Pharmacotherapy A Pathophysiologic Approach, 9th Ed.

48. Substance-Related Disorders I: Overview and Depressants, Stimulants, and Hallucinogens

Paul L. Doering and Robin Moorman Li


 Images Problems related to abuse of chemical substances can occur acutely (e.g., respiratory arrest from using heroin) or after some length of time (e.g., dependence or withdrawal from continued use of an opiate). The treatment approach is distinctly different depending on the type of problem.

 Images Certain drugs of abuse are marketed via the Internet and other unregulated outlets using names that would not immediately identify the substances as a dangerous drug. Health professionals must stay abreast of the latest marketing ruse to conceal the true nature of the substance.

 Images Synthetic chemists are constantly developing new drugs of abuse with pharmacology that mimics that of established controlled substances. Often, the dangers of these substances are greater than that of the parent compound.

 Images For a few drugs, there is a specific antidote that can be used in cases of overdoses. For others, treatment is symptomatic and supportive. Early recognition and treatment of acute drug intoxications can make a huge difference in the ultimate outcome for the patient.

 Images Withdrawal from certain classes of drugs (e.g., benzodiazepines or barbiturates) can be life-threatening, and steps must be taken to ensure that withdrawal is gradual and that it takes place in closely supervised settings.

 Images While there is much research focusing on drugs to treat the underlying addictive processes, to date the successes have been few. Whereas methadone, levo-α-acetylmethadol (LAAM), and now buprenorphine are used for narcotic maintenance, the logical approach at present should center on prevention.

 Images While the goal of therapy for substance dependence is to wean patients from a drug or drug category altogether, this is often difficult to do. For some, the treatment strategy is to manage the chemical dependency to allow the patient to lead as normal a life as is possible. This may require the substitution of one drug for the primary drug of dependency.

 Images Pharmacotherapy of substance-related disorders is most often adjunctive to other modes of therapy such as counseling and intense psychotherapy.

The book of Ecclesiastes wisely reminds us that “[W]hat has been will be again, what has been done will be done again; there is nothing new under the sun.”1 It is doubtful that the author of these sage words was referring to the repeating cycle of substance abuse, but when it comes to this subject there rarely is anything new under the sun, and this metaphor aptly applies.

Psychoactive drug use dates back to prehistoric times and the Neolithic era (8500 to 4000 BC) where the earliest human use of psychoactive substances consisted almost exclusively of plants and fruits whose mood-altering qualities were accidentally discovered but subsequently deliberately grown.2

Ancient civilizations (4000 BC to BC 400) such as the Sumerians, Egyptians, Indians, Chinese, and South Americans used opium, alcohol, cannabis, peyote, psychedelic mushrooms, and coca leaves. The Middle Ages (400 to 1400) saw the use of psychoactive plants such as belladonna and psilocybin mushroom, used by witches and shamans for healing and spiritual purposes, and distilled alcohol and coffee, tea, and opium spread along the trade routes.2

Almost 5,000 years ago at the Temple of Imhotep, a center for treating mental illness, opium was used in an attempt to cure the mentally ill by inducing vision, performing rituals, and praying to the gods.2Hippocrates, the father of medicine, recommended opium as a painkiller and as a treatment of female hysteria.2 Evidence of the inhalation of cannabis smoke can be found in the 3rd millennium BC, as indicated by charred cannabis seeds found in a ritual fire at an ancient burial site in present-day Romania.3 In 2003, a leather basket filled with cannabis leaf fragments and seeds was found next to a 2,500- to 2,800-year-old mummified shaman in the northwestern Xinjiang Uygur Autonomous Region of China.4 Thousands of years later, nearly every one of these drugs is still used today in one form or another for their mind-altering effects.

For any textbook to remain relevant, it must give emphasis to current information in any given content area. This means that space previously budgeted to one subject must give way to more recent trends. For example, if this chapter was written in the late 1960s, great attention would be given to the use and abuse of lysergic acid diethylamide (LSD) or methamphetamine.5,6 If it was written in the late 1970s, the epidemic abuse of hydromorphone (Dilaudid) would be featured.7

In the mid- to late 1970s great attention would be given to the abuse of methaqualone (Quaalude).8 Somewhere along the way, the abuse of pentazocine would take center stage.9 Amphetamine abuse has come, gone, and come back again.10 γ-Hydroxybutyric acid (GHB) made a sudden and dramatic appearance on the scene, but its use has lessened in the past years.11 The current epidemic of prescription drug abuse has skyrocketed its way into prominence. Hallucinogens such as dimethyltryptamine (DMT) and phenylethylamine derivatives are making a strong comeback.

By no means does this suggest that these above-mentioned drugs have disappeared, but instead many have taken a back seat to other, more commonly encountered drugs. For this reason, this rewrite of the present chapter and the one to follow will leave out some of the information from previous editions. The interested reader should consult prior editions of this textbook for information about these substances.

The lack of a common vocabulary in substance abuse treatment and prevention leads to several problems. Wide arrays of terms are in common use, many without precise meaning. This lack of universal agreement on language hampers effective communication among professionals and leads to difficulties in formulating public policy and administering third-party reimbursement programs.

In 2003, the Liaison Committee on Pain and Addiction, a collaborative effort of the American Academy of Pain Medicine, the American Pain Society, and the American Society of Addiction Medicine, developed definitions related to the use of medications for the treatment of pain consistent with current understanding of relevant neurobiology, pharmacology, and appropriate clinical practice. The definitions have been approved by each of the three collaborating organizations. The following definitions resulted from this consensus development committee12:

   1. Addiction is a primary, chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following five C’s: chronicity, impaired control over drug use, compulsive use, continued use despite harm, and craving.

   2. Drug abuse is a maladaptive pattern of substance use characterized by repeated adverse consequences related to the repeated use of the substance. Examples include failure to fulfill important obligations at work, school, or home; repeated use creating physical danger, such as driving under the influence; legal problems; and social or interpersonal problems such as arguments and fights.

   3. Physical dependence is a state of adaptation that is manifested by a drug class–specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist.

   4. Tolerance is a state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of the drug’s effects over time.


National Survey on Drug Use and Health

The National Survey on Drug Use and Health (NSDUH)13 is the primary source of statistical information on the use of illegal drugs by the U.S. population. Conducted by the federal government since 1971, the survey collects data from a representative sample of the population at their place of residence.

In 2011, it was estimated 22.5 million Americans aged 12 or older were current illicit drug users, which was defined by using an illicit drug during the month prior to the survey interview. This survey also found that marijuana continues to be the most commonly used illicit drug and has increased from 17.4 million past month users in 2010 to 18.1 million past month users in 2011. About 6.1 million Americans (2.4% of the population) admitted they abused prescription drugs in the past month in 2011, which is slightly lower than the 2010 data (7 million Americans), but still a monumental problem in our country.13

Monitoring the Future Study

Every year the Institute for Social Research at the University of Michigan conducts its Monitoring the Future Study (MTFS), supported under a series of research grants from the National Institute on Drug Abuse.14

A main purpose of this research is to study changes in the beliefs, attitudes, and behavior of young people in the United States, which requires frequent reassessment to identify the rapidly changing patterns.14

The 2012 samples included 45,449 students located in 395 secondary schools.14 After 4 straight years of increasing use among teens, annual marijuana use showed no further increase in any of the three grades surveyed in 2012. The 2012 annual prevalence rates (i.e., percent using in the prior 12 months) were 11%, 28%, and 36% for 8th, 10th, and 12th graders, respectively.

Daily use of marijuana, which had also been rising in all three grades in recent years, remained essentially flat between 2011 and 2012 at relatively high levels. The recent increases have been substantial—up by one quarter to one-third compared with their low points reached between 2006 and 2008 for the three grades. Today 1 in every 15 high school seniors (6.5%) is a daily or near-daily marijuana user. Researchers postulate that the increase of smoking marijuana is partly attributable to the national debate over medical use of cannabis, which may make the drugs seem safer to teenagers.14

Synthetic marijuana (see below) that contains designer chemicals included in the cannabinoid family (common names are K2, Spice, and Blaze) has been of increasing concern because of both its adverse effects and its high rates of use, first documented by this study in 2011. The annual prevalence rate held level among 12th graders in 2012—the second year of measurement—at 11.3%. Synthetic marijuana use was measured for the first time this year in 8th and 10th grades, and their annual prevalence rates were 4.4% and 8.8%, respectively. Aside from alcohol and tobacco, this is the second most widely used drug among 10th and 12th graders after marijuana, and the third most widely used among 8th graders after marijuana and inhalants.14

Illicit or street drug use has declined over the past decade (when marijuana use is not factored in). Unfortunately, the gradual decline has leveled off since 2010, and use has remained steady rather than declining when comparing 2011 data with 2008 data. The abuse of prescription drugs including sedatives, tranquilizers, and narcotic drugs other than heroin (most of which are analgesics) also continues to be a problem within this population group even though use has remained steady at 15.2% since 2008. Even though the use of these agents is not currently increasing in this specific population, they continue to be an important part of the nation’s drug abuse problem.14

Substance Abuse Emergencies: The DAWN Program

Since the early 1970s, the Drug Abuse Warning Network (DAWN),15 an ongoing national survey of hospital emergency departments (EDs), has collected information on patients seeking hospital ED treatment related to their use of an illegal drug or the nonmedical use of a legal drug. These data allow healthcare professionals to be better prepared to react to medical emergencies arising from illegal drug use and to target prevention and education programs to specific drug-using groups or populations.15

DAWN defines a drug-related episode as an ED visit that was induced by or related to the use of an illegal drug(s) or the nonmedical use of a legal drug for patients aged 6 to 97 years. In 2010, hospitals in the United States delivered a total of 136.1 million ED visits,16 and DAWN estimates that 2,201,050 ED visits were associated with drug misuse or abuse. This is a 94% increase since 2004—2.5 million visits in 2004 in comparison to 4.9 million visits in 2010.15 Of those ED visits, some key findings include the following:

   1. 23.8% involved illicit drugs only

   2. 27.4% involved pharmaceuticals only

   3. 3.8% involved alcohol only in patients under the age of 21

   4. 11.5% involved alcohol with other drugs


Substance abuse and addiction have an enormous impact on the economy. Over the years, the National Center on Addiction and Substance Abuse (CASA) at Columbia University has conducted studies aimed at quantifying the costs to local, state, and federal governments and agencies. The most recent figures17 are based on 2005 spending because that was the most recent year for which data were available over the course of the latest study.

Substance abuse and addiction cost federal, state, and local governments at least $467.7 billion in 2005 alone. The CASA report found that of $373.9 billion in federal and state spending, 95.6% ($357.4 billion) went to “shovel up the consequences and human wreckage of substance abuse and addiction”17; only 1.9% went to prevention and treatment, 0.4% to research, 1.4% to taxation and regulation, and 0.7% to interdiction.


Images Misuse of chemical substances causes problems of two types: those that occur acutely and those that arise after continued use of a drug. Acute problems are usually predictable, given the pharmacology of the drug. Chronic abuse of chemical substances can cause a wide array of physical, psychological, and psychiatric morbidities. The substance-induced disorders discussed here mainly include intoxication and withdrawal.

Images The essential feature of substance dependence is the continued use of the substance despite adverse substance-related problems. The criteria for substance dependence are the same for each of the drugs or drug classes, varying only to fit the unique pharmacologic properties of each drug. Patients who take prescribed drugs for appropriate medical indications and in correct doses may still show tolerance, physical dependence, and withdrawal symptoms if the drug is stopped abruptly rather than being tapered. Tolerance and physical dependence are inevitable consequences of chronic treatment with opioids and certain other drugs, but by themselves, tolerance and physical dependence do not imply “addiction.” To meet Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria18 for the diagnosis of substance dependence, at least three of the following must be present at any time in a 12-month period:

   1. Tolerance.

   2. Withdrawal, indicated by the appearance of the characteristic withdrawal syndrome or the use of the same or related drug to relieve or avoid withdrawal symptoms.

   3. Substance is taken in larger amounts or over a longer period of time than was intended.

   4. Patient has a persistent desire or unsuccessful efforts to cut down or control substance use.

   5. Considerable time is spent in activities necessary to obtain the substance, use the substance, or recover from its effects.

   6. Social, occupational, or recreational activities are given up or reduced because of substance use.

   7. Substance use is continued despite knowledge of having a persistent or recurrent physical or psychological problem caused or exacerbated by the substance.

The characteristic feature of substance abuse is a maladaptive pattern of substance use indicated by repeated adverse consequences related to the repeated use of the substance.18 Examples include failure to fulfill important obligations at work, school, or home; repeated use in situations in which it is physically dangerous, such as driving under the influence; legal problems; and social or interpersonal problems such as arguments and fights.18Intoxication refers to the development of a substance-specific syndrome after recent ingestion and presence in the body of a substance, and it is associated with maladaptive behavior during the waking state caused by the effect of the substance on the CNS. Examples include belligerence, mood lability, impaired judgment, and impaired social or occupational functioning. Evidence for recent intake of the substance can be obtained from the history, physical examination, or laboratory examination. The most common changes involve disturbances in perception, wakefulness, attention, thinking, judgment, motor behavior, and interpersonal behavior.

As with most illnesses, the course and prognosis of the disorders of substance use and dependence are variable. Getting patients who are drug dependent to stop using drugs is very difficult, and many patients return to drug use even after treatment. It has been reported that as many as 75% of treated, substance-dependent patients will relapse at least once. Many patients, however, are able to obtain recovery with treatment and continued care in 12-step programs such as Alcoholics Anonymous or Narcotics Anonymous (NA). Substance dependence or addiction can be viewed as a chronic illness that can be controlled successfully with treatment but cannot be cured and is associated with a high relapse rate. Without treatment, the course can progress to life-threatening severity, resulting from the effects of the drug, drug contaminants, or medical complications of use.18 Recently, the definitions used in the DSM-IV-TR criteria have been criticized.19 Although an in-depth discussion of the mechanism of drug addiction is beyond the scope of this chapter, the interested reader is directed to a review article that presents the current understanding of the biology of drug addiction.20


Opiates and Opioids

Deaths from prescription opioids have reached epidemic levels in the past decade. The number of overdose deaths is now greater than those of deaths from heroin and cocaine combined. In 2010, about 12 million Americans (age 12 or older) reported nonmedical use of narcotic analgesics in the past year. Nearly one third of people aged 12 and over who used drugs for the first time in 2009 began by using a prescription drug nonmedically.21 The Centers for Disease Control and Prevention (CDC) recently noted that, between 1997 and 2007, drug company distribution of prescription opioid analgesics increased 627%. The quantity of prescription painkillers sold to pharmacies, hospitals, and doctors’ offices was four times larger in 2010 than in 1999. According to the CDC, current distribution levels would allow “for every American to take 5 mg of Vicodin every 4 hours for 3 weeks.”22 Stated alternatively, enough prescription opioids were prescribed in 2010 to medicate every American adult around-the-clock for a month.21 Distribution by drug companies rose from 96 mg/person in 1997 to 698 mg/person in 2007. Although most of these drugs were prescribed for a medical purpose, many ended up in the hands of people who misused or abused them. Medical users in the last month numbered 9 million, while nonmedical users totaled 5.3 million.22

Nearly 15,000 people die every year of overdoses involving opioid analgesics. This is more than three times the people killed by these drugs in 1999. Nearly half a million ED visits in 2009 were due to people misusing or abusing prescription painkillers. For every overdose death there are 3 abuse treatment admissions, 35 ED visits for misuse or abuse, 161 people with abuse/dependence, and 461 nonmedical users. Nonmedical use of opioid analgesics costs health insurers up to $72.5 billion annually in direct healthcare costs.22

In the year 2000, retail pharmacies dispensed 174 million prescriptions for opioids, and by 2009, 257 million prescriptions were dispensed, which is an increase of 48%.23

Many states report problems with “pill mills,” where doctors prescribe large quantities of opioids to people without medical justification. Some people also obtain prescriptions from multiple prescribers by “doctor shopping.”

Clinical Controversy…

There is considerable debate about the appropriate use of prescribed opiates and how this might contribute to the overuse or abuse of these same drugs for nonmedicinal purposes. Not all decisions that physicians and other prescribers make are going to be correct. Likewise, pharmacists are going to occasionally make the wrong decision by either declining to fill a prescription that is proper and appropriate or filling one that is bogus. In the final analysis, mistakes in judgment are going to be made in both directions. Given this fact, in which direction should the health professional err? Should health practitioners give the patient the benefit of the doubt, writing or filling the prescription, even if their decision ultimately turns out to be wrong? Or should the mandate be in the other direction: refuse to prescribe pain medicines or refuse to fill the prescriptions, even when, in truth, the prescription is appropriate and valid? Most healthcare professionals assume that complaints of pain are real and prescribe accordingly.

Some states have a bigger problem with diversion and abuse of opioid analgesics than others. Prescription painkiller sales per person were more than three times higher in Florida, which has the highest rate, in comparison to Illinois, which has the lowest rate. From 2003 to 2009, a total of 16,550 drug overdose deaths were recorded by Florida medical examiners. The annual number of deaths increased 61%, from 1,804 to 2,905, and the death rate increased 47.5%, from 10.6 to 15.7 per 100,000 population. In 2009, approximately eight drug overdose deaths occurred each day. During 2003 to 2009, 85.9% of drug overdose deaths were unintentional, 11.1% were suicides, 2.6% were of undetermined intent, and 0.4% were homicides or pending. Prescription medications were implicated in 76.1% of all drug overdose deaths.24 Further, opiate overdoses, once almost always due to heroin use, are now increasingly due to abuse of prescription painkillers.25

Nearly every state has authorized prescription drug monitoring programs (PDMPs), and most are operational at this time. PDMPs are electronic systems for the monitoring of controlled substances and drugs of concern dispensed in the state or dispensed to an address in the state. They aim to detect and prevent the diversion and abuse of prescription drugs at the retail level, where no other automated information collection system exists, and to allow for the collection and analysis of prescription data more efficiently than states without such a program can accomplish.

The NSDUH indicated that illicit drug use is 16.2% among pregnant teens and 7.4% among pregnant women aged 18 to 25 years.13 Accordingly, in 2009, there were more than 13,000 babies born with neonatal abstinence syndrome (NAS) after being exposed to opioids in utero, a threefold increase since 2000.26 Between 2000 and 2009, the incidence of NAS among newborns increased from 1.20 (95% CI, 1.04 to 1.37) to 3.39 (95% CI, 3.12 to 3.67) per 1,000 hospital births per year. Antepartum maternal opiate use also increased from 1.19 to 5.63 (per 1,000 hospital births per year). In 2009, newborns with NAS were more likely than all other hospital births to have low birth weight (19.1% vs. 7%), and respiratory complications (30.9% vs. 8.9%), and to be covered by Medicaid (78.1% vs. 45.5%). Mean hospital charges for discharges with NAS increased from $39,400 in 2000 to $53,400 in 2009. By 2009, 77.6% of charges for NAS were billed to state Medicaid programs.


More than 30% of prescription opioid deaths involve methadone, even though only 2% of painkiller prescriptions are for this drug.27

Studies using medical examiner data suggested that more than three quarters of methadone overdoses involved persons who were not enrolled in programs treating opioid addiction with methadone and that most persons who overdosed were using it without a prescription.27 Recent analyses have shown that methadone was involved in one in three opioid-related deaths in 2008.28 Analysis of ED data29,30 indicates that the estimated number of ED visits resulting from nonmedical use of methadone alone or in combination with other drugs in 2009 (n = 63,031) was significantly greater than the estimated number in 2004 (n = 36,806).

Six times as many people died of methadone overdoses in 2009 than a decade before.31 More than 4 million methadone prescriptions were written for pain in 2009, despite US FDA warnings about the risks associated with methadone.

Methadone has pharmacologic properties unique among opioids, and as a result, a lack of knowledge about methadone among practitioners and patients has been identified as a factor contributing to the increased number of deaths observed in recent years.32 Methadone’s elimination half-life (8 to 59 hours) is longer than its duration of analgesic action (4 to 8 hours). In an FDA advisory issued in November 2006,33 healthcare professionals were reminded that methadone’s peak respiratory depressant effects typically occur later, and persist longer than its peak analgesic effects. The advisory notes that during treatment initiation, methadone’s full analgesic effect is usually not attained until 3 to 5 days of dosing.

Deaths have been reported during conversion from chronic, high-dose treatment with other opioid agonists to methadone. It is critical to understand the pharmacokinetics of methadone when converting patients from other opioids to methadone. Particular vigilance is necessary during treatment initiation, during conversion from one opioid to another, and during dose adjustments. Also, there are pharmacokinetic and pharmacodynamic drug interactions between methadone and many other drugs. Thus, drugs administered concomitantly with methadone should be evaluated for interaction potential.33

Benzodiazepines and Other Sedative–Hypnotics

ED visits involving benzodiazepines clearly outnumber those involving any of the other types of psychotherapeutic agents. DAWN estimates that 408,021 ED visits associated with nonmedical use of pharmaceuticals involved benzodiazepines in 2010.15 This is a dramatic increase from 2004 in which there were 170,471 ED visits attributed to benzodiazepines.

Because all benzodiazepines have abuse and dependence liability, patients cannot be switched from one benzodiazepine to another in hopes of decreasing a pattern of drug abuse or dependence behavior. Zolpidem, a nonbenzodiazepine, nonbarbiturate sedative, has been suggested to have little liability for physical dependence, but tolerance and withdrawal have been reported in association with its use as well.15 Recent reports in the lay press have linked use of zolpidem to sleep walking, erratic driving, binge eating, and other similarly bizarre activities.

CLINICAL PRESENTATION Benzodiazepine Intoxication and Withdrawal


    • The intoxicated patient may be in acute distress in overdoses or when benzodiazepines are combined with alcohol.

    • Patients in withdrawal may also be in acute distress and should be treated with a benzodiazepine taper to prevent seizures.


    • The patient may experience memory impairment, drowsiness, visual disturbances, confusion, and GI disturbances. Patients may appear intoxicated, with slurred speech, poor coordination, swaying, and bloodshot eyes, with or without the odor of alcohol.


    • Hypotension or nystagmus may be observed, and urinary retention may occur.

Laboratory Tests

    • Qualitative testing to confirm presence of benzodiazepines is useful for diagnostic purposes, but quantitative plasma concentrations are usually not clinically useful.

Benzodiazepines generally do not cause life-threatening respiratory depression (unless taken with other sedatives), as do the barbiturate-like drugs.16 Long-term use of even therapeutic doses of benzodiazepines can cause physical dependence and withdrawal symptoms after abrupt discontinuation.16 Occurrence of hallucinations or seizures would indicate severe physical withdrawal.

Gradual tapering of dosage is also associated with less withdrawal and rebound anxiety than abrupt discontinuation. Dependence on sedative–hypnotics and benzodiazepines is summarized in Table 48-1. For additional information on benzodiazepine withdrawal, refer to Chapter 53.

TABLE 48-1 Pharmacologic Treatment of Substance Intoxication



Carisoprodol is a prescription drug marketed since 1959 and used in primary care settings for the treatment of musculoskeletal conditions associated with muscle spasms and back pain. Its effectiveness for this use has been questioned.35 It is marketed in the United States as Soma as well as many generic versions. It is both structurally and pharmacologically related to meprobamate, a Schedule IV substance. In fact, a substantial percentage of the drug is metabolized to meprobamate,35 a drug with barbiturate-like properties.

In legitimate medical practice, carisoprodol is used as an adjunct to rest, physical therapy, and other measures for relief of acute, painful musculoskeletal conditions.35 Adverse effects are mostly related to the CNS: drowsiness, dizziness, vertigo, ataxia, tremor, agitation, irritability, headache, depressive reactions, syncope, and insomnia. Carisoprodol may also adversely affect cardiovascular (tachycardia, postural hypotension, and facial flushing), GI (nausea, vomiting, hiccup, and epigastric distress), and hematologic systems. Carisoprodol overdose has resulted in stupor, coma, shock, respiratory depression, and death.35

Recognizing that prolonged abuse of carisoprodol at high dosage can lead to tolerance, dependence, and withdrawal symptoms in humans,36 U.S. Drug Enforcement Administration (DEA) issued a final rule to classify carisoprodol as a Schedule IV Controlled Substance effective January 11, 2012.36

The number of carisoprodol-related ED visits involving misuse or abuse by patients aged 50 or older tripled between 2004 and 2009 (from 2,070 to 7,115 visits). The majority of ED visits involving carisoprodol also involved other pharmaceuticals (77%); the most common combinations involved narcotic pain relievers (55%) and benzodiazepines (47%).15


Dextromethorphan abuse is one of the most common (and most dangerous) examples of nonprescription drug abuse.37 Intoxication from consuming large doses of cough syrup is known on the street as “robodosing” or “robotripping.” Handsful of cough and cold remedies are sometimes called “skittles” because they look similar to the popular fruit candy. Dextromethorphan creates a depressant and sometimes profound hallucinogenic effect when taken in large doses. Since it is a nonprescription drug, it is easily procured by adolescents. Those who use the cough syrup to get high are sometimes called “syrup heads.”

High doses induce effects that include hyperexcitability, lethargy, ataxia, slurred speech, diaphoresis, hypertension, nystagmus, and mydriasis. When taken at much higher doses, it acts as a dissociative anesthetic, similar to phencyclidine (PCP, “angel dust”) and ketamine (“Special K”). These are the effects sought by those who use the drug to get high. At these high doses, dextromethorphan also is a CNS depressant.37

The recommended treatment for acute overdoses of dextromethorphan is naloxone. Although reports of its efficacy are mixed, it may be helpful in reversing the CNS depressant and neurologic effects.38



Cocaine is perhaps the most behaviorally reinforcing of all drugs of abuse. Clinicians estimate that approximately 10% of people who begin to use the drug recreationally will go on to serious, heavy use. Once having tried cocaine, an individual cannot predict or control the extent to which he or she will continue to use the drug.

The most characteristic pharmacologic effect of cocaine is stimulation of the CNS. In the CNS, cocaine appears to mediate its effects primarily by blocking reuptake of catecholamine neurotransmitters such as norepinephrine and dopamine.

Cocaine is absorbed rapidly from virtually all sites of application. For many years, cocaine has been administered as the hydrochloride salt form, usually by inhalation, but also by injection. In the last 18 to 20 years, as the purity of cocaine hydrochloride obtained on the street declined, many users converted the cocaine hydrochloride to cocaine base, also known as “crack” or “rock.” Smoking the drug leads to almost instant absorption and intense euphoria. Peak plasma concentrations of more than 900 ng/mL (mcg/L; 3 μmol/L) have been achieved following inhalation of cocaine base vapors, compared with concentrations of only 150 to 200 ng/mL (mcg/L; 0.49 to 0.66 μmol/L) achieved after inhalation of similar amounts of pure cocaine hydrochloride powder.39 The high from snorting can last 15 to 30 minutes, whereas that from smoking can last 5 to 10 minutes. Increased use can reduce the period of stimulation. An appreciable tolerance to the high can develop, and many addicts report that they seek but fail to achieve as much pleasure as they did from their first exposure. Scientific evidence suggests that the powerful neuropsychological reinforcing property of cocaine is responsible for an individual’s continued use despite harmful physical and social consequences.

Research has helped clarify certain patterns of cocaine use, such as combining cocaine and alcohol. Such drug use would seem counterintuitive because cocaine is a CNS stimulant, and alcohol a CNS depressant. In the presence of alcohol, cocaine is metabolized to cocaethylene, a longer-acting but potent psychoactive compound compared with the parent drug.40 The risk of death from cocaethylene is greater than from cocaine.41 The cocaine–alcohol combination is one of the most commonly identified among individuals who come to hospital EDs with acute substance abuse problems.

Cocaine is metabolized and eliminated rapidly. The elimination half-life of cocaine is approximately 1 hour, and the duration of effect is very short.39 The short duration of effect provides a powerful incentive for repeated use of the drug. Many users experience intense drug use cycling, sometimes lasting days, characterized by rapidly repeating doses of cocaine until their supply is exhausted. Laboratory monkeys, given a choice between food and cocaine around-the-clock for 8 days, consistently choose cocaine.

Complications of cocaine use frequently involve cardiovascular events.42,43 Cocaine is a psychotomimetic drug, sometimes even at nontoxic doses. A kindling phenomenon has been described with cocaine in which neuronal function becomes altered with each dose of the drug. The psychosis is qualitatively very similar to a paranoid schizophrenic psychosis.44 Although there is some controversy as to whether cocaine is associated with physical withdrawal on abrupt discontinuation, most clinicians feel that there is a characteristic syndrome of withdrawal effects, although they are not life-threatening.

Amphetamine, Methamphetamine, and Other Stimulants

The physiologic and psychological effects of amphetamines and other stimulants are qualitatively similar to those of cocaine—they diminish fatigue, increase alertness, and suppress appetite. Pharmacologically, amphetamines increase the activity of catecholamine neurotransmitters (e.g., norepinephrine and dopamine) by increasing release and by inhibiting the degradative enzyme monoamine oxidase.36

Methamphetamine is used orally, intranasally, rectally, by IV injection, and by smoking. Immediately after inhalation or IV injection, the methamphetamine user experiences an intense sensation, called a “rush” or “flash,” that lasts only a few minutes and is described as extremely pleasurable.

Because methamphetamine elevates mood, people who experiment with it tend to use it with increasing frequency and in increasing doses, although this was not their original intent. The timing and intensity of the “rush” that accompanies the use of methamphetamine, which is a result of the release of high levels of dopamine in the brain, depend in part on the method of administration. Specifically, the effect is almost instantaneous when smoked or injected, whereas it takes approximately 5 minutes after snorting or 20 minutes after oral ingestion. Prolonged use of methamphetamine can result in a tolerance for the drug and increased use at higher dosage levels, creating dependence. Such continual use of the drug with little or no sleep may lead to an extremely irritable and paranoid state. Discontinuing use of methamphetamine often results in a state of depression, as well as fatigue, anergia, and some types of cognitive impairment that can last from 2 days to several months.

Negative consequences of methamphetamine abuse range from anxiety and insomnia to convulsions, paranoia, and brain damage. Methamphetamine-induced caries, or “meth mouth,” is a characteristic pattern of dental decay commonly observed in patients who smoke methamphetamine.45

In addition to the many direct effects on methamphetamine users are the indirect impacts on individuals and society. Flammable ingredients that include acetone, red phosphorous, ethyl alcohol, and lithium metal are used in methamphetamine cookers, often with disastrous results. Fires and explosions often ensue, resulting in severe burns and uncovering laboratories to local law enforcement. Children of methamphetamine abusers are at high risk of neglect and abuse, and pregnant women’s use of methamphetamine can cause growth retardation, premature birth, and developmental disorders in neonates. Treatment for methamphetamine dependence is very difficult, and has a low success rate.46 The expanding global market is fed by an increase in clandestine manufacture of methamphetamine. Not only are there more laboratories in more countries, but their size and sophistication are also increasing. The number of reported domestic methamphetamine laboratory seizures in 2010 (6,768) represents a 12% increase over the total number of methamphetamine laboratories seized in 2009 (6,032).46 An increasing number of methamphetamine laboratories seized in the United States are small-scale operations capable of producing less than 2 oz (about 60 g) of the drug per production cycle. At least 81% of the laboratories seized every year since 2006 were small-scale. Most of the remaining laboratories seized were also relatively small, with capacities between 2 and 8 oz (about 60 and 230 g) per production cycle.46

CLINICAL PRESENTATION Amphetamine Intoxication and Withdrawal


    • Amphetamine intoxication is an acute condition that may result in death. Pharmacotherapy may be indicated for symptomatic control of seizures.

    • Patients may experience withdrawal symptoms for several days, but are usually not in acute distress. Treatment is supportive in nature. Pharmacotherapy is not effective to treat the symptoms of amphetamine withdrawal.


    • Depression, altered mental status, drug craving, dyssomnia, and fatigue are all symptoms of withdrawal.

    • Amphetamine intoxication may present as increased wakefulness, increased physical activity, decreased appetite, increased respiration, hyperthermia, and euphoria. Other CNS effects include irritability, insomnia, confusion, tremors, convulsions, anxiety, paranoia, chest pain, and aggressiveness. Hyperthermia and convulsions can result in death.


    • Patients with amphetamine intoxication may present with tachycardia, hypertension, or stroke.

Laboratory Tests

    • A qualitative drug of abuse urine screening is used for diagnostic purposes. Confirmatory blood tests with gas chromatography and mass spectrophotometry may be used for verification.

Methamphetamine is manufactured using the ephedrine or pseudoephedrine reduction method. In this process, ephedrine or pseudoephedrine is extracted from nonprescription cold and allergy tablets. Pharmacists should be wary of persons wishing to purchase large quantities of products containing nonprescription sympathomimetic products. As a precaution, federal legislation now mandates that pseudoephedrine-containing products be kept behind a counter, and suitable identification must be shown before they can be purchased.

Ecstasy and Other Methamphetamine Analogs

Several dozen analogs of amphetamine and methamphetamine are mildly hallucinogenic. Two methamphetamine analogs of most concern are 3,4-methylenedioxyamphetamine (MDA) and especially 3,4-methylenedioxymethamphetamine (MDMA or Ecstasy). The annual prevalence of Ecstasy declined significantly in 2012 in all three grades. Over the past dozen years, the use of Ecstasy has changed quite a bit, with rates being high in the early 2000s and decreasing through the mid-2000s. The 2012 annual prevalence rates are 1.1%, 3%, and 3.8% in grades 8, 10, and 12—less than half the peak rates observed in 2001.14

The effects of MDMA usually last approximately 4 to 6 hours. Users of the drug say that it produces profoundly positive feelings, empathy for others, elimination of anxiety, and extreme relaxation. MDMA is also said to suppress the need to eat, drink, or sleep, enabling users to endure 2- to 3-day parties. Consequently, MDMA use sometimes results in severe dehydration or exhaustion. MDMA generally reduces inhibitions and creates a sense of euphoria, but it also can evoke anxiety and paranoia. Heavier doses generate depression, irrationality, and psychosis. Users claim they experience feelings of closeness with others and a desire to touch them.

MDMA use can result in a variety of acute psychiatric disturbances, including panic, anxiety, depression, and paranoid thinking. Physical symptoms include muscle tension, nausea, blurred vision, faintness, chills, and sweating. MDMA also increases the heart rate and blood pressure. Other effects include hyperthermia, dehydration, vomiting, tremors, loss of control over body movements, insomnia, convulsions, rapid eye movements (REMs), and teeth and jaw clenching.

MDMA is perceived to be a harmless drug by many of its users, based in part on the fact that the risk of death is low compared with that with other drugs such as heroin and cocaine. However, mounting evidence points to neurotoxic effects of MDMA, involving a complex and incompletely understood mechanism. MDMA has been shown to destroy serotonin-producing neurons in animals, but further research is needed to understand the mechanism behind this loss of serotonin following MDMA exposure.

Researchers have found that heavy MDMA users have memory problems that persist for at least 2 weeks after they have stopped using the drug.47,48 McCann et al.49,50 conducted several studies to determine the effects of MDMA use on cognitive performance. MDMA users and controls were found to perform similarly on several cognitive tasks. However, MDMA subjects had significant performance deficits on a sustained-attention task requiring arithmetic calculations, a task requiring complex attention and incidental learning, a task requiring short-term memory, and a task of semantic recognition and verbal reasoning. The authors believe that their data provide further evidence that MDMA is neurotoxic to brain serotonin neurons in humans, and the behavioral data suggest that brain serotonin injury is associated with subtle but significant cognitive deficits.

Manufacturers of illicit drugs sometimes substitute other, potentially more dangerous substances for the one the buyer is expecting. Other suppliers produce products adulterated with chemical by-products of the incomplete processing of active ingredients. One such chemical, para-methoxyamphetamine, is a drastically more potent hyperthermic agent than MDMA, and deaths have been attributed to this agent.51

Synthetic Cathinones (aka Bath Salts)

Images Bath salts are a family of structurally related sympathomimetic, synthetic, designer drugs, known collectively as cathinones. Despite being marketed as “bath salts” or “plant food” and labeled “not for human consumption,” people use these substances for their amphetamine or cocaine-like effects. The name “bath salts” appears to have been selected to disguise the true nature of these substances. They are available in small quantities (milligram or 0.5 g packages) and are not the same as legitimate commercial bath products that are used for taking a soothing bath. Since the time of their appearance in the recreational drug market, there have been numerous confirmed cases of abuse, dependence, severe intoxication, and deaths related to the consumption of synthetic cathinones.

Catha edulis (khat) is an evergreen slow-growing shrub or tree native to Ethiopia and cultivated in East Africa and the South West Arabian Peninsula that in recent years has been grown widespread in Europe as well.52 In areas where it is grown people use the fresh vegetable material (leaves, stems, flower buds) of this plant for its stimulant effects. The fresh khat leaves contain 62 alkaloids, and 2 of these, cathine and cathinone, have been demonstrated to have amphetamine-like effects. Like amphetamines, cathine and cathinone are CNS stimulants, but their potency is less. Several studies have shown that the chronic use of this plant may produce various harmful effects, such as increased incidence of acute coronary vasospasm and myocardial infarction, esophagitis, gastritis, oral keratotic lesions, and liver toxicity.

Most of the synthetic cathinones, first appearing as recreational drugs in the mid-2000s, are a ring-substituted cathinone closely related to the phenethylamine family. The synthetic cathinones are the β-keto analogs of natural cathinone and differ from amphetamines by the presence of a ketone oxygen group at the β-position.

Images The pharmacology of these substances has not been extensively studied, but available information shows that these molecules may also inhibit monoamine oxidase.53 Within the class of synthetic cathinones there are considerable differences in pharmacology. The synthetic cathinones pyrovalerone and MDPV are highly potent and selective catecholamine transporter inhibitors but not substrate releasers. Mephedrone, methylone, ethylone, butylone, and naphyrone act as nonselective monoamine uptake inhibitors, similar to cocaine and, with the exception of naphyrone, also release serotonin, similar to MDMA. Cathinone and methcathinone are selective catecholamine uptake inhibitors and releasers, similar to their non–β-keto analogs amphetamine and methamphetamine.

Case reports have revealed a variety of adverse effects associated with the use of bath salts, including tachycardia, hypertension, diabetic ketoacidosis, delusions, paranoid psychosis, hyperthermia, dizziness, agitation, headaches, hyponatremia, acute liver failure, and suicide. Fatal intoxication has been associated with members of this class of drugs.54,55

On July 9, 2012, President Barack Obama signed a law that classifies synthetic cathinones and classes of related chemicals as Schedule I Controlled Substances.56



The drugs commonly classified as hallucinogens are LSD, psilocybin, DMT, mescaline, and other related compounds. LSD is one of the most potent mood-changing chemicals. It is manufactured from lysergic acid, which is found in ergot, a fungus that grows on rye and other grains.

Pharmacologically, LSD and related drugs stimulate both presynaptic (5-hydroxytryptamine [5-HT1A and 5-HT1B]) and postsynaptic (5-HT2) serotonin receptors in the brain, which functionally can cause either agonist or antagonist effects on serotonin activity. Precisely how the hallucinogens exert their effects remains unclear. LSD is an extraordinarily potent compound, producing observable CNS effects at doses as low as 25 mcg. For an in-depth review of LSD the reader is directed to a review by Passie et al.57

Designer Drugs

Images The past few years has witnessed the (re)-emergence of a number of very potent substances from three categories of drugs: the phenethylamines, the piperazines, and the tryptamines.58 These drugs are marketed largely through Internet sales, and are abused by people of all ages. They are illegally manufactured or synthesized in clandestine laboratories; many designer drugs are offered as a “research chemical,” “not for human consumption.”

Phenethylamines are ingested for their stimulant and hallucinogenic effects on the CNS. One group of the phenethylamine category that has received attention in recent years contains 2,5-dimethoxy or 2C derivatives, such as 4-bromo-2,5-dimethoxyphenethylamine (2C-B) or 2,5-dimethoxy-4-iodophenethylamine (2C-I).

Due to their stimulant and hallucinogenic effects, piperazines have entered the club or party scene. Piperazines of concern include N-benzylpiperazine (BZP), 1-(3-trifluoromethylphenyl)-piperazine (TFMPP), and 1-(3-chlorophenyl)-piperazine (meta-chlorophenylpiperazine [mCPP]). While mCPP is found in the illicit market, it is also a metabolite and starting material for the synthesis of several prescription drugs (e.g., trazodone, nefazadone).

Many of these emerging drugs have been added to DEA’s drugs and chemicals of concern list, and 2 drugs—BZP and TFMPP—appeared on the list of top 25 drugs reported to National Forensic Laboratory Information System (NFLIS) in 2008 (BZP only), 2009, and 2010.78 For example, N,N-DMT occurs naturally. South American snuffs and brews such as ayahuasca, prepared from a jungle vine (Banisteriopsis caapi), have been used in ancient medicinal and ritualistic practices that continue today. Like piperazines, tryptamines are hallucinogenic substances that are taken orally, or more rarely by smoking, snorting, or injection. Commonly abused tryptamines include DMT and 5-methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT). Several of the drugs presented in this NFLIS Special Report have been named and federally scheduled under the Controlled Substances Act.


Marijuana continues to be the most commonly used illicit drug among U.S. residents aged 12 and older.13 In 2011, an estimated 29.7 million residents reported using marijuana in the past year, a statistically significant increase from 25.9 million in 2008. According to the most recent MTFS,14 annual marijuana prevalence peaked among 12th graders in 1979 at 51%, following a rise that began during the 1960s. Then use declined fairly steadily for 13 years, bottoming at 22% in 1992—a decline of more than half. The 1990s, however, saw a resurgence of use. After a considerable increase (one that actually began among 8th graders a year earlier than among 10th and 12th graders), annual prevalence rates peaked in 1996 at 8th grade and in 1997 at 10th and 12th grades. After these peak years, use declined among all three grades through 2006, 2007, or 2008; since then there has been an upturn in use in all three grades, indicating another possible resurgence in use, although in 2011 there was some decline in use among 8th graders. In 2010 there was a significant increase in daily use in all three grades, followed by a nonsignificant increase in 2011 reaching 1.3%, 3.6%, and 6.6% in grades 8, 10, and 12, respectively. The rate for 12th graders is the highest rate since 1981, when it was 7%.

Most users smoke marijuana in hand-rolled cigarettes (joints), while some use pipes or water pipes (bongs). Marijuana cigars called blunts have also become popular.14 To make blunts, users slice open cigars and replace the tobacco with marijuana.

CLINICAL PRESENTATION Marijuana Intoxication

General Symptoms

    • Patients intoxicated with marijuana may experience euphoria, sensory intensification, increased appetite, apathy, hallucinations, and dry mouth. Occasionally, marijuana use produces anxiety, fear, distrust, or panic.


    • Tachycardia and conjunctival congestion may be observed in patients intoxicated with marijuana.

Laboratory Tests

    • Although the duration of effect of marijuana may be only several hours, THC is detectable on toxicologic screening for up to 4 to 5 weeks, especially in chronic users.

Marijuana’s effects begin immediately after the drug enters the brain and last from 1 to 3 hours. If marijuana is consumed in food or drink, the short-term effects begin more slowly, usually within 30 minutes to 1 hour, and last longer, for as long as 4 hours. Smoking marijuana delivers several times more of its major active ingredient, delta-9-tetrahydrocannabinol (THC), into the blood than does eating or drinking the drug.

Marijuana Potency

The principal psychoactive component of marijuana is THC. Hashish, the dried resin of the top of the plant, is much more potent than the plant itself. Increasingly sophisticated growing techniques have resulted in plants of greater potency. In 1976, an analysis of DEA seizures found an average THC content of 0.5% to 1%. In 2011, that figure was nearing 12%, with some samples containing THC levels above 20% and 30%.59

Harmful Effects of Marijuana

Marijuana has been used widely and is believed by many to be a relatively harmless, nonaddictive intoxicant. Chronic low doses of marijuana usually are not associated with significant physical withdrawal on abrupt discontinuation, but many chronic users exhibit compulsive drug-seeking and drug-use behaviors characteristic of addiction or dependence.

In point of fact, scientific research has found that 1 in 10 marijuana users will become addicted to the drug. And if one begins in adolescence, that number rises to one in six.60 Acutely, marijuana has many of the effects of alcohol—sedation, a decrease in reactivity and ability to perform complex tasks, and disinhibition. Endocrine effects including amenorrhea, decreased testosterone production, and inhibition of spermatogenesis have been demonstrated. Marijuana is associated with an amotivational syndrome characterized by a behavioral pattern of apathy, dullness, impaired judgment, decreased concentration and memory, loss of interest in personal hygiene, and a general reduction of goal-directed behavior.61

Science confirms62 that the adolescent brain, particularly the part of the brain that regulates the planning of complex cognitive behavior, personality expression, decision making, and social behavior, is not fully developed until the early to mid-20s. Developing brains are especially susceptible to all of the negative effects of marijuana and other drug use.62

One of the most well-designed studies63 on marijuana and intelligence, released in 2012, found that marijuana use reduces IQ by as much as eight points by age 38 among people who started using marijuana regularly before age 18 but then stopped. The purpose of the study was to test the association between persistent cannabis use and neuropsychological decline and determine whether decline is concentrated among adolescent-onset cannabis users. Participants were members of the Dunedin Study, a prospective study of a birth cohort of 1,037 individuals followed from birth (1972/1973) to age 38 years. Cannabis use was ascertained in interviews at ages 18, 21, 26, 32, and 38 years. Neuropsychological testing was conducted at age 13 years, before initiation of cannabis use, and again at age 38 years, after a pattern of persistent cannabis use had developed. Persistent cannabis use was associated with neuropsychological decline broadly across domains of functioning, even after controlling for years of education. Informants also reported noticing more cognitive problems for persistent cannabis users. Impairment was concentrated among adolescent-onset cannabis users, with more persistent use associated with greater decline. Further, cessation of cannabis use did not fully restore neuropsychological functioning among adolescent-onset cannabis users. Findings are suggestive of a neurotoxic effect of cannabis on the adolescent brain and highlight the importance of prevention and policy efforts targeting adolescents.63

Marijuana and Driving

Along with the increased prevalence of marijuana smoking, rates of driving under the influence of cannabis have also risen in recent year. Studies show that approximately 6% to 11% of fatal accident victims test positive for THC. In many of these cases alcohol is detected as well.64 A recent systematic review and meta-analysis65 was conducted to determine whether the acute consumption of cannabis by drivers increases the risk of motor vehicle collisions. The report included nine studies. The authors conclude that acute cannabis consumption is associated with an increased risk of a motor vehicle crash, especially for fatal collisions. An earlier meta-analysis66 showed that estimated odds ratios relating marijuana use to crash risk reported in included studies ranged from 0.85 to 7.16.

A double-blind, placebo-controlled, randomized, three-way crossover study67 was conducted to assess the effects of orally administered, normal therapeutic doses of dronabinol (10 and 20 mg) on driving performance in a standardized on-the-road driving test performed in normal traffic. About 25% of heavy users displayed driving impairments comparable to or worse than a blood alcohol concentration of 0.5 mg/mL (0.05 g%; 11 mmol/L).

Medical Marijuana

Since 1996, 18 states and the District of Columbia in the United States have enacted legislation to decriminalize marijuana for medical use.68 Some believe that the widespread use of medical marijuana is a thinly veiled strategy for the future legalization for recreational as well as medicinal use. Vague state laws governing medical marijuana have allowed recreational users of the drug to take advantage of marijuana dispensaries. Obtaining a license to use marijuana is not difficult. For example, on the boardwalk of Venice Beach, California, pitchmen dressed in marijuana green clothing approach passersby with offers of a $35, 10-minute evaluation for a medical marijuana recommendation for everything from cancer to appetite loss.69

Clinical Controversy…

The mere mention of the words “medical marijuana” is bound to evoke strong emotions among laypersons and healthcare professionals alike. While the federal government continues to enforce laws that make possession and use of marijuana illegal, regardless of the intended purpose, at last count 18 of the U.S. states have legalized medical marijuana, and 2 have legalized recreational use of the drug. While the safety and efficacy of marijuana to treat certain identifiable medical conditions has been confirmed, many other uses are supported by anecdote or limited clinical experience. However, the debate involves much more than whether cannabis works or not to treat illness. Instead, there are political, social, economic, and religious considerations that cloud the controversy over whether marijuana should be legalized for medical purposes. This debate will continue for years to come.

Designing and conducting adequate research studies of the beneficial effects of marijuana present some methodologic challenges.70,71 Smoked marijuana varies by dose, due to individual differences in absorption and metabolism in the liver, as well as puff frequency, depth of inhalation, and retention of inhaled smoke. Two comprehensive and dispassionate reviews72,73 of medical marijuana have been published, and the reader is encouraged to consult these for further information.

In the November 2012 election, both Colorado and Washington states passed laws allowing recreational use of marijuana, allowing adults to possess and grow marijuana with state regulation and taxation. The legalization measure in Oregon was defeated. Arkansas voters rejected the use of medicinal marijuana, but voters in Massachusetts joined 17 other states and the District of Columbia in supporting “medical” marijuana. Montana retained their “medical” marijuana law with more restrictions. Under federal law, any marijuana use is still illegal. Time will tell how this dilemma will be handled.

Synthetic Cannabinoids

Images Over the past several years, recreational use of synthetic cannabinoid compounds has been increasing in the United States. Known colloquially as “K2,” “Spice,” “Aroma,” “Mr. Smiley,” “Zohai,” “Eclipse,” “Black Mamba,” “Red X Dawn,” “Blaze,” and “Dream,” these products were not listed as controlled substances until recently. As a result, they were available at gas stations and convenience stores, and on the Internet.

Following identification of THC in 1964 and the CB1 and CB2 cannabinoid receptors in the 1980s, there was a pharmaceutical effort to synthesize cannabinoid receptor agonists for potential therapeutic indications such as nausea and pain. The largest structural group of synthetic cannabinoid receptor agonists are the JWH compounds named after John W. Huffman, an organic chemist at Clemson University, who synthesized many of these compounds.74 The vast majority of these efforts never reached commercial fruition. However, independent chemists now use this publicly available research to produce synthetic cannabinoids.

Images Currently there are over 100 compounds referred to as “synthetic marijuana.”75 The finished salable products consist of psychoactively inert dry plant material sprayed with these synthetic cannabinoid receptor agonists.76,77

NFLIS reported a dramatic increase in spice-related events, jumping from 15 in 2009 to 2,977 in 2010. Similarly, in 2011 there were a total of 6,959 calls to poison centers about exposures to synthetic marijuana, and from January 1, 2012 to October 31, 2012 alone, there were 4,710 calls.79

Symptoms of synthetic cannabinoid toxicity are similar to the euphoric and psychoactive effects of marijuana with additional sympathomimetic symptoms, including severe agitation and anxiety, extreme tachycardia, hypertension, nausea and vomiting, muscle spasms, seizures, tremors, diaphoresis, and restlessness. Intense hallucinations and psychotic episodes and suicidal and other harmful thoughts and/or actions have also been reported.80

Gunderson et al. have published a systematic review of the effects of synthetic cannabinoids and their psychosocial implications.81


Inhalants are a diverse group of substances that include volatile solvents, gases, and nitrites that are sniffed, snorted, huffed, or bagged to produce intoxicating effects similar to those of alcohol. These substances are found in common household products such as glues, lighter fluid, cleaning fluids, paint products, nail polish remover, gasoline, rubber glue, waxes, and varnishes. Chemicals found in these products include toluene, benzene, methanol, methylene chloride, acetone, methyl ethyl ketone, methyl butyl ketone, trichloroethylene, and trichloroethane. The gas used as a propellant in canned whipped cream and in small metallic containers called “whippets” (used to make whipped cream) is nitrous oxide or “laughing gas.”

Space limitation prevents an in-depth discussion of inhalants, and the interested reader is referred to past editions of this text.


Acute Drug Intoxications

Treatment of drug intoxication, summarized in Table 48-1, is primarily supportive. Vital functions are maintained while waiting for the drug to be eliminated. Whenever possible, drug therapy should be avoided because psychotropic drug therapy has the potential for worsening a toxic reaction to another psychoactive agent; however, when patients are agitated, combative, assaultive, hallucinating, or delusional, drug therapy may be required. Toxicology screens are useful in the evaluation and treatment process, but knowledge of the metabolism of the suspected drug and its excretion patterns is important for proper interpretation of test results.

Images Flumazenil can be used to reverse toxic effects of benzodiazepines. Naloxone can be used to reverse the effects of opiates. The usual dosage for naloxone in acute opiate toxicity is 0.4 to 2 mg IV, given approximately every 3 minutes as necessary. In some instances a naloxone infusion could be administered since the half-life of the opiate is likely to be longer than that of naloxone (see Table 48-2). Although naloxone is effective in reversing opiate overdose, it also can precipitate physical withdrawal in physically dependent patients. An excellent comprehensive review of the management of opioid analgesic overdose was recently published.83

TABLE 48-2 How to Use a Naloxone Infusion


CLINICAL PRESENTATION Opioid Intoxication and Withdrawal


    • Onset of the acute phase of withdrawal ranges from a few hours after stopping heroin to 3 to 5 days after stopping methadone. The duration of withdrawal ranges from 3 to 14 days.

    • Opioid withdrawal is not fatal unless there is a concurrent medical problem of major concern.

    • The presence of delirium should raise the question of concurrent withdrawal from another drug, such as alcohol, or another cause of delirium possibly secondary to drug use.


    • During withdrawal, patients can experience piloerection, insomnia, muscle aches, and yawning. While intoxicated, patients can experience euphoria, dysphoria, apathy, sedation, or attention impairment.


    • Fever, lacrimation, diaphoresis, or diarrhea may be observed during withdrawal. Motor retardation, slurred speech, and miosis may be observed during intoxication.

Laboratory Tests

    • Treatment is based more on clinical presentation because plasma opioid levels may not be clinically useful.

Other Diagnostic Tests

    • Arterial blood gases, pulse oximetry, and pulmonary function tests are useful to assess respiratory depression.

Intoxication with stimulants, including cocaine, is treated pharmacologically only if the patient is overtly psychotic and agitated.42,84 Injectable benzodiazepines, usually lorazepam 2 to 4 mg intramuscularly every 30 minutes to 6 hours as necessary, can be used for agitation. Antipsychotic drugs can be used on a short-term basis, primarily in patients with psychotic symptoms, and usually at relatively low doses, such as haloperidol 2 to 5 mg intramuscularly every 30 minutes to 6 hours as necessary, followed by 5 to 15 mg orally per day in single or divided doses if the patient is still psychotic after initial treatment.42

An evidence-based guideline gives precise recommendations for treating the cardiovascular complications of cocaine abuse and provides insight into the epidemiology, pathophysiology, treatment, and prognosis of the cardiac effects of cocaine.43 Seizures generally are treated supportively. IV lorazepam or diazepam can be used if seizures progress to status epilepticus.42

Hallucinogen intoxication is treated in a manner similar to stimulant intoxication. Drug therapy often can be avoided because patients can respond to careful reassurance, or so-called talk-down therapy. When necessary, short-term antianxiety and/or antipsychotic drug therapy can be used, as described previously.


Images Treatment of drug withdrawal is the primary indication for drug therapy in substance-related disorders. Goals of drug therapy include prevention of progression of withdrawal to life-threatening severity and enabling the patient to be sufficiently comfortable and functional to participate in a behavioral treatment program and supportive drug therapy. The clinician should remember that withdrawal is usually part of a substance dependence disorder. In drug therapy for withdrawal, it is important to avoid reinforcing the patient’s drug-seeking and drug-use behavior to the extent possible. Patients must be educated to deal with the stress of withdrawal without seeking drugs. Treatment of drug withdrawal is summarized in Table 48-3.

TABLE 48-3 Treatment of Withdrawal from Some Common Drugs of Abuse


CNS Depressant Withdrawal


Images Treatment of benzodiazepine withdrawal is very similar to the treatment of alcohol withdrawal. The major difference in management is the length of treatment.85 The onset of withdrawal symptoms in patients physically dependent on the long-acting benzodiazepines can be delayed up to 7 days after discontinuation of the drug. A common approach in detoxification of such patients is to initiate treatment at usual dosages (chlordiazepoxide orally 50 mg three times a day; lorazepam orally 2 mg three times a day) and to maintain the initial dosage for 5 days, with gradual tapering over an additional 5 days. Detoxification in patients physically dependent on shorter-acting benzodiazepines is similar to treatment of alcohol withdrawal.85

Among the benzodiazepines, alprazolam has been suggested to be more difficult to taper and discontinue than the other benzodiazepines.85 A longer, more gradual taper of the benzodiazepine used for detoxification can be needed. With all benzodiazepines, protracted minor abstinence symptoms—such as anxiety, insomnia, irritability, sensitivity to light and sound, and muscle spasms—can remain for several weeks in patients with a history of long exposure, even after the acute phase of benzodiazepine withdrawal is complete.

CLINICAL PRESENTATION Cocaine Intoxication and Withdrawal


    • In overdoses, cocaine is a CNS and cardiac stimulant. Cocaine-related deaths are often a result of cardiac arrest or seizures followed by respiratory arrest.


    • Symptoms of intoxication include motor agitation, elation, euphoria, grandiosity, loquacity, hypervigilance, sweating or chills, nausea, and vomiting.

    • Symptoms of withdrawal include fatigue, sleep disturbances, nightmares, depression, and changes in appetite.

    • High doses of cocaine and/or prolonged use can trigger paranoia.


    • Tachycardia, mydriasis, and either elevated or lowered blood pressure may be observed with overdose. Cardiac abnormalities (e.g., arrhythmias) and respiratory depression may be observed with overdose. Bradyarrhythmias, myocardial infarction, and tremors may be observed in acute withdrawal. Prolonged cocaine snorting can result in ulceration of the mucous membranes of the nose and can damage the nasal septum enough to cause it to collapse.

Laboratory Tests

    • Qualitative drugs of abuse urine screening tests are useful, followed by confirmatory testing if necessary. Levels of the primary metabolite, benzoylecgonine, may help diagnose acute cocaine toxicity.

Other Diagnostic Tests

    • Abnormal electroencephalograms may be observed with patients in acute withdrawal.


Opiate withdrawal syndrome is similar to a severe case of influenza. It is not life-threatening unless there is a concurrent life-threatening medical condition. Observable signs of withdrawal should be noted before initiation of drug therapy. Characteristic signs and symptoms of opiate withdrawal include pupillary dilation, lacrimation, rhinorrhea, piloerection (“gooseflesh”), yawning, sneezing, anorexia, nausea, vomiting, and diarrhea. Seizures do not occur. Onset and duration of withdrawal symptoms and the time of peak occurrence depend on the half-life of the drug involved. Typically heroin withdrawal reaches a peak within 36 to 72 hours of discontinuation and can last for 7 to 10 days. For methadone, symptoms peak at 72 hours but can last for 2 weeks or more.87

In the past, drug therapy for opioid withdrawal had typically been methadone, a synthetic opiate. Methadone is administered in decreasing doses over a period not exceeding 30 days (short-term detoxification) or 180 days (long-term detoxification). With methadone there were limited provisions for take-at-home dosing because of concern about the diversion of these drugs to illicit use.88

Use of Buprenorphine in Opiate Withdrawal and Maintenance

Images In 2002, buprenorphine was approved for opioid withdrawal. Prior to the passage of the federal Drug Addiction Treatment Act (DATA) of 2000,89 office-based management of opioid dependence was illegal because existing federal laws prohibited physicians from prescribing narcotics for the sole purpose of maintaining a patient in a narcotic-addicted state.

The first of two formulations approved, Subutex, contains only buprenorphine and is intended for use at the beginning of treatment. The other, Suboxone, contains both buprenorphine and the opiate antagonist naloxone, and is intended to be used in maintenance treatment of opiate addiction. When buprenorphine with naloxone is administered sublingually, the naloxone component produces no clinically significant effect; however, after parenteral administration, naloxone-induced opioid antagonism occurs resulting in symptoms of withdrawal.90,91

To qualify, physicians must be board certified in addiction medicine/psychiatry or hold other special credentials, and physicians are required to obtain 8 hours of authorized training before they can prescribe medications for office-based treatment of opioid dependence.90 DATA 2000, as amended in December 2006, specifies that an individual physician may have a maximum of 30 patients on opioid therapy at any one time for the first year. One year after the date on which a physician submitted the initial notification, the physician may submit a second notification of the need and intent to treat up to 100 patients.90,91

Medically supervised withdrawal with buprenorphine consists of an induction phase and a dose-reduction phase. Best practice guidelines collectively called Treatment Improvement Protocols (TIPs) are periodically issued for treatment of substance use disorders. TIP 40 (the guideline for the use of buprenorphine in the treatment of opioid addiction)92 provides consensus- and evidence-based guidance on the use of buprenorphine.

The statement recommends that patients dependent on short-acting opioids (e.g., hydromorphone, oxycodone, heroin) be inducted directly onto buprenorphine/naloxone tablets. The use of buprenorphine (as either buprenorphine monotherapy or buprenorphine/naloxone combination treatment) to taper off long-acting opioids should be considered only for those patients who have evidence of sustained medical and psychosocial stability, and should be undertaken in conjunction and in coordination with patients’ overall opioid treatment programs.

Images While there is much research focusing on drugs to treat the underlying addictive processes, to date the successes have been few. Whereas methadone, levo-α-acetylmethadol (LAAM), and now buprenorphine are used for narcotic maintenance, the logical approach at present should center on prevention.Images Maintenance treatment with buprenorphine for opioid addiction consists of three phases: (a) induction, (b) stabilization, and (c) maintenance.92Induction is the first stage of buprenorphine treatment and involves helping patients begin the process of switching from the opioid of abuse to buprenorphine. The goal of the induction phase is to find the minimum dose of buprenorphine at which the patient discontinues or markedly diminishes use of other opioids and experiences no withdrawal symptoms, minimal or no side effects, and no craving for the drug of abuse. The consensus panel recommends that the buprenorphine/naloxone combination be used for induction treatment (and for stabilization and maintenance) for most patients. The consensus panel further recommends that initial induction doses be administered as observed treatment; further doses may be thereafter provided via prescription. To minimize the chances of precipitating withdrawal, patients who are transferring from long-acting opioids (e.g., methadone, sustained-release morphine, sustained-release oxycodone) to buprenorphine should be inducted using buprenorphine monotherapy, but switched to buprenorphine/naloxone soon thereafter. Induction protocols are shown in Figure 48-1.


FIGURE 48-1 Determining the induction dose for days 1–2 of buprenorphine therapy.

The stabilization phase begins when a patient is experiencing no withdrawal symptoms, is experiencing minimal or no side effects, and no longer has uncontrollable cravings for opioid agonists. Dosage adjustments may be necessary during early stabilization, and frequent contact with the patient increases the likelihood of compliance. The longest period that a patient is on buprenorphine is the maintenance phase. This period may be indefinite. During the maintenance phase, attention must be focused on the psychosocial and family issues that have been identified during the course of treatment as contributing to a patient’s addiction.92

Some other issues related to opioid abuse that need to be addressed during maintenance treatment include, but are not limited to, the following92:

   1. Psychiatric comorbidity

   2. Somatic consequences of drug use

   3. Family and support issues

   4. Structuring of time in prosocial activities

   5. Employment and financial issues

   6. Legal consequences of drug use

   7. Other drug and alcohol abuse

A recent systematic review93 evaluating the withdrawal component of buprenorphine treatment, including 22 studies involving 1,736 participants, was published. The major comparisons for buprenorphine were with methadone (5 studies) and clonidine or lofexidine (12 studies). Five studies compared different rates of buprenorphine dose reduction.

The authors concluded that severity of withdrawal is similar for withdrawal managed with buprenorphine and withdrawal managed with methadone, but withdrawal symptoms may resolve more quickly with buprenorphine. It appears that completion of withdrawal treatment may be more likely with buprenorphine relative to methadone (RR 1.18; 95% CI, 0.93 to 1.49; P = 0.18), but more studies are required to confirm this.93

Images A rapid detoxification technique has been developed that is designed to shorten detoxification by precipitating withdrawal through the administration of opioid antagonists such as naloxone or naltrexone.93 This approach is thought to have the advantage of getting patients through detoxification rapidly, minimizing the risk of relapse, and initiating treatment more quickly with naltrexone maintenance combined with suitable psychosocial interventions. Ultra-rapid detoxification represents a variant of this technique in which patients undergo opioid antagonist–precipitated withdrawal while under general anesthesia or heavy sedation. In the United States, there has been a rapid proliferation of programs offering ultrarapid detoxification, with some programs charging up to $15,000 per treatment. Rapid detoxification remains unproven and controversial.

Antagonist-induced withdrawal is more intense but less prolonged than withdrawal managed with reducing doses of methadone, and doses of naltrexone sufficient for blockade of opioid effects can be established significantly more quickly with antagonist-induced withdrawal than withdrawal managed with clonidine and symptomatic medications. The level of sedation does not affect the intensity and duration of withdrawal, although the duration of anesthesia may influence withdrawal severity. There is a significantly greater risk of adverse events with heavy, compared with light, sedation (RR 3.21, 95% CI, 1.13 to 9.12, P = 0.03) and probably with this antagonist-induced withdrawal compared with other forms of detoxification.93

The potential risks and high cost of using opioid-blocking drugs during heavy sedation or anesthesia to bring on withdrawal outweigh the benefits.93


Substance Dependence

Images The treatment of drug dependence is primarily behavioral. The patient generally is taught that complete abstinence is the only realistic alternative to a life of uncontrollable drug use and despair that ultimately will end in death, and that there is no intermediate, controllable level of drinking or use of another drug. There may be an extremely few individuals who can return to controllable levels of drinking alcohol, but it is impossible to predict who these individuals are. The prospect of life without alcohol or other drugs is incomprehensible to many patients. Entry into treatment often is facilitated by some type of leverage that the drug-dependent person associates with negative consequences, such as potential loss of job, divorce, legal problems, or deteriorating physical health. Early treatment is directed at penetrating the denial of a problem that is always present. The patient must be educated as to the disease of addiction, the effects of drugs, and the permanence of the condition.

As evidenced by the approval of the two buprenorphine products, there has been a trend toward outpatient treatment for drug dependence, caused in part by cost-containment efforts. Inpatient treatment programs can cost as much as $20,000 for a 4-week stay. When withdrawal symptoms are mild to moderate and there are no other medical indications for hospitalization, outpatient treatment can be an attractive alternative to inpatient treatment. One critical criterion for outpatient treatment is the patient’s compliance with complete abstinence from the dependence-producing drug during the treatment experience.

Families must be involved in treatment. The course of the patient’s illness often has a devastating effect on other family members. Severely depleted self-esteem, denial of the family member’s addiction, feelings of responsibility for the family member’s drug use, and other behaviors that parallel the addiction process are often present.

Images Because at present there are no drugs to effectively treat the underlying addictive processes of drug dependence, treatment must be a lifelong process. Aftercare, or what is now being called continued care, should include regular and frequent treatment in some form. Most drug-dependence treatment programs embrace a treatment approach based on the 12 steps to recovery. Among chemically dependent healthcare professionals, treatment that incorporates both 12-step and peer-led self-help groups can be most effective.


The notion of using pharmacogenetic testing to individualize the treatment of substance abuse disorders is relatively new, but studies of several genes have yielded significant findings.94 Several gene variants have been shown to influence individual response to pharmacotherapy for drug addiction, notably in the μ-opioid receptor gene OPRM1 A118G (rs561720), polymorphisms of CYP2A6, and ANKK1 Taq1A. It remains to be seen how this genetic information will be incorporated into clinical practice. Prospective studies evaluating the use of genetic testing in a clinical setting and the effect on treatment outcome are warranted to further evaluate the benefits and risks of this approach.94




    1. Ecclesiastes 1:9 New International Version.

    2. Inaba DS, Cohen WE. Uppers, Downers, All Arounders: Physical and Mental Effects of Psychoactive Drugs, 7th ed. Medford, OR: CNS Productions Inc, 2011:1.1.

    3. Rudgley R. The Lost Civilizations of the Stone Age. New York: Free Press, 2000:138.

    4. Jiang HE, Xiao Li X, Zhaod YX, et al. A new insight into Cannabis sativa (Cannabaceae) utilization from 2500-year-old Yanghai Tombs, Xinjiang, China. J Ethnopharmacol 2006;108:414–422.

    5. Frosch WA, Robbins ES, Stern M. Untoward reactions to lysergic acid diethylamide (LSD) resulting in hospitalization. N Engl J Med 1965;273(23):1235–1239.

    6. James IP. A methylamphetamine epidemic? Lancet 1968;1(7548):916.

    7. Lindberg DK. A word of warning: Marked increase in hydromorphone (Dilaudid) addiction. J Fla Med Assoc 1978;65:822.

    8. Bridge TP, Ellinwood EH Jr. Quaalude alley: A one-way street. Am J Psychiatry 1973;130:217–219.

    9. Finkelstein IS. Pentazocine abuse. JAMA 1973;224:249.

   10. Derlet RW, Rice P, Horowitz BZ, Lord RV. Amphetamine toxicity: Experience with 127 cases. J Emerg Med 1989;7(2):157–161.

   11. Bechtel LK, Holstege CP. Criminal poisoning: Drug-facilitated sexual assault. Emerg Med Clin North Am 2007;25:499–525.

   12. Savage SR, Joranson DE, Covington EC, et al. Definitions related to the medical use of opioids: Evolution towards universal agreement. J Pain Symptom Manage 2003;26:655–667.

   13. Substance Abuse and Mental Health Services Administration. Results from the 2011 National Survey on Drug Use and Health: National Findings. Series H-44, HHS Publication No. (SMA) 12-4713. Rockville, MD: Substance Abuse and Mental Health Services Administration, 2012.

   14. Johnston LD, O’Malley PM, Bachman JG, Schulenberg JE. Monitoring the Future National Results on Adolescent Drug Use: Overview of Key Findings, 2012. Ann Arbor, MI: Institute for Social Research, the University of Michigan, 2013.

   15. Substance Abuse and Mental Health Services Administration, Center for Behavioral Health Statistics and Quality. The DAWN Report: Highlights of the 2010 Drug Abuse Warning Network (DAWN) Findings on Drug-Related Emergency Department Visits. Rockville, MD: Substance Abuse and Mental Health Services Administration, July 2, 2012.

   16. National Center for Health Statistics. National Hospital Ambulatory Medical Care Survey: 2009 Emergency Department Summary Tables. and

   17. National Center on Addiction and Substance Abuse at Columbia University. “You’ve Got Drugs!” V: Prescription Drug Pushers on the Internet. A CASA White Paper. New York, NY: National Center on Addiction and Substance Abuse at Columbia University, July 2008.

   18. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Washington, DC: American Psychiatric Association, 2000:212–214.

   19. Heit HA, Gourlay DL. DSM-V and the definitions: Time to get it right. Pain Med 2009;10:784–786.

   20. Koob GF, Volkow ND. Neurocircuitry of addiction. Neuropsychopharmacology 2010;35:217–238 [Erratum. Neuropsychopharmacology 2010;35:1051].

   21. Centers for Disease Control and Prevention. Prescription Painkiller Overdoses in the US.

   22. Centers for Disease Control and Prevention. Public Health Grand Rounds. February 17, 2011,

   23. Based on Data from SDI, Vector One: National. Years 2000-2009. Extracted June 2010, DrugsAdvisoryCommittee/UCM217510.pdf.

   24. Centers for Disease Control and Prevention. Drug overdose deaths—Florida, 2003-2009. MMWR Morb Mortal Wkly Rep 2011;60(26):869–872.

   25. Unintentional Drug Poisoning in the United States, National Center for Injury Prevention and Control, Centers for Disease Control and Prevention. July 2010,

   26. Patrick SW, Schumacher RE, Benneyworth BD, et al. Neonatal abstinence syndrome and associated health care expenditures: United States, 2000-2009. JAMA 2012;307:1934–1940 [Epub April 30, 2012].

   27. Substance Abuse and Mental Health Services Administration. Data Summary: Methadone Mortality, A 2010 Reassessment. Rockville, MD: US Department of Health and Human Services, Substance Abuse and Mental Health Services Administration, 2010,

   28. Warner M, Chen L, Makuc D, et al. Drug Poisoning Deaths in the United States, 1980–2008. NCHS Data Brief, No. 81. Hyattsville, MD: National Center for Health Statistics, 2011,

   29. Substance Abuse and Mental Health Services Administration, Center for Behavioral Statistics and Quality. The DAWN Report: Methadone-Related Emergency Department Visits Involving Nonmedical Use. Rockville, MD: Substance Abuse and Mental Health Services Administration, 2012,

   30. Warner M, Chen LH, Makuc DM, et al. Drug poisoning deaths in the United States, 1980-2008. NCHS Data Brief. 2011;81:1–8.

   31. Vital signs: Risk for overdose from methadone used for pain relief—United States, 1999-2010. MMWR Morb Mortal Wkly Rep 2012;61:493–497.

   32. Methadone-Associated Overdose Deaths; Factors Contributing to Increased Deaths and Efforts to Prevent Them. United States Government Accounting Office Report to Congressional Requesters. GAO-09-341. March 26, 2009,

   33. U.S. Food and Drug Administration. Information for Healthcare Professionals: Methadone. Issued November 27, 2006,

   34. Ruiz P, Strain EC. Lowinson and Ruiz’s Substance Abuse: A Comprehensive Textbook, 5th ed. Riverwoods, IL: Lippincott Williams & Wilkins, 2011:1074.

   35. Fass JA. Carisoprodol legal status and patterns of abuse. Ann Pharmacotherapy 2010;44:1962–1967 [Epub November 9, 2010].

   36. Department of Justice, Drug Enforcement Administration. 21 CFR Part 1308. Schedules of Controlled Substances: Placement of Carisoprodol into Schedule IV 21.

   37. Reissig CJ, Carter LP, Johnson MW, et al. High doses of dextromethorphan, an NMDA antagonist, produce effects similar to classic hallucinogens. Psychopharmacology (Berl) 2012;223(1):1–15 [Epub April 13, 2012].

   38. Chyka PA, Erdman AR, Manoguerra AS, et al. American Association of Poison Control Centers. Dextromethorphan poisoning: An evidence-based consensus guideline for out-of-hospital management. Clin Toxicol (Phila) 2007;45:662–677.

   39. Carrera MR, Meijler MM, Janda KD. Cocaine pharmacology and current pharmacotherapies for its abuse. Bioorg Med Chem 2004;12:5019–5030.

   40. Laizure SC, Parker RB. Pharmacodynamic evaluation of the cardiovascular effects after the coadministration of cocaine and ethanol. Drug Metab Dispos 2009;37:310–314.

   41. Farooq MU, Bhatt A, Patel M. Neurotoxic and cardiotoxic effects of cocaine and ethanol. J Med Toxicol 2009;5:134–138.

   42. Phillips K, Luk A, Soor GS, et al. Cocaine cardiotoxicity: A review of the pathophysiology, pathology, and treatment options. Am J Cardiovasc Drugs 2009;9:177–196.

   43. McCord J, Jneid H, Hollander JE, et al. American Heart Association Acute Cardiac Care Committee of the Council on Clinical Cardiology. Management of cocaine-associated chest pain and myocardial infarction: A scientific statement from the American Heart Association Acute Cardiac Care Committee of the Council on Clinical Cardiology. Circulation 2008;117:1897–1907 [Epub March 17, 2008].

   44. Mahoney JJ III, Kalechstein AD, De La Garza R II, et al. Presence and persistence of psychotic symptoms in cocaineversus methamphetamine-dependent participants. Am J Addict 2008;17:83–98.

   45. Hamamoto DT, Rhodus NL. Methamphetamine abuse and dentistry. Oral Dis 2009;15:27–37.

   46. U.S. Department of Justice National Drug Threat Assessment. 2011,

   47. Skelton MR, Williams MT, Vorhees CV. Developmental effects of 3,4-methylenedioxymethamphetamine: A review. Behav Pharmacol 2008;19:91–111.

   48. Indlekofer F, Piechatzek M, Daamen M. Reduced memory and attention performance in a population-based sample of young adults with a moderate lifetime use of cannabis, ecstasy and alcohol. J Psychopharmacol 2009;23(5):495–509.

   49. McCann UD, Kuwabara H, Kumar A, et al. Persistent cognitive and dopamine transporter deficits in abstinent methamphetamine users. Synapse 2008;62:91–100.

   50. McCann UD, Szabo Z, Vranesic M, et al. Positron emission tomographic studies of brain dopamine and serotonin transporters in abstinent (+/–)3,4-methylenedioxymethamphetamine (“ecstasy”) users: Relationship to cognitive performance. Psychopharmacology (Berl) 2008;200:439–450.

   51. Lamberth PG, Ding GK, Nurmi LA. Fatal paramethoxy-amphetamine (PMA) poisoning in the Australian Capital Territory. Med J Aust 2008;188:426.

   52. Coppola M, Mondola R. Synthetic cathinones: Chemistry, pharmacology and toxicology of a new class of designer drugs of abuse marketed as “bath salts” or “plant food”. Toxicol Lett 2012;211:144–149 [Epub March 21, 2012].

   53. Simmler LD, Buser TA, Donzelli M, et al. Pharmacological characterization of designer cathinones in vitro. Br J Pharmacol 2013;168(2):458–470. doi:10.1111/j.1476-5381.2012.02145.x [Epub ahead of print].

   54. Loeffler G, Hurst D, Penn A, Yung K. Spice, bath salts, and the U.S. military: The emergence of synthetic cannabinoid receptor agonists and cathinones in the U.S. Armed Forces. Mil Med 2012;177(9):1041–1048.

   55. Prosser JM, Nelson LS. The toxicology of bath salts: A review of synthetic cathinones. J Med Toxicol 2012;8(1):33–42.

   56. One Hundred Twelfth Congress of the United States of America. Synthetic Drug Abuse Prevention Act of 2012. Senate Bill 3187, the Food and Drug Administration Section 1152. Addition of Synthetic Drugs to Schedule I of the Controlled Substances Act. January 3, 2012.

   57. Passie T, Halpern JH, Stichtenoth DO, Emrich HM, Hintzen A. The pharmacology of lysergic acid diethylamide: A review. CNS Neurosci Ther 2008;14(4):295–314.

   58. National Forensic Laboratory Information System Special Report: Emerging 2C-Phenethylamines, Piperazines, and Tryptamines in NFLIS, 2006-2011. Springfield, VA: U.S. Drug Enforcement Administration, Office of Diversion Control. 2012,

   59. High potency marijuana concerns authorities. Star News Online May 21, 2012,

   60. Wagner FA, Anthony JC. From first drug use to drug dependence; developmental periods of risk for dependence upon cannabis, cocaine, and alcohol. Neuropsychopharmacology 2002;26:479–488.

   61. Cherek DR, Lane SD, Dougherty DM. Possible amotivational effects following marijuana smoking under laboratory conditions. Exp Clin Psychopharmacol 2002;10:26–38.

   62. Mills KL, Lalonde F, Clasen L, Giedd JN, Blakemore SJ. Developmental changes in the structure of the social brain in late childhood and adolescence. Soc Cogn Affect Neurosci 2012 [Epub ahead of print].

   63. Meier MH, Caspi A, Ambler A, et al. Persistent cannabis users show neuropsychological decline from childhood to midlife. Proc Natl Acad Sci U S A 2012;109(40):E2657–E2664. doi:10.1073/pnas.1206820109 [Epub August 27, 2012].

   64. Sewell RA, Poling J, Sofuoglu M. The effect of cannabis compared with alcohol on driving. Am J Addict 2009;18:185–193.

   65. Asbridge M, Hayden JA, Cartwright JL. Acute cannabis consumption and motor vehicle collision risk: Systematic review of observational studies and meta-analysis. BMJ 2012;344:e536. doi:10.1136/bmj.e536.

   66. Li MC, Brady JE, DiMaggio CJ, et al. Marijuana use and motor vehicle crashes. Epidemiol Rev 2012;34(1):65–72 [Epub October 4, 2011].

   67. Bosker WM, Kuypers KP, Theunissen EL, et al. Medicinal Δ(9)-tetrahydrocannabinol (dronabinol) impairs on-the-road driving performance of occasional and heavy cannabis users but is not detected in Standard Field Sobriety Tests. Addiction 2012;107(10):1837–1844. doi:10.1111/j.1360-0443.2012.03928.x [Epub July 12, 2012].

   68. Medical Marijuana. January 9, 2011,

   69. Onishi N. Marijuana only for the sick? A farce, some Angelenos say. New York Times October 7, 2012,

   70. Cerdá M, Wall M, Keyes KM, et al. Medical marijuana laws in 50 states: Investigating the relationship between state legalization of medical marijuana and marijuana use, abuse and dependence. Drug Alcohol Depend 2012;120(1–3):22–27 [Epub November 17, 2011].

   71. Gorelick DA, Heishman SJ. Methods for clinical research involving cannabis administration. In: Onaivi ES, ed. Methods in Molecular Medicine: Marijuana and Cannabinoid Research: Methods and Protocols. New Jersey: Humana Press, 2006.

   72. Medical marijuana: Answers to your burning questions. Pharmacist’s Letter/Prescriber’s Letter 2010;26:260906.

   73. Seamon MJ, Fass JA, Maniscalco-Feichtl M, Abu-Shraie NA. Medical marijuana and the developing role of the pharmacist. Am J Health Syst Pharm 2007;64:1037–1044.

   74. Federation of American Scientists. Synthetic Drugs: Overview and Issues for Congress.

   75. European Monitoring Centre for Drugs and Drug Addiction. Action on New Drugs Briefing Paper: Understanding the ‘Spice’ Phenomenon. 2009,

   76. Wells DL, Ott CA. The “new” marijuana. Ann Pharmacother 2011;45(3):414–417.

   77. Hudson S, Ramsey J, King L, et al. Use of high-resolution accurate mass spectrometry to detect reported and previously unreported cannabinomimetics in “herbal high” products. J Anal Toxicol 2010;34(5):252–260.

   78. U.S. Drug Enforcement Administration, Office of Diversion Control. National Forensic Laboratory Information System Special Report: Synthetic Cannabinoids and Synthetic Cathinones Reported in NFLIS, 2009-2010. Springfield, VA: U.S. Drug Enforcement Administration, 2011.

   79. American Association of Poison Control Centers. Synthetic Marijuana.

   80. Cohen J, Morrison S, Greenberg J, Saidinejad M. Clinical presentation of intoxication due to synthetic cannabinoids. Pediatrics 2012;129:e1064-e1067. doi:10.1542/peds.2011-1797 [Epub March 19, 2012].

   81. Gunderson EW, Haughey HM, Ait-Daoud N, et al. “Spice” and “K2” herbal highs: A case series and systematic review of the clinical effects and biopsychosocial implications of synthetic cannabinoid use in humans. Am J Addict 2012;21:320–326. doi:10.1111/j.1521-0391.2012.00240.x [Epub April 23, 2012].

   82. Nelson LS, Olsen D. Opioids. In: Nelson LS, Olsen D, eds. Goldfrank’s Toxicologic Emergencies, 9th ed. New York: McGraw-Hill, 2011,[chapter 38].

   83. Boyer EW. Management of opioid analgesic overdose. N Engl J Med 2012;367:146–155.

   84. Mathias S, Lubman DI, Hides L. Substance-induced psychosis: A diagnostic conundrum. J Clin Psychiatry 2008;69:358–367.

   85. Lader M, Tylee A, Donoghue J. Withdrawing benzodiazepines in primary care. CNS Drugs 2009;23:19–34. doi:10.2165/0023210-200923010-00002.

   86. Shoptaw SJ, Kao U, Heinzerling K, Ling W. Treatment for amphetamine withdrawal. Cochrane Database Syst Rev 2009;(2):CD003021.

   87. Soyka M, Kranzler HR, van den Brink W, et al. The World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the biological treatment of substance use and related disorders. Part 2: Opioid dependence. WFSBP Task Force on Treatment, Guidelines for Substance Use Disorders. World J Biol Psychiatry 2011;12:160–187.

   88. Amato L, Minozzi S, Davoli M, Vecchi S. Psychosocial and pharmacological treatments versus pharmacological treatments for opioid detoxification. Cochrane Database Syst Rev 2011;(9):CD005031.

   89. Drug Addiction Treatment Act of 2000 (DATA), Title XXXV of the Children’s Health Act of 2000 (Public Law No. 106-310, 116 Stat 1222).

   90. CSAT Buprenorphine Information Center. The Center for Substance Abuse Treatment (CSAT), Substance Abuse and Mental Health Services Administration (SAMHSA).

   91. Orman JS, Keating GM. Buprenorphine/naloxone: A review of its use in the treatment of opioid dependence. Drugs 2009;69:577–607.

   92. TIP 40 Center for Substance Abuse Treatment. Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction. Treatment Improvement Protocol (TIP) Series 40. DHHS Publication No. (SMA) 04-3939. Rockville, MD: Substance Abuse and Mental Health Services Administration, 2004,

   93. Gowing L, Ali R, White JM. Opioid antagonists under heavy sedation or anesthesia for opioid withdrawal. Cochrane Database Syst Rev 2010;(1):CD002022. doi:10.1002/14651858.CD002022.pub3.

   94. Sturgess JE, George TP, Kennedy JL, et al. Pharmacogenetics of alcohol, nicotine and drug addiction treatments. Addict Biol 2011;16(3):357–376. doi:10.1111/j. 1369-1600.2010.00287.x [Epub March 1, 2011].