Keywords

FormalPara High-Yield Review Points

  • Caffeine’s psychostimulatory effects are generally less than that of classical psychostimulants, and its effects are the result of A1 and A2A adenosine receptor antagonism.

  • The DSM-5 allows for formal diagnoses of Stimulant Intoxication, Stimulant Withdrawal, Other Stimulant-Induced Disorder, Unspecified Stimulant-Related Disorder, and Stimulant Use Disorder (addiction) with the categories of stimulants being amphetamine-type substances, cocaine, and other or unspecified stimulants (e.g., khât, cathinone derivatives). The DSM-5 also allows for Caffeine-Induced Disorders (e.g., anxiety and panic) as well as a characteristic Caffeine Withdrawal Syndrome.

  • Cocaine is a potent reuptake blocker of catecholamines, while amphetamine and most amphetamine-type stimulants both block reuptake and function as transporter substrates that cause a greater release of intracellular catecholamines.

  • There are no FDA-approved pharmacotherapies for cocaine use disorder and for amphetamine and amphetamine-type stimulant use disorders, despite trials of many potential different pharmacotherapies for this purpose.

  • Psychosocial and behavioral therapies remain the mainstay of treatment for cocaine use disorder and for amphetamine and amphetamine-type stimulant use disorders, with cognitive behavioral therapies and contingency management approaches having demonstrated efficacy.

Introduction

Stimulants is a term that describes a diverse range of naturally occurring and synthetic substances that are used for medical and non-medical purposes. Naturally occurring stimulants have been consumed for millennia and are found in various species of plants grown naturally and cultivated throughout the world including coca (cocaine), khât (cathinone), ephedra (ephedrine and pseudoephedrine), tea and coffee (caffeine), and tobacco (nicotine). Synthetic stimulants are legion, and include amphetamine, methylphenidate, methamphetamine, methylenedioxymethamphetamine (MDMA), modafinil and r-modafinil, benzphetamine, diethylpropion, mazindol, phendimetrazine, phenmetrazine, phentermine, and the cathinone derivatives ephedrone and mephedrone. While many stimulants are ingested orally, they are also widely ingested (both licitly and illicitly) via inhalation, injection, and intranasal, topical, and transrectal routes of administration.

Medical uses of stimulants are myriad and include the treatment of attention-deficit hyperactivity disorder (ADHD), nasal sinus congestion, migraine headaches, sleep disorders, obesity, altitude sickness, as well as topical anesthesia. Stimulants are also used in improving cognitive performance and for wakefulness enhancement.

As a class, stimulants act pharmacologically in both the central and peripheral nervous systems where they primarily enhance the transmission of the catecholamine neurotransmitters norepinephrine and dopamine, creating the characteristic hedonic, reinforcing and sympathomimetic effects attributed to stimulants: e.g., euphoria, increased libido, decreased appetite, increased attention and wakefulness, tachycardia and hypertension, and hyperthermia. Stimulants can also secondarily affect additional neurotransmitter systems (adenosine, serotonergic, and alpha and beta adrenergic systems, and neuronal sodium channel systems; they also inhibit monoamine oxidase function), which contribute to the variety of physiological and psychiatric effects attributed to stimulants.

The Diagnostic and Statistical Manual, fifth Edition (DSM-5), describes several disorders related to stimulants, which are divided into the following rubrics: intoxication, withdrawal, use disorder (addiction), other induced disorders, and unspecified stimulant-related disorders [1]. In this chapter, the main focus will be on intoxication, withdrawal, and use disorders related to stimulants. When relevant, other induced disorders and unspecified stimulant-related disorders will be highlighted, but it is sufficient to understand more broadly that other induced disorders and unspecified stimulant-related disorders represent the following: (1) other induced disorders are syndromes that resemble primary psychiatric disorders; however, the cause is stimulant related (e.g., caffeine-induced anxiety disorder, methamphetamine-induced psychotic disorder) and (2) unspecified stimulant-related disorders are syndromes wherein stimulant use results in clinically significant distress and/or impairment without meeting full diagnostic criteria for intoxication, withdrawal, or use disorder (e.g., unspecified caffeine-related disorder) [1].

Significantly, stimulants have a high potential for non-medical use as well as addiction, and are widely misused for their hedonic and reinforcing effects, temporary cognitive and sexual enhancement, and augmentation of alertness and energy. It is difficult to definitively pinpoint the proportion of those who use stimulants who will go on to develop a stimulant use disorder (addiction). National surveys of individuals not in treatment and those seeking treatment estimate that 15% to 50%, respectively, of those misusing stimulants will develop characteristics of a use disorder [2, 3]. Factors that increase the likelihood of developing a stimulant use disorder include: using via routes of administration that favor more rapid delivery to the brain (e.g., inhalation, injection), and greater amounts used [4].

Stimulants are also associated with various deleterious psychiatric consequences such as mood disorders, psychosis, aggression, impulse control disorders, and panic attacks. The negative physiologic effects of stimulant misuse are numerous and every organ system can be impacted. Negative psychiatric and physiological consequences result from either direct effect of the stimulant (e.g., the excessive dopamine release and consequent psychosis and movement disorders seen in methamphetamine use), or indirect stimulant effects (e.g., organ ischemia due to vasoconstriction). Additional negative consequences of stimulant misuse include trauma sustained while intoxicated, as well as the full range of social/economic/relational/legal consequences typical of all addictive disorders. While adulteration of illicit stimulant supplies with potentially toxic “fillers” and additives is not new, recent experience supports the increasingly widespread presence of the potent synthetic opioid fentanyl in illicit stimulant supplies, resulting in opioid overdose deaths.

In this chapter, particular focus will be on caffeine, cocaine, and amphetamines. Nicotine and MDMA will be considered in separate chapters. Over-the-counter stimulants and the wakefulness enhancers modafinil and r-modafinil will not be considered further in this chapter.

Caffeine

Caffeine is an alkaloid chemical that is consumed orally through food, drink, and dietary supplements and is present in over 60 different species of plants, such as tea, guarana, cacao, and yerba maté. Recently, caffeine has also become incorporated into cosmetic products under the auspices of facilitating hair growth (with limited preclinical evidence) [5]. Caffeine is the most widely used psychoactive substance in the world, with an estimated 85% of the US population 2 years old and older consuming one or more caffeinated beverages a day [6]. Caffeine use is generally not associated with significant deleterious health consequences when used in moderation, and caffeine ingestion may in fact provide some health benefits by preventing Parkinson’s disease, liver cirrhosis, and certain forms of dementia and depression, although the data on these effects are currently inconclusive [7,8,9].

Caffeine is used medically in conjunction with various analgesics such as acetaminophen and ibuprofen to enhance the pain-mitigating effects of these analgesics, to treat caffeine withdrawal, and to treat apnea in neonates and infants [10, 11]. Outside of medical indications, caffeine is widely consumed to improve alertness and enhance wakefulness and is commonly added in varying amounts to weight loss and energy products, sometimes in conjunction with alcohol.

Endogenous adenosine activity is responsible for escalating sleepiness following periods of prolonged wakefulness and also is implicated in several other aspects of sleep homeostasis. Caffeine’s psychomotor-reinforcing effects and hyperarousal are the result of the antagonism of central A1 and A2A adenosine receptors. Compared to classical psychostimulants such as cocaine and amphetamine, caffeine has comparatively less augmentation effect on dopaminergic and catecholaminergic neurotransmission. Nonetheless, caffeine ingestion increases both systolic and diastolic blood pressures, causes head and neck vasoconstriction as well as bronchodilation, and has diuretic and colonic stimulatory effects [12].

The ubiquity and relative minor health or psychological impact of caffeine make it difficult to pinpoint specific caffeine-related disorders and problems. The Diagnostic and Statistical Manual, fifth Edition (DSM-5), describes Caffeine-Related Disorders as Caffeine Intoxication, Caffeine Withdrawal, Other Caffeine-Induced Disorders, and Unspecified Caffeine-Related Disorders [1]. Caffeine Use Disorder (addiction) is listed as a condition for further study in DSM-5.

Affecting an estimated 7% of the US population, caffeine intoxication is marked by recent use of caffeine, typically in doses in excess of 250 mg, and five or more of the following factors, causing significant distress or impairments in social, occupational, or other important areas of functioning: restlessness, nervousness, excitement, insomnia, flushed face, diuresis, gastrointestinal disturbance, muscle twitching, rambling flow of thought and speech, tachycardia or cardiac arrhythmia, periods of inexhaustibility, and/or psychomotor agitation. Symptoms usually resolve without lasting consequence within 24 hours of onset, consistent with caffeine’s 4–6 hour half-life. However, deaths have been reported following extremely high-dose ingestions (5–10 grams) [1].

Frequent ingestion of caffeine can reliably result in the development of physiological tolerance. Development of tolerance is, in part, the result of adenosine A1 receptor upregulation in chronic caffeine exposure. Abrupt discontinuation or marked reduction in amount consumed of caffeine in a tolerant individual can result in a clinically significant withdrawal syndrome characterized by 24 hours of three or more of the following symptoms causing significant distress and impairments in social, occupational, or other important areas of functioning: headache; marked fatigue or drowsiness; dysphoric mood, depressed mood, or irritability; difficulty concentrating; flu-like symptoms such as nausea, vomiting, or muscle pain/stiffness. Headache is a particularly common symptom, affecting upwards of 50% of those with caffeine withdrawal. Most symptoms resolve within 2–9 days [1].

In part due to the difficulty in defining a caffeine use disorder (addiction), treatment of problematic caffeine use is poorly studied. One study utilized a combination of manualized cognitive behavioral therapy in conjunction with caffeine down-taper over 5 weeks and showed significant caffeine intake reduction that was successfully maintained at the 1-year follow-up timepoint [13].

Tobacco cigarette smokers and alcohol-dependent individuals have been shown to consume significantly higher amounts of caffeine than individuals without these disorders [14] Caffeine has also been shown to have a potentiating effect on other classical psychostimulants [15]. Furthermore, caffeine has been shown to decrease the metabolism of the atypical antipsychotic clozapine and lithium toxicity has been documented during withdrawal from caffeine related to changes in renal clearance of lithium following discontinuation of caffeine [16, 17].

Caffeine readily crosses the placenta, and meta-analytic data suggest that maternal caffeine consumption during pregnancy has a small but significant association with adverse pregnancy outcomes such as increased rates of spontaneous abortion, stillbirth, low birth weight, and small for gestational age (SGA) in a dose-response pattern [18]. However, the thresholds for risk increase are uncertain and several studies have presented conflicting conclusions about this association [19, 20]. As a result, the American College of Obstetrics and Gynecology, the American Pregnancy Association, and the March of Dimes recommend that pregnant women limit their caffeine intake, generally to 200 mg or less daily [21, 22]. The half-life of caffeine may increase significantly late in pregnancy [23], increasing the risk of toxicity. A small amount of caffeine is found in breastmilk of nursing mothers. The American Academy of Pediatrics indicates that caffeine consumption is safe during breastfeeding, but consumption in excess of two to three cups of coffee per day (300 mg) has been associated with irritability and poor sleeping patterns in nursing infants [24].

Diagnostic Considerations for Cocaine and Other Stimulants

The DSM-5 consolidates the diagnostic criteria for all non-caffeine/tobacco stimulants around 3 categories of substances: (1) amphetamine-type substances, (2) cocaine, and (3) other or unspecified stimulants (e.g., khât, cathinone derivatives). DSM-5 diagnoses in relation to stimulants parallel those of caffeine described above: Stimulant Intoxication, Stimulant Withdrawal, Other Stimulant-Induced Disorder, Unspecified Stimulant-Related Disorder, and Stimulant Use Disorder (addiction). For each diagnostic entity, the diagnostic criteria are shared, but the specific stimulant is specified (e.g., Cocaine Use Disorder, Methamphetamine Intoxication, khât withdrawal, etc.) [1]. While there are substance-specific considerations, it is efficient and clinically useful to consolidate (as the DSM-5 does) all non-caffeine/tobacco stimulant-related disorders. Therefore, in this section, the broad category of stimulant-related disorders will be outlined, followed by sections specifically highlighting unique considerations for cocaine, amphetamine, and amphetamine-type stimulants, in turn.

The DSM-5 diagnosis of Stimulant Intoxication is marked by clinically significant problematic behavioral or psychological changes such as hallucinations, agitation, euphoria, delusions (e.g., paranoia), and two or more of the following: tachycardia or bradycardia; pupillary dilation; elevated of lowered blood pressure; perspiration or chills; nausea or vomiting; evidence of weight loss; psychomotor agitation or retardation; muscle weakness, respiratory depression, chest pain, or cardiac arrhythmias; confusion, seizures, hyperpyrexia, dyskinesias, dystonias, or coma [1]. Psychomotoric activation and vital sign elevation typically predominate, with psychomotoric retardation and bradycardia/hypotension seen less frequently and if seen is more likely witnessed in chronic heavy stimulant users.

There are several acute medical complications of stimulant intoxication that are worth specifically highlighting. Stimulants are known to decrease seizure threshold, with case series describing generalized tonic-clonic seizures in individuals with no previously evident seizure disorder [25]. Hyperthermia and trauma resulting from the combination of psychomotoric activation and altered mentation (psychosis and/or delirium) resulting from acute stimulant ingestion can also be life-threatening. Cerebral and cardiac vasoconstriction can be marked with stimulant intoxication and can lead to stroke and myocardial infarction [26]. Pulmonary edema, hemorrhage, pneumothorax, and pneumomediastinum have all been documented with stimulant inhalation and intravenous use. A combination of intramuscular artery vasoconstriction, direct toxic effects of stimulants, and/or muscle damage secondary to seizures or hyperthermia can result in renal damage through ischemia and/or rhabdomyolysis [27]. Gastrointestinal and other organ ischemia are also possible through the potent vasoconstrictive effects of stimulants [27]. Therefore, appropriate medical work-up of the stimulant intoxicated individual is essential to diagnose acute, life-threatening, complications and make sure that they are appropriately managed in a timely fashion.

Psychiatrically, psychosis is common among stimulant-intoxicated individuals and can be profound. Hallucinations may be auditory, visual, or somatosensory (especially tactile hallucinations of bugs crawling under the skin known as fomication). The presence of visual or somatosensory hallucinations is unusual in schizophrenia, which is marked by predominance of auditory hallucinations and negative affective and cognitive symptoms, making this a potentially useful way of distinguishing between these two oft-conflated disease entities. Paranoid delusions are also common in stimulant intoxication, and may contribute to aggressive or violent behavior [28, 29]. Unfortunately, psychotic symptoms may persist long after stimulant intoxication, especially in the use of methamphetamine, in which the psychosis may last for a year or longer after discontinuation [30]. In part related to psychosis generated by stimulant use, an increased risk of violence has been associated with cocaine and AAT intoxication (even between episodes of intoxication [31]), but the association with methamphetamine use, in particular, is well documented [29, 32].

Treatment of stimulant intoxication involves a combination of environmental modifications to ensure safety as well as pharmacologic interventions to treat symptoms. Behavioral interventions are centered on decreasing environmental stimuli and providing calm reassurance and support. Physical restraints are a measure of last resort, since these may contribute to hyperthermia and rhabdomyolysis. Pharmacologically, sedative-hypnotics such as benzodiazepines are preferred, particularly those that are available through oral, intravenous, and intramuscular routes of administration. Diazepam [10–30 mg PO or 2–10 mg IM or IV] or lorazepam [2–4 mg PO or 1–2 mg IM or IV] are commonly used [33]. In the very agitated or psychotic stimulant-intoxicated individual, antipsychotic medications are used with caution. These medications may compound the seizure threshold lowering effects of stimulants, as well as exacerbate hyperthermia. Therefore, high potency antipsychotics are preferred, such as haloperidol, since these high potency neuroleptics are less likely to have anticholinergic side effects that are particularly implicated in the development of the risks highlighted above.

Prolonged use of stimulants can lead to the development of physiological tolerance, and upon abrupt discontinuation or dose reduction a clinically significant stimulant withdrawal syndrome can develop. Stimulant withdrawal is not typically life-threatening, and manifests characteristically as the opposite of intoxication; namely, a clinically distressing or impairing dysphoric mood and 2+ of the following: fatigue, vivid unpleasant dreams, insomnia or hypersomnia, increased appetite, psychomotor retardation or agitation [1]. Individual variability is significant, but onset of stimulant withdrawal is typically between several hours to days after last use and can last for several days, with some symptoms such as psychosis (see above) persisting even longer.

There are no specific pharmacologic treatments for stimulant withdrawal. Generally, stimulant withdrawal is marked by minimal physiological distress and targeted symptomatic treatment of non-specific musculoskeletal pain, tremors, chills, and other symptoms can be helpful. Psychiatric sequalae of stimulant withdrawal such as disproportionate dysphoria or low-level psychosis can be treated with antidepressants or antipsychotic medications, respectively.

Other Stimulant-Induced Disorders include those disorders that mimic other primary psychiatric disorders but are precipitated by the use of particular substances. In particular, in methamphetamine-induced psychotic disorder, significantly distressing or impairing delusions or hallucinations predominate the clinical presentation and by history, physical exam, or laboratory findings, these symptoms are temporally related to intoxication or withdrawal from methamphetamine use.

There are several approaches to screening for stimulant use and stimulant use disorders. Patient self-report has been demonstrated to be reasonably accurate, so long as there are not competing motivations for misrepresentation of use (e.g., legal ramifications) [34]. Other validated easy-to-use screening tools for stimulant use include the three question Tobacco, Alcohol, Prescription Medication, and Other Substance Use screening instrument [35], the single question screening test [36], and the 10-item Drug Abuse Screening Test [37], while the Screen of Drug Use can be effective in detecting stimulant use disorder [38]. For detection of stimulant use during pregnancy (in addition to other substances and alcohol), the 4Ps Plus is a five-item, validated screen that is easy-to-use [39].

Cocaine

Cocaine is a classical stimulant and analgesic alkaloid chemical that is present in the leaves of the Erythroxylum (coca) bush endemic to the higher altitude (1500–6000 feet) regions of the Andes Mountains in South America. For thousands of years, preparations using the coca plant have been used by local populations to stave off altitude sickness and enhance energy and performance in addition to the treatment of a wide range of physical disorders. Since then, cocaine has developed both medical and non-medical uses. Medically, in the United States, cocaine is a schedule II substance with FDA indication for local and topical analgesia. Historically, cocaine has found particular medical usage as anesthesia for dental, ophthalmologic, and nasal surgical procedures. However, due to the development of other synthetic local anesthetics with more favorable side effect profiles, cocaine is rarely used in modern medical practice. In the latter part of the nineteenth century, cocaine was also added to various consumer products such as alcoholic beverages and soft drinks (e.g., Coca-Cola), a practice which ended in the early 1900s.

Cocaine exerts its psychomotor and reinforcing effects primarily through augmentation of transmission of the catecholamines dopamine and norepinephrine. This is achieved through the blockade of transporters that would otherwise clear previously released catecholamines from the extracellular space. In other words, cocaine acts as a reuptake blocker that enables dopamine and norepinephrine to spend greater time in the extracellular space, where they can continue to activate psychostimulatory pathways to a greater extent than would be otherwise naturally possible. In particular, cocaine potently augments dopamine neurotransmission in the mesocorticolimbic pathway involved in reward processing which accounts for its extraordinarily rewarding and reinforcing effect. Secondarily, cocaine also blocks neuronal sodium channels, which accounts for its anesthetic properties.

Cocaine exists in two chemical forms, salt and base , each of which has unique characteristics that drive use patterns. Illicit cocaine is extracted in bulk from the coca leaf, concentrated, purified, and converted chemically into its salt form through acidification. As a salt, cocaine is readily absorbable through mucous membranes making it ideal for intranasal use (insufflation). The salt is also readily dissolvable in water making it thereby available for injection. However, cocaine salt has a high melting point which provides little margin between the vaporization point and “burning” point of the chemical. Since burning cocaine renders it pharmacologically useless, cocaine salt is therefore not ideal for vaporized inhalation. However, converting the cocaine salt into its base form through alkalization drops the melting point significantly and allows for vaporization that facilitates easy ingestion through inhalation. The base form, conversely, is poorly dissolvable making it less ideal for injection and insufflated administration. The so-called “freebase” cocaine results in what has been commonly known as “crack,” the use of which reached epidemic proportions in the 1980s. While it is often referred to as being “smoked,” technically freebase cocaine is vaporized, not burned, unlike other smoked substances such as tobacco.

Ingested orally the onset of effect is relatively slower (30–45 minutes) than via insufflation (1–5 minutes) intravenous (4–7 minutes) or vaporized inhalation (6–8 seconds) routes of administration, with times to peak effect being 60–90 minutes, 20–30 minutes, 3-5 minutes, and 3–5 minutes, respectively. Correspondingly, the duration of action is longer for cocaine ingested orally (3 hours), via insufflation (1 hour), than via intravenous or inhalation (15–30 minutes) routes of administration [40]. When consumed with alcohol a new compound, cocaethylene, is formed with less potency than cocaine but with a longer half-life, as well as the potential to cause cardiac arrhythmias [41].

Cocaine is primarily metabolized via ester bond hydrolysis in the liver to benzoylecgonine which is readily detectable via routine immunoassay in urine for 2–3 days in non-daily users, but upwards of 2 weeks in those who use cocaine heavily.Footnote 1 Cocaine may also be detected through hair, blood, sweat (via patches), and oral fluid samples, with varying times of positivity (up to 12 hours in blood and oral fluids, weeks for sweat, to months-years in hair, although hair testing results may vary significantly based on race/ethnicity, location of hair sample, and the presence of hair treatments) [42].

While a urine assay positive for benzoylecgonine is reliably indicative of cocaine use, test positivity does not, in-and-of itself, indicate the presence of a cocaine use disorder (addiction). Rather, cocaine use disorder is diagnosed through screening for the range of behavioral and physical criteria described in the DSM-5 for all other substance use disorders (described elsewhere in this text).

In 2017, 20%, 3%, and 1% of US residents 18 years and older reported use of cocaine in their lifetime, in the past year, and in the past month, respectively. The predominance of past year users are white or American Indian or Alaska Native unemployed men with some college education [43]. Most cocaine users use relatively infrequently (58% report using only 12 times a year), in what is typically described as a “binge ” involving long periods of little or no use punctuated by short periods of heavy use. Cocaine users frequently describe symptoms of depression and anxiety, and are likely to use other substances (in particular tobacco and alcohol) to mediate or enhance the effects of intoxication or withdrawal [44].

In addition to the medical and psychiatric sequelae discussed above for stimulants in general, cocaine use is associated with several specific consequences, acute and chronic: cognitive impairment [45], suicidality and suicide attempts [46], and increased risk of infections such as hepatitis and HIV (by any route of administration) [47]. Insufflated cocaine can cause perforation of the nasal septum, while cocaine use via any route of administration can cause acute and chronic movement disorders such as choreoathetosis, dystonia (especially in conjunction with neuroleptic medications), and akathisia [48]. Vaporized cocaine is also associated with a severe pulmonary syndrome characterized by fever, hypoxemia, hemoptysis, respiratory failure, and eosinophilic alveolar infiltrates—the so-called “crack lung.” [49]

Cocaine ingestion in pregnancy has been associated with several deleterious consequences (either as a direct result of cocaine use, or due to other environmental factors associated with its use), including: vaginal bleeding, abruptio placenta, placenta previa, premature rupture of membranes, premature birth, decreased head circumference, low birth weight, and autonomic instability [50]. In addition, cocaine is found in breastmilk and infants breastfed from mothers using cocaine may demonstrate irritability, sleep difficulty, and tremors [24].

For the treatment of cocaine use disorders, randomized trials have examined the roles of novel cocaine vaccines , as well as stimulant replacement medication strategies, dopamine agonists, various antidepressants (e.g., fluoxetine, desipramine, bupropion), GABAergic medications (e.g., topiramate, vigabatrin), cholinergic medications (e.g., galantamine), ondansetron, and disulfiram. None of these pharmacotherapies have demonstrated consistent efficacy in treating cocaine use disorder.

Relative to pharmacotherapeutic interventions, behavioral treatment strategies have met with greater success in the treatment of cocaine use disorders [51]. Behavioral therapies represent a wide array of interventions that target various aspects of the challenges inherent in addictive disorders, from helping to explore and resolve ambivalence around usage (motivational interviewing (MI), motivational enhancement therapy(MET)), enhancing coping strategies (cognitive behavioral therapy (CBT)), altering thought processes around use (cognitive therapy (CT), CBT), learning how to utilize techniques to avoid/prevent triggers (CBT), changing the environmental reinforcing contingencies (contingency management (CM), community reinforcement approach (CRA)), to promoting a sense of detachment from cravings, thoughts, and emotions that contribute to relapse (mindfulness/meditation therapies). A 2008 meta-analysis of psychosocial/behavioral treatments for multiple substance use disorders showed medium to large effect sizes in impacting cocaine use (d = 0.62) [52]. In addition to the treatment interventions included in the meta-analysis above, additional studies have demonstrated the effectiveness of MI/MET [53], especially when coupled with CBT treatment [54]. Mindfulness-based treatments such as Acceptance and Commitment Therapy (ACT), Dialectical Behavioral Therapy (DBT), Mindfulness-Based Stress Reduction (MBSR), and Transcendental Meditation (TM) are used widely in substance use treatment, but the data evaluating these in individuals using cocaine are limited [56].

Twelve-step fellowships (e.g., alcoholics anonymous, narcotics anonymous, cocaine anonymous) are ubiquitously available abstinence-based substance use treatment programming, often employed alone or in tandem with other treatment approaches, and have been shown to be helpful for some with cocaine use, especially those who actively participate in the fellowship programming [55].

Amphetamine and Amphetamine-Type Stimulants

Amphetamine and amphetamine-type (AAT) stimulants are a diverse array of compounds (amphetamine, methamphetamine, dextroamphetamine) that are either structurally related to a parent phenethylamine chemical compound, or have similar effects but are structurally unrelated (methylphenidate, Ephedra, cathinone). Unlike cocaine, AAT stimulants continue to be widely used in medical practice for the treatment of a wide array of FDA-approved indications, making them readily available through licit supply chains. Diversion of AAT stimulants from these licit sources, in combination with a robust illicit manufacture and supply chain, contributes to their widespread availability. National surveys indicate that non-medical use of stimulants has been increasing, with 2014 surveys highlighting that 0.6% of the population ages 12 or older reports current nonmedical use of stimulants (0.2% methamphetamine, specifically), which represents an increase over most years between 2005 and 2013 [56].

Ephedrine-containing Ephedra plants have been used in Chinese medicine for thousands of years, and continued to be used widely in weight loss products until being banned from the US market in 2006 due to ephedrine’s association with serious cardiac side effects. α-methylphenethylamine (amphetamine) was first synthesized in 1887 but lay fallow until 1927 when G.A. Alles brought the chemical to mainstream medicine while he was seeking a synthetic substitute for ephedrine [57]. Methamphetamine was first synthesized from ephedrine in Japan in 1897, but found significant widespread use during World War II where it was broadly distributed by German military leadership to enhance wakefulness and combat performance.

Amphetamine exists in two optically active isomers, dextro (or d-) and levo- (or l-), with the d-isomer (trade name, Dexedrine) being significantly more potent. Similar to amphetamine, methamphetamine exists in two isomers (l- and d-) with d-methamphetamine being a highly potent stimulant, while l-methamphetamine has virtually no intrinsic psychoactivity. Both l- and d-amphetamine and d-methamphetamine are Schedule II medications in the United States (indicative of their high abuse potential), while l-methamphetamine is available over the counter as a decongestant nasal spray.

Methamphetamine exists in both base and salt forms, with the former being liquid at room temperature and the latter being a clear crystal at room temperature (e.g., “crystal methamphetamine”). The crystalline form of methamphetamine is readily dissolved in water and injected, or vaporized and inhaled in a manner similar to crack cocaine. Anecdotally, methamphetamine is felt to be a more potent and dangerous psychostimulant than amphetamine; however, rat and human studies have not consistently supported this assertion [58]. However, it is conceivable that these anecdotal differences are based on actual chemical differences. For example, methamphetamine is more lipophilic than amphetamine and therefore more readily crosses the blood–brain barrier leading to more rapid onset of action which can have potent reinforcing effects. Additionally, methamphetamine may be more resistant to enzymatic degradation, thereby enhancing its effect through prolongation of action (t1/2 upwards of 30 hours) [59].

Like cocaine, AAT are ingested through several routes of administration, and the clinical presentations of use disorder, intoxication, and withdrawal are all similar to those of cocaine. Some significant differences are worth noting. Some AAT, such as methamphetamine have a significantly longer duration of action (as above, t1/2 upwards of 30 hours) relative to cocaine’s relatively short duration of action (t1/2 around 1.5 hours) [60]. In addition, chronic use of methamphetamine is particularly correlated with significant xerostomia which can lead to noteworthy dental pathology (e.g., “meth mouth”). Chronic AAT use is also tied to significant cognitive deficits and long-lasting psychotic symptoms, both of which are attributable to amphetamine’s different mechanism of action (see below) relative to cocaine.

Methamphetamine is metabolized into amphetamine which is then further metabolized via three different metabolic pathways in the liver, unlike cocaine’s primary hepatic hydrolytic metabolic pathway. Amphetamine is readily detectable in urine, hair, sweat, blood, and oral fluids. As above, detection windows are dependent on a number of factors, but generally amphetamines are detectable in urine and oral fluids for 2–4 days post-exposure, and up to 90 days in hair. The detection window for amphetamines in blood may be only several hours, depending on amount taken. False-positive test results have been documented on amphetamine immunoassays , especially in individuals also taking buproprion, certain tricyclic antidepressant medications, quetiapine, l-methamphetamine nasal inhalers, or ephedrine/pseudoephedrine containing cold medications. Confirmatory testing via gas or liquid chromatography can provide definitive results when false positives may be suspected [31].

While cocaine exerts its pharmacological effect by blocking reuptake of catecholamines, AAT (particularly d-amphetamine and d-methamphetamine) both block reuptake and stimulate direct release of catecholamines. Both amphetamine and d-methamphetamine achieve this added pharmacologic effect on catecholaminergic neurons by a complex pathway that involves (1) co-transportation alongside sodium ions into the neuronal cytoplasm, (2) disruption of monoamine vesicular storage causing an intracellular release of catecholamine stores, and (3) increased release of synaptic catecholamines resulting from the increased intracellular availability of these chemicals. Therefore, amphetamine and d-methamphetamine are referred to as “transporter substrates ,“ [61] that, in sum, result in relatively higher synaptic release of catecholamines than cocaine. This substantial synaptic and intracellular catecholamine release may have neuronal toxic effects, which has been tied to the prolonged psychosis and significant cognitive impairments that are associated with chronic amphetamine and d-methamphetamine use [45]. In addition, chronic use of amphetamine and d-methamphetamine has been tied to decreased brain serotonin receptor density, which, in animal models has been associated with increased aggression or violence [62]. Other AATs, however, such as methylphenidate, function pharmacologically more similarly to cocaine (reuptake blockade), whereas khât (cathinone) and its synthetic derivatives (e.g., mephedrone) possess catecholamine transporter substrate and reuptake blockade activity (particularly dopamine) and also enhance synaptic serotonin release [63, 64]. Together, these findings highlight the vast diversity of compounds and their respective mechanisms of action that make up this class of drugs.

AAT use during pregnancy can present a complex set of considerations. For example, prescription psychostimulants (amphetamine, methylphenidate) can cross the placental barrier, but used as directed have not been shown to have clinically significant associations with preeclampsia, placental abruption, small-for-gestational age neonates, and preterm delivery, despite concerns about vasoconstrictive effects of these medications on placental circulation [65]. On the other hand, pregnant users of illicit methamphetamine have been shown to have greater risks of preeclampsia and gestational hypertension, fetal demise, abortion, and preterm labor [66, 67]. When taken as prescribed, methylphenidate and amphetamine levels in breastmilk are very low and risk-benefit of continued use should be discussed carefully with nursing women. While some guidelines indicate that use of prescribed psychostimulants during breastfeeding is acceptable, others do not [68].

Similar to the situation with cocaine use disorder, studies of various pharmacotherapies for the treatment of amphetamine and methamphetamine use disorders have not shown significant efficacy, such as prescription psychostimulants, tricyclic antidepressants, SSRIs, ondansetron, topiramate, and amlodipine [69]. However, a small controlled trial of mirtazapine showed significant reductions in methamphetamine use [70], as has risperidone [71], while naltrexone has shown some effect on amphetamine use but not methamphetamine [72].

Behavioral/psychosocial therapies for the treatment of AAT stimulant use disorders span the same gamut as those described above for cocaine. Of those outlined above for cocaine use disorder, however, those with supportive evidence specifically in the treatment of AAT include CBT and contingency management [73]. For some patients, the structure and programmatic organization of an intensive outpatient therapy program for stimulant use disorder may be beneficial. One way of systematically operationalizing these varied treatment approaches has been through use of the manualized Matrix Model , which incorporates educational materials on the effects of stimulant use, family education, 12-Step program participation, and positive reinforcement for behavior change and treatment compliance [74].