1. • Apply evidence-based screening methods to identify patients who are dependent or at risk of becoming dependent on substances of abuse

2. • Provide preventive counseling and brief interventions for patients at risk of becoming addicted/dependent

3. • Apply evidence-based treatment strategies to individuals with substance use disorders

4. • Include strategies for monitoring improvement and addressing adherence as part of the treatment plan for patients with substance use disorders

5. • Recognize the clinical, behavioral, and neurobiological links between substance use disorders and other disorders of impulsivity

Heroin was first synthesized in the late 1800s and has proven to be one of the most addictive substances known to man. Prescription opioids, including morphine and oxycodone, also have high abuse potential; but until relatively recently, these agents were restricted mainly to palliative care and cancer patients. Now, however, prescription opioid use for the treatment of chronic noncancer pain has gained acceptance and become much more common. Correspondingly, misuse, abuse, and diversion of prescription opioids has increased dramatically and now far exceeds that of heroin. This has substantial consequences; thousands more Americans die each year from unintentional overdose with prescription opioids than from overdose with either heroin or cocaine. Opioid use disorder is therefore a significant public health concern. This chapter reviews the neurobiological effects of opioids as well as screening and management strategies for opioid use disorder.

Mu receptors in the VTA are critically involved in reinforcement and are also involved in drug dependence. Kappa receptors induce dysphoria, counteract mu receptors, and are involved in stress-related drug intake. Delta receptors are involved in emotional control.

Exogenous opioids are also thought to act at mu, delta, and kappa receptors, particularly mu receptors. Specifically, mu and possibly delta receptors in the VTA and the nucleus accumbens mediate the positive reinforcing properties of exogenous opioids.

If opioid misuse is suspected, a screening tool may be used for further assessment. There is no single accepted tool. Examples of self-report tools include the Current Opioid Misuse Measure and the Opioid Risk Tool. Examples of comprehensive tools include the Drug Abuse Screening Test, CAGE-AID, and UNCOPE.

It is also possible to manage patients undergoing withdrawal in an outpatient clinic or office. Clinicians in group or individual practices may provide naltrexone or, if they obtain a DEA DATA 2000 waiver, buprenorphine. Outpatient opioid treatment programs are also an option. These primarily offer methadone, although some may offer buprenorphine.

Individuals who have undergone withdrawal may have ongoing outpatient medication maintenance or may join a drug-free program, which does not provide opioid agonists but may provide naltrexone.

Methadone is orally active and can be administered once daily. The goal of methadone dosing is to suppress the patient's specific withdrawal symptoms and craving; thus, dosing is very individualized, but generally falls in the 40–100 mg/day range. Specifically, 40–60 mg/day is often sufficient to block opioid withdrawal symptoms, whereas higher doses are usually needed to block craving.

The goal of neurobiological drug abuse research is to identify the mechanisms that mediate the progression from occasional and impulsive drug use to compulsive drug use, as well as how these mechanisms contribute to the high risk for relapse even after prolonged abstinence. It is known that chronic drug use affects not only dopamine and the reward circuit, but also other neurotransmitters and circuits involved in memory, motivation, executive function, and stress. Thus, the mechanisms by which addiction may develop are widespread, and although research is plentiful and rapidly expanding, many unanswered questions still remain.

This chapter covers what is best understood about the neurobiology of the reward system and the acute effects of drug exposure; chronic drug exposure and the progression to addiction; and the neurobiology of tolerance, withdrawal, and the risk for relapse.

The rate of drug uptake is subject to the route of administration, with intravenous administration and inhalation producing the fastest drug uptake, followed by snorting. In addition, different drugs of abuse have different “reward values” (i.e., different rates at which they increase DA) based on their individual mechanisms of action.

The reflective reward system is built and maintained over time based on various influences, including neurodevelopment, genetics, peer pressure, the learning of social rules, and the learning of the benefits of suppressing current pleasure for more valuable future gain. When fully developed and functioning properly, the reflective reward system can shape the final output of the reward system into long-term beneficial goal-directed behaviors.

• (A) When drug anticipation occurs, (1) this signals an impulsive choice (2) to the VTA to release dopamine in the nucleus accumbens (3), which in turn produces output to engage in behavior that leads to drug ingestion again. In the prefrontal cortex, the orbitofrontal cortex signals drug-induced cravings and thus supports the “vote” for drug ingestion (4). The dorsolateral prefrontal cortex interprets the various signals and, showing cognitive flexibility, decides whether to take the action of drug ingestion (5).

• (B) If the reflective reward system (prefrontal circuitry) is activated (shown here by the prefrontal neurons turning red), this can prevent impulses (temptation) from being expressed as behavior.

Marijuana is the most widely used substance of abuse in the world. It has less dependence potential than other major substances of abuse; however, its abuse can be associated with social, cognitive, and other problems, including an increased risk of other substance use. Unfortunately, research into the treatment of marijuana dependence has been limited. This chapter covers what is known about the neurobiology and treatment of marijuana use disorder.

One complication of long-term, heavy, frequent use is the “amotivational syndrome,” which is characterized by the emergence of decreased drive and ambition. Heavy marijuana use is also associated with other socially and occupationally impairing symptoms, including a shortened attention span, poor judgment, easy distractibility, impaired communication skills, introversion, and diminished effectiveness in interpersonal situations. Personal habits may deteriorate, and there may be a loss of insight and even feelings of depersonalization.

There is currently no pharmacotherapy specifically recommended for either marijuana withdrawal or the maintenance of abstinence following marijuana cessation. Bupropion, divalproex, and naltrexone have all been studied in human trials of marijuana withdrawal, but all the trials have had negative results. Dronabinol, a synthetic formulation of THC, has been preliminarily studied for marijuana withdrawal, but current results are not sufficient to recommend its use. Instead, marijuana dependence and any associated withdrawal is usually treated with psychosocial therapies, as shown in Table 7.1. Withdrawal symptoms typically resolve within 1–2 weeks.

These books are designed to be fun, with all concepts illustrated by full-color images and the text serving as a supplement to figures, images, and tables. The visual learner will find that this book makes psychopharmacological concepts easy to master, while the non-visual learner may enjoy a shortened text version of complex psychopharmacological concepts. Each chapter builds upon previous chapters, synthesizing information from basic biology and diagnostics to building treatment plans and dealing with complications and comorbidities.

Novices may want to approach this book by first looking through all the graphics, gaining a feel for the visual vocabulary on which our psychopharmacological concepts rely. After this once-over glance, we suggest going back through the book to incorporate the images with supporting text. Learning from visual concepts and textual supplements should reinforce one another, providing you with solid conceptual understanding at each step along the way.

Readers more familiar with these topics should find that going back and forth between images and text provides an interaction with which to vividly conceptualize complex psychopharmacology. You may find yourself using this book frequently to refresh your psychopharmacological knowledge. And you will hopefully refer your colleagues to this desk reference.

This book is intended as a conceptual overview of different topics; we provide you with a visual-based language to incorporate the rules of psychopharmacology at the expense of discussing the exceptions to these rules. The References section at the end gives you a good start for more in-depth learning about particular concepts presented here.

From a behavioral perspective, addiction can be conceptualized as an impaired ability to inhibit drug seeking in response to environmental information that should normally suppress the behavior. Neurobiologically, this is linked to alterations in reward and other circuitry that may precede initial drug use (e.g., genetic risk factors) and/or be caused by chronic drug exposure itself.

In this book, we provide the biological background that will enable the reader to understand not only how chronic drug exposure is thought to alter reward circuitry, but also how currently available treatments for various substance use disorders work in the brain. We also review screening, treatment, and general management strategies for patients with addiction to various substances of abuse. In addition, we briefly touch on impulse control disorders that may have neurobiological similarities to drug addiction.

This chapter serves as an introduction to these topics by providing clinical definitions of the various terms used to describe substance use and addiction as well as an understanding of the behavioral progression from occasional, impulsive drug use to compulsive use and addiction.

For most individuals, occasional and controlled drug use remains an impulsive choice driven by positive reinforcement from the drug's rewarding effects. However, for those with risk factors for addiction or excessive drug exposure (see Figure 1.3), this occasional drug use causes neurobiological changes that lead to the development of drug craving, reduced reward on drug exposure, and withdrawal/negative affect state during abstinence (right). Thus, drug addiction can be conceptualized as a compulsive disorder driven by negative reinforcement, wherein the withdrawal symptoms and negative affect during abstinence lead to craving and preoccupation with the drug, with drug use providing relief from these symptoms.

Genetics are also known to affect the vulnerability to addiction; however, there is no single gene linked to addiction. Instead, the data to date suggest that genetic contributions to addiction are the result of the interaction of numerous genetic factors, much like with other psychiatric disorders. It is also possible that epigenetic mechanisms (i.e., changes in gene expression rather than in the genes themselves) contribute to the risk for addiction. For example, early life experiences (e.g., prenatal or early life stress) can cause changes in gene expression that can alter the brain's circuitry and thus increase the risk for the development of addiction.

Cigarette smoking is one of the leading causes of preventable death in the world. It is estimated that about 20% of the general population in the United States smoke. Rates are even higher in those with medical or psychiatric illnesses; 30% of individuals who regularly see a physician smoke, and 40–50% of those who see a mental health professional smoke. Yet only about 10% of smokers report being offered treatment proactively by clinicians.

This chapter reviews the neurobiological effects of nicotine as well as management strategies for patients addicted to nicotine, from screening and diagnosis to treatment selection and monitoring.

Nicotine directly causes dopamine release in the nucleus accumbens by binding to alpha 4 beta 2 nicotinic postsynaptic receptors on dopamine neurons in the VTA. In addition, nicotine binds to alpha 7 nicotinic presynaptic receptors on glutamate neurons in the VTA, which in turn leads to dopamine release in the nucleus accumbens. Nicotine also seems to desensitize alpha 4 beta 2 postsynaptic receptors on GABA interneurons in the VTA; the reduction of GABA neurotransmission disinhibits mesolimbic dopamine neurons and is thus a third mechanism for enhancing dopamine release in the nucleus accumbens.

• (A) In the resting state, alpha 4 beta 2 nicotinic receptors are closed (left). Nicotine administration, as by smoking a cigarette, causes the receptor to open, which in turn leads to dopamine release (middle). Long-term stimulation of these receptors leads to their desensitization, such that they temporarily cannot react to nicotine (or to acetylcholine); this occurs in approximately the same amount of time it takes to finish a single cigarette (right).

• (B) With chronic desensitization, alpha 4 beta 2 nicotinic receptors upregulate to compensate.

• (C) If one continues smoking, however, the repeated administration of nicotine continues to lead to desensitization of all of these alpha 4 beta 2 receptors, and thus, the upregulation does no good. In fact, the upregulation can lead to amplified craving as the extra receptors resensitize to their resting state.

All patients should be asked about their tobacco use, and all patients who use tobacco should be advised to quit. This involves assessing each patient's readiness to quit, and, if they are ready to make a quit attempt, assisting them with counseling and pharmacotherapy as well as arranging follow-up support. These steps are called the 5 As (ask, advise, assess, assist, arrange).