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A drug is a chemical substance produced exogenously (outside of the body) that, when taken into the body, changes normal body functions. Psychologists are very interested in psychoactive drugs that change central nervous system (CNS; brain and spinal cord) activity, and thereby affect perception, thought, emotion, and behavior. Although people use many psychoactive drugs for acceptable medicinal reasons (see Chapter 18), this research-paper focuses on those psychoactive drugs that people use primarily for recreational, nonmedicinal reasons (e.g., to feel good, be more alert, alter or avoid reality). An adult drinking alcohol to relax or smoking cigarettes to stop the jitters are examples of recreational use of licit (legal) drugs in this country, and smoking crack to feel euphoric or injecting heroin for the “rush” are examples of illicit (illegal) recreational drug use. Most of the information about how drugs make a person feel come from self-reports of licit and illicit users of drugs, whereas most of the data about how the body affects drugs and how drugs work in the brain comes from well-controlled experimental studies using nonhuman animals (see Chapter 15).
Drug Use, Misuse, Abuse, And Addiction
With pills to treat everything from the symptoms of the common cold to the positive symptoms of schizophrenia, drug use is prevalent in the United States, and pharmaceuticals are a multibillion-dollar industry. Nonetheless, society sends mixed messages about drug use, with commercials warning against the evils of illicit drug use and advertisements offering wonder treatments in a “purple pill.” Drugs in and of themselves are not “evil,” but every drug can be misused and abused. Misuse generally refers to the deviation from instructions on the label of over-the-counter drugs or the doctor’s instructions for prescription drugs. For example, taking more or fewer pills per dose or day, not using the drug the full time course as prescribed (e.g., antibiotics), using the drug past the expiration date, using the drug with other drugs (e.g., alcohol with barbiturates), or sharing prescriptions with others without a doctor’s permission are all forms of drug misuse. Although most of these acts may not seem very serious, they all can lead to very dangerous, even deadly, consequences (e.g., alcohol with other drugs, especially other CNS depressants). Drug abuse, which also can occur with licit and illicit drugs, refers here to use of a psychoactive substance to the extent that it produces some sort of physical, cognitive, behavioral, or social impairment. Keep in mind, how-ever, that the public often thinks of drug abuse as specific to illicit drugs like methamphetamine, cocaine, heroin, and LSD (lysergic acid diethylamide), even though alcohol, for example, is a licit drug that people can abuse. What follows is an introduction to the use, misuse, and abuse of psychoactive drugs and their effects on behavior, beginning with how drugs enter the body and what happens to them once they do.
Drug Administration, Absorption, Metabolism, And Excretion
Pharmacokinetics is the study of how drugs are absorbed into the body, metabolized once in the body, and excreted from the body. The goal of drug absorption is for the drug to circulate in the blood, and more specifically for a psychoactive drug, the goal is for it to circulate in the brain. Administration for the purpose of absorption in blood and brain can take various forms depending on type of substance (lipid soluble vs. water soluble, gaseous vs. solid) and desired rate of absorption (rapid vs. slow, acute vs. continuous). Most humans administer drugs either orally (swallowed by mouth), sublingually (substance placed under the tongue), subcutaneously (injecting under the skin), intramuscularly (injecting into muscle tissue), intravenously (injecting directly into the bloodstream via a vein), transdermally (applied to outer layer of skin), intrarectally (using suppositories), intranasally (sniffed into the nostrils), or by inhalation (breathing gases and solids into the lungs). Intraperitoneal (into the peritoneal cavity), intraventricular (via a cannula into the ventricles of the brain), and intracranial (directly into a target area of the brain) injections are forms of administration used mostly in research with laboratory animals. Psychoactive drugs administered directly into the brain will have the most rapid effects because they will reach their CNS sites of action most quickly. Drugs administered through all other routes must be lipid-soluble in order to get through the formidable solid lipid barrier of the brain known as the blood brain barrier (BBB). Provided the psychoactive drugs administered directly into the bloodstream can pass the BBB, they will reach their CNS sites of action relatively quickly. Inhalation results in fast absorption into the bloodstream because gases and drugs in smoke (e.g., nicotine) are readily absorbed into the intricate network of capillaries that line the large surface area of the elaborately pocketed lungs. Although swallowing a pill is a simple, common method of drug administration, absorption is a tenuous process. Drugs taken orally must survive the harsh environment of the digestive system (e.g., stomach acids and digestive enzymes). Rates of absorption via other routes of administration are somewhere between those of inhalation and oral administration, depending somewhat on the availability of capillaries at the site of administration. Users of psychoactive drugs choose their favorite drug partially because of how quickly the drug exerts its psychoactive effects. For example, heroin is the preferred drug for some opiate addicts because it is more lipid soluble, is absorbed into the brain faster, and produces a faster, more intense “rush” than morphine does.
Before drugs can stop working in the body, they must be either broken down into other substances (metabolized) or removed from the body (excreted). Enzymes in the liver metabolize most of the psychoactive drugs described in this research-paper into less lipid-soluble chemical products (metabolites). Some metabolites have their own effects on the body and brain. Several variables affect the rate of metabolism, including species, genetics, age, drug experience, and drug interactions. Regarding the latter, some drugs will inhibit or enhance the activity of enzymes responsible for metabolizing certain drugs—for example, SSRI-type antidepressants like fluoxetine inhibit some of the enzymes responsible for metabolizing codeine into the active analgesic morphine.
Subsequent to metabolism and recirculation in the blood, the kidneys excrete the more water-soluble metabolites from the body in urine, although there is excretion of small amounts of the drugs and their metabolites in exhaled breath, sweat, saliva, feces, and breast milk. Not surprisingly, urine drug tests are frequently used to determine the presence of metabolites sometime after the metabolism of the original drug, rather than the presence of the original drug at time of administration.
How Drugs Work In The Brain
Pharmacodynamics is the study of how drugs work in the body. Psychoactive drugs work in the CNS. The brain (see Chapter 13) is made of supporting glial (fat) cells and excitable neurons. Neurons are responsible for the electrochemical transmission of information, enabling cells to communicate with one another. The structure and arrangement of neurons allows for the transmission, integration, storage, and interpretation of information received via sensory receptors, as well as the control of bodily organs and muscles. In other words, these specialized cells (neurons) are responsible for everything we think, feel, and do.
Psychoactive drugs work in the brain primarily by affecting neurotransmitter activity at the synapses (see Chapter 14). Neurons produce neurotransmitters that are stored in vesicles within the terminal buttons. When an action potential reaches the terminal buttons, vesicles release the neurotransmitter into the synaptic cleft. Neurotransmitter molecules then briefly bind to postsynaptic receptors causing ion channels to open, letting ions enter or exit, resulting in either excitatory or inhibitory postsynaptic potentials. Once released from the postsynaptic receptors, the neurotransmitter molecules undergo reuptake into the presynaptic terminal button or are destroyed by enzymes in the synaptic cleft. The effect of psychoactive drugs on synaptic activity can occur anywhere in the process of neurotransmitter production, storage, release, receptor binding, and reuptake or degradation.
More specifically, the administration of neurotransmitter precursors can increase the amount of neurotransmitter molecules available in the brain. For example, physicians prescribe L-DOPA, the precursor of dopamine, to patients with Parkinson’s disease in order to increase levels of dopamine in the brain. Other drugs can destroy or block the enzymes necessary for conversion of the precursors into neurotransmitters (e.g., p-chlorophenylalanine, PCPA, prevents the synthesis of serotonin). The vesicles that house neurotransmitters also can be the target site of drugs. Reserpine, occasionally used to treat high blood pressure, interferes with the transporter molecules that fill vesicles with neurotransmitters, thereby leaving the vesicles empty with no neurotransmitter available for release. A common target site of psychoactive drugs is the postsynaptic receptors where neurotransmitters bind. Drugs that bind to receptors and mimic the actions of a particular neurotransmitter are direct agonists (e.g., nicotine binds to nicotinic acetylcholinergic receptors). Drugs that bind to receptors without stimulating the receptor and prevent neurotransmitter molecules from occupying the receptor binding sites are direct antagonists (e.g., curare causes paralysis by binding to acetylcholinergic receptors). There are also drugs that work as agonists or antagonists by binding to sites other than where the neurotransmitter molecule binds (noncompetitive sites). Finally, drugs can affect what happens to neurotransmitters after they are released from their receptors by interfering with either the enzymes that break the neurotransmitters down (e.g., physostygmine deactivates the enzyme acetylcholinesterase, which breaks down acetylcholine) or reuptake mechanisms (e.g., cocaine deactivates the dopamine reuptake transporters).
Each type of neurotransmitter binds to a specific set of receptors that typically bear their own name (e.g., dopamine to dopaminergic receptors). The set of receptors belonging to a specific neurotransmitter can have quite different reactions to the neurotransmitter. Various drugs bind to receptor sites with different strengths, and may selectively bind to just one or a few receptor subtypes or nonselectively bind to multiple receptor subtypes. The selective serotonin reuptake inhibitors (SSRIs), used as antidepressants (see Chapters 18 and 89), bind specifically to receptor sites on the presynaptic serotonin reuptake pumps. Recent technological advances have allowed scientists to isolate the unique subtypes of receptor proteins, such that they can produce large quantities of each of the specific receptor proteins and then test the affinity of new drugs at each of the receptor subtypes. Drugs that bind to only a very specific receptor subtype or have greatly enhanced affinities for very specific subtypes of receptors will have fewer side effects as compared to drugs that bind less discriminately to an entire set of receptors. A good example is the drugs used to treat Parkinson’s disease. Some of the older drugs (e.g., bromocriptine) that are structurally more similar to dopamine have more negative side effects than the newer developed drugs (e.g., ropinerole) that have more discriminate receptor affinity for D3 than D2 receptors.
Clearly, not all drugs are equal. Scientists who study drugs, pharmacologists, typically measure many participants’ responses to doses so low that they cause no measurable effect to doses so high that they cease to cause any additional effect. They then plot the number (or percent) of participants who respond to the drug at each of the doses tested (dose response curve). The plot indicates the drug’s potency (number of drug molecules required to elicit a given response), efficacy (the maximum effect of the drug, with additional amounts resulting in no increase in response), and variability (individual differences in responsiveness to the drug).
Drug Safety And Toxicity
The federal Food and Drug Administration (FDA) has extremely specific guidelines in place for the testing of a new drug’s effectiveness and safety (for more about the FDA’s Office of Drug Safety go to http://www.fda.gov/ cder/Offices/ODS/default.htm/). Safety refers to the drug’s potential to produce everything from predictable, tolerable, unpleasant side effects to unpredictable, intolerable, severe toxicities. Unfortunately, all drugs have multiple effects, with some effects less desirable. Given that undesirable side effects are unavoidable, the goal is the most favorable combination of the most desired drug effects and the least unwanted side effects. The ED is the effective dose that produces the desired effect in 50 percent of the participants. The LD50 is the lethal dose that produces death in 50 percent of the subjects. Typically, the ED50 and LD50 are determined in several species and over many trials to reduce the risk of toxicity in humans. The greater the distance between the ED,„ and LD,„ the less the risk of drug-induced toxicity at beneficial dosages. The margin of safety is the ratio of LD1 to ED99 (effective dose in 99 percent of the participants). Ratios of one or greater suggest greater safety. Be cautious, though—this margin of safety is under the best of controlled testing conditions, far from the circumstances under which many humans may take the drug (e.g., mixing drugs). One drug can alter the effects of another drug in many different ways. A second drug can have an additive effect, a synergistic effect (a greater effect than would be expected when just adding the two drugs), or an antagonistic effect (the second drug reduces or blocks the effect of the target drug). Even drugs not meant to have any effect (placebos) can influence a target drug’s effects because of the user’s expectations.
Tolerance, Dependence, And Withdrawal
Tolerance is the need to take increasing doses of a drug in order to achieve the same effects as previously achieved with lower doses. Likewise, when the same dose of drug has less and less of an effect with repeated administrations, tolerance has occurred. A good example is the tolerance that some people have for the caffeine in coffee. A novice coffee drinker may feel the stimulatory effects of coffee after a single cup of coffee containing about 100 mg of caffeine. After drinking coffee daily for a few weeks, it may take two or three cups of caffeinated coffee to feel that same excitation. There are several types of tolerance including metabolic tolerance, cellular tolerance, and behavioral tolerance. Metabolic tolerance occurs when, with repeated administrations of the drug, the body produces more and more metabolic enzymes, thereby speeding up the rate of metabolism of that drug. Thus, one must take more and more drug with each administration to maintain the same concentration of drug in the body as during previous episodes. Cellular tolerance is down regulation (reduction in numbers) of the receptors in the brain or reduced sensitivity of those receptors to the drug because of the continuous or repetitive presence of the drug. The result is the need for more drug in order to get the same level of effect in the brain. Behavioral tolerance involves learning (see Chapters 33 and 34). Behavioral tolerance can be observed in the presence of conditioned drug-taking cues and be absent in novel environments or situations. The drug serves as the unconditioned stimulus (US) and the drug effect as an unconditioned response (UR). Drug administering paraphernalia (e.g., white uniform, syringe and needle, bong and roach clips) and a specific location (e.g., doctor’s office, nightclub, crack house) where the drug is administered can serve as conditioned stimuli (CSs) that, when paired with the drug (US), come to elicit conditioned responses (CRs) that are similar to the UR or opposite the UR (compensatory responses). For example, when Siegel (1975) gave rats morphine (US), they showed reduced sensitivity (UR analgesia) to heat applied to their paws, but with repetitive administrations of morphine in the presence of the same environmental cues (CS), the rats showed increased sensitivity (CR hyperalgesia) to those environmental cues.
A drug may develop different types of tolerance, and to all, some, or none of its effects. Some effects of a drug may even show acute tolerance, which occurs during a single administration of the drug. As a drug is absorbed into the blood, there is a gradual increase in the blood drug concentration, the ascending portion of the blood concentration curve. As long as drug administration has ceased, the blood concentration will eventually reach a peak level. When more metabolism than absorption is occurring, the concentration of drug in the blood begins to decline, depicted as the descending portion of the blood concentration. Acute tolerance is evident when, during a single administration, the measured effect is stronger on the ascending portion of the blood concentration curve than at the same concentration on the descending portion of the curve. Some effects of alcohol show acute tolerance in humans and rats. Finally, cross-tolerance is tolerance that occurs to one specific drug and subsequently tolerance occurs to the first administration of a different drug.
Drug dependence sometimes accompanies tolerance but does not require it. Dependence exists when a person must continue taking a drug in order to function normally and avoid the symptoms of withdrawal (physiological changes associated with the cessation of the drug). In other words, to determine dependence requires one to stop taking the drug. Physical dependence signifies that the body has adjusted physiologically to the repeated or continued presence of the drug. Removing the drug upsets the balance the body has established with the drug present, and results in often-unpleasant symptoms opposite those produced by the drug (e.g., heroin causes constipation whereas withdrawal from heroin causes diarrhea). Interestingly, long-term alcohol consumption can produce considerable tolerance without causing physical dependence; however, abstention from chronic alcoholism can cause life-threatening tremors, nausea, seizures, and delirium. Although the public tends to associate aversive withdrawal symptoms with drug “addiction” (e.g., chills, runny nose, fever, increased sensitivity to pain with opiate addiction), dependence and withdrawal are not unique to illicit drugs. Many legally prescribed and appropriately used therapeutic drugs result in dependence (e.g., SSRI-type antidepressants). It takes the body from several days to several weeks to readjust to the absence of a previously administered drug that has produced dependence. Thus, physiological dependence and withdrawal promote drug-taking behaviors, as people continue to take the drug, at least partially, to avoid the terrible effects of withdrawal. Several drugs that do not cause physiological dependence (e.g., cocaine, marijuana) do, however, produce psychological dependence. That is, an individual may be dependent on a drug for its pleasurable effects (i.e., positive reinforcement). Rats prefer to lever press for cocaine over food, even to the point of starvation.
Specific Psychoactive Drugs
Psychoactive agents are categorized a number of different ways. For example, drugs are categorized according to their chemical structure (e.g., amphetamines), whether they are legal or illegal (e.g., caffeine and nicotine vs. cocaine and amphetamines), how they affect the CNS (e.g., stimulants and depressants), and the type of behavioral, affective, and/or cognitive effects they produce (e.g., hallucinogens, analgesics). What follows is a description of a few of the most well-studied drugs with emphasis on the use of the drug; behavioral, cognitive, and mood-related effects of the drug; and the CNS mechanisms by which the drug produces its effects on behavior.
Stimulants produce behavioral excitation, increased motor activity, and increased alertness by enhancing excitation at neuronal synapses. The most commonly used stimulants include caffeine (a xanthine), nicotine, amphetamines, and cocaine. Many consider caffeine and nicotine to be “minor” stimulants and amphetamines and cocaine to be “major” stimulants. These stimulants have medicinal purposes, but most people are more familiar with their recreational uses. Stimulants vary greatly in the degree to which they affect behavior and in their potential for dependence and abuse.
Xanthines are a family of stimulants that includes caffeine, theobromine, and theophylline, the most widely used stimulants in the world. Caffeine is in many products (e.g., over-the-counter medications, baked goods, candy) but most commonly is associated with coffee and soft drinks. Tea contains caffeine, theophylline, and trace amounts of theobromine, and both caffeine and theobromine are in chocolate. Caffeine and theophylline are approximately equal with regard to stimulatory effects, but theobromine is only about one-tenth as strong as the other two.
How much caffeine is in coffee depends on the type of coffee bean (coffea robusta having twice the caffeine content of coffee Arabica) and how it is brewed (caffeine in a 5-ounce cup: instant about 60 mg, percolated about 85 mg, drip-brewed about 112 mg). Caffeine content in 12-ounce soft drinks ranges from about 38 mg (Diet Pepsi) to 54 mg (Mountain Dew), and as high as about 110 mg in special “energy” sodas (Red Bull). A 5-ounce cup of medium brewed black tea has about 60 mg of caffeine, and a strong brew of tea contains as much as 100 mg of caffeine. A 5-ounce cup of brewed tea contains a much smaller amount of theophylline (< 1 mg). A 1-ounce piece of milk chocolate contains 1 to 6 mg caffeine and about 40 mg of the 10 times less stimulating theobromine. There is 75 to 150 mg of xanthines in a cup of hot cocoa, and cocoa products contain enough caffeine and theobromine to affect behavior.
Orally consumed caffeine is absorbed in the stomach and mostly intestines, with peak blood levels occurring at 30 to 60 minutes. Caffeine easily crosses the blood brain and placenta barriers. Some foods, alcohol, smoking, hormones, age, and species affect the metabolism of caffeine. Xanthines are antagonists at adenosine A1 and A2a receptors, affecting the release of several neurotransmitters. When activated by adenosine, receptors located on pre-synaptic terminals inhibit spontaneous and stimulated neurotransmitter release. By blocking activation of adenosine receptors, xanthines lead to increased neurotransmitter release and increased excitation. At high concentrations, xanthines also block benzodiazepine receptors located on the GABA receptor complex, which may account for some of the increased anxiety after consumption of enormous amounts of coffee. Because outside of the CNS theophylline is particularly good at causing smooth muscles to relax, theophylline is useful therapeutically to dilate the bronchi of the lungs in the treatment of asthma.
Often people consume products containing moderate levels of caffeine because of their subjective experiences of increased alertness, improved attention, reduced fatigue, and more clear cognition. Experimental evidence suggests the most prominent effect of caffeine is enhancing performance of noncognitive tasks, like athletic and perceptual tasks, by reducing fatigue and boredom (see review by Weiss & Laties, 1962). Additionally, caffeine augments brainstem reflexes, enhances some visual processing, improves reaction time and self-reported alertness, reduces the detrimental effects of sleep deprivation on psychomotor performance, increases wakefulness, and produces insomnia.
Tolerance develops to some of the subjective effects of caffeine. Small and moderate, but not large, doses of caffeine appear to have reinforcing properties. Most people manage their caffeine intake, avoiding the anxiety, tremors, rapid breathing, and insomnia associated with high doses of caffeine. Within 12 to 24 hours of cessation, caffeine withdrawal often causes mild to severe headaches, drowsiness, muscle aches, and irritability, suggesting caffeine has some potential for producing limited physiological dependence. However, after reviewing caffeine studies, Nehlig (1999) concluded that caffeine does not affect the dopaminergic CNS centers for reward and motivation, as do cocaine and amphetamines.
Nicotine is one of the most-used psychoactive drugs in the world. The primary psychoactive active ingredient in tobacco is nicotine. According to the 2005 National Survey on Drug Use and Health (Department of Health and Human Services, 2006), about 71.5 million Americans (> 12 years old) used a tobacco product within the previous month. Only 30.6 percent of full-time college students ages 18 to 22 reported using in the previous month, as compared to 42.7 percent of same-aged part-time and noncollege students. Many of the toxic chemical compounds, other than nicotine, in tobacco products are the source of serious health problems (e.g., emphysema, chronic lung disease, cancer, cardiovascular disease) and death.
Nicotine is easily absorbed into the body. When inhaled, nicotine in cigarette smoke particles (tar) is quickly absorbed into the bloodstream via the capillaries lining the lungs. Smokers experience a sudden “rush” with that first cigarette of the day because the nicotine-saturated blood rapidly reaches the brain and crosses the BBB. Even though cigarettes contain about 0.5 to 2.0 mg of nicotine, smokers absorb only about 20 percent of that nicotine into blood. Smokers easily avoid nicotine toxicity by controlling the depth and rate of smoke inhalation. The liver metabolizes about 90 percent of the nicotine in the bloodstream before excretion. Urine tests measuring nicotine’s major metabolite cotinine do not distinguish between tobacco use and environmental exposure.
Nicotine is an agonist at acetylcholinergic nicotinic receptors. Peripherally, nicotine’s activation of receptors increases blood pressure, heart rate, and adrenal gland release of adrenaline. Nicotine activation of CNS nicotinic receptors located on presynaptic terminal buttons facilitates release of dopamine, acetylcholine, and glutamate throughout the brain. Physiological and psychological dependence of nicotine is due to nicotinic-induced release of dopamine from neurons projecting from the ventral tegmental area to forebrain regions (mesolimbic system) and prefrontal cortex (mesocortical system), brain areas responsible for reinforcement. Nicotine-induced release of acetylcholine is the likely cause of improved cognition and memory, as well as increased arousal. Increased glutamatergic activity due to nicotinic presynaptic facilitation contributes to enhanced memory of nicotine users.
Plenty of evidence exists regarding nicotine’s facilitating effects on cognition and memory in humans and animals (for reviews see Levin, McClernon, & Rezvani, 2006; Levin & Simon, 1998). Individual differences in the cognitive effects of nicotine may be due to genetic variations in dopaminergic activity. Nicotine administered via a patch to adult carriers of the 957T allele (alters D2 receptor binding in humans) impaired working verbal memory performance and reduced processing efficiency in brain regions important for phonological rehearsal (Jacobsen, Pugh, Mencl, & Gelernter, 2006). Additionally, nicotine stimulates activity in brain regions involved in attention, motivation, mood, motor activity, and arousal.
Tolerance appears to develop to the subjective mood effects of nicotine, but not to nicotine-induced changes in physiology or behavioral performance (for review see Perkins, 2002). However, most smokers do develop both physiological and psychological dependence on nicotine. Typically, withdrawal from cigarettes causes intense persistent cravings, irritability, apprehension, irritation, agitation, fidgeting, trouble concentrating, sleeplessness, and weight gain. Even people deprived of smoking just overnight report higher stress, irritability, and lower pleasure (e.g., Parrott & Garnham, 1998). Abstinence symptoms can last for several months, and many smokers find the cravings to be so intense that they relapse. It is common for smokers to quit smoking many times. Decreased activity in reward brain areas (e.g., dopaminergic mesolimbic system) that occurs during nicotine withdrawal may be responsible for the motivation of cravings, relapse, and continued smoking.
In 1932 amphetamine, a synthetic drug similar in structure to ephedrine, was patented. That amphetamine is a potent dilator of nasal and bronchial passages easily administered as an inhalant made it a viable treatment for asthma in the early 1900s. During World War I and World War II, governments gave amphetamines to soldiers to prevent fatigue and improve mood. Subsequently, college students used amphetamines to stay awake studying for exams, and truck drivers for staying awake on cross-country hauls. It did not take long for word to spread that amphetamines (speed) caused euphoria, quickly making them an abused recreational drug. As Schedule II drugs, amphetamines have high potential for abuse and dependence, but also have accepted medicinal use with strict restrictions. Currently, treatments for narcolepsy and attention deficit hyperactivity disorder (ADHD) are accepted uses of amphetamines and amphetamine-like drugs (methylphenidate).
Amphetamines are a group of similarly structured synthetic chemicals that cause euphoria and behavioral stimulation. The d form of amphetamine is more potent than the 1 form. Administration is typically oral for current medicinal purposes, and inhalation or injection with a freebase form of methamphetamine (ice, crank) for a faster recreational “rush.” Amphetamines easily cross the BBB and readily disperse throughout the brain. The liver metabolizes about 60 percent of methamphetamine, amphetamine being the major active metabolite, and then the kidneys excrete the metabolites and unchanged methamphetamine.
Amphetamines work both in the periphery and in the CNS. In the CNS, these drugs increase activity at synapses that release epinephrine, norepinephrine, and dopamine by either causing the neurotransmitters to leak out of their vesicles into the synaptic cleft and/or blocking reuptake into presynaptic terminal buttons. Recreational users typically prefer methamphetamine to other amphetamines because it has fewer unpleasant peripheral effects (e.g., increased heart rate, increased blood pressure, dry mouth, headaches) and stronger, longer-lasting CNS.
Amphetamines improve mood, decrease fatigue, increase vigilance, energize, impair ability to estimate time, and diminish the desire for food and drink. “Fen-Phen,” a combination of fenfluramine and the amphetamine phentermine, was widely prescribed as an effective appetite suppressant in the 1990s, at least until it was removed from the market in late 1997 because of its association with heart valve problems and lung disease. Most of the performance-enhancing effects of amphetamines are limited to tasks that are routine, well-rehearsed, and well-practiced activities. Intravenously or intranasally administered high doses of amphetamine cause a “rush” of intense exhilaration and pleasure. The euphoria and strong reinforcing properties of amphetamines are due to increased dopamine activity in the mesolimbic system. Increased repetitive movements (stereotypy in laboratory rats) and behaviors (punding in humans) to the exclusion of eating, grooming, and sleeping are probably due to amphetamine stimulation in the nigrostriatal dopamine system. High acute doses and chronic use probably over stimulate the mesolimbic dopamine system, producing violently aggressive paranoia and amphetamine psychosis, delusions, hallucinations, and a split from reality. The sensation that insects are crawling under the skin (formication) may be the basis for the self-mutilation observed in laboratory animals. Long-term chronic use of methamphetamines is particular neurotoxic, leading to irreversible brain damage and psychosis.
Acute and chronic tolerance to amphetamines’ desired effects of enhanced mood and euphoria occurs rapidly. The positively rewarding feelings associated with intravenously injected amphetamine, especially methamphetamine, leads to overwhelming psychological dependence. Physiological dependence on amphetamines is evident from the withdrawal symptoms of ravenous hunger, fatigue, lethargy, depression, and suicidal tendencies. Many of the characteristics of amphetamines are similar to those of cocaine.
For thousands of years, the natives of the South American Andes have increased endurance and stamina as they traveled the harsh mountain terrain by chewing the leaves of the coca plant. The plant became of interest to Europeans and Americans in the mid to late 1800s when entrepreneurs began adding the extract of the coca leaves to many products (e.g., wine, nerve tonics, home remedies, teas, and colas). In the 1860s Dr. W. S. Halstead discovered cocaine’s local anesthetic properties. Because cocaine is readily absorbed in mucous membranes, it is still a local anesthetic of choice in some surgeries (e.g., nasal, esophageal). Currently, U.S. federal law categorizes cocaine as a Schedule II drug (high potential for abuse and dependence, but has currently accepted medicinal use with strict restrictions). In 2005 an estimated 2.4 million people were using cocaine, and about 2,400 persons per day used cocaine for the first time (Department of Health and Human Services, 2006).
Cocaine administration takes several forms, all with fairly quick but short-lived results (1 to 2 hours’ duration). Users snort the powdered hydrochloride salt form of cocaine, and when they dissolve that in water, they can inject the drug. In the 1970s users developed a smokeable free-base form of cocaine by extracting the hydrochloride with the very volatile gas ether. The safer smokeable rock crystal crack cocaine forms when producers treat cocaine with baking soda and water. The crack user inhales the vapors as the rock heats and makes a crackling sound. When inhaled, cocaine is rapidly absorbed by capillaries in the lungs, whereas snorted cocaine hydrochloride is absorbed more slowly into mucous membranes. Cocaine readily crosses the BBB and quickly distributes throughout the brain, where it remains for as long as 8 hours. The major metabolite benzoylecgonine is inactive and, when excreted by the kidneys in urine, is detectable for 48 hours, even as long as 2 weeks in chronic cocaine users. Cometabolism of cocaine and alcohol produces the pharmacologically active, longer-lasting, and toxic metabolite cocaethylene.
Cocaine blocks presynaptic reuptake transporters for dopamine, epinephrine, norepinephrine, and serotonin. This blockade prolongs the presence of these neurotransmitters in the synapse, allowing the neurotransmitters to bind repetitively to postsynaptic receptors. Cocaine’s enhancement of dopaminergic activity in the reward/reinforcement centers of the brain (e.g., the nucleus accumbens and other mesolimbic systems) is responsible for the highly addictive nature and powerful psychological dependence of cocaine. Serotonin receptors also play a role in the reinforcing effects of cocaine.
Cocaine is an extremely addictive psychostimulant that in low to moderate doses produces euphoria and increases alertness, mental acuity, self-consciousness, talkativeness, and motor behavior. Moderate to high doses cause more intense confusion, agitation, paranoia, restlessness, tremors, and seizures. Chronic use of cocaine produces impulsive and repetitive behavior. High-dose cocaine use can cause cocaine-induced psychosis characterized by extreme agitation and anxiety; exaggerated compulsive motor behaviors; delusions of paranoia and persecution; visual, auditory and tactile hallucinations; loss of touch with reality; and permanent brain damage. Medical risks associated with cocaine use include increased risk of cerebral ischemia, intracranial bleeding, heart attack and heart complications due to cocaine’s vasoconstrictive proper-ties, respiratory failure, strokes, seizures, and risks with snorting that include nasal lesions, perforations, bleeding, and infections.
Tolerance to cocaine’s effects and physiological dependence to high doses of cocaine can occur. Regarding withdrawal syndrome, as the stimulatory CNS effects of cocaine subside, the user experiences depression, anxiety, lingering sleepiness, boredom, reduced motivation, and an intense craving for the drug. Much more powerful is the development of psychological dependence, because of cocaine’s strong reinforcing properties, and therefore relapse.
Depressants decrease CNS neuronal activity such that behavior is depressed, anxiety is lessened, and sedation and sleep are increased. This group of drugs includes barbiturates, benzodiazepines, some abused inhalants, and alcohol. Many of these drugs work at the GABA receptor complex, and all have potential for misuse, abuse, and dependence. The focus here is alcohol; see Chapters 18 amd 89 for discussion of the depressants used in pharmacotherapy.
Alcohol (ethanol) is a CNS depressant used throughout the world and history. In the United States, alcohol sales are an important part of the economy, with Americans spending over a hundred billion dollars annually on beer, wines, and distilled liquors. Based on alcohol sales in the Unites States, total ethanol consumption in 2004 was 377,002,000 gallons, including 4,368,000 gallons of ethanol and 97,065,000 gallons of beer (National Institute on Alcohol Abuse and Alcoholism, n.d.). Alcohol consumption in the United States costs in terms of increased risky behavior, injuries on the job, relational strain, and hospitalization. Chronic users develop vitamin deficiencies because alcohol is high in calories and not nutritious, and they are at risk for pancreatitis, chronic gastritis, gastric ulcers, stomach and intestinal cancers (alcohol is a gastric irritant), as well as death due to cirrhosis of the liver. Alcohol is involved in costly traffic-related injuries and fatalities. According to the National Highway Traffic Safety Administration, automobile crashes involving alcohol in 2000 cost the public almost $115 billion, with an estimated 513,000 people injured and 16,792 killed (Pacific Institute for Research and Evaluation, n.d.).
People typically absorb alcohol orally, and ethanol is easily absorbed via the gastrointestinal system. Generally, beers have 3.2 to 5 percent ethanol, wines 12 to 14 percent, and hard liquors (distilled spirits) 40 to 50 percent. An adult can metabolize the amount of ethanol contained in a 12-ounce, 3.2 percent beer, a 3 %-ounce, 12 percent wine, or 1-ounce, 40 percent (80 proof) hard liquor in approximately one hour. The enzyme alcohol dehydrogenase metabolizes about 95 percent of the ethanol consumed into acetaldehyde at a constant rate of 0.25 ounces/hour, and that metabolizes to acetyl-coenzyme, which then converts to water and carbon dioxide. The other 5 percent is excreted unchanged mostly through breath (hence the use of Breathalyzers to estimate alcohol concentration). Women have less ethanol-metabolizing enzyme in their stomach wall and therefore absorb more ethanol than men do. Water and fat-soluble ethanol easily crosses the BBB and placental barriers. Ethanol diffuses rapidly throughout the brain, and ethanol concentrations in a fetal brain reach those of the alcohol-drinking mother.
Ethanol nonspecifically affects neuronal membranes and directly affects synaptic activity and ionic channels of several neurotransmitters. Ethanol dose dependently inhibits NMDA-type glutamate receptors (reduces post-synaptic excitation) and enhances inhibition produced by GABAA receptor-mediated influx of chloride ions (increases postsynaptic inhibition). Ethanol also induces synaptic release of opioids that trigger dopamine release in the brain reinforcement areas, explaining how the antagonist naltrexone reduces cravings for alcohol and relapse in alcohol-dependent persons attempting to abstain. Specific serotonin receptors (5HT2, 5HT3) located in the nucleus accumbens may also be a site of ethanol action. Antagonists of those receptors reduce ethanol consumption in some persons with alcoholism. Additionally, ethanol leads to a decrease in the number of cannabinoid receptors (down-regulation) affecting the craving of alcohol.
Water excretion in urine increases (diuretic) as the blood alcohol concentration (BAC) rises, and water is retained (antidiuretic) as the BAC declines, causing swelling in the extremities. Although it makes the drinker feel warmer to the touch, ethanol actually causes hypothermia. Because ethanol causes blood vessels in skin to dilate, persons with white skin appear flushed. Behaviorally, ethanol has a biphasic effect, with low doses inhibiting inhibitions (disinhibition), and high doses depressing all behaviors. Alcohol reduces the latency to fall to sleep and inhibits REM sleep. Generally, low to moderate doses increase rate and tone of speech, impair visual perception, disrupt balance, worsen reaction time, exaggerate mood, reduce fear and apprehension (anxiolytic), and affect learning and memory in a state-dependent manner. However, there are huge individual differences in ethanol-induced effects because genetics, motivation, environment, experience with alcohol, and tolerance vary greatly. Chronic consumption of higher doses of alcohol can lead to memory storage problems, with heavy drinkers experiencing blackouts, periods during which they cannot remember events even though they were awake and active. Long-term heavy drinking can cause irreversible neuronal damage, producing dementia and severe cognitive deficits known as Korsakoff’s Syndrome.
Each of the forms of tolerance can develop to some of the effects of ethanol (e.g., depression of REM) depending on pattern of drinking and amount consumed, with tolerance more apparent in regular and heavy drinkers. Physiological dependence is evident when withdrawal from ethanol results in agitation, confusion, tremors, cramps, sweating, nausea, and vomiting. Persons with severe alcoholism may experience delirium tremens (DTs) characterized by disorientation, hallucinations, and life-threatening seizures.
The opiates, also known as narcotics, are a class of potent analgesics that have similar behavioral effects, including opium, opium extracts (e.g., morphine, codeine), several opiate derivatives (e.g., heroin), and several chemically unrelated synthetic opiates (e.g., methadone). Opium is harvested from the opium poppy, and has been used for centuries. In the 1800s, women and children alike ingested opium in everything from cure-alls to cough syrups. In the mid-1800s morphine as a medical analgesic increased with the invention of the hypodermic needle during the Civil War. When heroin was put on the market in the late 1890s it was considered a powerful and safe cough suppressant, and it was at least a decade before its full potential for abuse and dependence was realized. In the United States, opium, morphine, codeine, and methadone are all Schedule II drugs (high potential for abuse and dependence with acceptable medicinal uses with strict restrictions), whereas heroin is a Schedule I drug (high potential for abuse and dependence with no acceptable medicinal use). Although it is illegal in this country, it is widely used as a recreational drug. An estimated 108,000 persons age 12 and older used heroin for the first time in 2005 (Department of Health and Human Services, 2006).
Opiates are administered orally, as rectal suppositories, or as is most common with medicinal and recreational use, via injection. Morphine, because it is more water than fat soluble, crosses the BBB slowly, whereas more lipid soluble heroin crosses the BBB much more rapidly and produces a faster more intense “rush.” Metabolism of morphine in the liver produces the metabolite mor-phine-6-glucuronide that is an even more potent analgesic. Heroin, which is three times more potent than morphine, metabolizes to monoacetylmorphine, which then converts to morphine. Urine tests detect the opiates as well as their metabolites, and therefore are not useful in determining the exact form of the drug used. Furthermore, poppy seeds and cough syrups contain ingredients that metabolize and test positive for opiate metabolites.
Exogenous opioids (produced outside of the body) bind to opioid receptors and mimic the actions of endogenous opioids (endorphins). Most of their analgesic effects are due to their presynaptic inhibition of pain-producing neurotransmitter release. There are Mu, Kappa, and Delta opiate receptors. Morphine is an agonist at Mu receptors located in several brain areas including the nucleus accumbens (addiction and abuse), thalamus, striatum, and brain-stem (respiratory depression, nausea and vomiting), in the spinal cord (analgesia), and periphery. In the brain, Delta receptors in the nucleus accumbens and limbic system are involved in opioid-related emotional responses, and Kappa receptors may be Mu receptor-antagonists.
Opiates alter the perception of pain without affecting consciousness. They also produce a feeling of drowsiness, putting the person in a sort of mental fog that impairs cognitive processing. Opiates cause the user to feel carefree, content, and euphoric. Respiration becomes slow, shallow, and irregular, at therapeutic doses, and breathing may stop with high doses. Combined use of opiates and depressants can be particularly hazardous. Other physiological effects of opiate use include constricted pupils, histamine-induced red eyes and itching, lowered blood pressure, constipation, cough suppression, nausea and vomiting, and changes in the immune system.
Key features of frequent repetitive opiate use are tolerance to analgesia and euphoria, and cross-tolerance to other opiates. The severity of the withdrawal symptoms—anxiety, agitation, despair, irritability, physical pain, cramping, and diarrhea—depends on how long, how often, and how much of the opiate was used. Depression and intense cravings for the drug last for several months after the individual has stopped using heroin, for example.
Marijuana and Hashish
For centuries, people in many parts of the world have used some form of the Cannabis sativa hemp plant as a recreational drug. The plant grows as a weed in many parts of the United States, and is cultivated in other countries. Marijuana production consists of drying and shredding the leaves of the plant, whereas hashish is a dried form of the resin from the flowers of the plant. Marijuana and hashish are both Schedule I drugs in the United States. Each day in 2005, an estimated 6,000 persons, 59.1 percent under 18, used marijuana for the first time (Department of Health and Human Services, 2006). The main psychoactive substance in these products is delta-9-tetrahydocaanabinol (THC). Most marijuana has a THC content of about 4 to 8 percent.
Often THC is ingested via hand-rolled marijuana cigarettes called joints or reefers, but it is also consumed in cookies and brownies. Only about half of the THC in a marijuana cigarette is absorbed, but absorption via the capillaries in the lining of the lungs is very rapid. Peak blood levels of THC occur within 10 minutes of the beginning of smoking, and detectable blood levels continue for 12 hours after a single cigarette. Absorption and onset of effects after oral ingestion is slower, with peak THC blood levels not occurring for at least 2 hours. THC easily crosses the BBB and placenta barrier, and collects in fatty parts of the body. It slowly metabolizes into active 11-hydroxy-delta-9-THC, which then converts into inactive metabolites detectable in urine tests for as long as a month in heavy or chronic smokers.
The actions of THC in the brain were unknown until the 1990s identification of the weaker and shorter-lasting endogenous THC-like substance, anandamide, and the cannabinoid receptor. THC is an anandamide agonist that, when bound to cannabinoid receptors, inhibits the release of other neurotransmitters at those synapses, especially GABA. These g-protein-linked receptors are located mostly on presynaptic terminals and exist in large numbers throughout the brain, but not in the brainstem. That there are none of these receptors in the brainstem, where regulations of major life-support functions are controlled (e.g., heart rate, respiration), is probably why even high doses of marijuana are not likely lethal, although they can peripherally affect the cardiovascular and immune systems.
The psychoactive effects of THC are dependent upon type of administration, experience with the drug, environment, and expectations. Interestingly, the effects of marijuana on appetite and sexual behavior are culturally dependent, with Americans experiencing “the munchies” and Jamaicans decreased appetite, Americans enhanced sexual responsiveness and persons of India reduced sexual interest. Generally, people use marijuana because it has a mellowing, mildly euphoric effect. Other psychoactive effects include poorer attention, distorted perception of time and colors, altered auditory and gustatory perceptions, diminished anxiety, slowed reaction time, and impaired cognitive processing. Poor learning and memory are due to the numerous cannabinoid receptors in the hippocampus. Impaired balance and abnormal movements occur because of THC’s activation of receptors in the basal ganglia, and the cognitive effects are due to receptors in the cerebral cortex. Poor reaction time, decreased attention to peripheral visual stimuli, difficulty concentrating, and impairment of complex motor tasks under the influence of marijuana hinders driving ability. High doses of marijuana produce panic and anxiety, and extremely high doses produce additional disorientation, delusions, and hallucinations.
Tolerance, receptor-down regulation with repeated use, develops to THC. Withdrawal symptoms, which begin about 48 hours after the last marijuana use, include restlessness, irritability, despair, apprehension, difficulty sleeping, nausea, cramping, and poor appetite. Withdrawal symptoms are mild as compared to those that occur with most other drugs (e.g., alcohol, opiates) and occur for only about half of regular users. Thus, physiological dependence does occur for many, and most experience craving for marijuana when they stop using the drug.
The Hallucinogens LSD, MDMA, and PCP
Although the hallucinogens lysergic acid diethylamide (LSD), methylene-dioxy-methamphetamine (MDMA; Ecstasy), and phencyclidine (PCP; Angel Dust) affect very different neurotransmitter systems, they are grouped here because of their similar psychological effects at nontoxic doses. The commonality among hallucinogens (psychedelic drugs) is their ability to cause users to disconnect from reality and hallucinate. Although there are a large number of natural hallucinogenics, LSD, MDMA, and PCP are all synthetic drugs originally synthesized with hopes of medicinal value. Albert Hoffman accidentally experienced a “psychedelic trip” in 1943, and since then LSD has become one of the most widely known hallucinogens. PCP was used as an anesthetic prior to being taken off the market in 1965, when it made it to the streets as a recreational drug, and MDMA became a club drug in the 1960s. Estimates of first time users of hallucinogens for each year from 2000 to 2005 have been close to one million people age 12 and older per year, with about 615,000 first-time Ecstasy users in 2005 (Department of Health and Human Services, 2006).
Users ingest LSD orally, and the drug is absorbed in about 60 minutes with peak blood levels within 3 hours. LSD easily crosses both brain and placenta barriers. Metabolism takes place in the liver, where LSD is converted to 2-oxo-3phydroxy-LSD, and then excreted in urine. People use MDMA orally, snort it, smoke it, and inject it, with absorption being slowest with oral use. Most of MDMA metabolizes to 3,4-dihydroxymethamphet-amine (DHMA), and urine tests detect metabolites for up to 5 days. People either take PCP orally (peak blood levels in 2 hours) or smoke the drug (peak blood levels in 15 minutes), and it is well absorbed into blood with both methods. Urine tests detect PCP for as long as a week after use.
LSD is a serotonergic receptor agonist, and most of the psychoactive effects of LSD are thought to be due to agonist actions at serotonin receptors in the pontine raphe (filters sensory stimuli). MDMA is structurally similar to but more potent than mescaline and metamphetamine, and stimulates release of both serotonin and dopamine in the CNS. Prolonged use of MDMA results in serotonergic neurotoxicity, and can lead to long-term verbal and visual memory loss. PCP blocks the ionic channels of glutamatergic-NMDA receptors, preventing calcium ions from entering into the dendrites of postsynaptic neurons when glutamate binds to these receptors, and blocking synaptic excitation.
Very small doses of LSD cause vivid visual hallucinations like colorful kaleidoscope lights and distorted images, lights to be heard and sounds to be seen, moods that oscillate from jubilation to dread, and frightening cognitions that surface. The LSD “trip” is often unpleasant, resulting in panic and confusion. A unique feature of LSD use is the infamous “flashback,” a reoccurrence of the drug’s effects without warning, even a long time after LSD use. At low doses MDMA has behavioral effects similar to those of methamphetamines, but at higher doses it has the psychoactive effects of LSD. Low doses of PCP produce agitation, dissociation from self and others, a “blank stare,” and major alterations in mood and cognition. Higher doses of PCP can cause the user to have violent reactions to stimuli in his or her environment, along with analgesia and memory loss. Extremely high doses of PCP result in coma.
Tolerance and cross-tolerance develops to the psychological and physiological effects of most hallucinogens rather quickly, making it difficult to stay repetitively “high” on these drugs. Furthermore, there are few if any withdrawal symptoms and therefore little or no physiological dependence with LSD, MDMA, and PCP in most users.
Psychoactive drugs change cognitions, emotions, and behavior. Drugs, per se, are neither good nor bad. People use psychoactive drugs for medicinal and recreational reasons. Regardless of the initial reason for using a drug, some people misuse and even abuse some psychoactive drugs because of the drugs’ effects on mood, thought, and behavior. How people administer the drug (by ingestion, injection, inhalation, or absorption through the skin) affects how fast and intense the drug’s effects are. The route of administration can affect how quickly the drug is absorbed into the bloodstream, how rapidly it is broken down, and how long it takes to be excreted from the body. The primary site of action for psychoactive drugs is the synapse of neurons in the brain. Often drugs work by either mimicking or blocking the actions of one or more neurotransmitters in the CNS. All drugs have multiple effects, and most are toxic at some dose. Dependence, withdrawal, and/or tolerance develop to some of the effects of most, but not all, psychoactive drugs.
Psychoactive drugs can be categorized many different ways. For example, by chemical structure, whether their use is legal or illegal, or the type of CNS or behavioral effects they produce. Stimulants, like cocaine and amphetamines, increase neuronal and behavioral activity. Depressants, like alcohol, reduce neuronal and behavioral activity. Opiates, some having legal uses (e.g., morphine) and others not (e.g., heroin), reduce pain and, in high enough doses, cause an addictive “rush.” Low doses of marijuana have a mellowing, mildly euphoric effect, whereas very high doses can cause hallucinations. Drugs like LSD, MDMA, and PCP are all classified as hallucinogens because at even low doses they cause sensory and perceptual distortions. Although a great deal is known about how many psychoactive drugs act in the brain and affect behavior, researchers continue to identify the most effective pharmacological, cognitive, and behavioral treatments for persons who abuse these drugs.
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