twitches and odd posturing. An amphetamine high is invariably associated with a noticeable crash , and tolerance develops with continued amphetamine use. With the increased prescription use of methylphenidate (Ritalin, Concerta) for treatment of ADHD over the past decade, the incidence of its nonmedical use (via snorting and injecting) has also grown. The pharmacological effects of injected or snorted methylphenidate are qualitatively the same as amphetamines, although structurally different. Because it is easily accessible from siblings and classmates, methylphenidate is increasingly becoming a gateway drug for many adolescents. It is also in demand on college campuses for appetite suppression and late- night studying. The Monitoring the Future survey of substance use and attitudes in teens found that about 6% of high school seniors reported past-year nonmedical use of the prescription stimulant Adderall in 2017 (NIDA, 2018e). The total number of stimulant prescriptions in the United States grew by more than 500% from 2002 to 2013 (Schwartz, 2013). Although nonmedical use of Adderall increased between 2009 and 2013, it decreased between 2013 and 2017 (NIDA, 2018e). specific BZD receptors in the brain that increase the affinity of GABA for its postsynaptic receptors. This results in neuronal hyperpolarization at lower release levels of GABA. More importantly, this mechanism imparts a “ceiling effect” on the central actions of BZDs, compared with the more direct actions of the barbiturates. Accordingly, BZDs were safer and less toxic than their predecessors. In 1970, the Upjohn Company (later acquired by Pfizer) introduced the first triazolo- benzodiazepine, known as alprazolam (Xanax, Nivravam). These derivatives were considerably more potent than diazepam and were heavily marketed. Although they supplanted diazepam in sales, partially due to the company’s contention that they did not cause dependence, they in fact produced far more intense dependence than other BZDs. At least 10% of patients prescribed with Xanax became addicted (Skolniek & Poul, 1982). Early BZDs, such as diazepam, and those that followed, such as alprazolam, were marketed as anxiolytics (anxiety-reducing agents). In the early 1970s, flurazepam (Dalmane) was introduced as the first of several BZDs to treat insomnia. Another BZD, midazolam (Versed), is one of the most common intravenous anesthetics in use. Despite their drawbacks, BZDs turned out to be safer than barbiturates for all these uses and essentially signaled the end of the clinical use of barbiturates. Benzodiazepines are Schedule IV controlled substances. Because of this designation, they are more readily prescribed than many other prescription drugs of abuse. As many as one third of drug-related emergency room visits involve the use of BZDs (DEA, 2013). Virtually all such admissions involve the presence of one or more other drugs and/or alcohol. Although BZD abuse as a sole agent occurs, most BZD abuse occurs in combination with other abused substances. For example, in 2015, 23% of people who died of an opioid overdose also tested positive for benzodiazepines (NIDA, 2018a). A 2016 report by the Philadelphia Department of Public Health found benzodiazepine involvement in 90% of opioid overdose deaths in that city (Philadelphia Department of Behavioral Health and Intellectual Disability Services, 2018). This situation is discussed further in the section on drug combinations. Selective benzodiazepine agonists The BZD receptors of the CNS are classified into several subtypes depending on the responses to their binding and their substrate specificity. According to this scheme, BZD-1 receptors are hypothesized to mediate the sedative-hypnotic effects of BZD, whereas BZD-2 receptors are hypothesized to mediate adverse effects such as respiratory depression. Based on this thinking, a series of BZD-1 selective agonists were introduced in the 1980s that were supposedly more effective hypnotics with reduced respiratory depression and addiction potential.
Amphetamine and methamphetamine are contained in several products that are marketed for three purposes: weight loss and the treatment of narcolepsy and attention-deficit/hyperactivity disorder (ADHD). From a regulatory viewpoint, amphetamines are classified as Schedule II drugs, whereas “diet drugs” such as phendimetrazine (Prelu-2) are classified as Schedule III. Adderall is a mixture of two amphetamine salts and two dextroamphetamines that is marketed for the treatment of ADHD. Methylphenidate (Ritalin, Concerta), also indicated for ADHD, differs structurally from amphetamines, but has similar indirect sympathomimetic activity. Amphetamine abuse often involves altering oral dosage forms to prepare solutions for injection or powder for inhalation. The pleasurable experience and urge to continue drug use are primarily related to increased dopamine levels in the pleasure centers of the brain. As levels become excessive, the pleasurable effects can transform into hallucinations and delusions. Excessive levels of dopamine in the brainstem can lead to salivation, burning tongue, and nausea, whereas excessive levels in the motor areas of the brain can lead to involuntary muscle Central nervous system (CNS) depressants In general, CNS depressants produce dose-dependent pharmacological actions, including sedative/hypnotic, anticonvulsant, and anesthetic effects. All tend to produce similar adverse effects, such as respiratory depression, but to varying degrees. All CNS effects result from various interactions with actions of the inhibitory neurotransmitter gamma- aminobutyric acid (GABA). The three main classes of CNS depressants are barbiturates, benzodiazepines (BZDs), and selective BZD agonists. Barbiturates The oldest of the CNS depressants, barbiturates have been used in clinical practice since the beginning of the twentieth century. It is currently hypothesized that barbiturates bind near postsynaptic GABA receptors in the CNS and prolong chloride channel opening in response to GABA binding. This increases postsynaptic chloride influx, which causes the neuron to hyperpolarize, resulting in generalized CNS depression. This dose-dependent depression can produce effects ranging from mild sedation to sleep, unconsciousness, and, in extreme cases, death due to respiratory depression. Like many other centrally acting drugs, tolerance develops to the therapeutic effects of barbiturates (e.g., sedation and sleep). Tolerance to the respiratory depressant effects develops more slowly, however; as patients increase the dose to overcome tolerance, blood drug levels rapidly approach toxicity. Although their use as daytime sedatives has been largely replaced by the use of benzodiazepines, barbiturates still have limited use as anticonvulsants and anesthetics. Phenobarbital (Luminal, Solfoton) continues to be used in the treatment of seizure disorders, and the “ultra” short-acting injectable barbiturates, such as thiopental (Pentothal) and methohexital (Brevital), are used as adjuncts in surgical anesthesia. The prevalence of barbiturate abuse is low relative to other classes of abused substances. Unfortunately, this is not the result of recognition of the dangers of barbiturates, but rather of their decreased availability. Prescriptions for barbiturates as daytime sedatives or nighttime hypnotics have been steadily declining since the introduction of the benzodiazepines in the early 1960s. From a practical viewpoint, barbiturate abuse is not a significant problem today; it has been replaced by benzodiazepine abuse. Benzodiazepines Benzodiazepines (BZDs) were first introduced with the release of chlordiazepoxide (Librium, Libritabs) in 1960, followed 4 years later by diazepam (Valium, Diastat). These drugs rapidly replaced the barbiturates, and by the mid-1970s were being enthusiastically prescribed (Skolniek & Poul, 1982; Wick, 2013). BZDs also act on the GABA system of the CNS. Unlike the barbiturates, BZDs are hypothesized to bind to
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