Psychomotor Stimulants: Cocaine, Amphetamine, and Related Drugs
Background and History
Basic Pharmacology of Cocaine
Mechanisms of Cocaine Action
- Cocaine is an alkaloid derived from the leaves of the shrub Erythroxylon coca, which is indigenous to the northern and central Andes Mountains of South America.
- Although the peoples of that region have been chewing coca leaves for perhaps 5000 years, cocaine use did not become popular in Western cultures until after the pure compound was isolated in the late 1850s. Freud was one of many notable cocaine users in nineteenth-century Europe.
- In the United States, cocaine was a constituent of numerous popular beverages and over-the-counter pharmaceutical products in the late nineteenth and early twentieth centuries until its nonprescription use was banned by the Harrison Narcotic Act in 1914. Cocaine then went “underground” until the 1970s, at which time the first of two waves of increased cocaine use began in this country.
- Recent household survey data indicate that about 1.9 million people in the United States are current users of cocaine, although not all of these individuals are dependent on the drug.
- Cocaine HCl is water soluble and therefore can be taken orally, intranasally, or by IV injection. On the other hand, cocaine base (including crack cocaine) is the chemical form most suitable for smoking.
- The most rapid absorption and distribution of cocaine occur following IV injection and smoking, which may account for the highly addictive properties of these routes of consumption.
- One of the main cocaine metabolites is benzoylecgonine, whereas a compound called cocaethylene is also formed when alcohol is ingested along with cocaine.
- At typical doses, cocaine acts mainly to block synaptic uptake of DA, 5-HT, and NE by binding to their respective membrane transporters. This enhances transmission at monoaminergic synapses by increasing the synaptic concentrations of each transmitter. However, inhibition of DA uptake is most important for cocaine’s behavioral effects and abuse potential.
- A second mechanism by which cocaine enhances dopaminergic transmission is an increased frequency of transient DA release events. This effect may be mediated by cocaine’s inhibition of NE uptake in the PFC, causing an α1-adrenoceptormediated stimulation of glutamatergic pyramidal neurons that project to the VTA.
- Not all DA uptake inhibitors share cocaine’s euphoric effects and abuse potential. Such atypical uptake inhibitors seem to interact with the transporter protein in a different manner than cocaine.
- At higher concentrations, cocaine also blocks voltage- gated Na+ channels, which leads to a local anesthetic effect.
Acute Behavioral and Physiological Effects of Cocaine
- Cocaine exerts powerful effects on mood and behavior. The cocaine “high” is characterized by feelings of exhilaration, euphoria, well-being, heightened energy, and enhanced self-confidence. Smoked or intravenously injected cocaine also causes a “rush” in the user.
- At high doses and/or with prolonged use, cocaine can give rise to a number of negative effects such as irritability, anxiety, exhaustion, total insomnia, and even psychotic symptomatology.
- In animal studies, cocaine elicits locomotor stimulation and, at higher doses, stereotyped behaviors.
- Cocaine can function as a discriminative stimulus, and it exhibits powerful reinforcing effects in standard self-administration paradigms.
- Physiologically, cocaine produces sympathomimetic effects such as increased heart rate, vasoconstriction, hypertension, and hyperthermia. High doses can be toxic or even fatal as the result of seizures, heart failure, stroke, or intracranial hemorrhage.
- Microinjection, lesion, and gene knockout studies have demonstrated that most of the behavioral effects of cocaine are attributable to DAT inhibition and the resulting activation of dopaminergic transmission, particularly in the NAcc and striatum.
- Other research performed in outbred rats found that naturally occurring differences in sensitivity to cocaine’s locomotor activating effects were related to differences in DAT levels in the NAcc and dorsal striatum.
- Brain imaging studies in humans have found that the subjective effects (e.g., the “high”) of psychostimulants are related to the amount of DAT occupancy, the rate at which occupancy occurs, and baseline DA activity.
- Of the various DA receptor subtypes, the D1 receptor plays the most critical role in mediating cocaine’s locomotor activating and reinforcing effects in animals.
Cocaine Abuse and the Effects of Chronic Cocaine Exposure
- Early use of other substances seems to be an important risk factor for the initiation of cocaine use.
- Some users quickly stop taking cocaine for various reasons, some maintain controlled use for long periods, and still others progress to a pattern of uncontrolled use (i.e., abuse). Such a progression may come about through dose escalation and/or switching from intranasal use to smoking or IV injection—routes of administration with greater abuse potential.
- Maladaptive use of psychostimulants generally is categorized as stimulant use disorder in the DSM-5. Maladaptive cocaine use can be categorized more specifically as cocaine use disorder.
- Maladaptive cocaine use (i.e., cocaine abuse) may be manifested by daily or near-daily use or by a pattern of bingeing. Many individuals who abuse cocaine also suffer from other psychiatric disorders.
- Cocaine craving and relapse to cocaine use increase over time following withdrawal, which has been called incubation of cocaine craving.
- Neuroimaging studies have found that cocainedependent individuals show abnormal prefrontal cortical functioning and that cocaine-related cues elicit DA release in the dorsal striatum. The midbrain–striatal DA pathway is part of a larger circuit comprising various cortical and limbic structures that are activated when cocaine users experience craving for the drug.
- Animal models of cocaine dependence include such features as escalation of drug intake, relapse to cocaine seeking after a period of abstinence, cocaine-seeking behavior despite aversive consequences, and increased motivation to take cocaine, as shown by an elevated breaking point on a progressive-ratio schedule.
- Animal models have supported the hypothesis that both sensation seeking and impulsivity are traits that contribute to the development of compulsive cocaine use.
- Chronic exposure to cocaine or other psychostimulants can lead to tolerance and/or sensitization. Changes in drug responsiveness depend on the pattern of drug exposure, the outcome measure, and the time since the last dose.
- Animal studies have implicated increased dopaminergic activity in the VTA and increased NAcc DA release as being important for locomotor sensitization to psychostimulants.
- Human cocaine-dependent study participants show reduced DA release in the striatum compared with controls. This finding is consistent with evidence for tolerance to the drug’s euphoric effects over time, thus leading to increased drug-taking behavior by these individuals.
- Individuals suffering from cocaine abuse or dependence show deficits in many cognitive domains, including sustained attention, impulse control, working memory, verbal learning and memory, performance on psychomotor tasks, and decision making in reward-based learning tasks. These deficits are additionally associated with structural and functional differences in several cortical and subcortical brain areas, including the PFC, orbitofrontal cortex, and dorsal striatum. Evidence from both human and experimental animal studies suggests that at least some of these cognitive and neurobiological differences are caused by repeated cocaine exposure.
- The adverse effects of repeated or high-dose cocaine use include stroke or seizure, abnormalities in both gray and white matter in the cortex, cardiovascular problems including heart attack, damage to other organ systems, and possible abnormalities in the development of offspring exposed prenatally to cocaine. High-dose cocaine use can also lead to panic attacks or the onset of a paranoid psychotic reaction.
- Much effort in the area of treating cocaine abuse has been focused on the development of medications that might reduce craving and promote abstinence among users. Some of these medications act on the dopaminergic system (e.g., DA receptors or the DA transporter), whereas others that are being tested target the noradrenergic, serotonergic, glutamatergic, and GABAergic systems. The psychostimulants amphetamine, methylphenidate, and modafinil have been investigated as potential replacement drugs for cocaine. Despite these efforts, there is currently no FDA-approved medication to treat cocaine dependence.
- Yet another approach still under consideration is to use an anticocaine vaccine that either traps the drug in the bloodstream or breaks the drug down enzymatically.
- Current behavioral and psychosocial treatments include various types of counseling, cognitive behavioral therapies aimed at relapse prevention, 12-step programs like Narcotics Anonymous and Cocaine Anonymous, and contingency management programs based on a combination of vouchers and a community reinforcement approach. Contingency management programs seem to have the greatest success rates in treating cocaine dependence; however, such programs are labor-intensive and costly compared to other approaches, which has limited their application.
Background and History
Basic Pharmacology of the Amphetamines
Mechanisms of Amphetamine and Methamphetamine Action
Behavioral and Neural Effects of Amphetamines
- Amphetamine and methamphetamine are synthetic psychomotor stimulants that are closely related structurally to two similarly acting plant compounds, cathinone and ephedrine.
- Amphetamine was first introduced in the United States in 1932 in the form of a nasal inhaler. People soon realized that they could achieve powerful stimulatory and euphoric effects by consuming the drug orally or by injecting it. The incidence of amphetamine use and abuse grew until a peak was attained in the 1970s. Since that time, the drug has been largely supplanted by cocaine, except for a recent upsurge in methamphetamine use in certain parts of the country.
- Amphetamine is typically taken orally or by IV or subcutaneous injection. Crystalline methamphetamine, which is more potent than amphetamine, can also be taken by snorting or smoking. Some amphetamine or methamphetamine users take the drug repeatedly in binges called speed runs. Both drugs are metabolized slowly by the liver, thus causing a longer duration of action than cocaine.
- Amphetamine and methamphetamine are indirect catecholamine agonists. They stimulate release of DA and NE from nerve terminals and block the reuptake of these neurotransmitters. At high doses, there is also an inhibition of the catecholamine-degrading enzyme monoamine oxidase. Central DA release has been demonstrated in both animals and humans. Acute release of DA is followed by a period of DA depletion due to an inability of the dopaminergic nerve terminals to resynthesize the transmitter at a sufficiently fast rate.
- Amphetamine and methamphetamine also have sympathomimetic effects that are due to their effects on NE in the sympathetic nervous system.
- Acute administration of amphetamine to humans leads to a well-known constellation of behavioral reactions, including increased arousal, reduced fatigue, and feelings of exhilaration. Sleep is delayed, and performance of simple, repetitive tasks is improved.
- Amphetamine and another stimulant, methylphenidate, are widely prescribed for children with attention deficit hyperactivity disorder (ADHD). At relatively low doses, these stimulants produce calming and attention-enhancing effects that differ from the typical responses seen in adults taking higher drug doses.
- In experimental animals, amphetamine acts much like cocaine. It elicits dose-dependent stimulation of locomotion and stereotyped behaviors, and it is highly reinforcing in self- administration and place-conditioning paradigms.
- Heavy use of amphetamine or particularly methamphetamine can result in a number of adverse consequences, including the development of dependence, cognitive deficits, psychotic reactions that closely resemble paranoid schizophrenia, and dysfunction neurotoxicity of the DA system. Chronic methamphetamine users may be at elevated risk for developing Parkinson’s disease.
- Other health consequences of repeated methamphetamine exposure include cardiovascular problems, increased risk of stroke, oral diseases, premature aging, and increased mortality rate.
Methylphenidate, Modafinil, and Synthetic Cathinones
- Methylphenidate is a prescription psychostimulant that activates catecholamine transmission by blocking DAT and NET, thereby increasing extracellular levels of DA and NE.
- Methylphenidate has typical psychostimulant subjective and behavioral effects, including increased arousal and alertness, perceived ability to concentrate, elevated mood, and (at higher doses) anxiety. Low to medium doses of methylphenidate exert a positive influence on various cognitive functions such as working memory, cognitive processing speed, verbal learning and memory, and vigilance and attention.
- Methylphenidate is frequently diverted for nonprescription use, particularly by students. Although users feel more alert and less fatigued, current evidence does not indicate that use of this drug enhances academic performance.
- Recreational use of methylphenidate can lead to abuse and dependence, particularly when the drug is taken by snorting or by IV injection.
- The primary clinical application of methylphenidate is for the treatment of ADHD. This disorder is characterized by extreme inattentiveness, impulsivity, and hyperkinesis. Other pharmacological treatments for ADHD include various amphetamine formulations, the NE reuptake inhibitor atomoxetine, and two different α2A-receptor agonists.
- Individuals with ADHD are thought to have deficient catecholaminergic activity in multiple neural circuits that subserve cognitive functioning. One of the principal sites of action of ADHD medications may be the PFC, which is a key brain area participating in several of the abovementioned circuits. In this brain area, DA is taken up primarily by NET instead of DAT, which helps explain why catecholamine releasing agents (i.e., amphetamines), catecholamine reuptake inhibitors (methylphenidate), and a selective NE reuptake inhibitor (atomoxetine) share the ability to reduce ADHD symptomatology.
- Modafinil is an unusual psychostimulant that is often prescribed to treat daytime sleepiness associated with the sleep disorder narcolepsy, obstructive sleep apnea, and being employed as a shift worker.
- Modafinil is a weak DA reuptake inhibitor, which helps account for its stimulant properties. However, there are several downstream effects of the drug that are also thought to be important, including increased release of NE, orexin, and histamine, and an inhibition of GABA release.
- In recent years, a variety of synthetic cathinone derivatives have become available for recreational use under names such as “bath salts,” “plant food,” “meow meow,” and “flakka.” Four such compounds are mephedrone, methylone, MDPV, and α-PVP.
- Synthetic cathinones are most commonly taken by snorting or oral ingestion, although other routes of administration such as IV injection have been reported.
- Acute subjective and physiological effects of low to moderate doses are like those of other psychostimulants. However, higher doses can produce severe adverse reactions all the way up to organ failure, psychotic episodes, and death.
- Mechanistically, mephedrone and methylone are similar to amphetamine in that they are substrates for DAT, NET, and SERT, thereby causing acute release of DA, NE, and 5-HT. In contrast, MDPV and α-PVP are selective reuptake inhibitors of DA and NE, which is similar to the neurochemical action of methylphenidate.
- Animal studies have shown that synthetic cathinones are highly rewarding and reinforcing, which suggests that these compounds have the potential to produce dependence in regular users. Other studies indicate that certain synthetic cathinones could produce neurotoxic deficits in the dopaminergic or serotonergic systems, depending on the conditions of exposure. More research is needed to define the conditions for such neurotoxic effects in animal and in cell culture models and to determine whether these effects may be occurring in human cathinone users.