Psychostimulants

Psychostimulants

George F. Koob, PhD

National Institute on Alcohol Abuse and Alcoholism and National Institute on Drug Abuse at the National Institutes of Health, Bethesda, MD, USA

Michael A. Arends

Department of Neuroscience, The Scripps Research Institute, La Jolla, CA, USA, Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA; Department of Psychiatry, University of California, San Diego,La Jolla, CA, USA

Department of Psychiatry, University of California, San Diego,La Jolla, CA, USA

Mandy L. McCracken

National Institute on Drug Abuse, National Institutes of Health, Bethesda, MD, USA

Michel Le moal

University of Bordeaux, Neurocentre Magendie, Inserm, Bordeaux, France

Table of Contents

Cover image

Title page

PSYCHOSTIMULANTS: Volume 2 of Neurobiology of Addiction series:

Copyright

Preface

Volume TWO. Psychostimulants

1. Definitions

2. History of psychostimulant use

3. Physiological effects

4. Behavioral effects

5. Pharmacokinetics

6. Behavioral mechanism of action

7. Medical use, abuse, and addiction

8. Neurobiological effects

9. Overall summary

Index

PSYCHOSTIMULANTS: Volume 2 of Neurobiology of Addiction series:

Volume 1: Introduction to Addiction

Volume 2: Psychostimulants

Volume 3: Alcohol

Volume 4: Opioids

Volume 5: Nicotine and Marijuana

Copyright

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Preface

The present series of volumes on the Neurobiology of Addiction are a direct extension of our original book from 2006, Neurobiology of Addiction (Koob and Le Moal, 2006, Elsevier). As we embarked on updating the original book years ago, we quickly realized that a prodigious amount of new work had been done on the neurobiology of addiction during the ensuing 13 years. From 2006 until 2019, the number of PubMed citations for cocaine alone (41,439 as of Feb 2019) had nearly doubled over the total number up until 2006 (∼25,000). This extraordinary progress in the field of the neurobiology of addiction required a different theoretical and practical approach to writing our second book.

From a theoretical perspective, we chose to use a heuristically identified domain model that originated in our seminal Science paper on addiction: Drug abuse: hedonic homeostatic dysregulation [1]. Here, based on the social psychology of self-regulation theory, experimental psychology, and psychiatry, we originally defined addiction as a cycle that consists of three stages: binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation. Eventually, three corresponding domains and neurocircuits coalesced around these three stages: binge/intoxication (incentive salience/pathological habits domain, basal ganglia neurocircuits), withdrawal/negative affect (negative affect domain, extended amygdala), and preoccupation/anticipation (executive function, prefrontal cortex). A recent human clinical, behavioral, and self-report study confirmed these three neurofunctional domains, at least for alcohol use disorder [2]. Thus, the new revised book, Neurobiology of Addiction, is now organized along the three stage/three domain construct while retaining synthesis at the circuit, cellular, and molecular levels of analysis.

Our new book series incorporates components of an experimental medicine approach. Volume 1 of the series, Introduction to Addiction, includes three chapters. Chapter 1 (What is Addiction?) covers the disease construct and associated symptoms in humans at the three stages of the addiction cycle. Chapter 2 (Animal Models of Addiction) goes back to the laboratory and elaborates the various animal models that have been developed to explore the intricacies of each domain. Chapter 3 (Neurobiological Theories of Addiction) links neurobiology to pathophysiology. In this latter chapter, we sought to include as many of the different theoretical perspectives that we could find, including theories of different levels of intensity of addiction (based on the Diagnostic and Statistical Manual of Mental Disorders, fifth edition), different components of the addiction syndrome, and translational pathophysiology. The unique elements of addiction that are defined by different major drug classes—psychostimulants, alcohol, opioids, nicotine, and marijuana—are explored as separate volumes in this series.

From a practical perspective, the organization of the original book in different volumes was necessitated by the prodigious increase in publications from 2006 to present. We had prided ourselves in finding virtually all of the published work in 2006 and citing as much of it as possible. Most of the early cited literature has been retained in the present series, but such an approach of citing every study from 2006 to present was not humanly possible for the present series. As a result, for many of the topics, we rely on key seminal papers and review articles. For each seminal advance, where possible, we have included summary figures. We hope readers will see how the field has evolved at the level of refined techniques and consolidated theoretical approaches and apologize in advance to researchers who may have a key seminal paper that we missed.

We are very excited and encouraged about the tremendous advances that have been made in unveiling the neurobiology of addiction, both clinically and preclinically. We look forward to further insights that tomorrow's research will provide.

George F. Koob

Michael A. Arends

Mandy McCracken

Michel Le Moal

References

[1] Koob G.F, Le Moal M. Drug abuse: hedonic homeostatic dysregulation.  Science . 1997;278:52–58.

[2] Kwako L.E, Schwandt M.L, Ramchandani V.A, Diazgranados N, Koob G.F, Volkow N.D, Blanco C, Goldman D.Neurofunctional domains derived from deep behavioral phenotyping in alcohol use disorder.  American Journal of Psychiatry . 2019;176:744–753.

Volume TWO

Psychostimulants

Abstract

Psychostimulant drugs, such as cocaine and amphetamines, of the indirect sympathomimetic class have a long history as tonics and other preparations to allay fatigue and sustain performance. These drugs also have a long history of abuse and dependence. Abuse potential varies with the availability of the drug both environmentally and physiologically, with intravenous and smoked forms of both cocaine and amphetamines producing much more severe substance use disorder. Cocaine and amphetamines have a characteristic abuse cycle that involves binge administration, withdrawal dysphoria, paranoia, and psychosis-like symptoms as the cycle continues or intensifies. Significant advances have been made in our understanding of the mechanisms of action of psychomotor stimulant drugs at the behavioral, neuropharmacological, cellular, and molecular levels that can be heuristically framed in the three-stage cycle of addiction:  binge/intoxication, withdrawal/negative affect, and  preoccupation/anticipation. Eventually, three corresponding domains and neurocircuits coalesced around these three stages: binge/intoxication (incentive salience/pathological habits domain, basal ganglia neurocircuits), withdrawal/negative affect (negative affect domain, extended amygdala), and preoccupation/anticipation (executive function, prefrontal cortex). Thus, the new revised book, Neurobiology of Addiction, is now organized along the three stage/three domain construct while retaining synthesis at the circuit, cellular, and molecular levels of analysis.

Keywords

Addiction; Amphetamine; Cocaine; Dark side; Dependence; Methamphetamine; Neurobiology; Neurocircuitry; Psychostimulant; Withdrawal

Acknowledgements

1. Definitions

2. History of psychostimulant use

3. Physiological effects

4. Behavioral effects

5. Pharmacokinetics

6. Behavioral mechanism of action

7. Medical use, abuse, and addiction

7.1 Medical uses

7.2 Psychostimulant abuse cycle

7.3 Withdrawal

8. Neurobiological effects

8.1 Binge/intoxication stage: acute reinforcing and stimulant effects

8.1.1 Neurobiological mechanism: neurocircuitry

8.1.2 Neurobiological mechanism: cellular

8.1.3 Neurobiological mechanism: molecular

8.1.4 Sex differences

8.1.5 Summary of binge/intoxication stage

8.2 Withdrawal/negative affect stage: withdrawal and dependence

8.2.1 Neurobiological mechanism: tolerance

8.2.2 Neurobiological mechanism: neurocircuitry

8.2.3 Neurobiological mechanism: cellular

8.2.4 Neurobiological mechanism: molecular

8.2.5 Summary of withdrawal/negative affect stage

8.3 Preoccupation/anticipation stage: reinstatement

8.3.1 Neurobiological mechanism: neurocircuitry

8.3.2 Neurobiological mechanism: cellular

8.3.3 Neurobiological mechanism: molecular

8.3.4 Summary of preoccupation/anticipation stage

9. Overall summary

References

1. Definitions

Psychostimulant drugs, such as cocaine, D-amphetamine, and methamphetamine, have medical uses but also considerable abuse potential. There are two major classes of psychomotor stimulants (Table 1, Fig. 1): (1) direct or indirect sympathomimetics, such as cocaine and amphetamine, and (2) nonsympathomimetics. This volume focuses on indirect sympathomimetics. Indirect sympathomimetic compounds, such as cocaine and amphetamines, share a common molecular structure—a benzene ring with an ethylamine side chain. Amphetamine differs from the parent compound, β-phenethylamine, by the addition of a methyl group, whereas methamphetamine has two additional methyl groups. Psychomotor stimulants are drugs that produce behavioral activation that is usually accompanied by increases in arousal, alertness, and motor activity. The term sympathomimetic derived originally from the description of the mechanism of action of these drugs. Sympathomimetics mimic the action of the sympathetic nervous system when it is activated. The term sympathin was originally used to describe the hormone noradrenaline (norepinephrine) in the central nervous system [1–3]. Thus, sympathomimetic drugs mimic the peripheral actions of norepinephrine in the autonomic system and neuropharmacologically either directly or indirectly activate monoamine receptors. Indirect sympathomimetics mimic this action by acting on neuronal mechanisms that do not involve the direct activation of postsynaptic receptors. The present volume focuses only on the neurobiological mechanisms that are involved in the addiction liability of indirect sympathomimetics. Nonsympathomimetics act via different neuropharmacological mechanisms altogether.

Table 1

Fig. 1 Chemical structures of various psychostimulants.

Historically, there have been numerous eras of stimulant addiction that are often linked to ease of access and distorted or misinformed perceptions of the abuse potential of these drugs [4] (Fig. 2).

2. History of psychostimulant use

Cocaine is derived from the coca plant (Erythroxylum coca) and has a long history as a stimulant. Cocaine has been used for centuries in tonics and other preparations to allay fatigue, sustain performance, and treat a large variety of ailments [5,6]. Cocaine was once a component of Coca Cola®, and its extract from the coca plant (without cocaine) is still used as an ingredient today. In 1886, the druggist John Styth Pemberton devised a patented medicine that contained two natural stimulants, cocaine and caffeine, to formulate the syrup base for Coca-Cola®. He blended a whole-leaf extract of coca with an extract from the African kola nut that contains caffeine. Coca-Cola® was initially manufactured and marketed as an intellectual beverage and brain tonic, and until 1903 Coca-Cola® contained approximately 60   mg cocaine per 8 ounce serving. It was also touted as a temperance drink because it had no alcohol though cocaine was still a key ingredient. The manufacturer believed that their product should not only be strongly associated with cocaine by the product name but also that the product package should stand out as unique. Thus, the unique shape of the Coca-Cola® bottle, designed by C.J. Root Co. (Terre Haute, Indiana, USA), was originally intended to resemble the shape of a coca bean. In reality, however, the bottle shape resembled a cacao (i.e., cocoa) bean because the production artists mistakenly used a cacao bean instead of a coca bean as the model for the bottle design. In 1903, soon after the dangers of cocaine were publicized, the manufacturer of Coca-Cola® removed it from its formulation [7–9].

The use of cocaine was even advocated briefly by Dr. Sigmund Freud to treat a variety of disorders, including psychiatric disorders and drug addiction [10], but he quickly lost his enthusiasm after observing his first cocaine-induced psychosis (for a review of Freud's writings on cocaine, see Ref. [11]), and cocaine and other indirect sympathomimetics have been involved in more than one epidemic of drug abuse in the United States and worldwide ([12]; Table 2). Presumably because cocaine was used in numerous tonics, it was extensively cultivated in South America and exported to the United States and Europe [6,13,14]. Widespread use followed. The first restriction of coca products commenced in the United States with the Harrison Narcotics Act of 1914 [15]. This act penalized its illicit possession and sale but mislabeled cocaine-containing preparations as narcotics.

Fig. 2 From non-humans to humans, cocaine and related psychostimulants exert myriad effects on the brain and behavior. 

Taken with permission from Sanchez-Ramos JR. Neurological complications of cocaine abuse include seizure and strokes. Psychiatric Times February 1990. p. 20, 22.

Table 2

In the 1960s, a rise in the smuggling and use of cocaine started, based on the high monetary profit that could be gained by engaging in its illegal trafficking [6], culminating in an epidemic of cocaine use in the 1980s. In the 1970s, cocaine was usually administered intranasally in powder form (i.e., cocaine hydrochloride). The perception among users was that it was safe and non-addictive. In fact, the 1980 edition of the Comprehensive Textbook of Psychiatry stated, used no more than two-three times a week, cocaine creates no serious problems. In daily and fairly large amounts, it can produce minor psychological disturbances. Chronic cocaine abuse does not appear as a medical problem [16]. Somewhat later, during the mid-1980s, came the availability of a smokable form of cocaine—freebase or crack ([17]; Fig. 3). Freebase cocaine or crack cocaine is generally prepared from its hydrochloride salt by one of two techniques. In one procedure, freebase, the hydrochloride salt is first mixed with buffered ammonia, then the alkaloidal cocaine is extracted from the solution using ether, and finally the ether is evaporated to yield cocaine crystals. When heated, the crystals release vaporized cocaine that can be inhaled. This form of cocaine is very pure. It was generally called freebase on the street and began to be seen in the late 1970s and was popular in the mid-1980s [8]. In the second procedure, crack, cocaine hydrochloride is dissolved in water and combined with baking soda (sodium bicarbonate), and the solution is heated until a solid forms, called crack cocaine. When dried, the product becomes hard and when heated makes a popping sound, thus possibly explaining the origin of the term crack cocaine. The hydrochloride salt of cocaine cannot be smoked itself because it is quickly destroyed at high temperatures [18,19]. Cocaine freebase and crack melt at 98   °C [20] and vaporize at 260   °C [21]. A large percentage of cocaine effluent from a crack pipe consists of particulate matter, and only 6% cocaine vapor [19]. However, at higher temperatures, the cocaine is destroyed [21]. Since the mid-1980s, this has been the preferred method of production for smokable cocaine because it is simpler and safer than the ether extraction method. Today, most of the available crack cocaine in the United States is produced in this manner [7,8].

Fig. 3 Estimated prevalence (%) of active cocaine use by year of survey and age of respondent (any cocaine use in the 30 days prior to interview). Data from the National Household Survey on Drug Abuse, 1972–90. 

Taken with permission from Anthony JC. Epidemiological research on cocaine use in the USA. In: Bock GR, Whelan J, editors. Cocaine: scientific and social dimensions. Ciba foundation symposium, vol. 166. Chichester: John Wiley; 1992. p. 20–39.

Amphetamines had widespread medical use in the treatment of narcolepsy and various other disorders from 1936 to the mid-1940s [6]. In the 1960s, the illegal diversion of amphetamines paralleled the greater use of the drugs, resulting in a cyclic pattern of abuse that involved individuals who abused amphetamines, including methamphetamine. These individuals were called speed freaks [6,22]. There was a parallel epidemic of abuse of phenmetrazine, an amphetamine-like stimulant, in Sweden in the 1950s and 1960s [23].

Methamphetamine was first synthesized in Japan in 1893 [24] and came into widespread use during World War II to increase the endurance and performance of military personnel. Methamphetamine was sold over-the-counter in Japan as Philopin and Sedrin as a product to fight sleepiness and enhance vitality [25]. The most common manufacturing process uses ephedrine or pseudoephedrine in a reduction process with a mixture of iodine and red phosphorous to yield both the dextro (D) and levo (L) isomers of methamphetamine [26]. The D-isomer is 5- to 10-times more potent than the L-isomer in producing central nervous system effects [27]. Methamphetamine can still be prescribed in the United States for attention deficit/hyperactivity disorder (ADHD) and as a short-term adjunct treatment in a regimen for weight loss based on caloric restriction [28]. The L-isomer, called desoxyephedrine (Levmetamfetamine), remains the active ingredient in nasal decongestant inhalers [28].

An epidemic of methamphetamine abuse occurred in Japan after World War II (1945–57) when military stockpiles flooded the market, with estimates in 1954 of 550,000 methamphetamine abusers in Japan [25,29]. In the 1960s, methamphetamine was synthesized from other precursors and was a mixture of the D- and L-isomers, called crank, that dominated the speed market [30]. Manufacture shifted to the San Diego area in the 1980s with the production of crystal meth, also from ephedrine [31]. Crystal methamphetamine is the D-isomer salt of methamphetamine (also called ice because of its resemblance to ice crystals) [26,32] and its ability to be smoked or snorted. Smokable methamphetamine became a popular drug of abuse in the 1980s in Hawaii, the Pacific Coast of the United States, and Southern California and has subsequently spread to the rest of the United States [33,34].

National surveys indicate that the prevalence of cocaine use reached its peak in 1985 as reported by the National Household Survey on Drug Use and Health (formerly the National Household Survey on Drug Abuse). A total of 7.1 million individuals in the United States had used cocaine within the past year, with the number steadily declining since that time [35,36]. The percentage of young adults aged 18–25 who had ever used cocaine was below 1% during the mid-1960s, but this number rose steadily throughout the 1970s and early 1980s, reaching a high of 17.9% in 1984. Others have argued that because this drug use survey missed many drug-active populations, these were underestimations. During this period, upwards of 25% of American adults (50 million) had experimented with the drug [37]. By 1996, the percentage of people who had ever used cocaine dropped to 10.1% but then climbed to 15.4% in 2002 and remained at roughly that level (14.9%) in 2017 [38]. In the European Union in 2017, 17.0 million adults aged 15–64 years (or 5.1% of this age group) reported having tried cocaine during their lifetimes. Among these were 2.3 million adolescents and young adults aged 15–34 years (1.9% of this age group) who used the drug in the past year, with estimates ranging from 0.2% to 4.0%. The European countries with the highest prevalence of past-year cocaine use among adolescents and young adults include the Netherlands, Denmark, Spain, Ireland, and the United Kingdom, which had prevalence estimates of 2.5% or higher [39].

The 2017 United States National Survey on Drug Use and Health [38] estimated that, among those aged 12 and older, 40.1 million (14.9%) had ever engaged in cocaine use, and 14.7 million (5.4%) had ever engaged in methamphetamine use. An estimated 5.9 million people (2.2%) 12 and older used cocaine in the past year, and 2.2 million (0.8%) used cocaine in the last month. For methamphetamine, 14.7 million individuals aged 12 and older (5.4%) used at some point in their lifetimes, 1.6 million (0.6%) were last-year users, and 774,000 (0.3%) were users in the month prior to the survey. Other notable statistics from the survey included the following. In 2017, of those people aged 12 or older who used cocaine in the last year, 966,000 (16.4%) presented cocaine abuse or dependence. Among those who used methamphetamine in the past year, 964,000 reached the criteria for abuse or dependence based on the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV; [40]) and DSM-IV-TR [41] or reached the criteria for Substance Use Disorder based on the DSM-5 [42].

3. Physiological effects

Both cocaine and amphetamine increase systolic and diastolic blood pressure. In humans, an intravenous dose of 10   mg D-amphetamine increases blood pressure to a level that is equal to an intravenous dose of 32   mg cocaine ([43]; Fig. 4). Cocaine and amphetamines also stimulate heart rate, but amphetamines may cause less of an effect than one would expect based on other physiological measures because of a reflex slowing of heart rate. These drugs also produce bronchial dilation and pupillary dilation and decrease glandular secretions—effects that are observed after activation of the sympathetic nervous system.

The mechanism of action of the autonomic effects of indirect sympathomimetics, such as amphetamines and cocaine, has long been known. Both drugs indirectly cause the release of norepinephrine and epinephrine by blocking both reuptake and potentiating release [44,45]. Chronic post-ganglionic adrenergic denervation or treatment with reserpine (which dramatically depletes tissue stores of catecholamines) abolishes the autonomic effects of amphetamine, indicating that these effects are attributable to an indirect sympathomimetic action [46].

4. Behavioral effects

Intranasal cocaine administration produces stimulant effects that are similar to amphetamines but with a much shorter duration of action (20–45   min) that includes feelings of having much energy, fatigue reduction, a sense of well being, greater confidence, and greater talkativeness. Intoxication includes a euphoric effect that has been described as exhilarating, with a kind of rush that goes straight to one's brain, mild elation, and a greater ability to concentrate. Sigmund Freud wrote,

The psychic effect of cocaine in doses of 50–100   mg consists of exhilaration and lasting euphoria, which does not differ in any way from the normal euphoria of a healthy person.

In a letter to his fiancé Martha dated June 2, 1884, he wrote,

Fig. 4 (A) Median percent change in heart rate in humans for 1   h after