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Stimulant Use Disorder
NEUROBIOLOGY AND GENERAL CHARACTERISTICS
Stimulants refer to a heterogeneous class of substances with the action of stimulating the central nervous system, primarily through noradrenergic and dopaminergic effects. The stimulants discussed in this chapter include amphetamines, methamphetamines, methylphenidates, cocaine, cathinones, 3,4-methylenedioxymethamphetamine (MDMA), and over-the-counter medications such as phenylephrine and pseudoephedrine. Many stimulants share a common structure, a phenethylamine component—this is present on amphetamine, methamphetamine, cathinone, pseudoephedrine, dopamine, serotonin, and bupropion ( Table 9.1 ).
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Cocaine is an alkaloid that can be found in the leaves of the Erythroxylum genus of plants.
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Cocaine exists in two chemical forms: as a salt or base. Cocaine in powder form is typically a salt. Cocaine in base form, commonly known as “crack,” is typically smoked.
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Low-potency stimulants, such as ephedrine and phenylephrine, usually act only on noradrenergic receptors in contrast to high-potency stimulants, such as cocaine and amphetamines, which act as indirect but potent dopamine and noradrenergic receptor agonists.
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Methamphetamine has two isomers, d-methamphetamine and l-methamphetamine. D-methamphetamine has stimulant effects, and l-methamphetamine affects the sympathetic nervous system but has little activity in the central nervous system.
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Methamphetamine exists in base and salt forms. It is also more lipophilic than amphetamine, crossing the brain barrier more easily and leading to a more rapid onset of action than amphetamines.
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Variable-number tandem repeats (VNTRs) in the dopamine transporter 1 ( DAT1 ) gene is associated with cocaine- and methamphetamine-induced psychosis, as well as attention-deficit disorder.
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The presence of specific variants of the nicotinic acetylcholine receptor (CHRNB3-A6) locus on chromosome 8 reduces the response to nicotine and cocaine, causing desensitization and risk for cocaine and nicotine use disorder.
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Specific variants of the calcium/calmodulin kinase IV (CAMK4) are linked with a higher susceptibility for cocaine use disorder.
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Animals that lack the period circadian regulator ( PER1 ) gene have abnormal locomotor sensitization and conditioned preference for cocaine.
Table 9.1
Mechanism of Action and Molecular Targets of Common Stimulants
| Drug | Mechanism of Action | Molecular Target |
|---|---|---|
| Cocaine | Stimulates CNS by inhibiting presynaptic reuptake of dopamine and norepinephrine. Blocks neuronal sodium channels, accounting for its local anesthetic properties | DAT, neuronal plasma membrane transporters for norepinephrine and serotonin, and neuronal sodium channels |
| Methamphetamine | Increases release of monoamine neurotransmitters through its effects on VMAT2 in addition to some inhibition of dopamine and norepinephrine reuptake | VMAT2 DAT, and neuronal plasma membrane transporters for norepinephrine and serotonin |
| Amphetamine analogues | Similar to mechanism of action for methamphetamine | VMAT2 DAT, and neuronal plasma membrane transporters for norepinephrine and serotonin |
| Methylphenidate | Similar to mechanism of action for methamphetamine, but methylphenidate does not enhance dopamine release from synaptic vesicles | DAT, and neuronal plasma membrane transporters for norepinephrine and serotonin |
| Khat and Cathinones | Similar to mechanism of methamphetamine | VMAT2 DAT, and neuronal plasma membrane transporters for norepinephrine and serotonin |
| MDMA (3,4-Methylenedioxymethamphetamine) |
Promotes release of serotonin, dopamine, and norepinephrine into synaptic clefts; prevents serotonin reuptake; acts as agonist at serotonin, dopamine, and alpha- and beta-adrenergic receptors | VMAT2, TA1-receptor (TAAR1), serotonin (5-HT1A, 5-HT2A, 5-HT2B, 5-HT2C), dopamine (D1, D2), and alpha- and beta-adrenergic receptors |
| Pseudoephedrine | Stimulates alpha- and beta-2-adrenergic receptors, causing vasoconstriction of blood vessels and relaxation of smooth muscle in airways | alpha- and beta-2-adrenergic receptors |
| Phenylephrine | Agonist at alpha-1-adrenoceptors, causing vasoconstriction of blood vessels | alpha-1-adrenergic receptors |
| Nicotine (discussed in detail in Chapter 7) | Agonist at nicotinic acetylcholine receptors | Nicotinic acetylcholine receptors |
| Caffeine (discussed in detail in Chapter 10) | Nonselective adenosine receptor antagonist and phosphodiesterase inhibitor | Adenosine-1, adenosine-2a, and adenosine-2b receptors |
CNS, Central nervous system; DAT, dopamine transporter; MDMA, 3,4-methylenedioxymethamphetamine; VMAT2 , vesicular monoamine transporter-2.
Epidemiology of Stimulant Use Disorder
According to the National Survey on Drug Use and Health of 2018, more than 16% of people aged 26 years or older had used cocaine in their lifetime; prevalence of past-month cocaine use was 0.6% in people aged 12 years or older. One-third of people prescribed stimulants misused their prescriptions. Based on the Treatment Episode Data Set Admissions from 2017, men are hospitalized for cocaine overdoses at nearly double the rate of women, and women show higher dropout rates and more use during treatment than men. Studies have found that the 12-month prevalence of cocaine use is significantly higher among Hispanic youth when compared to non-Hispanic youth. Death from overdose due to cocaine use is more prevalent among Black individuals.
Prescription stimulant misuse prevalence ranges from 5% to 9% in grade school- and high school-aged children and 5% to 35% in college-age individuals. Cognitive performance and an improvement in attention were the most reported reasons for misusing stimulants, and the most likely source for misuse was obtaining them from relatives or friends. Among college students, the illicit use of amphetamine-dextroamphetamine is more prevalent than the illicit use of methylphenidate formulations.
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Speedballing is the action of using cocaine followed by an opioid, typically intravenously or by insufflation.
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Stimulant use can cause sexual dysfunctions during the intoxication period.
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Cocaine is metabolized via ester bond hydrolysis in the liver to form benzoylecgonine, which is the metabolite readily detectable by standard urine immunoassays for up to 2 or 3 days following last use.
STIMULANT INTOXICATION
Stimulants are used for their energizing and mood-elevating effects. In states of intoxication, they can cause unpleasant signs and symptoms summarized in the table below:
| Physiological | Psychological |
|---|---|
| Tachycardia or bradycardia Elevated or lowered blood pressure Nausea or vomiting Weight loss Psychomotor agitation or retardation Physical complications (e.g., respiratory depression, cardiac arrhythmia, cerebrovascular accident, hypertension crises, hyperthermia) Sexual dysfunction |
Anxiety Impaired memory Anhedonia Irritability Paranoia Mood swings Drug-induced psychoses Confusion |
Stimulant intoxication should be managed with supportive care, hydration, and a low-stimulus environment. If severe, medications can be used. Benzodiazepines are first-line treatment for stimulant toxicity where agitation and violence are present. Antipsychotics, such as haloperidol and olanzapine, may be added if benzodiazepines are not sufficient. Caution should be used when using antipsychotic medications due to their effect on lowering the seizure threshold. Complicated intoxication states may require airway management, fluid resuscitation, or vigorous cooling measures. Remember to assess for rhabdomyolysis and, if present, manage it using alkalinized intravenous fluids with sodium bicarbonate, agitation control, and temperature regulation.
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Beta-blockers should be avoided in stimulant intoxication to prevent unopposed vasoconstriction (alpha-adrenergic effect). If needed, labetalol can be used to manage tachycardia and hypertension due to its combined beta-/alpha-blocker effects.
Methamphetamine use is associated with higher rates of xerostomia and extensive dental disease, sometimes referred to as “meth mouth.”
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