Over the last 20 years, the use of stimulants has risen to national and international prominence. Stimulant use and its consequences have brought havoc to many communities across the United States and have prompted strong responses from Federal, State, and local governments and organizations.

For example, the relatively minor problems of cocaine use in the 1960s and 1970s have grown to become major medical, legislative, and law enforcement issues in the 1990s. The devastation wrought by the crack cocaine epidemic is familiar to most Americans.

Similarly, the use and abuse of another stimulant, methamphetamine (MA), have risen dramatically in recent years. Widespread use and abuse of MA have led to a greater awareness of the problem and have inspired policymakers, legal officials, and service providers to focus increased efforts toward the personal and societal effects of this drug. Concerns that MA abuse may result in another epidemic led to passage of the Comprehensive Methamphetamine Control Act of 1996.

The explosive growth of stimulant use triggered a flurry of research. The results are tremendous advances in fundamental knowledge of stimulant use disorders and on the basic function of the brain and addictive disorders in general. Yet today, there are few reports that describe either the fundamentals of stimulant use disorder treatment or the success of various treatment interventions.

This Treatment Improvement Protocol (TIP) describes basic knowledge about the nature and treatment of stimulant use disorders. More specifically, it reviews what is currently known about treating the medical, psychiatric, and substance abuse/dependence problems associated with the use of two high-profile stimulants: cocaine and MA.

The scientifically based information in this TIP is presented in a manner that makes it available and relevant for clinicians and other "front line" substance use disorder treatment providers.

It offers recommendations on treatment approaches, recommendations to maximize treatment engagement, strategies for planning and initiating treatment, and strategies for initiating and maintaining abstinence. Also included are recommendations for the medical management of stimulant users and recommendations regarding special groups and settings.

The Consensus Panel that developed this TIP tried to emphasize those treatment techniques and principles that have been established with empirical support. However, because the "science" of treating stimulant use disorders is barely a decade old, the Panel also reviewed and synthesized a set of techniques and principles developed and supported by leading addiction specialists, but with less empirical support.

This document delineates those treatment suggestions and recommendations that are empirically supported and those that are currently based on consensus opinion.

The purpose of this TIP is to advance the understanding of treating the substance use disorders associated with the abuse of cocaine and MA. The Consensus Panel's recommendations summarized below are based on both researched and clinical experience.

Those supported by scientific evidence are followed by (1); clinically based recommendations are marked (2). Citations to the former are referenced in the body of this document, where the guidelines are presented in full detail. To avoid sexism and awkward sentence construction, the TIP alternates between "he" and "she" in generic examples.

For purposes of this TIP, the substances included in the category of "stimulants" include the derivatives of the coca plant (cocaine hydrochloride and its freebase form, "crack") and the synthetically produced amphetamines, with a primary emphasis on illicitly produced MA (and its smokable form, "ice"). Certainly there are other stimulants that are more widely used (e.g., caffeine) or that produce major health problems (e.g., nicotine); however, an extensive discussion of issues associated with these substances is beyond the scope of this document.

Summary of Recommendations

Because of recent health care reforms, most individuals who seek help for stimulant dependence now receive treatment at structured outpatient treatment programs. Accordingly, this document provides recommendations for treatment strategies and techniques that are most relevant to the treatment of stimulant-dependent patients in structured outpatient treatment programs. However, many, if not most, of these strategies and techniques can be integrated into other types of programs, regardless of the setting or therapeutic orientation.

Psychosocial Treatment Approaches

Psychosocial treatment approaches that incorporate well established psychological principles of learning are appropriate for and effective in treating stimulant users. In an effort to make these approaches consistently effective, the Consensus Panel recommends the use of carefully prepared treatment manuals to minimize differences among therapists. (2)

Treatment manuals increase the likelihood that therapists will deliver a uniform set of services to their clients. However, the therapist's clinical judgment and flexibility are extremely important to the treatment process.

The Consensus Panel recommends a contingency management approach for treating stimulant users. (1) A particularly successful version is the community-reinforcement-plus-vouchers approach in which couples counseling, vocational training, and skills training are combined with rewards for negative drug tests (i.e., "clean" urinalysis results).

Relapse Prevention

Relapse prevention systematically teaches clients

How to cope with substance craving
Substance refusal assertiveness skills
How seemingly irrelevant decisions may affect the probability of later substance use
General coping and problem-solving skills
How to apply strategies to prevent a full-blown relapse should an episode of substance use occur

The Consensus Panel recommends this approach for use with stimulant users. (1)

Other Interventions With Supportive Research

Research indicates that the following may be appropriate interventions for stimulant users:

Permitting women entering residential treatment to be accompanied by some or all of their children (1)

Supportive-expressive psychotherapy (1)

"Node-link mapping," which uses flowcharts and other methods to diagram relationships between clients' thoughts, actions, feelings, and substance use (1)

Other Models of Psychosocial Treatment

A number of other psychosocial models and approaches have been described, and some used widely, for the treatment of stimulant use disorders, including:

Network therapy, in which clients receiving individual psychotherapy develop a network of stable, nonsubstance-abusing support persons, such as family, partners, and close friends (2)

Acupuncture (2)

Therapeutic communities (the most common type of long-term residential treatment) (1)

Maximizing Treatment Engagement

Make treatment accessible

To maximize treatment engagement, programs must make treatment accessible. Having treatment programs in areas convenient to clients is associated with lower attrition rates. (1) Treatment should be provided during the hours and on the days that are convenient for clients. (2) Programs should be located near public transportation and in a part of town viewed as safe for evening visits. (2)

Provide support for treatment participation

Address clients' concrete needs, including transportation, housing, and finances. (1) Some logistical barriers can be overcome by onsite services, through agreements with subcontractors, or by referrals. These can include onsite child care services, referrals to temporary shelters, vouchers for lunches, targeted financial assistance, assistance with paperwork regarding insurance, or filing for disability benefits. (2)

Respond quickly and positively to initial telephone inquiries

Because ambivalence about treatment is common among treatment-seeking stimulant users, methods to "screen out" those who are "in denial" are counterproductive and impede treatment entry. (2) The initial interview should be scheduled within 24 hours after the client initially contacts the program. (2)

Assessments and Orientations

Keep initial assessments brief

Initial assessments should be brief, focused, and nonrepetitive. (2)

Provide clear orientations

Individuals need a thorough, clear, and realistic orientation about stimulant use disorder treatment. Clients should acquire a good understanding about the treatment process, the rules of the treatment program, expectations about their participation, and what they can expect the program to do for them and in what time frame. (2)

Offer clients options

Addiction treatment is more effective when a client chooses it from among alternatives than when it is assigned as the only option. Thus, it is important to provide clients with options and negotiate with them regarding the treatment approaches and strategies that are the most acceptable and promising. (1)

Involve significant others

Whenever possible, family and significant others who support the treatment goals should be involved in the treatment process. (2)

Convey empathetic concern

Counselors should be warm, friendly, engaging, empathetic, straightforward, and non-judgmental. Authoritarian and confrontational behavior by the staff can substantially increase the potential for violence. (2)

Planning Treatment

To organize treatment strategies, it can be helpful to view the treatment process as consisting of

A treatment initiation period
An abstinence attainment period
An abstinence maintenance phase
A long-term abstinence support plan

The Consensus Panel recommends treatment for 12 to 24 weeks followed by some type of support group participation. (2)

Clients should have a written schedule of expected attendance they can keep and give to family members who may be involved in treatment. It does not appear appropriate to deliver these services on an ad hoc or as needed basis. (2)

Initiating Treatment

The initial period of stimulant abstinence is characterized by symptoms of depression, difficulty concentrating, poor memory, irritability, fatigue, craving for cocaine/MA, and paranoia (especially for MA users). The duration of these symptoms varies; in general, symptoms typically last 3 to 5 days for cocaine users and 10 to 15 days for MA users. (2)

The first several weeks of treatment have some relatively simple and straightforward priorities.

Establish treatment attendance

During the first 2 or 3 weeks, clients should be scheduled for multiple weekly visits, even if the visits are 30 minutes in duration or less. (2)

Discontinue use of psychoactive substances and initiate urinalysis schedule

Immediately upon entering the treatment program, clients should be placed on a mandatory, vigilant, and frequent urine testing schedule. This schedule should continue throughout the treatment process, although the frequency of testing can be tapered as treatment progresses. Urine samples should be taken every 3 or 4 days so as not to exceed the sensitivity limits of standard laboratory testing methods. (2) Participation in self-help groups should be strongly encouraged but not required.

Assess psychiatric comorbidity

During the initial 2 weeks of treatment, it is important to assess the possible existence of other psychiatric conditions and, if present, initiate appropriate treatment, including medication. (2)

Assess stimulant-associated compulsive sexual behaviors

Research has revealed an association between stimulant use and a variety of compulsive sexual behaviors. These behaviors include promiscuous sex, AIDS-risky behaviors, compulsive masturbation, compulsive pornographic viewing, and homosexual behavior for otherwise heterosexual individuals. In order for treatment to be effective, these issues must be discussed openly and nonjudgmentally. (2)

Remediate stimulant "withdrawal" symptoms

Remind clients that proper sleep and nutrition are necessary to allow the neurobiology of the brain to "recover." Giving them "permission" to sleep, eat, and gradually begin a program of exercise, can help establish some behaviors that will have long-term utility. These behaviors will help them begin to think more clearly and begin to feel some benefit from their initial efforts in treatment. (1)

Initiating Abstinence

Establish structure and support. After the initial treatment engagement of 1 to 2 weeks, the focus is on the achievement of abstinence. Although there is no clear delineation between clients who are initiating abstinence and those maintaining abstinence, the initiating period occurs roughly from 2 to 6 weeks into treatment. (2)

Establish structure and support

Short-term goals should be set immediately and should be reasonably achievable. One such goal is complete abstinence from all substances for 1 week. (2)

Brief, frequent counseling sessions can reinforce the short-term goal of immediate abstinence and establish a therapeutic alliance between the client and counselor. Events of the past 24 hours are reviewed in each session and recommendations are provided for navigating the next 24 hours. (2)

Address secondary drug use

For many clients, their secondary substance use may not have been associated with adverse consequences or compulsive use. As a result, such clients need help to identify the connections between the use of other substances and their stimulant addiction. (2)

Clients should be encouraged to throw out all substance-related items. (2) Family members, sober friends, or 12-Step sponsors should help with this task.

Initiate avoidance strategies

Clients must develop specific action plans to break contacts with dealers and other stimulant users and to avoid high-risk places that are strongly associated with stimulant use. (2)

Provide client education

Educate clients about learning and conditioning factors associated with stimulant use and the impact of stimulants and other substances on the brain and behavior, such as cognitive impairments and forgetfulness. (2)

Other steps to initiate abstinence include

Identify cues and triggers (2)
Develop action plan for cues and triggers (2)
Enlist family participation (2)
Establish social support systems (2)
Address stimulant abuse-associated compulsive sexual behaviors (2)

Respond to early slips

Early slips should not be considered tragic failures but rather simple mistakes. When slips occur, counselors can make a verbal or behavioral contract with clients regarding short-term achievable goals. (2)

Maintaining Abstinence

Teach functional analysis of stimulant use

The core components of a functional analysis are

Teaching clients to examine the types of circumstances, situations, thoughts, and feelings that increase the likelihood that they will use stimulants

Counseling clients to examine the positive, immediate, but short-term consequences of their stimulant use

Encouraging clients to review the negative and often delayed consequences of their stimulant use (2)

Teach relapse prevention techniques

Relapse prevention techniques fall into the following categories:

Psychoeducation about the relapse process and how to interrupt it

Identification of high-risk situations and relapse warning signs

Developing coping and stress management skills

Enhancing self-efficacy in dealing with potential relapse situations

Counteracting euphoric recall and the desire to test control over use

Developing a balanced lifestyle including healthy leisure and recreation activities

Responding safely to slips to avoid escalation into full-blown relapse

Establishing behavioral accountability for slips and relapse via urine monitoring and/or Breathalyzer testing (2)

Enhance self-efficacy regarding high-risk situations

Once clients learn to identify, manage, and avoid high-risk situations, the counselor and client should try to determine if the client is confident in her ability to use those skills in the real world through role-playing and other therapeutic techniques. (2)

Counteract euphoric recall and desire to test control

So-called "war stories" that include euphoric recall and selective memory are powerful relapse triggers and should be strongly discouraged in recovery groups. (2)

Medical Aspects

The following recommendations are for medical personnel to help them recognize and treat problems that may arise for stimulant users with acute or chronic intoxication or in various phases of withdrawal.

The most common reasons for emergency room visits by cocaine users are cardiopulmonary symptoms (usually chest pains or palpitations); psychiatric complaints, ranging from altered mental states to suicidal ideation; and neurological problems, including seizures and delirium.

The major presenting symptoms for MA users pertain primarily to altered mental status, including confusion, delusions, paranoid reactions, hallucinations, and suicidal ideation. The rapid development of tolerance to its physiological effects among chronic MA users may explain the relative infrequency of cardiac complications in this group. (1)

The lethal dose of cocaine for 50 percent of novice users (LD50) is 1.5 grams. The LD50 for MA has not specifically been established, and there is significant individual variability to its toxicity. For example, doses of 30 milligrams can produce severe reactions, yet doses of 400 to 500 milligrams are not necessarily fatal. (1)

Management of stimulant intoxication

Uncomplicated intoxication requires only observation and monitoring in a subdued environment until symptoms subside over several hours.

Physical exertion and an overheated room can potentiate adverse effects because stimulants affect the body's heat-regulating mechanism at the same time that blood vessel constriction conserves heat.

Indications that agitation is escalating and moving toward paranoia and potential psychosis (losing touch with reality), with increasing risk for violence, may warrant pharmacological intervention. Fast-acting benzodiazepines such as lorazepam (Ativan) or diazepam (Valium) are useful for calming an anxious, agitated client. (1)

Management of potentially lethal overdose

Manage hyperthermia by sedating to slow down and stop agitated movements and by rapidly cooling the client with body ice packs, mist and fan techniques, or cooling blankets. (1)

If restraints are required to start an intravenous administration, use mesh-type blankets only transiently to avoid interfering further with heat loss. (2)

Uncontrolled hypertension can be managed by intravenous administration of phentolamine (Regitine) or dopamine (Intropin). (1)

Treat seizures like status epilepticus with intravenous diazepam or other benzodiazepine. Diazepam is most effective if administered before or shortly after cocaine ingestion but is less effective after seizures begin. (1)

Management of stimulant withdrawal

The greatest risk from the distinctive stimulant abstinence syndrome is that one may do harm to oneself or others. Because withdrawal-related dysphoria and depression can be particularly severe in stimulant users, risk of suicide is intensified, and sensitive management is essential. (1, 2)

Continuing agitation and persistent inability to fall asleep during withdrawal may also be treated symptomatically by using the antidepressant trazodone (Desyrel). Diphenhydramine (Benadryl) can also be used for its sedating properties. (1, 2)

Common physiological symptoms of chronic stimulant abuse/dependence

Extreme fatigue--with physical and mental exhaustion and disrupted sleep patterns

Nutritional disorders--extreme weight loss, anemia, anorexia, cachexia (body wasting)

Poor hygiene and self-care

Skin disorders and secondary skin infections--itching, lesions, hives, urticaria

Hair loss

Muscle pain/tenderness--may indicate rhabdomyolysis

Cardiovascular damage--from toxicity and contaminants in MA production, with concomitant renal and hepatic problems

Hypertensive crises with renal damage from sustained hypertension

Difficulty breathing--may reflect pulmonary edema, pneumonitis, obstructive airway disease, barotrauma, and other complications

Myocarditis, infarcts

Headaches, strokes, seizures, vision loss

Choreoathetoid (involuntary movement) disorders

Impaired sexual performance and reproductive functioning

Cerebrovascular changes, including evidence of cerebral hemorrhages and atrophy with associated cognitive deficits

Ischemic bowel, gastrointestinal complaints

Common psychological/behavioral symptoms of chronic stimulant abuse/dependence

Paranoia--with misinterpretation of environmental cues; psychosis with delusions, and hallucinations

Apprehension--with hopelessness and fear of impending doom that resembles a panic disorder

Depression--with suicidal thinking and behavior

Acute anxiety

Eating disorders

Distinctive indicators of chronic stimulant abuse/dependence

Nasal perforations and nose bleeds among snorters

Dental problems, including missing teeth, bleeding and infected gums, dental caries

Muscle cramping related to dehydration with low magnesium and potassium levels

Dermatitis around the mouth from smoking hydrochloride salt

Stale urine smell due to ammonia constituents used in manufacturing MA

Various dermatologic conditions, including excoriated skin lesions

Serious constipation due to dehydration and insufficient dietary fiber

Reducing the risk of violence

Medical personnel must be prepared for the paranoia, aggression, and violence that often accompany stimulant use. These personnel should

Keep the client in touch with reality by identifying themselves, using the client's name, and anticipating his concerns. (2)

Place the client in a quiet, subdued environment with only moderate stimuli. Ensure sufficient space so that the client does not feel confined. Have the door readily accessible to both the client and the interviewer, but do not let the client get between the interviewer and the door. (2)

Acknowledge agitation and potential for escalation into violence by reassuring the client that they are aware of his distress; asking clear, simple questions; tolerating repetitive replies; and remaining nonconfrontational. (2)

Foster confidence by listening carefully, remaining nonjudgmental, and reinforcing any progress made. (2)
Reduce risk by removing objects from the room that could be used as weapons and discreetly ensuring that the client has no weapons. (2)

Be prepared to show force if necessary by having a backup plan for help and having chemical and physical restraints immediately available. (2)

Train all medical or emergency staff to work as a team in managing volatile clients. (2)

There are a number of medical and psychiatric disorders that frequently accompany stimulant abuse and dependence. An awareness of these conditions is important for the safe and effective treatment of stimulant disorders. The conditions include

Cardiovascular system effects
Respiratory-pulmonary effects
Cerebrovascular complications
Muscular and renal toxicity
Gastrointestinal complaints
Infections
Effects on reproduction/formation of fetus/newborn children
HIV/AIDS and hepatitis
Toxic psychosis
Aggression and violence
Polysubstance abuse
Traumatic injury

Assessment and diagnosis

A diagnosis can be based on established DSM-IV criteria for amphetamine or cocaine use/abuse/dependence and other listed composites. (1)

An appropriate substance use history should include the substance(s) and medications used during the last 30 days; the specific substance(s) or combinations typically used with the usual dose, frequency, and route of administration; the duration of use/abuse; and the time and amount of last use as well as when the symptoms or complaints developed and how they have progressed. (2)

Stimulants typically can be detected in urine for approximately 24 to 48 hours following use and, maximally, for 3 days.

Special Groups and Settings

The Consensus Panel feels strongly that cultural competence in treatment extends beyond racial/ethnic sensitivity to understanding the mores of groups bound together by gender, age, geography, sexual preferences, criminal activity, substance use, and medical and mental illnesses. The Consensus Panel therefore recommends the following:

Counselors should be trained in cultural sensitivity and cultural competency issues to enhance the counselor's understanding and appreciation of both the client's background and his needs within that context. (1, 2)

Intravenous drug users should have access to multicomponent HIV prevention programs, which include instruction on bleach disinfection along with skills training, counseling, and HIV testing. Needle exchange programs may also be helpful. (1, 2)

For counselors working with gay men, education of the sexual and social behaviors that are common among this population (including the widespread use of MA), as well as the stigma associated with substance abuse in the gay community, should be available. (2)

For clients in narcotic replacement treatment, including methadone and LAAM, cocaine use is a major clinical problem. The most effective method of addressing this particular community appears to be contingency management approaches. (2)

Clients with co-occurring psychiatric disorders have high levels of stimulant abuse and dependence. Successful treatment of these individuals requires close coordination of psychiatric and stimulant use disorder treatments. (2)

Treatment for individuals in the criminal justice system is a rapidly expanding area of need. Stimulant users represent a substantial portion of the individuals in the court and prison treatment population. (2)

For rural populations, forming linkages between social service agencies, providing treatment services that are flexible in scope and structure, and using nontraditional outreach sites such as mobile or satellite offices are all important interventions. (2)

Counselors should be aware of the special needs of women and adolescents, including domestic issues, medical problems, child care needs, academic performance, and so on. Gender-specific treatment groups and school-based clinics can be helpful in reaching these particular groups. (1, 2)

Conclusion

In stimulant use disorder treatment today, providers have the opportunity to move the role of scientifically based approaches into the forefront of the treatment effort. Recent findings from basic and clinical research serve as the foundation of the evolving treatment system for stimulant use disorders and have yielded an entirely new set of strategies and tools to assist in the treatment of stimulant-related clinical disorders.

As knowledge of stimulants and brain functioning continues to grow, new approaches are likely to be forthcoming.

The development of pharmacotherapies for the treatment of stimulant use disorders is a major priority of current research efforts, and it is likely that these efforts will provide some important new options in the near future.

As these new treatments are introduced into the service delivery system and integrated into mainstream care, it will be essential for training tools, including this TIP, to be regularly updated.

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From SAMHSA/CSAT Treatment Improvement Protocols
TIP 33: Treatment for Stimulant Use Disorders
http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=hstat5.chapter.57310

In the early 1980s, thousands of people began to seek treatment to help them with their struggle to stop using cocaine. The U.S. health care system was rapidly overwhelmed. To many treatment experts who had spent their careers treating heroin addicts and alcoholics, the idea that someone would require "treatment" to discontinue cocaine use was a novelty.

Among the first questions asked of the individuals seeking treatment were, "What do you need treatment for?" and "Why don't you just stop using?" Today, much more is known about addiction to cocaine and other stimulants.

Although researchers, clinicians, and treatment providers have gained insights into why it is so difficult for stimulant users to stop using and why they need treatment, it is only recently that the substance use disorder treatment field has determined the most appropriate treatment approaches for these individuals.

When the U.S. cocaine epidemic was just beginning, there was a generally held assumption, even among addiction experts, that cocaine was not "truly addicting." A popular joke during this period was that "cocaine is God's way of telling you that you have too much money."

The cocaine epidemic that began in the 1970s peaked in the 1980s and slowly declined in the mid 1990s (Golub and Johnson, 1997). The pattern was similar to the first epidemic that occurred 30 years after cocaine hydrochloride was first isolated from coca leaves in 1885.

During the first epidemic, physicians mistook cocaine's powerful stimulant properties as a cure for depression, morphine addiction, chronic tuberculosis, and a long list of other disorders. Physicians and other "healers" prescribed the drug for a range of maladies, and cocaine soon became the major active ingredient in many popular medicines, tonics, and elixirs (including the original formulation of Coca-Cola ).

Eventually, however, the adverse effects of high-dose and consistent use were recognized. This recognition soon led to legislative responses. First, the Pure Food and Drug Act of 1906 required the proper labeling of cocaine "and other narcotics" on proprietary medicines. Second, the Harrison Act of 1914 virtually eliminated the use of cocaine-containing patent medicines by forbidding their manufacture and sale.

But cocaine did not simply go away, and sometime after 1970, a complex set of social and economic circumstances conspired to prompt its return. Increased demand for the drug initially drove supply, and subsequently, its widespread availability and reduced cost fostered greater demand and abuse.

The cocaine epidemic of the 1980s and early 1990s affected a broad spectrum of American society, with the advent of crack cocaine hitting major cities the hardest. A less publicized and more geographically circumscribed stimulant epidemic is the rise of methamphetamine (MA) in the West and Midwest. The spread of MA has brought many of the health, legal, and social problems like those associated with cocaine to smaller and more rural communities.

These stimulant epidemics have had a devastating impact on American society. The impact of illicit stimulant abuse has affected international politics, the U.S. legal system, and the U.S. health care system. "Freebasing," "crack houses," and "coke fiend" have all entered the American lexicon to describe elements of the stimulant epidemic.

As the end of the 20th century nears, the powerful psychostimulants cocaine and MA and their derivatives have joined opiates and alcohol as primary targets in the efforts to combat substance abuse and dependence. But on the positive side, the pressing need to effectively deal with stimulant epidemics and treat people with stimulant use disorders has produced a tremendous amount of scientific and clinical research. The results of this research have broadened our knowledge of the human brain and expanded our understanding of substance use disorders.

The slow response of major U.S. institutions to the dangers of cocaine and MA was partly due to an ignorance of the basic biological and psychological effects of these powerful psychostimulants. The knowledge gained over the past two decades on the properties of these substances can help treatment providers and other health professionals to understand, prevent, and treat the problems created by the use and abuse of cocaine and MA. This Treatment Improvement Protocol (TIP) summarizes the latest research as well as first-hand clinical experience of substance use disorder treatment professionals.

Purpose of the TIP [Treatment Improvement Protocols]

Since the mid-1980s, there has been an explosion of knowledge about the effects of cocaine and MA. Because these psychostimulants alter the functioning of the body and the brain so profoundly, physicians, nurses, psychologists, social workers, marriage and family counselors, and substance abuse counselors must understand the profound biological aspects of stimulant addiction.

New areas of expertise include the relevant pharmacology, neurobiology, psychiatric and psychological manifestations, and appropriate treatment approaches for stimulant abuse and dependence. The new findings suggest that neurological impairments may last up to 2 years after cessation of stimulant use (Hoff et al., 1996; Melega et al., 1997a).

This TIP presents current knowledge of the nature and treatment of stimulant use disorders. The TIP is designed to be a resource that provides scientifically established information and presents it in a manner that makes it available and relevant for both clinicians and "front line" treatment providers. In addition, the document reviews what is known about treating the medical, psychiatric, and substance abuse/dependence problems associated with the use of cocaine and MA. The treatment section emphasizes those approaches that have been established with empirical support. However, because the field of treating stimulant use disorders is barely a decade old, a set of treatment techniques supported by leading addiction specialists has been included after review and synthesis by the members of the Consensus Panel.

Importance of Science in Building the Treatments Of the Future

The Consensus Panel believes that scientifically derived knowledge should serve as the foundation of treatment for stimulant use disorders. Findings from basic and clinical research efforts funded by the National Institute on Drug Abuse (NIDA), as well as other government and private institutions, have given treatment providers an entirely new set of strategies and tools to assist those with stimulant-related clinical disorders.

The field of stimulant use disorder treatment presents the perfect opportunity to move the role of scientifically based approaches into the forefront of the treatment effort. There is very little in the way of a "traditional treatment system" for stimulant use disorders, and therefore, there should be fewer "turf battles" over the implementation of new treatment approaches.

The Consensus Panel recognizes that most traditional treatment approaches are still viable and highly regarded by providers, and that new treatment techniques may be initially viewed with distrust. Continuing research and clinical experience will ultimately reveal the efficacy of such treatments.

At this time, the approaches with the greatest empirical support are a variety of psychosocial-behavioral strategies, delivered in outpatient settings. However, as knowledge of stimulants and brain functioning rapidly increases, thanks to active research funded by Federal agencies and private foundations, new approaches will soon be forthcoming. The development of pharmacotherapies for the treatment of stimulant use disorders is a major priority of the current research efforts, and it is likely that these efforts will provide some important new options in the near future.

Scope of the TIP

For purposes of this TIP, the substances included in the category of "stimulants" include the derivatives of the coca plant (cocaine hydrochloride and its derivatives) and the synthetically produced amphetamines, with emphasis on the major illicitly produced and abused drug of this category, MA (in its various forms). Certainly there are other stimulants that are more widely used (e.g., caffeine) and that produce major health and social problems (e.g., nicotine); however, an extensive discussion of issues associated with these substances is beyond the scope of this document.

Although considered drugs of abuse, MA analogs--compounds with similar molecular structures but not necessarily similar effects, sometimes called "designer drugs"--such as MDA (3,4-methylenedioxy-amphetamine) and MDMA (3,4-methylene-dioxymethamphetamine)--have not been studied adequately for inclusion in this document.

A Brief History of Stimulant Use in the United States

Cocaine

Cocaine hydrochloride is extracted from the leaves of the coca plant (Erythroxylon coca), which is indigenous to the Andean highlands of South America. In its extracted and purified form, it is one of the most potent stimulants of natural origin (Drug Enforcement Agency [DEA], 1995). For thousands of years, the Native Americans in the Andean region have chewed coca leaves to relieve fatigue, much as present-day Americans chew tobacco. Just as tea and coffee are brewed as refreshments or "pick-me-ups," the Andean natives brewed coca leaves into a tea.

Furthermore, Andean groups have historically burned or smoked various parts of the coca plant as part of their religious and medicinal practices (Siegel, 1982). However, none of these other uses has had the same impact as purified cocaine hydrochloride.

German chemist Albert Niemann recognized the stimulant properties of the cocaine plant, and in the mid-1800s (ca. 1862) extracted the pure chemical, cocaine hydrochloride. In the early 1880s, the drug's anesthetic properties were discovered, and it was soon used in eye, nose, and throat surgery. As physicians and other prescribers became aware of cocaine's psychoactive properties, it was widely dispensed for anxiety, depression, and addiction treatment (primarily for morphine use).

Extravagant claims of its curative powers increased cocaine's popularity; by the early 1900s, it was the main active ingredient in a wide range of patent medicines, tonics, elixirs, and fluid extracts. It is believed that the original formula of Coca-Cola that was developed in 1886 by Georgia pharmacist John Pemberton contained approximately 2.5 mg of cocaine per 100 mL of fluid (Coca-Cola Bottling of Shreveport, Inc., et al., vs. The Coca-Cola Company, a Delaware Corporation, 769 F.Supp.671). This formula was sold as a headache cure and stimulant. Another pharmacist bought the rights and founded the Coca-Cola Company in 1892.

By the early 1900s, public health officials were becoming alarmed by the medical, psychiatric, and social problems associated with excessive cocaine use. These concerns from health officials and legal authorities played a major role in initiating and supporting the effort to pass the Harrison Narcotic Act of 1914. This Federal legislation severely restricted the legal uses for cocaine and, for all practical purposes, ended the extensive use and abuse of cocaine in the early part of the 20th century. Interestingly, cocaine hit a low during the 1930s when the advent of amphetamine almost eradicated demand.

From the time of the Harrison Narcotic Act until the 1970s, cocaine use was generally limited to groups on the periphery of society. Legal prohibitions and severely restricted supplies of the drug helped to maintain its low profile. But microcultures of cocaine snorters, swallowers, and shooters remained, and cultivation of coca plants continued in the South American countries that traditionally grew them--Bolivia, Peru, Colombia, and Ecuador.

As the cultural proscriptions against the use of drugs for recreational purposes weakened during the 1960s, cocaine again became part of the American drug scene. Its use increased along with the use of many other psychoactive substances. Snorting was the initial mode, and most experimenters were occasional consumers. They experienced the cocaine euphoria and generally went back to their "normal" lives. Because of this casual use, the fictitious notion arose that cocaine was harmless.

In the 1960s, limited supplies and high prices combined to restrict the use of cocaine to relatively small amounts used by a small number of individuals. Although serious clinical problems were being connected with the use of hallucinogens, barbiturates, and amphetamines, little attention was given to the problems associated with cocaine use because they were rarely seen.

As recently as the late 1970s, many experts and public health officials believed that cocaine was a relatively benign substance and primarily of interest as a "recreational" drug. It was thought that only those who had access to very large supplies of the drug and/or those who were somewhat mentally unstable were at risk for developing problems with cocaine. A notable exception among these experts was the voice of two San Francisco addiction experts who sounded a prophetic warning about cocaine:

In summary, cocaine is a central nervous system stimulant of moderately high abuse potential. At the present time the preferred route of administration is intranasal and the dosage patterns are relatively low. The social rituals surrounding the drug endorse primarily recreational use while the high cost and low availability of the drug produce the current low rate of cocaine abuse in the United States...Most users now use cocaine by the intranasal route at moderately low dosages, while a relatively small percentage use cocaine intranasally or intravenously at high dosages. However, if the drug were more readily available at a substantially lower cost, or if certain socio-cultural rituals endorsed and supported the higher dose patterns, more destructive patterns of abuse could develop. (Wesson and Smith, 1977, pp. 149-150)

Within 5 years of the observation by Wesson and Smith, both essential developments they predicted had occurred. The production of coca in South America expanded from a cottage industry of small groups of subsistence farmers into a major agricultural business that was financed by organized families or "cartels." The manufacture and trafficking of cocaine became a multibillion dollar industry, with profit margins high enough that governments and entire legal systems became corrupted by the influx of cocaine industry money. Supplies of cocaine into the United States increased exponentially. During the early to mid-1980s, according to DEA reports, the estimated amounts of cocaine entering the United States doubled and tripled year after year. These supplies of cocaine made the drug available in purer form and at a more affordable cost to consumers.

Cocaine hydrochloride is generally distributed as a white crystalline powder or as an off-white chunky material. The powder form is usually snorted intranasally. As cocaine became plentiful and less expensive in the early 1980s, its users began to experiment with its various forms and with different routes of administration. Some users began to smoke the powder form by mixing it with tobacco or marijuana. However, those who smoked the powder reported little if any intoxication.

At the same time, users in South America began to smoke base (coca paste), which is one of the products from which cocaine powder is derived (Siegel, 1987). Coca paste is more concentrated than the powder form. Paste smokers report immediate intoxication, with effects similar to those reported by intravenous users. The first hospital admissions for adverse effects of coca paste smoking were in Peru in 1972 (Jeri, 1984). The practice of smoking coca paste appears to have traveled to other countries via illicit cocaine trafficking corridors.

Drug traffickers in the United States learned of the effects of smoking base, but they confused its preparation with that of cocaine freebase, in which the cocaine alkaloid in cocaine hydrochloride is "freed" from the other components (Siegel, 1982). So it was quite by accident that this new process of "freebase" cocaine was discovered. However, its properties were quite unlike those of either coca paste or cocaine powder. Freebase cocaine does not dissolve easily in the blood or mucous membranes of the nasal passages, but it is readily volatilized and can be effectively smoked. The phenomenon of smoking this freebase form was first reported in California in 1974, and by 1980, its use was reported throughout the United States (Siegel, 1982). Today, chunks of the freebase form are most often known as "rock" or "crack."

The next phase in the American cocaine epidemic came when cocaine traffickers saw an opportunity to expand the retail market by delivering to the consumer smaller, more affordable packages of the drug. Chunks of rock cocaine were soon being sold in small glass vials or plastic containers at a cost of $10 to $20. This new retailing effort made a product that was extremely desirable and inexpensive readily available to a much wider user base. The strategy worked extraordinarily well for the cocaine industry.

By late 1985 and early 1986, the retailing of freebase cocaine had swept through most urban centers of the United States. This form was introduced into new markets by highly organized and sophisticated distribution networks. In an effort to make the product distinctive, it was marketed under the new name "crack." There are numerous versions of the origin of the term "crack," but the most likely is that as the freebase cocaine is being heated and volatilized into its smokable form, it makes a characteristic crackling or popping sound.

The crack epidemic was at its worst from 1985 through the end of the decade, although it still remains a serious health and social problem. The introduction of crack into urban communities produced devastating consequences. Health-related problems, rapidly escalating rates of addiction, and an extraordinary wave of street crime and property crime swept through most major American cities. In many areas, street gangs of young males were central to the distribution and sales of crack. Warfare between street gangs battling over turf resulted in many fatalities among gang members as well as innocent bystanders in the community. As drug-related crime escalated dramatically, legal penalties for sales of cocaine and crack were increased, and U.S. jails and prisons rapidly filled with crack users, dealers, distributors, and those involved in the violence associated with the crack trade.

At the peak of the cocaine epidemic, a conservative estimate in the mid-1980s suggested that as many as 8 million Americans used cocaine regularly and that 5 to 8 percent of them had developed a serious cocaine dependence (Cregler and Mark, 1986). The 1988 National Household Survey on Drug Abuse (NHSDA) found that the number of heavy crack and cocaine users rose significantly from 1985 to 1988 (Substance Abuse and Mental Health Services Administration [SAMHSA], 1988). During this period, there was a 33 percent increase among those using crack or cocaine once a week or more; for those using crack or cocaine on a daily or near-daily basis, the rate rose by 19 percent (SAMHSA, 1989).

By the mid 1980s, the use of crack cocaine had replaced heroin use as the main illicit drug problem in the United States. According to the 1997 NHSDA, the number of Americans who used cocaine within the preceding month of the survey numbered about 1.5 million; occasional users (those who used cocaine less often than monthly) numbered approximately 2.6 million, down from 7.1 million in 1985 (SAMHSA, 1998). Only recently have researchers been able to demonstrate a clear decline or stabilization in the use of crack cocaine in U.S. cities (Golub and Johnson, 1997).

   ~~~~

Source: SAMHSA/CSAT Treatment Improvement Protocols
TIP 33: Treatment for Stimulant Use Disorders
www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=hstat5.chapter.57310

Over the last several decades, research on substances of abuse has vastly improved our understanding of human behavior and physiology and the nature of substance abuse and dependence. Basic neurobiological research has enhanced our understanding of the biological and genetic causes of addiction.

These discoveries have helped establish addiction as a biological brain disease that is chronic and relapsing in nature (Leshner, 1997). By mapping the neural pathways of pleasure and pain through the human brain, investigators are beginning to understand how abused psychoactive substances, including stimulants, interact with various cells and chemicals in the brain.

This new information has also improved our understanding of appropriate treatment approaches for different substance use disorders. This chapter describes the effects that cocaine and methamphetamine (MA) use have on the user's brain and behavior, which in turn leads to the stimulant users' unique needs. Knowledge of these effects provides the foundation for stimulant-specific treatment approaches. This knowledge will give treatment providers greater insight into stimulant users and why certain treatment approaches are more effective.

Stimulant Abuse And the Brain

According to National Institute on Drug Abuse Director Alan I. Leshner, Ph.D., the fundamental problem in dealing with any substance of abuse is to understand "the target" (i.e., the user). Therefore, to understand why people take drugs such as cocaine and MA and why some people become addicted, we must first understand what these drugs are doing to their target; that is, how stimulants affect the user.

Discussions of substance abuse and dependence often involve some discussion of the root causes--the societal and risk factors that lead to these conditions. To date, investigators have identified as many as 72 risk factors for substance use and dependence (Leshner, 1998). Among them are poverty, racism, social dysfunction, weak families, poor education, poor upbringing, and substance-abusing peer groups.

These risk factors--as well as other environmental and genetic factors--only influence an individual's initial decision to use substances of abuse. But after initial use, an individual continues to use a substance because she likes its effects: Use modifies mood, perception, and emotional state. All of these effects are modulated through the brain; in order to understand this phenomenon, it is important to understand some basic neuroscience.

For substances of abuse to exert their effects, they must first get to the brain. The four most common routes of administering psychoactive (mood-changing) substances are (1) oral consumption (i.e., swallowing), (2) intranasal consumption (i.e., snorting), (3) inhalation into the lungs (generally by smoking), and (4) intravenously via hypodermic syringe.

A swallowed substance goes to the stomach and on to the intestinal tract. Some substances easily pass through the digestive tract into the bloodstream. Other substances are broken down into their chemical components (i.e., metabolized) in the digestive system, thereby destroying the substance.

Substances that are inhaled into the lungs adhere to the lining of the nasal passages (the nasal mucosa) through which they enter directly into the bloodstream. Inhaled substances are usually first changed into a gaseous form by igniting (e.g., marijuana) or volatilizing by intense heat (e.g., crack cocaine, the ice form of MA). The lungs offer a large surface area through which the gaseous form may quickly pass directly into the bloodstream.

Injected substances obviously enter the bloodstream directly, although at a somewhat regulated rate. In these last three routes of administration, substances enter the bloodstream in their unmetabolized form.

Once a substance enters the bloodstream, it is transported throughout the body to various organs and organ systems, including the brain. Substances that enter the liver may be metabolized there. Substances that enter the kidney may be excreted. If a female substance user is pregnant, and the substance is able to cross the placenta, then the substance will enter the fetus' bloodstream. Nursing babies may ingest some substances from breast milk.

To enter the brain, a substance's molecules must first get through its chemical protection system, which consists mainly of the blood-brain barrier. Tight cell-wall junctions and a layer of cells around the blood vessels keep large or electrically charged molecules from entering the brain. However, small neutral molecules like those of cocaine and MA easily pass through the blood-brain barrier and enter the brain. Once inside the brain, substances of abuse begin to exert their psychoactive effects.

Fundamentals of the Nervous System

The human nervous system is an elaborately wired communication system, and the brain is the control center. The brain processes sensory information from throughout the body, guides muscle movement and locomotion, regulates a multitude of bodily functions, forms thoughts and feelings, modulates perception and moods, and essentially controls all behavior.

The brain is organized into lobes, which are responsible for specialized functions like cognitive and sensory processes and motor coordination. These lobes are made up of far more complex units called circuits, which involve direct connections among the billions of specialized cells that the various substances of abuse may affect.

The fundamental functional unit of the brain's circuits is a specialized cell called a neuron, which conveys information both electrically and chemically. The function of the neuron is to transmit information: It receives signals from other neurons, integrates and interprets these signals, and in turn, transmits signals on to other, adjacent neurons (Charness, 1990).

A typical neuron (see Figure 2-1) consists of a main cell body (which contains the nucleus and all of the cell's genetic information), a large number of offshoots called dendrites (typically 10,000 or more per neuron), and one long fiber known as the axon. At the end of the axon are additional offshoots that form the connections with other neurons.

Within neurons, the signals are carried in the form of electrical impulses. But when signals are sent from one neuron to another, they must cross the gap at the point of connection between the two communicating neurons. This gap is called a synapse. At the synapse, the electrical signal within the neuron is converted to a chemical signal and sent across the synapse to the target (i.e., receiving) neuron. The chemical signal is conveyed via messenger molecules called neurotransmitters that attach to special structures called receptors on the outer surface of the target neuron (Charness, 1990).

The attachment of the neurotransmitters to the receptors consequently triggers an electrical signal within the target neuron. Approximately 50 to 100 different neurotransmitters have been identified in the human body (Snyder, 1986).Figure 2-2 illustrates a typical synaptic connection and depicts the chemical communication mechanism.

Neurotransmitters may have different effects depending on what receptor they activate. Some increase a receiving neuron's responsiveness to an incoming signal--an excitatory effect--whereas others may diminish the responsiveness--an inhibitory effect. The responsiveness of individual neurons affects the functioning of the brain's circuits, as well as how the brain functions as a whole (how it integrates, interprets, and responds to information), which in turn affects the function of the body and the behavior of the individual.

The accurate functioning of all neurotransmitter systems is essential for normal brain activities (National Institute on Alcohol Abuse and Alcoholism [NIAAA], 1994; Hiller-Sturmhfel, 1995).

The Limbic Reward System

The brain circuit that is considered essential to the neurological reinforcement system is called the limbic reward system (also called the dopamine reward system or the brain reward system). This neural circuit spans between the ventral tegmental area (VTA) and the nucleus accumbens(see Figure 2-3). Every substance of abuse--alcohol, cocaine, MA, heroin, marijuana, nicotine--has some effect on the limbic reward system.

Substances of abuse also affect the nucleus accumbens by increasing the release of the neurotransmitter dopamine, which helps to regulate the feelings of pleasure (euphoria and satisfaction). Dopamine also plays an important role in the control of movement, cognition, motivation, and reward (Wise, 1982; Robbins et al., 1989; Di Chiara, 1995).

High levels of free dopamine in the brain generally enhance mood and increase body movement (i.e., motor activity), but too much dopamine may produce nervousness, irritability, aggressiveness, and paranoia that approximates schizophrenia, as well as the hallucinations and bizarre thoughts of schizophrenia. Too little dopamine in certain areas of the brain results in the tremors and paralysis of Parkinson's disease.

Natural activities such as eating, drinking, and sex activate the nucleus accumbens, inducing considerable communication among this structure's neurons. This internal communication leads to the release of dopamine. The released dopamine produces immediate, but ephemeral, feelings of pleasure and elation. As dopamine levels subside, so do the feelings of pleasure. But if the activity is repeated, then dopamine is again released, and more feelings of pleasure and euphoria are produced. The release of dopamine and the resulting pleasurable feelings positively reinforce such activities in both humans and animals and motivate the repetition of these activities.

Dopamine is believed to play an important role in the reinforcement of and motivation for repetitive actions (Di Chiara, 1997; Wise, 1982), and there is an increasing amount of scientific evidence suggesting that the limbic reward system and levels of free dopamine provide the common link in the abuse and addiction of all substances. Dopamine has even been labeled "the master molecule of addiction" (Nash, 1997).

When the nucleus accumbens is functioning normally, communication among its neurons occurs in a consistent and predictable manner. First, an electrical signal within a stimulated neuron reaches its point of connection (i.e., the synapse) with the target neuron.

The electrical signal in the presynaptic neuron triggers the release of dopamine into the synapse. The dopamine travels across the synaptic gap until it reaches the target neuron. It then binds to the postsynaptic neuron's dopamine-specific receptors, which in turn has an excitatory effect that generates an internal electrical signal within this neuron.

However, not all of the released dopamine binds to the target neuron's receptors. Extra dopamine may be chemically deactivated, or it may be quickly reabsorbed by the releasing neuron through a system called the dopamine reuptake transporter(see Figure 2-4).

As soon as the extra dopamine has been deactivated or reabsorbed, the two cells are "reset," with the releasing neuron prepared to send another chemical signal and the target neuron prepared to receive it. Substances of abuse, and especially stimulants, affect the normal functioning of the dopamine neurotransmitter system (Snyder, 1986; Cooper et al., 1991).

Neurological Reinforcement Systems

Psychologists have long recognized the importance of positive and negative reinforcement for learning and sustaining particular behaviors (Koob and LeMoal, 1997). Beginning in the late 1950s, scientists observed in animals that electrically stimulating certain areas of the brain led to changes in mental alertness and behavior.

Rats and other laboratory animals could be taught to self-stimulate pleasure circuits in the brain until exhaustion. If stimulants such as cocaine or amphetamine were administered, for example, sensitivity to pleasurable responses was so enhanced that the animals would choose electrical stimulation of the pleasure centers in their brains over eating or other normally rewarding activities.

The process just described in which a pleasure-inducing action becomes repetitive is called positive reinforcement. Conversely, abrupt discontinuation of the psychoactive substances following chronic use was found to result in discomfort and behaviors consistent with craving. The motivation to use a substance in order to avoid discomfort is called negative reinforcement. Positive reinforcement is believed to be controlled by various neurotransmitter systems, whereas negative reinforcement is believed to be the result of adaptations produced by chronic use within the same neurotransmitter systems.

Experimental evidence from both animal and human studies supports the theory that stimulants and other commonly abused substances imitate, facilitate, or block the neurotransmitters involved in brain reinforcement systems (NIAAA, 1994). In fact, researchers have posited a common neural basis for the powerful rewarding effects of abused substances (for a review, see Restak, 1988).

Natural reinforcers such as food, drink, and sex also activate reinforcement pathways in the brain, and it has been suggested that stimulants and other drugs act as chemical surrogates of the natural reinforcers. A key danger in this relationship, however, is that the pleasure produced by substances of abuse can be more powerfully rewarding than that produced by natural reinforcers (NIAAA, 1996).

Stimulants' Mechanisms of Action

On a short-term basis, stimulants exert their effects by disrupting or modifying the normal communication that occurs among brain neurons and brain circuits. Cocaine and MA have both been shown to specifically disrupt the dopamine neurotransmitter system. This disruption is accomplished by overstimulating the receptors on the postsynaptic neuron, either by increasing the amount of dopamine in the synapse through excessive presynaptic release or by inhibiting dopamine's pattern of reuptake or chemical breakdown (Cooper et al., 1991).

The use of cocaine and MA increases the amount of available dopamine in the brain, which leads to mood elevation (e.g., feelings of elation or euphoria) and increased motor activity. With cocaine, the effects are short-lived; with MA the duration of effect is much longer. As the stimulant level in the brain decreases, the dopamine levels subside to normal, and the pleasurable feelings dwindle away.

A growing body of scientific research based on animal research and brain imaging studies in humans suggests that the chronic use of stimulants affect dopaminergic neurons in limbic reward system structures (e.g., the VTA, nucleus accumbens).

These effects may underlie addiction to stimulants. Although the neurochemical pathways of stimulant addiction are not definitively established, a few researchers have found evidence of changes in the structure and function of brain neurons after chronic stimulant use in humans.

Some researchers propose that the changes may come from dopamine depletion, changes in neurotransmitter receptors or other structures, or changes in other brain messenger pathways that could cause the changes in mood, behavior, and cognitive function associated with chronic stimulant abuse (Self and Nestler, 1995).

Animal studies have demonstrated that high doses of stimulants can have permanent neurotoxic effects by damaging neuron cell-endings (e.g., Selden, 1991). The question of whether stimulants can produce similar effects in humans remains to be answered. Researchers hope that recently developed brain imaging techniques will help provide the answer.

At this time, there is only speculation that such permanent damage may underlie the long-term cognitive impairments seen in some chronic stimulant users. The continuing development and application of new technologies will help expand our knowledge of the neurological effects of stimulants in humans. (The medical aspects of stimulant use disorders are discussed in Chapter 5.)

Abuse and Dependence

Addiction is a complex phenomenon with important psychological and social causes and consequences. However, at its core, it involves a biological process: the effects of repeated exposure to a biological agent (a substance) on a biological substrate (the brain) over time (Nestler and Aghajanian, 1997).

Ultimately, adaptations that substance exposure elicits in individual neurons alter the functioning of those neurons, which in turn alters the functioning of the neural circuits in which those neurons operate. This eventually leads to the complex behaviors (e.g., dependence, tolerance, sensitization, craving) that characterize addiction (Koob, 1992; Kreek, 1996; Wise, 1996; Koob and LeMoal, 1997).

A general definition of substance abuse is the habitual use of a substance not needed for therapeutic purposes, such as solely to alter one's mood, affect, or state of consciousness. The continued abuse of the substance may lead to adverse physiological, behavioral, and social consequences. A substance-dependent individual will continue his use despite these adverse consequences. Moderate chronic use or severe short-term use of substances may lead to abuse, which may eventually lead to addiction components (Ellinwood, 1974; Hall et al., 1988; Kramer, 1969).

Chronic substance abuse results in a complex set of physiological and neurological adaptations. These adaptations are simply the body's attempt to adjust to or compensate for substance-induced impairments. Repeated exposure to a substance can also lead to adaptations in the reward circuitry that opposes and/or neutralizes a substance's effects (i.e., counteradaptation).

Substance addiction (or substance dependence) is manifested by (1) psychological craving (see the following section); (2) tolerance (the need for increasing amounts of the substance to reproduce the initial level of response, or sometimes to simply stave off the unpleasant effects of withdrawal); (3) sensitization (discussed in the section on the medical effects of stimulants); and (4) symptoms of withdrawal upon cessation of use, indicating physiological dependence.

Social and behavioral manifestations of dependence include the reduced ability to function at work or home and may include displays of erratic, moody, or anxious behavior.

Similar to other substances of abuse, moderate chronic use or severe short-term use of stimulants in any form may lead to abuse or dependence (Ellinwood, 1974; Hall et al., 1988; Kramer, 1969).

Clinical observations of abuse patterns for both cocaine and MA have noted that, in general, there is an estimated 2- to 5-year latency period between first use and full-blown addiction. However, clinical experience and anecdotal evidence suggest that the latency period may be shortened to less than 1 year by rapid routes of administration (e.g., injection, smoking) and increased stimulant purity (e.g., ice, crack).

With increasing use, the user may develop tolerance to the effects of stimulants and may need to keep increasing the amount taken to produce the desired psychological effects. As chronic abuse progresses, users prefer the stimulant over enjoyable activities and eventually may prefer it over food and sex (Hall et al., 1988). At that point, the individual will usually continue her use even when faced with continuing adverse consequences--the hallmark of substance dependence.

Abrupt discontinuation of the psychoactive substance following chronic use generally results in discomfort, dysphoria, and behaviors consistent with craving. The user is now motivated to use a substance in order to avoid discomfort and dysphoria.

This shift from substance use as positive reinforcement to negative reinforcement is, perhaps, one of the foremost characteristics of late-stage addiction.

Drug Craving and Memory

The degree to which learning and memory sustain the addictive process has only recently been addressed. Researchers believe that each time a neurotransmitter like dopamine floods across a synapse, circuits that trigger thoughts and memories and that motivate action become hardwired in the brain. The neurochemistry supporting addiction is so powerful that people, objects, and places associated with substance use are also imprinted on the brain.

Craving, a central aspect of addiction, is a very strong learned response with powerful motivational properties often associated with specific memories (i.e., conditioned cues and triggers).

Cues--any stimuli (substance-using friends, locations, paraphernalia, moods) repeatedly paired with substance use over the course of a client's addiction--can become so strongly associated with the substance's effects that the associated (conditioned) stimuli can later trigger arousal and an intense desire for the substance and lead to relapse.

High relapse rates are common in cocaine addiction even after physical withdrawal and abstinence have been achieved.

Brain-imaging studies have shown that cue-induced drug craving may be linked to distinct brain systems involved in memory (e.g., London et al., 1990; Stapleton et al., 1995). Brain structures involved in memory and learning, including the dorsolateral prefrontal cortex, amygdala, and cerebellum, have been linked to cue-induced craving (Grant et al., 1995).

A network of these brain regions integrates emotional and cognitive aspects of memory and triggers craving when it reacts to cues and memories. These cues and memories also play an important role in reinforcing substance use (Grant et al., 1995).

Most substance treatment programs recognize the power of these factors in triggering relapse and warn clients to avoid everything previously associated with their substance use--a tall order for a client in an urban environment saturated with the substance and its associated reminders.

Treatment approaches that address these learning and memory issues of addiction may prove effective. For example, Childress developed treatment strategies to help clients reduce craving and arousal during encounters with substance-related stimuli (Childress, 1994). In the laboratory, clients are given repeated, passive exposure to substance-reminding cues in a substance-free protected environment.

The research finds that initial arousal and strong craving produced by the cues eventually decrease (Childress, 1994). Better understanding of the relationship of learning and memory to the addiction process may lead to new treatment approaches.

Role of New Technologies

The recent development of noninvasive brain imaging has created a powerful new tool for demonstrating not only the short-term effects of substance use, but also the longer term consequences of chronic substance abuse and addiction.

These tools have allowed researchers to boldly go where they previously could not--literally into the depths of a living human brain. Such noninvasive techniques can depict normal and abnormal functioning of different brain areas by measuring metabolic activity (i.e., glucose utilization). They can identify substance-induced structural changes and physiological adaptations.

Through a combination of techniques, they can observe the altered "processing" of information in various circuits as the brain responds to substance use.

Using these techniques, investigators have been able to identify brain structures involved in craving, map the emotions of substance users, plot the neurobiological basis of substance-induced euphoria, and more.

For example, researchers have used magnetic resonance imaging (MRI) and spectroscopy to see how brain structures change as substances produce their effects. Others have used a functional imaging technique called phosphorus magnetic resonance spectroscopy (31P MRS) to show that chronic substance abuse is accompanied by abnormal metabolism in some areas of the brain that seems to return to normal when people stop using substances (Christensen et al., 1996).

Positron emission tomography (PET) has revealed subtle alterations in the dopamine receptors of stimulant users' brains (Iyo et al., 1993). More recent PET studies have demonstrated long-term vulnerability to chronic stimulant abuse (Melega et al., 1997a; Volkow et al., 1996, 1997b).

Another PET study has established a dose-response relationship between cocaine and the drug's subjective effects: The greater the amount of cocaine that is administered, the greater the high experienced by the user (Volkow et al., 1997a).

Other researchers combined electroencephalograms (EEGs) and MRI to produce a topographic brain map showing increased electrical activity (in the form of beta waves) during stimulant withdrawal (Herning et al., 1997). Mapping EEG activity during stimulant use and withdrawal may allow researchers to further document substance-induced neuropsychological impairments.

Although much is known about the effects of stimulants in animals, there is little such knowledge of these effects in humans (CSAT, 1997). The continuing development and application of new technologies such as noninvasive brain imaging will allow researchers to improve their understanding of how stimulants affect the human brain. Greater understanding of the underlying neuronal impairments of stimulant abuse will aid in the development of new, more effective treatment approaches.

General Effects Of Stimulants

Substances of abuse--and stimulants in particular--appear to increase the brain's levels of free dopamine in a dose-dependent manner; that is, more dopamine is available when higher doses of the substance are administered (Nash, 1997). The higher the substance dose, the greater the feelings of elation, euphoria, and satisfaction, and as the dopamine levels and pleasurable feeling subside, there is an intense desire to replicate the feelings of pleasure by administering another dose of the substance.

This tendency toward repeated administration is characteristic of stimulant abuse and underlies most of the other effects of stimulants, as well as most other addictive substances.

Continued use often leads to adverse consequences, which may include neuropsychological impairment and diminished physical health. Work performance and social and family relations can be adversely affected, and the risk of arrest and conviction on drug-related charges increases.

Even after a stimulant user discontinues use, impairments in cognition and functioning may persist, and there may even be persistent psychiatric symptoms (Wada and Fukui, 1990). Cravings for the stimulant's effects tend to linger, even after abstinence has been achieved, and the potential for relapse is high.

Medical Effects 

Acute effects  

The general acute effects of stimulants have been well documented. Among a range of physiological responses, stimulants are known to raise both systolic and diastolic blood pressure, increase heart rate, increase respiration rate, increase body temperature, cause pupillary dilation, heighten alertness, and increase motor activity (CSAT, 1997). 

Acute effects from excessive doses include dangerously rapid and erratic heartbeat, cerebral hemorrhaging, seizures/convulsions, respiratory failure, stroke, heart failure, brain damage, coma, and death (CSAT, 1997).  Stimulants are also known to cause sensitization (i.e., the opposite of tolerance), for which multiple drug exposures eventually produce some new adverse reaction.

For example, in animals, seizures do not typically occur after single low-to-moderate doses. But with repeated exposure, an animal can become sensitized to the stimulant and may have a seizure after a single, previously harmless, dose. 

Chronic effects  

Although the effects of chronic stimulant abuse in humans has not been well documented, some of the chronic effects include organ toxicity, compromised health (e.g., underfed, malnourished, poor hygiene), dental problems, and dermatitis. (For a complete discussion of the medical aspects of stimulant use, see Chapter 5.) 

Psychological Effects  

The immediate psychological effects of stimulant administration include a heightened sense of well-being, euphoria, excitement, heightened alertness, and increases in motor activity. Stimulants also reduce food intake, reduce sleep time, and may increase socialization activities. Stimulants may also enhance performance of certain types of psychomotor tasks. 

High doses may result in restlessness and agitation, and excessive doses may produce stereotypic behaviors (repetitive and automatic acts). Chronic psychological effects of stimulant use include various psychiatric disorders such as psychosis, paranoia, and suicidal tendencies. 

There may also be neurological impairments and cognitive deficits. Tolerance eventually develops to many of the behavioral effects of stimulants, so that increasing doses are required to achieve the same effect.  The administration of stimulants--particularly if smoked or injected intravenously--can have immediate and often very intense effects on the user.

However, the "rush" and subsequent feelings of euphoria may just as quickly fade. The intense effects can be followed by a dysphoric "crash." To stave the crash, the user will administer another dose of the stimulant, which again produces a rush and subsequent crash.  This cycle will go on again and again.

This pattern of frequently repeated dosing known as bingeing may continue for up to 3 sleepless days. During this period, the user may not eat and may lapse into a severe depression, followed by worsening paranoia, belligerence, and aggression--a period known as tweaking. 

Bingeing eventually ends when the user depletes his supply of stimulants or simply collapses from sheer exhaustion. The stimulant user may then sleep for several days, only to awaken and begin the cycle again. 

There is a great amount of anecdotal evidence on the relationship of stimulant use and various sexual behaviors. Stimulants may be used during sexual activities to intensify sexual acts, heighten pleasure, lengthen the duration of intercourse, and lessen inhibitions.

The abuse of stimulants is also known to lead to uncharacteristically aberrant or deviant sexual behaviors, the use of prostitutes, and HIV high-risk behaviors (Rawson et al., 1998b). 

Effects of Route of Administration  

Cocaine and MA can be smoked, snorted, injected, or ingested orally. These various routes of administration differ in dosage and in the rapidity and intensity of effect, which may affect the course of abuse and dependence. Some evidence
 suggests that the onset of dependence varies according to the route of administration (DEA, 1995). The route of administration affects the amount (i.e., the dosage) of stimulant delivered to the brain, the speed at which it is delivered, and the resulting intensity of the stimulant's effects. 

The intensity of the psychological effects of stimulants, as with most psychoactive drugs, depends on the dose and rate of entry to the brain. For example, when snorted, stimulants generally reach the brain within 3 to 5 minutes, and the resulting rush or "high" may not be perceived as immediate; intravenous administration produces a rush in about 15 to 30 seconds; whereas smoking produces an almost immediate effect (ONDCP, 1998a). 

Because of the rapidity of delivery and higher dosages, the smoking of stimulants produces a high that is said to be far more intense than those produced through other routes of administration.  Route of administration has been shown to affect the resulting level of stimulant in the body. In a comparison of oral ingestion versus smoking, Cook measured plasma levels of MA after oral administration and after smoking (see Figure 2-5)(Cook, 1991).

For the oral dose of 0.25 mg/kg, plasma levels began to rise 30 minutes after ingestion and reached peak levels (approximately 38 ng/mL) at about 3 hours after ingestion. Plateau levels were maintained until about hour 4 and then
 slowly declined over the next 4 hours. After smoking (dose of about 21 mg/subject), MA plasma levels approximated 80 percent of peak levels within minutes, peaked (approximately 42 ng/mL) at about 2 hours after administration, maintained a peak plateau for another 2 hours, and then slowly declined over the next 4 hours.

By comparison, plasma levels of smoked cocaine and smoked MA both peaked rapidly (Cook, 1991). Plasma levels of smoked cocaine (dose of 21 to 22 mg/subject) peaked at approximately 240 ng/mL at about 5 to 10 minutes after administration. Cocaine plasma levels then declined rapidly, dropping to 50 percent of maximum level (half-life) within 1 hour. Smoked MA (dose of 21 to 22 mg/subject) neared peak levels (approximately 50 ng/mL) within minutes and continued to climb until about 2 hours after administration before slowly tapering off.

However, half-life levels were not reached until 11 to 12 hours after administration (see Figure 2-6). The long plateau effect and the much longer half-life of MA versus cocaine suggests considerable dangers in repeated smoking of MA because remarkably higher plasma concentrations could be expected to occur if the dose is repeated, even at fairly long intervals (Cook, 1991).

Because stimulants exert their effects in a dose-dependent manner, the route of administration has serious neurological, medical, psychiatric, and neurocognitive implications for the stimulant user and the treatment provider. The intense highs produced by smoking crack cocaine or ice MA can lead to equally intense "lows" during withdrawal (e.g., dysphoria, depression, irritability, anxiety, paranoia, dramatic mood swings).

The subsequent cravings can also be extremely intense. Prolonged high doses of stimulants (e.g., during bingeing) may cause greater and longer lasting neurological damage, which in turn may lead to greater and longer lasting cognitive deficits. The onset of stimulants' chronic effects varies across individuals, and although there are few data to predict how long it will take for any user to begin suffering from the chronic effects of stimulant abuse and dependence, onset is probably related to the size of the doses, the frequency of dosing, and the route of administration.

However, in general, the higher the doses and the more frequently the doses are administered, the more quickly the chronic effects will appear. From a treatment provider's perspective, a stimulant user's preferred route of administration affects the extent and depth of chronic effects and, therefore, has implications for choosing the most appropriate treatment approach. (See Chapter 4 for a full discussion on the practical applications of treatment strategies.

For a discussion on route-of-administration effects on toxicity and adverse reactions, see Chapter 5.) 

Cocaine Acute Effects  

Cocaine has two main pharmacological actions. It is both a local anesthetic and a central nervous system (CNS) stimulant--the only drug known to possess both of these properties. Cocaine exerts its local anesthetic actions by blocking the conduction of sensory impulses within nerve cells. This effect is most pronounced when cocaine is applied to the skin or to mucous membranes. Cocaine hydrochloride has approved medical use as a local anesthetic in surgery of the nose, throat, and larynx. 

As a CNS stimulant, cocaine affects a number of neurotransmitter systems, but it is through its interaction with the dopamine and the limbic reward system that cocaine produces some of its most important effects, including its positive reinforcing effects.

The major influence of cocaine on the dopamine system is its ability to block the synaptic reuptake of dopamine. As shown in Figure 2-7, cocaine does not directly "stimulate" the dopamine system; rather, it causes the system to be stimulated by preventing dopamine from being removed from the intracellular space.

Cocaine blockade of the dopamine reuptake transporter extends the availability of dopamine in the synaptic space where it continues to occupy the dopamine receptor and causes the postsynaptic neurons to fire for a longer than normal period. This extended firing of the postsynaptic neurons resulting from prolonged dopamine receptor activity is initially experienced subjectively by the cocaine user as a positive sensation involving increased energy, arousal, and stimulation.

A recent study has demonstrated a relationship between the intensity of cocaine's subjective effects and the degree to which the dopamine reuptake transporter is blocked (Volkow et al., 1997a). The effects experienced by users of cocaine during the initial period of their use are generally mood-altering in a positive manner (Washton, 1989).

For most individuals, the subjective experience of the acute effects includes a generalized state of euphoria in combination with feelings of increased energy, confidence, mental alertness, and sexual arousal.  Under the proper environmental circumstances, individuals also report that cocaine heightens their ability to concentrate, increases sexual excitement, increases their sociability, and decreases any preexisting shyness, tension, fatigue, depression, or boredom.

Many people feel more talkative, more intensely involved in their interactions with others, and more playful and spontaneous when high on cocaine. As they come down from their cocaine high, some users experience temporary unpleasant reactions and aftereffects, which may include restlessness, anxiety, agitation, irritability, and insomnia.

During this "rebound" period, suspiciousness, confusion, hyperarousal, and other elements of paranoid thinking may also appear.  With continued escalating use of cocaine, the user becomes progressively tolerant to the positive effects while the negative effects steadily intensify (Washton, 1989). Users report that the highs are not so high anymore and the rebound aftereffects increasingly lead to a dysphoric, depressed state.

These new "lows" may reinitiate the desire for more cocaine in a futile attempt at mood normalization. The search for the previously experienced high will eventually leave the user in the depths of depression and despair.  When snorted, smoked, or injected intravenously, cocaine quickly produces an intense high. But because it is rapidly metabolized in the body, this high is short-lived.

Efforts to replicate the initial high prompt users to take it often and repeatedly. Because of its mechanism of action, cocaine may produce strong craving and strong conditioning of cues associated with its use. The results of a recent brain imaging study revealed that cocaine's fast uptake in the brain has a major role in its rewarding effects and that its fast clearance from the brain sets the stage for frequent abuse, craving, and the binge pattern in cocaine addiction (Volkow et al., 1996).

These researchers postulated that dopaminergic activation of the limbic reward system is involved in the rewarding effects of cocaine (and perhaps most, if not all, substances of abuse) and that continued activation of this system may lead to long-term changes in the associated neural circuits that perpetuate the compulsive administration of this drug (see below). 

Cocaine use also has acute adverse physiological effects involving the respiratory, cardiovascular, and central nervous systems. Systemic toxicity to cocaine is characterized by profound sympathetic stimulation of the respiratory,
 cardiovascular, and central nervous systems, producing a combination of medical and psychological effects sometimes known as the "cocaine reaction." (For additional details on the medical aspects of cocaine abuse, see Chapter 5.) 

Chronic Effects  

For many cocaine users, the initial experimental use begins to give way to more frequent or regular use. With continued, intensified use, the "casual" user will progress to the abuse stage, requiring larger and larger doses to achieve the desired effects. The abuser may become obsessed with the rituals of cocaine administration and may find that many common items or situations trigger cravings for the drug.

For some, abuse will lead to full-fledged addiction. There will be overwhelming urges and cravings for cocaine, and there may be an inability to self-limit or control use. The cocaine addict will deny that she has a drug use problem and will continue use of cocaine despite the negative consequences. At this
 stage, the adverse consequences of cocaine addiction have probably affected all aspects of the user's life.

The addict has succumbed to what Dr. Sidney Cohen called cocaine's "pharmacological imperative" (Washton, 1989). Figure 2-8 lists the characteristics of the stages of cocaine addiction.  The timetable for the onset of the chronic effects of cocaine use varies across individuals and may depend on the size of the doses, the frequency of dosing, and the route of administration. There are no data to base a prediction on how long it will take for any individual to begin to suffer from the chronic effects of cocaine use.

However, similar to the effects of MA, the higher the doses and the more frequently the doses are administered, in general, the more quickly the chronic effects of cocaine will appear. In addition, intranasal administration (snorting) is associated with slower onset of chronic effects than if cocaine is smoked (freebase or crack) or injected intravenously.

Clearly, there are tremendous individual differences in this timetable, with some individuals reporting an ability to use for extended periods with few signs of negative consequences and others reporting a very dramatic onset of severe detrimental effects as soon as a few weeks or months after initiation of cocaine use.  Physically, the cocaine addict may appear thin or even emaciated. Personal hygiene and self-care may be neglected, and medical and dental needs may go unmet.

Because cocaine suppresses appetite, the user fails to eat properly and may
 suffer from vitamin deficiencies. Severe addicts may ignore food, clothing, shelter, and sexual needs.  Psychologically, cocaine's chronic effects are exactly the opposite of the desired initial effects. Continued cocaine use increases paranoia and confusion and causes an inability to concentrate and an inability to perform sexually. The same substance that acutely produced a mild sensation of arousal and decreased fatigue, on a chronic basis results in chest pain, insomnia, anorexia, episodic depression, and extreme fatigue. 

From a treatment perspective, the curious thing is that the user often accurately perceives and attributes the pleasurable, acute effects to the use of cocaine.

However, he frequently is unable or unwilling to recognize the relationship of the negative, chronic effects to the use of cocaine. Although it may be dramatically apparent to family and friends that the effects of cocaine are highly detrimental and destructive to the user, the user may insist that the use of cocaine is very helpful and beneficial.

The extensive health-compromising effects of cocaine abuse are apparent when examining the behavioral and psychological profile of clients as they enter substance treatment. Generally, these clients exhibit a pronounced disruption in healthy behaviors and an elevation in dysphoric emotions including anxiety, depression, and paranoia (Castro et al., 1992). 

Chronic abuse of cocaine may cause neuropsychological impairments (O'Malley et al., 1992) as well as neuropsychiatric syndromes (Herning et al., 1997). Cocaine-induced cognitive deficits can last up to 3 months after heavy use before baseline functioning is restored. In their review, Weinrieb and O'Brien found a strong association between the chronic use of cocaine and deficiencies in short-term auditory recall, memory, concentration--especially for nonverbal abstracting and problem solving--and slowed reaction time (Weinrieb and O'Brien, 1993). 

The physical, psychological, and cognitive effects of chronic cocaine use reflect the underlying physiological effects; at the heart of these effects is cocaine's impact on the neurotransmitter dopamine.

Methamphetamine

Acute Effects

Although research efforts continue to focus on the effects of MA, there are limited data on MA's effects on humans (CSAT, 1997). Much of the available information has been surmised from the literature on cocaine. However, the physiological effects of MA are generally similar to those of cocaine: increased heart rate, elevated blood pressure, elevated body temperature, increased respiratory rate, and pupillary dilation. Other acute effects include rapid heart rate, irregular heart rate, and irreversible, stroke-producing damage to small blood vessels in the brain.

MA's psychological effects, like those of cocaine, include a heightened sense of well-being or euphoria, increased alertness, increased vigor, decreased food intake, and decreased sleep time. Acute administration has been shown to increase socialization in humans. High doses may produce repetitive and automatic acts in both humans and animals, and in humans, may cause irritability, aggressive behavior, excitement, auditory hallucinations, and paranoia (delusions and psychosis).

Dangerously elevated body temperature and convulsions occur with MA overdoses, and if not treated immediately, can result in death. With continued use, tolerance develops to the behavioral effects, and repeated exposure may produce sensitization. MA users tend to engage in violent behavior. Mood changes are common, with the user rapidly changing from friendly to hostile.

The course of addiction to MA is believed to be similar to that of cocaine. Even the underlying neurological effects of MA are similar to the effects produced by cocaine: increased levels of free dopamine in the brain's limbic reward system. The MA "withdrawal syndrome" is like that of cocaine, but due to the longer effects of MA, withdrawal may be more intense and protracted.

Several hours after last use, the MA user experiences a drastic drop in mood and energy levels. Sleep--which may be promoted by the use of secondary substances such as alcohol, barbiturates, and benzodiazepines--finally begins and may last for several days. Upon awakening, the user may experience severe depression, perhaps lasting for several weeks. While in this depressed state, the user has an increased risk of suicide. But once the user feels that she "has recovered" from a bingeing episode, cravings set in, and the cycle often begins again.

There are three essential differences between cocaine and MA. First, MA is thought to enhance CNS neurotransmission by increasing the presynaptic release of dopamine within the limbic reward system. Second, recent research has demonstrated MA's neurotoxicological effects in animals and has begun to support the hypothesis that MA is neurotoxic in humans. Unlike cocaine, MA does cross neuronal cell membranes and will enter into the microscopic sacs (called vesicles) where neurons store dopamine.

MA is believed to damage the storage sacs and the neurons' axonal endings such that dopamine leaks uncontrollably into the synapse (see Figure 2-9). MA can also cause neurotoxicity indirectly by mobilizing dopamine out of the safe storage vesicles within the neuron and into the neuron's cytoplasm (i.e., the cell's internal material) where it is converted to toxic and reactive chemicals. Third, cocaine is rapidly metabolized by plasma and tissue enzymes, whereas MA is metabolized at a much slower rate, which results in a longer duration of action (Cook, 1991; ONCDP, 1998b). Although the half-life (effective duration of action) of cocaine is 1 to 2 hours, a single dose of MA may produce an effect for 8 to 12 hours. The fact that MA is metabolized at a slower rate also allows more time for MA to exert its neurotoxicological effects.

The sustained high plasma levels suggest considerable dangers in repeated smoking of MA because remarkably higher plasma concentrations could be expected to occur if the dose is repeated, even at fairly long intervals (Cook, 1991).

Chronic Effects

Chronic abuse of MA may result in inflammation of the heart lining and, among users who inject the drug, damaged blood vessels and skin abscesses. Chronic users may also have episodes of violent behavior, paranoia, anxiety, confusion, and insomnia. Heavy users show progressive social and occupational deterioration. Psychotic symptoms may sometimes persist for months or years after use has ceased.

Some of the most frightening research findings about MA suggest that its prolonged use not only modifies behaviors, but literally changes the brain in fundamental and long-lasting ways. Animal studies have shown that chronic use of MA can significantly reduce brain dopamine levels for up to 6 months after last use, with less significant reductions persisting for up to 4 years. MA impairs the functioning of both the dopamine system and the serotonin system (serotonin is another important CNS neurotransmitter).

MA-induced neuronal toxicity is specific to certain brain regions (primarily the limbic reward system), and this toxicity is reflected both biochemically and anatomically. The adverse effects produced by MA are often long-lasting, and there is some speculation that some types of damage may be permanent. Finally, these impairments in brain functioning may underlie the cognitive and emotional deficits seen in many MA users. Understanding the chronic effects of MA use is essential for treatment providers who serve this population.

Animal studies have shown that high dose regimens of MA significantly deplete neurotransmitter levels, particularly those of dopamine (e.g., Seiden et al., 1976). Subsequent studies replicated these findings (e.g., Ricaurte et al., 1980) and demonstrated that these depletions were evident up to 4 years after cessation of MA administration (Woolverton et al., 1989). A more recent study demonstrated that chronic amphetamine exposure in monkeys could produce long-term effects on the brain's ability to produce dopamine (Melega et al., 1997a).

Significant depletion of dopamine persisted 6 months later; even after 1 year, the brain dopamine levels were only at 80 percent of their preexposure levels. In a radiotracer study of humans, Iyo and colleagues (Iyo et al., 1993) revealed reductions in dopamine receptor binding availability in brain areas such as the frontal cortex and striatum in MA users. Although there is little current evidence on MA's chronic effects in humans, animal research has proven that prolonged or heavy use of MA dramatically reduces the brain's ability to produce dopamine.

Numerous animal studies have demonstrated that MA can damage both dopamine and serotonin systems (e.g., Peat et al., 1983; Robinson and Becker, 1986; Seiden et al., 1976; Trulson and Trulson, 1982a, 1982b; Wagner et al., 1979). MA toxicity occurs after repeated high-dose administration, and it is selective for certain neuronal systems, particularly those in the limbic reward system (e.g., striatum, substantia nigra, nucleus accumbens).

Within these brain circuits, MA has been shown to reduce the number of nerve fibers, impair normal physiological functioning, and destroy both axons and axon terminals (i.e., at synaptic junctions). These studies have also shown that MA toxicity is highly dependent on dose, route of administration, and frequency with which the drug is given.

Prolonged or heavy use of MA decreases the brain's ability to manufacture dopamine. This impairment may persist for up to 1 year after the user has stopped taking MA. Researchers now believe that those changes in dopamine and the damage done to dopamine and serotonin neurons are responsible for the chronic effects of MA use that are much more pronounced than the acute effects.

If MA does indeed cause damage to dopamine and serotonin systems in humans, then there are ramifications to consider. One of the outcomes of chronic MA use is psychosis. Psychotic individuals are often treated with drugs to reverse or return their brain functions to normal, and most antipsychotic medications work by changing the activities of the dopamine and serotonin neurons.
 
The unanswered question is: Will antipsychotic medications be able to effectively treat MA-induced psychoses in individuals whose dopamine and serotonin systems have been impaired by chronic MA abuse? To date, there have been few, if any, studies investigating antipsychotic medications for the treatment of chronic MA abuse and dependence.

In summary, although there is much evidence of MA's neurotoxicity in animals, the issue of whether MA causes permanent damage to dopamine and serotonin neurons in humans remains very much an unanswered question. Because of the inherent dangers associated with this type of research, the information will have to come from postmortem studies, advanced neuroimaging studies, and the development of new strategies for detecting neurotoxicity--possibly through the use of operant behavioral pharmacology. Finally, the degree of neurotoxicity must be placed in perspective, and the functional consequences require further scrutiny to determine the impact of chronic MA abuse on human brain function.

Summary

Recent research has shown how stimulants such as cocaine and MA exert their effects on the user's nervous system and change the user's feelings, emotions, and behavior. There is now a greater understanding of neurological reinforcement systems, how substance use can lead to dependence, and the roles that craving and memory play in sustaining addiction.

Although there is currently a dearth of research regarding the neurologic, medical, psychiatric, and neurocognitive effects of stimulants in humans (CSAT, 1994b, 1997), animal studies have demonstrated cocaine's and MA's ability to disrupt normal brain function and cause long-lasting and perhaps permanent neurological impairments.
 
With continuing research and the development of new imaging technologies, the full extent of these stimulants' effects on humans will eventually be revealed. This new information should continue to assist in the development of new and improved approaches for treating stimulant use disorders.

~~~~

SAMHSA/CSAT Treatment Improvement Protocols
TIP 33: Treatment for Stimulant Use Disorders
http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=hstat5.chapter.57310

As large numbers of people with substance use disorders began to seek treatment in the early and mid-1980s, "treatment" for stimulant abuse and dependence was invented.

The treatment system that responded most quickly was the 28-day Minnesota Model hospital industry. The number of these 28-day, for-profit treatment units grew at an astonishing rate. Tens of thousands of cocaine users were treated in these programs with strategies adapted from the treatment of alcoholics. Today, there is little empirical evidence to assess the efficacy of these efforts.

During this same period, all sorts of unconventional remedies, including health foods, amino acids, hot tubs, electronic brain tuners, and other "New Age" treatments emerged and disappeared. Research efforts to develop scientifically based treatments began during this period with behavioral techniques like contingency contracting (Anker and Crowley, 1982) and medication evaluations including the use of desipramine (Norpramine) (Tennant and Rawson, 1983; Gawin and Kleber, 1984). Over the 15-year period since these early efforts, an entire stimulant use disorder treatment literature has developed.

This chapter reviews the current state of knowledge on the treatment of stimulant use disorders, beginning with the approaches that have the most rigorous empirical support. Other approaches with less support in the scientific literature are presented later in the chapter. At the end of the chapter is a review of the current state of medications research in the treatment of stimulant use disorders.

Although at the time of this writing there were no medications with demonstrated clinical efficacy, the ongoing program of research sponsored by the National Institute on Drug Abuse (NIDA) holds great promise for important treatment advances. For this reason, the current state of this research effort will be reviewed.

Documented Treatment Approaches

How To Measure Effectiveness

This chapter reviews what is scientifically known about effective treatments for stimulant use disorders. To be judged effective, a treatment must have been tested and demonstrated to be effective in a randomized clinical trial. Many psychosocial and pharmacological treatments have been investigated in such trials. Several psychosocial treatments for stimulant abuse and dependence have been found to be effective, but to date, no reliably effective pharmacological treatments have been found.

What has been learned so far about the use of psychosocial and pharmacological treatments for stimulant use is summarized below. Almost all of the information has been gleaned from studies conducted with cocaine users. Similar studies with methamphetamine (MA) users have not been reported. However, evidence from at least one study indicates that cocaine and MA users respond similarly to psychosocial interventions, suggesting that what has been learned from cocaine users may be applicable to MA users (Huber et al., 1997).

Randomized clinical trials are the best available method for determining whether an intervention improves health. A randomized clinical trial is a prospective study comparing the effect of some intervention against a control intervention in groups of clients who are assigned randomly to the respective treatment groups (see Friedman et al., 1983).

In such trials, clients from a particular population sample (e.g., all admissions to clinic X during 1998 meeting a particular list of inclusion and exclusion criteria) are randomly assigned to the intervention under study or to a control condition. Random assignment ensures against possible bias in assigning particular kinds of clients to the respective groups and helps to distribute evenly between the groups any subject characteristics that might influence outcomes.

Prospective means that clients in the groups are studied from the start of the intervention as opposed to retrospectively compiling the information after the intervention is completed. Retrospective observations tend to be less accurate because of relevant information not being collected, getting lost, or being distorted through reliance on people's recall.

Having a comparison or control group is essential because most problems have some level of variability (i.e., they wax and wane over time) and because many health problems resolve over time without any formal treatment. The most effective way to determine whether any observed changes are due to the treatment being investigated rather than natural variability is by comparing against a similar group of clients who either received no treatment or received a standard treatment.

Some of the alternatives to randomized clinical trials common in the substance use disorder treatment field can provide useful information but have serious limitations that must be recognized.

For example, following a group of clients who received a particular treatment in the absence of a comparison group can be informative in terms of characterizing what has happened to them (e.g., percentage relapsed, percentage who received additional treatment, amount of change from pre- to posttreatment), but such observations do not permit any scientifically valid inferences regarding the role of the treatment provided to any of the changes observed during followup.

For that purpose, a comparison group is necessary. Any changes observed might have occurred in the absence of treatment. Without a comparison group there simply is no way to rule out that possibility. Similarly, when clients themselves select group membership, as opposed to being assigned by the researcher, one cannot make valid inferences about the role of treatment to outcome.

For example, comparing treatment completers to dropouts is common and may be informative in terms of characterizing how the groups fared, but it is not scientifically valid to infer that any differences observed between them were due to the different amounts of treatment received. It very well could be that some other factor (e.g., differences in the amount of other demands on their time) was responsible both for the differential retention rates and for the subsequent differences observed at followup.

Psychosocial Treatment Approaches

The psychosocial interventions demonstrated thus far to be efficacious in randomized clinical trials with stimulant users share a common feature of incorporating well established psychological principles of learning.

It is impossible to quantify all aspects of psychosocial treatment. Often therapists working in the same clinic and using the same treatment approach differ greatly in terms of the progress their clients make. Put simply, some therapists appear to be very effective and others relatively ineffective. The use of carefully prepared treatment manuals reduces such between-therapist differences. Treatment manuals increase the likelihood that therapists will deliver a uniform set of services to their clients.

That does not come at the cost of eliminating therapists' clinical judgment or flexibility. A carefully prepared manual recognizes the importance of clinical judgment and flexibility in addressing the individual needs of clients and incorporates those features into the manual. Considering that effective treatments and associated manuals are available, using them is prudent and will help ensure that clients receive the services that research has shown to be effective.

Community-Reinforcement-Plus-Vouchers Approach

Community reinforcement is an individualized treatment designed to promote lifestyle changes in several key areas that are conducive to successful recovery (see Meyers and Smith, 1995; Sisson and Azrin, 1989). First, clients with spouses who are not themselves users are offered marital therapy to improve the quality of their relationships in a reciprocal and rewarding manner. Second, clients who are unemployed, employed in jobs that are high-risk for substance abuse, or need vocational assistance for some other reason receive help in that domain.

Third, clients are counseled and assisted in developing new social networks and recreational practices that promote and support recovery. Self-help participation is not mandatory but is often used as an effective means of developing a new social network.

Fourth, various types of skills training are provided depending on individualized client needs, including substance refusal and associated skills, social skills, time management, and mood regulation training. Finally, clients with alcohol use disorders and no medical contraindications are offered a program of disulfiram (Antabuse) therapy coupled with strategies to support medication compliance.

Voucher-based incentive programs are designed to facilitate retention in treatment and to promote initial abstinence from stimulants. Such incentive programs are known as contingency management interventions, which are discussed further below. In this treatment, clients earn vouchers that are exchangeable for retail items contingent on stimulant-free urinalysis results during the initial 12 weeks of the 24-week treatment. Urinalysis monitoring is conducted thrice weekly during that period.

The voucher system used in studies evaluating this treatment included incentives worth a maximum of approximately $980 across the course of treatment. Since those studies were completed, others have reported effective voucher programs using lower cost incentives (Tusel et al., 1995); another program obtained all its incentives via donations from community businesses (Amass, 1997), although the efficacy of this program was not evaluated. How valuable the incentives must be to significantly improve outcomes has not yet been evaluated.

The efficacy of the community-reinforcement-plus-vouchers approach, delivered as a comprehensive, stand-alone treatment, is supported by three randomized clinical trials (Higgins et al., 1993b, 1994b, 1997), with several additional trials supporting the efficacy of particular components of that approach (e.g., Silverman et al., 1996). The first trial examined the efficacy of this treatment compared with standard outpatient counseling (Higgins et al., 1993b).

Treatment was 24 weeks in duration with 6 months of additional followup. The community-reinforcement-plus-vouchers treatment retained clients significantly longer and documented significantly longer periods of continuous stimulant abstinence than did standard counseling. For example, 58 percent of clients assigned to the community-reinforcement-plus-vouchers treatment completed 24 weeks of treatment compared with 11 percent of those assigned to standard counseling.

Furthermore, of the clients in the community-reinforcement-plus-vouchers group, 68 percent were documented to have achieved 8 weeks of continuous cocaine abstinence, and 42 percent had 16 weeks of continuous abstinence. Of the clients in the standard counseling group, only 11 percent were documented to have achieved 8 weeks of continuous cocaine abstinence, and only 5 percent had achieved 16 weeks of continuous abstinence.

Followup assessments revealed another important difference: Greater cocaine abstinence was documented--at 6, 9, and 12 months after treatment entry--in the group that received community-reinforcement-plus-vouchers treatment than in those who received standard counseling (Higgins et al., 1995).

A detailed manual (Budney and Higgins, 1998) that was designed specifically to guide clinicians in the day-to-day implementation of this approach was published recently by NIDA and is available at no cost via the NIDA Clearinghouse (1-800-729-6686) or can be downloaded from the website http://www.nida.nih.gov/TXManuals/CRA/CRA1.html

Contingency Management

The voucher system mentioned above is a contingency management intervention (also referred to as contingency contracting). Contingency management is a well-known behavioral intervention that is designed to increase or decrease desired behaviors by providing immediate reinforcing or punishing consequences when the target behavior occurs.

Contingency management has been used with considerable effectiveness in the treatment of a variety of types of substance use disorders and is very useful for treatment planning because it sets concrete short-term and long-term goals and emphasizes positive behavioral changes (Stitzer and Higgins, 1995). However, relying exclusively on punitive consequences in contingency management interventions is not recommended because doing so can promote early treatment dropout (Stitzer et al., 1986).

The voucher program has been demonstrated to be efficacious when delivered apart from the community reinforcement treatment. Silverman and colleagues, for example, demonstrated that vouchers contingent on cocaine-negative urinalysis results increase cocaine abstinence in methadone maintenance clients who abuse cocaine (Silverman et al., 1996). Tusel and colleagues demonstrated reductions in all illicit substance abuse with contingent vouchers (Tusel et al., 1995).

Although vouchers are a well-supported contingency management intervention for increasing abstinence in stimulant users, other methods are also effective. Examples among methadone maintenance clients are take-home methadone doses (which eliminate the need for methadone clients to visit the clinic daily to consume their medication under staff supervision) (Stitzer et al., 1992), continuance of methadone maintenance treatment contingent on abstinence from cocaine (Kidorf and Stitzer, 1993), and even a simple system wherein publicly displayed gold stars and inexpensive gifts (e.g., coffee cups, gasoline coupons) are earned for substance abstinence and counseling attendance (Rowan-Szal et al., 1994).

Contingent methadone take-home doses have been used effectively when coupled with other treatment services. An excellent example of this was provided by McLellan and colleagues (McLellan et al., 1993). Methadone maintenance clients were randomly assigned to one of three conditions that provided increasing levels of services. Two of the three groups received methadone take-home doses contingent on negative urinalysis results and proof of current employment. These groups also received additional services not provided to the minimal-service group. The two groups given the opportunity to earn contingent take-home methadone doses achieved higher rates of cocaine and opiate abstinence than did clients receiving noncontingent take-home doses.

Iguchi and colleagues investigated whether cocaine abstinence could be increased through contingent reinforcement of compliance with individualized treatment plans rather than negative urinalysis results (Iguchi et al., 1997). Newly admitted methadone maintenance clients were assigned to one of three groups: (1) a control group receiving standard treatment at the methadone clinic (the standard group); (2) a group receiving standard treatment plus monetary vouchers contingent on the submission of substance-free urine specimens (urinalysis-contingent group), or (3) a group receiving standard treatment plus the same monetary vouchers but contingent on completing treatment plan tasks (treatment plan group). The third group demonstrated significantly greater reductions in illicit substance use than did the other two groups.

Contingency management can be effective with more-difficult-to-treat subgroups of stimulant users. For example, a contingency management approach that was efficacious in homeless stimulant users combined nonhospital day treatment with access to work therapy and housing contingent on substance abstinence (Milby et al., 1996). Nearly three-fourths of the subjects in this study were primarily crack cocaine users. They were randomly assigned to receive either enhanced or usual care. Enhanced care consisted of 2 months of clinic attendance for 5.5 hours each weekday, transportation to and from the clinic, lunch, psychoeducational groups, and individualized counseling.

During the last 4 months of the trial, the intensity of day treatment was reduced to allow subjects to participate in a work-therapy program refurbishing condemned houses in which they could live for a modest rental fee. Participation in the work program and housing were contingent on the provision of weekly random urinalysis testing.

Drug-positive results precluded subjects from working in the program and required them to vacate the housing within 2 weeks. The work and living arrangements could be resumed on submission of two consecutive substance-free urine specimens.

Usual care consisted of twice-weekly, 12-Step-oriented group and individual counseling, medical evaluation and treatment or referral, and referrals to community agencies for housing and vocational services. Enhanced care increased cocaine abstinence significantly at the 2-month assessment, although not at the 6- or 12-month assessments. Enhanced care also produced greater reductions in alcohol use at each assessment and significantly fewer days homeless at the 6- and 12-month assessments.

Pregnant women are another important subgroup with whom contingency management has been evaluated, although only in the form of preliminary studies. In two pilot studies, pregnant women were offered incentives for attendance at prenatal clinics and/or maintaining cocaine abstinence (Elk, in press).

Monetary vouchers of increasing value were awarded for each successive substance-free urine specimen and for increased or consistent attendance at prenatal and substance use disorder treatment clinics. Abstinence, retention rates, and compliance with prenatal care visits were generally higher in the contingency groups.

In another study, pregnant clients were randomly assigned to receive standard or enhanced methadone maintenance treatment (Carroll et al., 1995a). Standard treatment consisted of daily methadone, weekly group counseling, and thrice-weekly urine testing. Enhanced treatment consisted of weekly prenatal care, weekly relapse prevention groups, and monetary vouchers for every three consecutive substance-free urine samples.

Treatment retention was similar in the two groups, and there were no significant differences in the percentage of cocaine-positive urine samples provided by the two groups.

This treatment approach with pregnant women with stimulant use disorders is very preliminary and needs more thorough evaluation. However, these efforts further illustrate the potential utility of contingency management for addressing some of the more daunting clinical challenges in treating stimulant abuse.

Other important examples are recent pilot studies (Roll et al., 1998; Shaner et al., 1997) suggesting that contingent monetary reinforcement can reduce cigarette and cocaine use in adult schizophrenic clients and providing evidence that contingent monetary reinforcement can be used to increase medication compliance in tuberculosis-infected stimulant users (Elk, in press).

When considered as a group, contingency management interventions have by far the greatest amount of empirical support for their efficacy in promoting therapeutic behavioral change among stimulant users.

Stimulant users are sensitive to systematically applied contingency management interventions. Presently, there is no other treatment strategy about which one can make an equally strong positive statement.

Relapse Prevention

Relapse prevention (RP) systematically teaches clients (1) how to cope with substance craving, (2) substance refusal and assertiveness skills, (3) how seemingly irrelevant decisions can affect the probability of later substance use, (4) general coping and problem solving skills, and (5) how to apply strategies to prevent a full-blown relapse should an episode of substance use occur (Marlatt and Gordon, 1985).

Carroll and colleagues have adapted and demonstrated the efficacy of this treatment approach with cocaine users (Carroll et al., 1991a, 1991b, 1994a, 1994b). In an initial study, RP was compared with interpers