Historically, people of almost every culture have used chemical agents to induce sleep, relieve stress, and allay anxiety. While alcohol is one of the oldest and most universal agents used for these purposes, hundreds of substances have been developed that produce central nervous system depression. These drugs have been referred to as downers, sedatives, hypnotics, minor tranquilizers, anxiolytics, and anti-anxiety medications. Unlike most other classes of drugs of abuse, depressants are rarely produced in clandestine laboratories. Generally, legitimate pharmaceutical products are diverted to the illicit market. A notable exception to this is a relatively recent drug of abuse, gamma hydroxybutyric acid (GHB).

Choral hydrate and paraldehyde are two of the oldest pharmaceutical depressants still in use today. Other depressants, including gluthethimide, methaqualone, and meprobamate have been important players in the milieu of depressant use and abuse. However, two major groups of depressants have dominated the licit and illicit market for nearly a century, first barbiturates and now benzodiazepines.

Barbiturates were very popular in the first half of the 20th century. In moderate amounts, these drugs produce a state of intoxication that is remarkably similar to alcohol intoxication. Symptoms include slurred speech, loss of motor coordination, and impaired judgment. Depending on the dose, frequency, and duration of use, one can rapidly develop tolerance, physical dependence, and psychological dependence to barbiturates. With the development of tolerance, the margin of safety between the effective dose and the lethal dose becomes very narrow. That is, in order to obtain the same level of intoxication, the tolerant abuser may raise his or her dose to a level that may result in coma or death. Although many individuals have taken barbiturates therapeutically without harm, concern about the addiction potential of barbiturates and the ever-increasing number of fatalities associated with them led to the development of alternative medications. Today, less than 10 percent of all depressant prescriptions in the United States are for barbiturates.

Benzodiazepines were first marketed in the 1960s. Touted as much safer depressants with far less addiction potential than barbiturates, today these drugs account for about one out of every five prescriptions for controlled substances. Although benzodiazepines produce significantly less respiratory depression than barbiturates, it is now recognized that benzodiazepines share many of the undesirable side effects of the barbiturates. A number of toxic central nervous system effects are seen with chronic high-dose benzodiazepine therapy, including headaches, irritability, confusion, memory impairment and depression. The risk of developing over-sedation, dizziness, and confusion increases substantially with higher doses of benzodiazepines. Prolonged use can lead to physical dependence even at doses recommended for medical treatment. Unlike barbiturates, large doses of benzodiazepines are rarely fatal unless combined with other drugs or alcohol. Although primary abuse of benzodiazepines is well documented, abuse of these drugs usually occurs as part of a pattern of multiple drug abuse. For example, heroin or cocaine abusers will use benzodiazepines and other depressants to augment their "high" or alter the side effects associated with over-stimulation or narcotic withdrawal.