David A. Gorelick, MD, PhD, DLFAPA , and Michael H. Baumann, PhD
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FORMULATIONS AND METHODS OF USE AND ABUSE
Cocaine
Cocaine is a tropane ester found in leaves of the coca bush, Erythroxylon coca, which grows in the Andean region of South America. Cocaine is available for illicit use in two forms: base, which has a low melting point (98°C) and vaporizes before pyrolytic destruction, allowing it to be smoked; and salt, which has a high melting point, so it is destroyed by heating. Cocaine salt is water soluble, making it easy to dissolve for injection. Regardless of chemical form, cocaine exerts the same actions in the brain and other target organs.
Ephedra
Ephedrine and pseudoephedrine are phenethylamines found in several Ephedraceae plant species. Ephedra was banned from the US market in 2006.
Khat
Khat is the common term for preparations of the Catha edulis plant, which is native to East Africa and the Arabian Peninsula. Fresh khat leaves contain at least two phenethylamine stimulants: cathinone and cathine (norpseudoephedrine). Synthetic analogues of cathinone are increasingly being misused in the form of “bath salts” (see Side Bar).
Synthetic Stimulants
More than a dozen synthetic stimulant medications are legally available in the United States, either by prescription or over the counter (OTC). Most represent variations on the phenethylamine structure.
Clinical Uses
Cocaine is used clinically in the United States as a local or topical anesthetic. Other prescription stimulants have various FDA-approved indications: attention deficit hyperactivity disorder (ADHD), narcolepsy and excessive daytime sleepiness, and weight loss. Prospective, longitudinal studies of children receiving stimulant treatment for ADHD find no increased risk of developing substance abuse. OTC stimulants generally are used for decongestion and bronchodilation or for weight loss. Oral stimulants are used for non–FDA-approved indications, for example, as quick-acting, short-term antidepressants.
Nonmedical Use, Abuse, and Dependence
Stimulants of all types are banned by the World Anti-Doping Agency and many other sports organizations. All stimulants have a potential for misuse, abuse, and dependence. Cocaine and amphetamines have high abuse potential—one in six persons who use cocaine and one in nine who use prescription stimulants for nonmedical purposes will become dependent. Those who use intravenous and smoked routes are more likely to become dependent, which is related to the faster rate of drug delivery to the brain, resulting in a faster onset of psychological effects and intense pleasurable response (the so-called “rate hypothesis”). “Binge” stimulant use involves short periods of heavy use separated by long periods of little or no use. A small number of users may use low doses daily without dose escalation over time.
EPIDEMIOLOGY
In 2011, there were an estimated 17 million cocaine users worldwide and an estimated 33.7 million nonmedical users of amphetamine-type stimulants. Cocaine is the second most widely used illegal drug in the United States, after marijuana. An estimated 821,000 Americans met psychiatric diagnostic criteria (DSM-IV) for cocaine abuse or dependence, and 511,000 people received specialty treatment for their cocaine use. Cocaine was the illicit drug associated most often with visits to hospital emergency departments, with an estimated half-million visits.
In 2011, an estimated 20.4 million Americans were nonmedical users of stimulants other than cocaine at some time during their lifetimes; 0.97 million were past-month users. An estimated 390,000 Americans met psychiatric diagnostic criteria (DSM-IV) for noncocaine stimulant abuse or dependence. There were 15,514 stimulant-related deaths among 15- to 64-year-olds in the United States from 1999 through 2009.
PHARMACOKINETICS
Absorption and Distribution
Smoked stimulants are rapidly absorbed by the lungs, reaching the brain in 6 to 8 seconds. The onset and peak effects occur within minutes. Intravenous administration produces peak brain uptake in 4 to 7 minutes. A rapid decline in drug effects is experienced as a “crash” by users of smoked or intravenous stimulants. Intranasal and oral stimulants have a slower absorption and onset of effect (30 to 45 minutes), a longer peak effect, and a gradual decline from peak. Cocaine is well absorbed through mucous membranes but less so through skin or by passive inhalation. Stimulants distribute into most tissues, including blood, urine, hair, sweat, saliva, nails, and breast milk, and across the placenta.
Metabolism
In humans, 95% of cocaine is metabolized to benzoylecgonine and ecgonine methyl ester by the action of carboxylesterases in the liver and butyrylcholinesterase in the liver, plasma, brain, lung, and other tissues. The remaining 5% is N-demethylated to norcocaine by the CYP 3A4 isozyme of the liver cytochrome P-450 enzyme system. Amphetamines are metabolized in the liver via three different pathways: deamination to inactive metabolites, oxidation to norephedrine and other active metabolites, and para-hydroxylation to active metabolites. Amphetamine is a metabolite of methamphetamine.
Elimination
Stimulants and their metabolites are largely eliminated in the urine. Benzoylecgonine is the cocaine metabolite found in highest concentration in urine for several days after cocaine use, so this substance is measured in routine urine tests for cocaine exposure.
DRUG–DRUG INTERACTIONS
The primary clinically relevant drug–drug interaction for stimulants is with other stimulants or medications that enhance catecholamine activity. A major potential for interaction is presented by monoamine oxidase inhibitors (MAOIs). Potent prescription stimulants should not be used within 2 weeks of MAOI use. Stimulants should be used cautiously in conjunction with tricyclic antidepressants, which block presynaptic reuptake of catecholamines.
PHARMACODYNAMIC ACTIONS
Central Nervous System
All stimulants produce a similar range of effects, with intensity and duration depending on potency, dose, route of administration, and duration of use. Initial effects include increased energy, alertness, and sociability; elation or euphoria; and decreased fatigue, need for sleep, and appetite. With increasing potency, dose, duration of use, or more efficient route of administration, stimulant effects often progress to dysphoric effects such as anxiety, irritability, panic attacks, hypervigilance, paranoia, grandiosity, impaired judgment, and psychotic symptoms. Tactile hallucinations are especially typical of stimulant psychosis. Associated behavioral effects include restlessness, agitation, tremor, dyskinesia, and repetitive behaviors such as picking at the skin or foraging for drug. Physiologic effects include tachycardia, pupil dilation, diaphoresis, and nausea.
Chronic cocaine or amphetamine use is associated with cognitive impairment that may persist for several months of abstinence. Chronic amphetamines use can cause a psychotic syndrome that persists for years after the last drug use, even in persons with no history of psychiatric disorders. Psychotic flashbacks have been reported in methamphetamine abusers up to 2 years after their last drug use.
The stimulant withdrawal syndrome does not have prominent physiologic features. Withdrawal symptoms generally are the opposite of those associated with stimulant intoxication.
Other Central Nervous System Effects
Stimulant use is associated with seizures, even in persons without a preexisting seizure disorder. Cocaine and amphetamine use is associated with cerebral vasoconstriction, cerebrovascular atherosclerosis, cerebrovascular disease, and stroke as well as certain movement disorders.
Cardiovascular System
Stimulants increase heart rate, blood pressure, and systemic vascular resistance, which may lead to acute myocardial infarction. Cocaine use is a factor in about one fourth of nonfatal heart attacks in persons younger than 45 years. Frequent cocaine users are up to seven times more likely to have a nonfatal heart attack than are nonusers. Cocaine use is associated with cardiac arrhythmias and sudden death.
Pulmonary
Acute respiratory symptoms develop in up to half of cocaine users within minutes to hours after smoking. Symptoms include productive cough, shortness of breath, wheezing, chest pain, hemoptysis, and exacerbation of asthma.
Gastrointestinal
Major gastrointestinal effects of cocaine include gastroduodenal ulceration and perforation, intestinal infarction and perforation, and ischemic colitis.
Endocrine
Acute cocaine use activates the hypothalamic–pituitary–adrenal (HPA) axis, stimulating secretion of epinephrine, corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and cortisol.
Musculoskeletal
Stimulants cause rhabdomyolysis by a direct toxic effect (rare except at very high doses), indirectly by vasoconstriction resulting in ischemia, and secondary to stimulant-induced hyperthermia or seizures. Up to one third of patients with rhabdomyolysis develop acute renal failure.
Head and Neck
Intranasal cocaine use is associated with chronic rhinitis, perforated nasal septum and nasal collapse, oropharyngeal ulcers, and osteolytic sinusitis. Cocaine or methamphetamine use by any route reduces salivary secretions and causes bruxism. Chronic use is associated with dental problems, including caries, cracked enamel, and loss of teeth.
Immune System
Cocaine use is associated with a variety of vasculitic syndromes primarily affecting skin and muscle. These may mimic rheumatologic conditions such as Henoch-Schönlein purpura, Steven-Johnson syndrome, or Raynaud phenomenon.
Sexual Function
Stimulants are commonly thought of as aphrodisiacs, but chronic use reduces libido and impairs sexual function. Men may experience erectile dysfunction or delayed or inhibited ejaculation. Women may develop irregular menses.
Reproductive, Fetal, and Neonatal Health
Prescription stimulants are classified by the FDA in pregnancy category C (risk cannot be ruled out because human studies are lacking). Prenatal cocaine exposure is associated with small but statistically significant impairments in sustained attention and behavioral self-regulation among preschool- and school-aged children, and in language and memory among adolescents. Cocaine and amphetamines appear in breast milk and may cause irritability, sleep disturbance, and tremors in the infant.
NEUROBIOLOGY
Molecular Mechanisms
All stimulant drugs enhance extracellular concentrations of monoamine neurotransmitters by disrupting the function of plasma membrane transporter proteins. Stimulants can be divided into two classes based on their mechanism: (1) transporter blockers and (2) transporter substrates. Transporter blockers (often called reuptake blockers), like cocaine and methylphenidate, bind to the extracellular face of transporters and inhibit the reuptake of previously released monoamine neurotransmitters. Transporter substrates (often called releasers), like amphetamine and phentermine, bind to transporters, are transported into the neuronal cytoplasm, and trigger release of intracellular monoamines by reversing the normal direction of transporter flux. Once inside the neuronal cytoplasm, transporter substrates interact with vesicular monoamine transporters to disrupt monoamine storage, thereby greatly increasing cytoplasmic concentrations of amines available for release.
Potent stimulants like cocaine and amphetamine are active at dopamine and norepinephrine transporters, whereas weaker stimulants like (−) ephedrine preferentially target norepinephrine transporters. Many stimulant drugs have nontransporter sites of action that contribute to their pharmacologic effects. Ephedrine, pseudoephedrine, phenylephrine, and phenylpropanolamine are weak agonists at alpha-adrenergic receptors, which mediate vasoconstriction (hence their use as decongestants and antihypotensive agents). Ephedrine also acts at beta-adrenergic receptors, which mediate bronchodilation.
Neural Circuits and Systems
Rewarding effects of stimulants are mediated by activation of the mesocorticolimbic dopamine system: cell bodies in the ventral tegmental area (VTA) that send axonal projections to the prefrontal cortex (PFC), nucleus accumbens, and amygdala. Mesocorticolimbic dopamine neurons are part of a complex cortical–striatal–pallidal circuitry that is involved with the selection of adaptive behavioral responses. The nucleus accumbens is a critical node in the circuitry, receiving stimulatory glutamate afferents from hippocampus, amygdala, and cortex. The primary cell type in the nucleus accumbens is the GABA-containing medium spiny neuron, which receives direct synaptic contacts from both dopamine and glutamate inputs. Natural rewards induce transient, localized changes in extracellular dopamine in nucleus accumbens that enhance stimulatory drive in spiny neurons. By contrast, stimulant drugs induce sustained supraphysiologic elevations in extracellular dopamine that cause widespread excitation of spiny neurons, and repeated drug exposure changes circuit function.
The nucleus accumbens and PFC are key sites for stimulant reward. In rodents, selective dopamine lesions or administration of dopamine receptor blockers in the nucleus accumbens, but not in other sites, abolish the rewarding effects of cocaine or amphetamine. The evidence for brain localization of stimulant effects in humans is consistent with the animal studies. Brain imaging studies using PET, SPECT, or functional magnetic resonance imaging have found stimulant-induced changes in blood flow or metabolic rate in a variety of brain regions, including frontal cortex, anterior cingulate, ventral striatum (which includes the nucleus accumbens), and amygdala. Exposure to cocaine-associated stimuli that elicit cocaine craving is associated with increased blood flow or metabolic activity in the PFC, amygdala, and anterior cingulate gyrus.
Dopamine
The cocaine-binding site on the dopamine transporter overlaps with the binding sites for dopamine and amphetamine. Acute administration of cocaine or amphetamine transiently increases brain extracellular dopamine concentrations in animals and humans. Fluctuations in extracellular dopamine and neuronal firing in the nucleus accumbens parallel cocaine self-administration. Dopamine D1 and D2/D3 receptors play reciprocal roles in the behavioral effects of stimulants. Blockade of D1 receptors in the brain reward circuit reduces the rewarding effects of cocaine or amphetamine in the rat, as does stimulation of D3 receptors.
Evidence from human brain imaging studies using PET or SPECT is largely consistent with an important role for dopamine in the acute psychological effects of stimulants. The acute euphoria or “high” response to cocaine or methylphenidate correlates in time course and intensity with drug concentration in the brain, with dopamine transporter occupancy, and with extracellular dopamine release in the striatum. Exposure to cocaine-associated cues is associated with dopamine release in the striatum.
Norepinephrine
Cocaine, amphetamines, methylphenidate, phentermine, and ephedrine enhance norepinephrine neurotransmission by acting at norepinephrine transporters. Intravenous cocaine increases plasma norepinephrine and epinephrine concentrations within minutes of injection. There is a significant positive correlation between potency of norepinephrine release and the oral stimulant dose that produces stimulant-like subjective effects in humans. Chronic cocaine exposure increases norepinephrine transporter function in monkey and human brain.
Serotonin
Knockout mice lacking the serotonin transporter still find cocaine rewarding, whereas double knockout mice lacking both the dopamine and serotonin transporters do not. Knockout mice lacking both the norepinephrine and serotonin transporters show increased sensitivity to cocaine reward. These findings suggest a permissive, but not obligatory, role for the serotonin transporter in cocaine reward.
Endogenous Opiates
Stimulants do not act directly on opiate receptors but do influence endogenous opiate systems in the brain. Human cocaine users show increased mu opiate receptor binding in some brain regions with PET scanning, and this increased binding correlates with self-reported cocaine craving.
Glutamate
The acute administration of cocaine or amphetamine increases glutamate release in the ventral tegmental area, nucleus accumbens, dorsal striatum, ventral pallidum, septum, and cerebellum. Low doses of cocaine enhance glutamate-evoked neuronal firing. Chronic cocaine treatment produces persisting changes in nucleus accumbens glutamate transmission and a marked decrease in nonsynaptic extracellular glutamate levels. Treatment with the prodrug N-acetylcysteine restores extracellular glutamate to normal levels and attenuates reinstatement of extinguished cocaine-seeking behavior.
Other Actions
Amphetamines and phentermine inhibit monoamine oxidase, but this action probably is not significant at the drug concentrations achieved clinically. Cocaine is unique in also blocking voltage-gated membrane sodium ion channels. This action accounts for its effect as a local anesthetic and may contribute to cardiac arrhythmias.
Signal Transduction
Stimulants activate several intracellular signaling pathways within neurons of the brain reward circuit, including cAMP, extracellular signal-regulated kinase, mitogen-activated protein kinase, and phosphoinositide-3-kinase.
Gene Expression
Acute administration of stimulants to rodents promptly activates several “immediate early” genes in the brain, such as cAMP response element-binding protein (CREB), c-fos, zif268, and c-jun. Repeated administration of stimulants results in a long-lasting blunting of the gene activation effect in many brain regions. Chronic stimulant administration leads to accumulation of some transcription factors, which may mediate the development of sensitization.
Neuroadaptation
Repeated exposure to stimulants results in two distinct neuroadaptations: sensitization (increased drug response) and tolerance (decreased drug response). Behavioral sensitization to stimulants has been suggested as a mechanism for drug craving and relapse and for stimulant-induced psychosis, but neither has been directly demonstrated in humans. Tolerance to the behavioral, cardiovascular, hyperthermic, and lethal effects of stimulants has been demonstrated in animals after high-dose, frequent, or continuous administration. Stimulant tolerance dissipates after 7 to 14 days of no exposure. There is significant cross-tolerance among various stimulants but not between stimulants and other drug groups, such as opiates.
Stimulant tolerance is pharmacodynamic rather than pharmacokinetic; chronic stimulant exposure does not cause substantial changes in stimulant pharmacokinetics. In clinical use, patients typically become tolerant to the appetite-suppressing effects of stimulants within several weeks of daily use, whereas the beneficial effects in narcolepsy or ADHD remain over months of treatment.
Neurotoxicity
In animal studies, transporter blockers like cocaine and methylphenidate do not produce neurotoxicity in dopamine or serotonin neurons. In contrast, high doses of transporter substrates like amphetamine or methamphetamine produce substantial dopamine and serotonin neurotoxicity, probably because these drugs enter nerve terminals and increase production of reactive oxygen species. Such neurotoxicity in human users has not been conclusively demonstrated.
ACKNOWLEDGMENTS
Dr. Baumann is supported by the Intramural Research Program, National Institutes of Health, National Institute on Drug Abuse.
KEY POINTS
1. All stimulants produce a similar range of effects, including increased energy, alertness, and sociability; elation or euphoria; and decreased fatigue, need for sleep, and appetite.
2. The acute euphoria or “high” response to cocaine or methylphenidate correlates in time course and intensity with drug concentration in the brain, with dopamine transporter occupancy, and with extracellular dopamine release in the striatum.
3. Those who use intravenous and smoked routes are more likely to become dependent, which is related to the faster rate of drug delivery to the brain, resulting in a faster onset of psychological effects and intense pleasurable response.
REVIEW QUESTIONS
1. The primary enzyme that metabolizes cocaine in humans is:
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