Did you know that most psychoactive drugs and their effects were discovered by accident? Scientists and pharmaceutical companies have experimented ever since, to explain drug action, to synthesize alternative forms for therapeutic treatments, and to modify drugs to reduce side effects. But the process is complex. Drugs with similar chemical structure can have different effects, and drugs with different structure can have similar effects. And a single drug usually acts on many neurochemical systems and has many effects.

A full appreciation of any drug’s action requires a multifaceted description, such as can be found in compendiums of drug action. Unambiguously grouping psychoactive drugs is virtually impossible, because most drugs influence many behaviors. Behavioral descriptions undergo constant review, as illustrated by continuing revisions of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). Published by the American Psychiatric Association and now in its fifth edition, the DSM offers a classification system for diagnosing neurological and behavioral disorders.

Table 6-1 groups psychoactive drugs based on their most pronounced behavioral or psychoactive effects (Advokat et al., 2014). Each of the five groups may contain a few to thousands of chemicals in its subcategories. In the following sections we highlight drug actions, both on neurochemical systems in the brain and on synaptic function.

Most psychoactive drugs have three names: chemical, generic, and branded. The chemical name describes a drug’s structure; the generic name is nonproprietary and is spelled lowercase; and the proprietary, or brand, name, given by the pharmaceutical company that sells it, is capitalized. Some psychoactive drugs also sport street names or are known as club drugs.

At low doses, antianxiety drugs and sedative-hypnotics reduce anxiety; at medium doses, they sedate; at high doses, they anesthetize or induce coma. At very high doses, they can kill (Figure 6-6). Even so, antianxiety drugs are safer at high doses than sedative-hypnotics are. Indeed, the prescribing of sedative-hypnotics for all purposes is decreasing.

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Many psychoactive drugs have sedative-hypnotic and antianxiety actions. They include phencyclidine (PCP, angel dust) and two drugs—gamma-hydroxybutyric acid (GHB) and ketamine (Special K)—that gained notoriety as date rape drugs. Both are soluble in alcohol, act quickly, and, like other sedative-hypnotics, impair memory of recent events. Because they can be dissolved in a drink, partygoers and clubbers should never accept drinks from anyone, drink from punch bowls, or leave drinks unattended.

Drug Action in the Brain

The best-known antianxiety agents, or minor tranquilizers, are the benzodiazepines. One, diazepam, is marketed as the widely prescribed brand-name drug Valium. Others are alprazolam (Xanax) and clonazepam (Klonopin). Benzodiazepines are often used by people who are having trouble coping with a major life stress, such as a traumatic accident or a death in the family. They aid sleep and also are used as presurgical relaxation agents.

Sedative-hypnotics include alcohol and barbiturates. Both induce sleep, anesthesia, and coma at doses only slightly higher than those that sedate. Alcohol is well known to most people and widely consumed. While sometimes prescribed as a sleeping medication, today barbiturates are mainly used to induce anesthesia before surgery.

A characteristic feature of sedative-hypnotics is that the user who takes repeated doses develops a tolerance for them. A larger dose is then required to maintain the drug’s initial effect. Cross-tolerance results when the tolerance for one drug is carried over to a different member of the drug group.

Drug Action at the Synapse

Cross-tolerance suggests that antianxiety and sedative-hypnotic drugs act on the nervous system in similar ways. One target common to both alcohol and barbiturate drugs is a receptor for gamma-aminobutyric acid (GABA), the inhibitory neurotransmitter that is widely distributed in the CNS. The GABA_A receptor, illustrated in Figure 6-7, contains a chloride ion channel.

Excitation of the GABA_A receptor produces an influx of Cl^– through its pore. An influx of Cl^– increases the concentration of negative charges inside the cell membrane, hyperpolarizing it and making it less likely to propagate an action potential. GABA therefore has its inhibitory effect by decreasing a neuron’s firing rate. Widespread reduction of neuronal firing underlies the behavioral effects of drugs that affect the GABA_A synapse.

The GABA_A receptor illustrated in Figure 6-7 has different binding sites for GABA, barbiturates, and benzodiazepines. Activation of each site promotes an influx of Cl^–, but in different ways. Because the effects of actions at these three sites summate, sedative-hypnotics, including alcohol and antianxiety drugs, should not be consumed together. Combined doses of drugs reportedly contribute to as many deaths as occur annually from automobile accidents in the United States. Such was the case in 2012, when singer Whitney Houston drowned.

The GABA_A receptor also has binding sites that block the ion pore when active, reducing the flow of Cl^– and increasing the target neuron’s excitability. Picrotoxin, a compound that blocks the pore, produces epileptic discharges in postsynaptic neurons. Administering GABA_A agonists can block picrotoxin’s action. Sedative-hypnotic and antianxiety drugs are thus useful in treating epileptic discharges.

Drugs that act on GABA receptors may affect brain development, because GABA is one of the substances that regulate brain development. Clinical Focus 6-2, Fetal Alcohol Spectrum Disorder, explores alcohol’s potentially devastating effects on developing fetuses.

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The term psychosis is applied to behavioral disorders such as schizophrenia, which is characterized by hallucinations (false sensory perceptions) and delusions (false beliefs), among a host of symptoms. The use of antipsychotic drugs has improved the functioning of schizophrenia patients. Since 1955, when psychoactive drugs were introduced into widespread therapeutic use, resident patient populations in state and municipal mental hospitals in the United States have decreased dramatically.

The success of antipsychotic agents is an important therapeutic achievement, because the incidence of schizophrenia is high—about 1 in every 100 people. Although antipsychotic agents make mental disorders manageable, they do not constitute cures. In fact, according to the National Institute on Disability and Rehabilitation Research, although the number of people in mental institutions remains relatively low, as many as 75% of the homeless and 50% of incarcerated people have mental health issues. According to Human Rights Watch, in 2015, 10 times as many mentally ill people were incarcerated as resided in mental institutions.

Antipsychotic agents have been widely used since the mid-1950s, beginning with the development of what are now called first-generation antipsychotics (FGAs). They include the drug classes phenothiazines (e.g., chlorpromazine, Thorazine) and butyrophenones (e.g., haloperidol, Haldol). FGAs act mainly by blocking the dopamine D₂ receptor. Beginning in the 1980s, newer drugs such as clozapine (Clozaril) and several other compounds emerged as the second-generation antipsychotics (SGAs). SGAs weakly block dopamine D₂ receptors but also block serotonin 5-HT₂ receptors. Antipsychotic drugs now in development will likely form a third generation.

Antipsychotic agents’ therapeutic actions are not understood fully, and these drugs can produce many unwanted side effects. Joint experimentation by patients and physicians with different drugs and doses is common (Pouget et al., 2014). The dopamine hypothesis of schizophrenia holds that some forms of the disease may be related to excessive dopamine activity—especially in the frontal lobes. Other support for the dopamine hypothesis comes from the schizophrenialike symptoms of chronic users of amphetamine, a stimulant.

As Figure 6-8 shows, amphetamine is a dopamine agonist. It fosters dopamine release from the presynaptic membrane of D₂ synapses and blocks dopamine reuptake from the synaptic cleft. The logic is that if amphetamine causes schizophrenialike symptoms by increasing dopamine activity, perhaps naturally occurring schizophrenia is related to excessive dopamine action too. Both FGAs and SGAs block the D₂ receptor, which immediately reduces motor activity and alleviates the excessive agitation of some schizophrenia patients. Because schizophrenia involves more than just D₂ receptors, changes in dopamine synapses do not completely explain the disorder or the effects of antipsychotic agents.

Major depression—a mood disorder characterized by prolonged feelings of worthlessness and guilt, disruption of normal eating habits, sleep disturbances, a general slowing of behavior, and frequent thoughts of suicide—is rather common. At any given time, about 6 percent of the U.S. adult population has major depression, and in the course of a lifetime, 30 percent may have at least one episode that lasts for months or longer. Depression is diagnosed in twice as many women as men.

Inadequate nutrition, stress from difficult life conditions, acute changes in neuronal function, and damage to brain neurons are among the factors implicated in depression. These factors may be related: nutritional deficiencies may increase vulnerability to stress; stress may change neuronal function; and if unrelieved, altered neuronal function may lead to neuron damage. Section 6-5 offers more information on stress.

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Among the nutrient deficiencies that may be related to depression (Smith et al., 2010) are folic acid and other B vitamins and omega-3 fatty acids, a rich source of vitamin D obtained from fish. Our skin synthesizes vitamin D on exposure to sunlight, but our body cannot store it. Vitamin D deficiency is reportedly widespread in people living in northern climates because they don’t eat enough fish and they lack exposure to sunlight in winter. Although vitamin D deficiency is associated with depressive symptoms, little is known about the relations among long-term deficiencies in nutrients, depression and associated brain changes, and the effectiveness of dietary supplements (Kerr et al., 2015).

Not surprisingly, alongside improved nutrition, a number of pharmacological approaches to depression are available. They include normalizing stress hormones, modifying neuronal responses, and stimulating neuronal repair.

Antidepressant Medications

Three types of drugs have antidepressant effects: the monoamine oxidase (MAO) inhibitors; the tricyclic antidepressants, so called because of their three-ring chemical structure; and the second-generation antidepressants, sometimes called atypical antidepressants (see Table 6-1). Second-generation antidepressants lack a three-ring structure but do share some similarities to the tricyclics in their actions.

Antidepressants are thought to act by improving chemical neurotransmission at serotonin, noradrenaline (norepinephrine), histamine, and acetylcholine synapses, and perhaps at dopamine synapses as well. Figure 6-9 shows the actions of MAO inhibitors and second-generation antidepressants at a 5-HT synapse, on which most research is focused. MAO inhibitors and the tricyclic and second-generation antidepressants all act as agonists but have different mechanisms for increasing serotonin availability.

MAO inhibitors provide for more serotonin release with each action potential by inhibiting monoamine oxidase, an enzyme that breaks down serotonin in the axon terminal. In contrast, the tricyclics and second-generation antidepressants block the reuptake transporter that takes serotonin back into the axon terminal. The second-generation antidepressants are thought to be especially selective in blocking serotonin reuptake; consequently, some are also called selective serotonin reuptake inhibitors (SSRIs). Because the transporter is blocked, serotonin remains in the synaptic cleft, prolonging its action on postsynaptic receptors.

Although these drugs begin to affect synapses very quickly, their antidepressant actions take weeks to develop. One explanation is that antidepressants, especially SSRIs, stimulate second messengers in neurons to activate the repair of neurons damaged by stress. Of interest in this respect, one SSRI, fluoxetine (Prozac), increases the production of new neurons in the hippocampus, a limbic structure in the temporal lobes. As detailed in Section 6-5, the hippocampus is vulnerable to stress-induced damage, and its restoration by fluoxetine is proposed to underlie one of the drug’s antidepressant effects (Hill et al., 2015).

Most people recover from depression within a year of its onset. If left untreated, however, depression’s incidence of suicide is high, as described in Clinical Focus 6-3, Major Depression, on page 186. Of all psychological disorders, major depression is one of the most treatable, and cognitive and intrapersonal therapies are as effective as drug therapies (Comer, 2011).

Even so, about 20 percent of patients with depression fail to respond to antidepressant drugs. Accordingly, depression likely can have many other causes, including dysfunction in other transmitter systems and even brain damage, including frontal lobe damage. Some people have difficulty tolerating the side effects of antidepressants—increased anxiety, sexual dysfunction, sedation, dry mouth, blurred vision, and memory impairment among them.

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Mood Stabilizers

Bipolar disorder, once referred to as manic-depressive psychosis, is characterized by periods of depression alternating with normal periods and periods of intense excitation, or mania. According to the National Institute of Mental Health, bipolar disorder may affect as much as 2.6% of the adult population of the United States.

The difficulty in treating bipolar disorder with drugs relates to the difficulty in understanding how a disease produces symptoms that appear to be opposites: mania and depression. Consequently, bipolar disorder often is treated with numerous drugs, each directed toward a different symptom. Mood stabilizers, which include the salt lithium, mute the intensity of one pole of the disorder, thus making the other less likely to occur. Lithium does not directly affect mood and so may act by stimulating mechanisms of neuronal repair, such as the production of neuron growth factors.

A variety of drugs for epilepsy (carbamazepine, valproate) have positive effects; perhaps they mute the excitability of neurons during the mania phase. And antipsychotic drugs that block D₂ receptors effectively control the hallucinations and delusions associated with mania. It is important to remember, though, that all these treatments have side effects: enhancing beneficial effects while minimizing side effects is a major focus of new drug development (Grande and Vieta, 2015).

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An opioid is any compound that binds to a group of morphine-sensitive brain receptors. The term narcotic analgesic was first used to describe these drugs because opioid analgesics have sleep-inducing (narcotic) and pain-relieving (analgesic) properties. There are two natural sources of opioids.

One source is opium, an extract of the seeds of the opium poppy, Papaver somniferum, shown at left in Figure 6-10 and named for Morpheus, the Greek god of dreams, is a powerful pain reliever. Despite decades of research, no other drug has been found that exceeds morphine’s effectiveness as an analgesic.

The second natural source of opioids is the brain. In the 1970s, several groups of scientists injected radioactive opioids into the brain of experimental animals and identified receptors there to which opioids bind. At roughly the same time, other groups of investigators identified several brain peptides as the neurotransmitters that naturally affect these receptors. The peptides in the body that have opioidlike effects are collectively called endorphins (endogenous morphines).

Research has identified four classes of opioid peptides: endorphins, enkephalins, dynorphins, and endomorphins. The three receptors on which each endorphin is relatively specific are, respectively, mu, kappa, and delta. All endorphins and their receptors occur in many CNS regions as well as in other areas of the body, including the enteric nervous system. Morphine most closely mimics the endomorphins and binds most selectively to the mu receptors.

In addition to the natural opioids, synthetic opioids such as heroin affect mu receptors. Heroin, shown at right in Figure 6-10, is synthesized from morphine. It is more fat-soluble than morphine and penetrates the blood–brain barrier more quickly, allowing it to produce very rapid but shorter-acting pain relief. Heroin is a legal drug in some countries but is illegal in others, including the United States. Notwithstanding, in some parts of the country, heroin use is on the rise.

Among the synthetic opioids prescribed for clinical use in pain management are hydromorphone, levorphanol, oxymorphone, methadone, meperidine, oxycodone, and fentanyl. All opioids are potently addictive, and abuse of prescription opioids is growing more common. Opioids are also illegally modified, manufactured, and distributed. People who use opioids for relief of chronic pain and take them when they are not in pain can become addicted; some obtain multiple prescriptions and sell them illicitly.

Many drugs, including nalorphine (Lethidrone, Nalline) and naloxone (Narcan, Nalone), act as antagonists at opioid receptors. These drugs are competitive inhibitors: they compete with opioids for neuronal receptors. Because they can enter the brain quickly, they rapidly block the actions of morphine and so are essential aids in treating morphine overdoses. Many people addicted to opioids carry a competitive inhibitor as a treatment for overdosing. Because they can also be long-acting, competitive inhibitors can be used to treat opioid addiction after the addicted person has recovered from withdrawal symptoms.

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Researchers have extensively studied whether opioid peptides produced in the brain can be used as drugs to relieve pain without morphine’s addictive effects. The answer so far is mixed, and one of the objectives of pain research, producing an analgesic that does not produce addiction, may be difficult to realize.

Opioid drugs, such as heroin, are addictive and are abused worldwide. The hypodermic needle was developed in 1853 and used in the American Civil War for the intravenous injection of morphine for pain treatment. This practice is said to have produced 400,000 cases of the “Soldier’s Disease,” morphine addiction. Morphine has many routes of administration, but intravenous injection is preferred because it produces a euphoria described as a rush. Morphine does not readily cross the blood–brain barrier, but heroin does and is even more likely to produce a rush.

If opioids are used repeatedly, they produce tolerance such that within a few weeks the effective dose may increase tenfold. Thereafter, many desired effects with respect to both pain and addiction no longer occur. An addicted person cannot simply stop using the drug: a severe sickness called withdrawal results if drug use is abruptly stopped.

Because morphine results in both tolerance and sensitization, the morphine user is always flirting with the possibility of overdosing. The unreliability of appropriate information on the purity of street forms of morphine contributes to the risk. A lack of sterile needles for injections also leaves the morphine user at risk for many other diseases, including AIDS (acquired immunodeficiency syndrome) and hepatitis.

Opioid ingestion produces wide-ranging physiological changes in addition to pain relief, including relaxation and sleep, euphoria, and constipation. Other effects include respiratory depression, decreased blood pressure, pupil constriction, hypothermia, drying of secretions (e.g., dry mouth), reduced sex drive, and flushed, warm skin. Withdrawal is characterized by symptoms that are physiologically and behaviorally opposite those produced by the drug. A major part of the addiction syndrome, then, is the drive to prevent withdrawal symptoms.

Psychotropic drugs are stimulants that mainly affect mental activity, motor activity, arousal, perception, and mood. Behavioral stimulants affect motor activity and mood. Psychedelic and hallucinogenic stimulants affect perception and produce hallucinations. General stimulants mainly affect mood.

Behavioral Stimulants

Behavioral stimulants increase motor behavior as well as elevating mood and alertness. Rapid administration of behavioral stimulants is most likely to be associated with addiction. As shown in Figure 6-1, the quicker a drug reaches its target—in this case, the brain—the quicker it takes effect. Further, with each obstacle eliminated en route to the brain, drug dosage can be reduced by a factor of 10, making it cheaper per dose. Two behavioral stimulants are amphetamine and cocaine.

Amphetamine is a synthetic compound. It was discovered in attempts to synthesize the CNS neurotransmitter epinephrine, which also acts as a hormone to mobilize the body for fight or flight in times of stress (see Figure 6-20). Both amphetamine and cocaine are dopamine agonists that act first by blocking the dopamine reuptake transporter. Interfering with the reuptake mechanism leaves more dopamine available in the synaptic cleft. Amphetamine also stimulates dopamine release from presynaptic membranes. Both mechanisms increase the amount of dopamine available in synapses to stimulate dopamine receptors. As noted in Focus 6-1, amphetamine-based drugs are widely prescribed to treat ADHD.

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One form of amphetamine was first used as an asthma treatment: Benzedrine was sold in inhalers as a nonprescription drug through the 1940s. Soon people discovered that they could open the container and ingest its contents to obtain an energizing effect. Amphetamine was widely used in World War II—and is still used today to help troops and pilots stay alert, increase confidence and aggression, and boost morale—and also was used then to improve wartime workers’ productivity. Today, amphetamine is also used as a weight loss aid. Many over-the-counter compounds marketed as stimulants or weight loss aids have amphetaminelike pharmacological actions.

An illegal amphetamine derivative, methamphetamine (also known as meth, speed, crank, smoke, or crystal ice) continues in widespread use. Lifetime prevalence of methamphetamine use in the U.S. population, once estimated to be as high as 8 percent (Durell et al., 2008), is related to its ease of manufacture in illicit laboratories and to its potency, thus making it a relatively inexpensive, yet potentially devastating, drug.

Cocaine is a powder extracted from the Peruvian coca shrub, both shown in Figure 6-11. The indigenous people of Peru have chewed coca leaves through the generations to increase their stamina in the harsh environment and high elevations where they live. Refined cocaine powder can either be sniffed (snorted) or injected. Cocaine users who do not like to inject cocaine intravenously or cannot afford it in powdered form sniff or smoke rocks, or crack, a potent, highly concentrated form shown at right in Figure 6-11. Crack is chemically altered so that it vaporizes at low temperatures, and the vapors are inhaled.

Sigmund Freud (1974) popularized cocaine in the late 1800s as an antidepressant. It was once widely used in soft drinks and wine mixtures promoted as invigorating tonics. It is the origin of the trade name of Coca-Cola, which once contained cocaine (Figure 6-12). Its addictive properties soon became apparent, however.

Freud also recommended that cocaine be used as a local anesthetic. Cocaine did prove valuable for this purpose, and many derivatives, such as xylocaine (often called Novocain), are used today. These local anesthetic agents reduce a cell’s permeability to sodium ions and so reduce nerve conduction.

Psychedelic and Hallucinogenic Stimulants

Psychedelic drugs alter sensory perception and cognitive processes and can produce hallucinations. We categorize the major groups of psychedelics by their actions on specific neurotransmitters, here and in Table 6-1 on page 181.

ACETYLCHOLINE PSYCHEDELICS These drugs either block (atropine) or facilitate (nicotine) transmission at ACh synapses.

ANANDAMIDE PSYCHEDELICS Results from numerous lines of research suggest that the endogenous neurotransmitter anandamide enhances forgetting. Anandamide prevents the brain’s memory systems from being overwhelmed by all the information to which we are exposed each day. Tetrahydrocannabinol (THC) is one of 84 cannabinoids and the main psychoactive constituent in marijuana, obtained from the hemp plant Cannabis sativa, shown in Figure 6-13. THC alters mood primarily by interacting with the anandamide CB1 receptor found on neurons, and it also binds with the anandamide CB2 receptors found on glial cells and in other body tissues. THC has low toxicity but may have a detrimental effect on memory as well as a positive effect on mental overload.

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Evidence points to the usefulness of THC, or other cannabinoids, as a therapeutic agent for a number of disorders. It relieves nausea and emesis (vomiting) in patients undergoing cancer chemotherapy who are not helped by other treatments and stimulates the appetite in AIDS patients with anorexia–cachexia (wasting) syndrome. THC has been found helpful for treating chronic pain through mechanisms that appear to be different from those of the opioids. It has also proved useful for treating glaucoma (increased pressure in the eye), for spastic disorders such as multiple sclerosis, for disorders associated with spinal cord injury, and for epilepsy. THC may also have some neuroprotective properties (see Section 6-4). Many people self-prescribe THC for a wide range of ailments, including PTSD (Roitman et al., 2014).

Synthetic and derived forms of THC have been developed in part to circumvent legal restrictions on its use. Nevertheless, legal restrictions against THC use hamper investigations into its useful medicinal effects.

GLUTAMATE PSYCHEDELICS PCP (angel dust) and ketamine (Special K) can produce hallucinations and out-of-body experiences. Both drugs, formerly used as anesthetics (see Table 6-1, Group I), exert part of their action by blocking glutamate NMDA receptors involved in learning. Other NMDA receptor antagonists include dextromethorphan and nitrous oxide (NO).

Although PCP’s primary psychoactive effects last for a few hours, its total elimination rate from the body can extend its action for 8 days or longer. That psychotropic drugs, including PCP and ketamine, can produce schizophrenialike symptoms, including hallucinations and out-of -body experiences, suggests the involvement of excitatory glutamate synapses in schizophrenia.

NOREPINEPHRINE PSYCHEDELICS Mescaline, obtained from the peyote cactus, is legal in the United States for use by Native Americans for religious practices. Mescaline produces pronounced psychic alterations, including a sense of spatial boundlessness and visual hallucinations. The effects of a single dose last up to 10 hours.

SEROTONIN PSYCHEDELICS The synthetic drug lysergic acid diethylamide (LSD) and naturally occurring psilocybin (obtained from various mushrooms) stimulate some 5-HT receptors and block the activity of other serotonergic neurons through 5-HT autoreceptors.

Serotonin psychedelics may stimulate other transmitter systems, including norepinephrine receptors. MDMA (Ecstasy), one of several synthetic amphetamine derivatives, induces a sense of well-being and disembodiment as well as visual distortions. Repeated MDMA use is associated with sleep, mood, and anxiety disorders and may also be associated with memory and attention deficits. Drug models of schizophrenia include LSD, which produces hallucinations and is a serotonin agonist that acts at the 5-HT₂ receptor. Again, that hallucinations are a symptom of schizophrenia suggests that excess 5-HT action can be involved.

General Stimulants

General stimulants cause an overall increase in cells’ metabolic activity. Caffeine, a widely used stimulant, inhibits an enzyme that ordinarily breaks down the second messenger cyclic adenosine monophosphate (cAMP). The resulting increase in cAMP leads to increased glucose production, making more energy available and allowing higher rates of cellular activity.

A cup of coffee contains about 100 mg of caffeine; many common soft drinks contain almost as much; and some energy drinks pack as much as 500 mg. You may be using more caffeine than you realize. Excessive levels can lead to the jitters. Regular caffeine users who quit may have headaches, irritability, and other withdrawal symptoms.

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Grouping Psychoactive Drugs

Before you continue, check your understanding.

Question 1

Question 2

Question 3

Question 4

Question 5

Question 6

Answers appear in the Self Test section of the book.