for physostigmine in the treatment of tricyclic toxicity as it may increase cardiac toxicity and cause seizures. In cases of severe TCA overdose that are refractory to conventional therapy, intravenous lipid emulsion therapy has been reported to improve signs and symptoms in moribund patients suffering from toxicities involving several types of lipophilic substances, therefore lipids may have a role in treating severe cases of refractory TCA overdose.

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.

CNS depression is treated within a hospital setting by maintaining breathing and circulation. Individuals with reduced breathing may be given supplemental oxygen, while individuals who are not breathing can be ventilated with bag valve mask ventilation or by mechanical ventilation with a respirator. Sympathomimetic drugs may be used to attempt to stimulate cardiac output in order to maintain circulation. CNS Depression caused by certain drugs may respond to treatment with an antidote.

There are two antidotes that are frequently used in the hospital setting and these are Naloxone and Flumazenil. Naloxone is an opioid antagonist and reverses the central nervous depressive effects seen in opioid overdose. In the setting of a colonoscopy, Naloxone is rarely administered but when it is administered, its half life is shorter than some common opioid agonists. Therefore, the patient may still exhibit central nervous system depression after Naloxone has been cleared. Typically, Naloxone is administered in short intervals with relatively small doses in order to prevent the occurrence of withdrawal, pain, and sympathetic nervous system activation. Flumazenil is a benzodiazepine antagonists and blocks the binding of benzodiazepines to GABAa. Similarly to Naloxone, Flumazenil has a short half life, and this needs to be taken into account because the patient may exhibit central nervous depression after the antidote has been cleared. Benzodiazepines are used in the treatment of seizures and subsequently, the administration of Flumazenil may result in seizures. Therefore, slow administration of Flumazenil is necessary to prevent the occurrence of a seizure. These agents are rarely used in the setting of a colonoscopy as 98.8% of colonoscopies use sedatives but only 0.8% of them result in the administration of one of these antidotes. Even if they are rarely used in colonoscopies they are important in preventing the patient from entering a coma or developing respiratory depression when sedatives are not properly dosed. Outside of the colonoscopy setting, these agents are used for other procedures and in the case of drug overdose.

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.

Numerous medications have been investigated for use in cocaine dependence, but , none of them were considered to be effective. Anticonvulsants, such as carbamazepine, gabapentin, lamotrigine, and topiramate, do not appear to be effective as treatment. Limited evidence suggests that antipsychotics are also ineffective for treatment of cocaine dependence. Few studies have examined bupropion (a novel antidepressant) for cocaine dependence; however, trials performed thus far have not shown it to be an effective form of treatment for this purpose.

The National Institute on Drug Abuse (NIDA) of the U.S. National Institutes of Health is researching modafinil, a narcolepsy drug and mild stimulant, as a potential cocaine treatment. Ibogaine has been under investigation as a treatment for cocaine dependency and is used in clinics in Mexico, the Netherlands and Canada, but cannot be used legally in the United States. Other medications that have been investigated for this purpose include acetylcysteine, baclofen, and vanoxerine. Medications, such as phenelzine, have been used to cause an "aversion reaction" when administered with cocaine.

Twelve-step programs such as Cocaine Anonymous (modeled on Alcoholics Anonymous) have been widely used to help those with cocaine addiction. Cognitive behavioral therapy (CBT) combined with motivational therapy (MT) have proven to be more helpful than 12 step programs in treating cocaine dependency. However, both these approaches have a fairly low success rate. Other non-pharmacological treatments such as acupuncture and hypnosis have been explored, but without conclusive results.

One strategy for reducing harm done by acetaminophen overdoses is selling paracetamol pre-combined in tablets either with an emetic or an antidote. Paradote was a tablet sold in the UK which combined 500 mg paracetamol with 100 mg methionine, an amino acid formerly used in the treatment of paracetamol overdose.

There have been no studies so far on the effectiveness of paracetamol when given in combination with its most commonly used antidote, acetylcysteine.

Calcitriol, the active metabolite of vitamin D, appears to be a catalyst for glutathione production. Calcitriol was found to increase glutathione levels in rat astrocyte primary cultures on average by 42%, increasing glutathione protein concentrations from 29 nmol/mg to 41 nmol/mg, 24 and 48 hours after administration; it continued to have an influence on glutathione levels 96 hours after administration. It has been proposed that co-administration of calcitriol, via injection, may improve treatment outcomes.

Paracetamol ester prodrug with L-pyroglutamic acid (PCA), a biosynthetic precursor of glutathione, has been synthesized to reduce paracetamol hepatotoxicity and improve bioavailability. The toxicological studies of different paracetamol esters show that L-5-oxo-pyrrolidine-2-paracetamol carboxylate reduces toxicity after administration of an overdose of paracetamol to mice. The liver glutathione values in mice induced by intraperitoneal injection of the ester are superimposable with the GSH levels recorded in untreated mice control group. The mice group treated with an equivalent dose of paracetamol showed a significative decrease of glutathione of 35% (p<0.01 vs untreated control group). The oral LD50 was found to be greater than 2000 mg kg-1, whereas the intraperitoneal LD50 was 1900 mg kg-1. These results taken together with the good hydrolysis and bioavailability data show that this ester is a potential candidate as a prodrug of paracetamol.

Naloxone is used for the emergency treatment of an overdose. It can be given by many routes (e.g., intramuscular, intravenous, subcutaneous, intranasal, and inhalation) and acts quickly by displacing opioids from opioid receptors and preventing activation of these receptors by opioids. Naloxone kits are recommended for laypersons who may witness an opioid overdose, for individuals with large prescriptions for opioids, those in substance use treatment programs, or who have been recently released from incarceration. Since this is a life-saving medication, many areas of the United States have implemented standing orders for law enforcement to carry and give naloxone as needed. In addition, naloxone could be used to challenge a person's opioid abstinence status prior to starting a medication such as naltrexone, which is used in the management of opioid addiction.

Buprenorphine sublingual preparations are often used to manage opioid dependence (that is, dependence on heroin, oxycodone, hydrocodone, morphine, oxymorphone, fentanyl or other opioids). Preparations were approved for this indication by the United States Food and Drug Administration in October 2002. Some formulations of buprenorphine incorporate the opiate antagonist naloxone during the production of the pill form to prevent people from crushing the tablets and injecting them, instead of using the sublingual (under the tongue) route of administration.

If there is evidence of overdose or it is suspected, the patient should be given gastric lavage, activated charcoal, or both; this could make the difference between life and death in a close situation. It can however aggravate the patient which should be taken into account.

The first line treatments are diazepam and a non-selective beta blocker; other antihypertensive drugs may also be used. It is important to note that not all benzodiazepines and beta blockers are safe to use in an adrenergic storm; for instance, alprazolam and propranolol; alprazolam weakly agonizes dopamine receptors and causes catecholamine release while propranolol mildly promotes some catecholamine release - each worsening the condition.

Adrenergic storms are often idiopathic in nature; however if there is an underlying condition, then that must be addressed after bringing the heart rate and blood pressure down.

Hemodialysis can be used to enhance the removal of salicylate from the blood. Hemodialysis is usually used in those who are severely poisoned. Example of severe poisoning include people with high salicylate blood levels: 7.25 mmol/L (100 mg/dL) in acute ingestions or 40 mg/dL in chronic ingestions, significant neurotoxicity (agitation, coma, convulsions), kidney failure, pulmonary edema, or cardiovascular instability. Hemodialysis also has the advantage of restoring electrolyte and acid-base abnormalities while removing salicylate.

Initial treatment of an acute overdose involves resuscitation followed by gastric decontamination by administering activated charcoal, which adsorbs the aspirin in the gastrointestinal tract. Stomach pumping is no longer routinely used in the treatment of poisonings but is sometimes considered if the patient has ingested a potentially lethal amount less than one hour before presentation. Inducing vomiting with syrup of ipecac is not recommended. Repeated doses of charcoal have been proposed to be beneficial in cases of aspirin overdosing, although one study found that they might not be of significant value. Regardless, most clinical toxicologists will administer additional charcoal if serum salicylate levels are increasing.

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.

A related issue is overprescription, which occurs when doctors give prescription drugs to patients who do not need them. Antibiotics are a common example, as are narcotic painkillers. Aggressive marketing by drug companies is sometimes cited as a reason for overprescription.

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.