Are prescription stimulants "smart pills"? The epidemiology and cognitive neuroscience of prescription stimulant use by normal healthy individuals.

Use of prescription stimulants by normal healthy individuals to enhance cognition is said to be on the rise. Who is using these medications for cognitive enhancement, and how prevalent is this practice? Do prescription stimulants in fact enhance cognition for normal healthy people? We review the epidemiological and cognitive neuroscience literatures in search of answers to these questions. Epidemiological issues addressed include the prevalence of nonmedical stimulant use, user demographics, methods by which users obtain prescription stimulants, and motivations for use. Cognitive neuroscience issues addressed include the effects of prescription stimulants on learning and executive function, as well as the task and individual variables associated with these effects. Little is known about the prevalence of prescription stimulant use for cognitive enhancement outside of student populations. Among college students, estimates of use vary widely but, taken together, suggest that the practice is commonplace. The cognitive effects of stimulants on normal healthy people cannot yet be characterized definitively, despite the volume of research that has been carried out on these issues. Published evidence suggests that declarative memory can be improved by stimulants, with some evidence consistent with enhanced consolidation of memories. Effects on the executive functions of working memory and cognitive control are less reliable but have been found for at least some individuals on some tasks. In closing, we enumerate the many outstanding questions that remain to be addressed by future research and also identify obstacles facing this research.

Related papers:

title: Diagnosis and treatment of adult attention-deficit/hyperactivity disorder at US ambulatory care visits from 1996 to 2003
abstract: To determine national-estimates and characteristics of United States (US) ambulatory care visits made by adults, aged 18 years or older, with attention-deficit hyperactivity disorder (ADHD) diagnosis, treatment patterns, and significant factors associated with adult-ADHD treatment.  Retrospective analyses were conducted of the National Ambulatory Medical Care Survey and the National Hospital Ambulatory Medical Care Survey over a combined 8‐year period (1996–2003). Mental-health disorder (including ADHD) visits were identified using International Classification of Diseases, 9th revision, Clinical Modification (ICD‐9‐CM) diagnostic codes. Significant factors of adult-ADHD treatment were determined in multivariable logistic regression analyses.  An estimated total 10.5 million ambulatory-ADHD visits accounted for 3.5% of 301 million adult mental-health disorder visits. The census-adjusted visit rate was 0.3–0.4%. Increasing in numbers from the year 2000, ADHD visits were most often to psychiatrists, by Caucasian men, aged 18 to 40 years. Significantly fewer ADHD visits without, versus with, psychiatric comorbidity (mainly depression) received various treat-ments – behavioral (46% vs. 83%), antidepressant (18% vs. 66%), or combined behavioral and ADHD-specific (stimulant or atomoxetine) pharmacotherapy (36% vs. 57%) respectively. However, more ADHD visits without than with psychiatric comorbidity received ADHD-specific pharmacotherapy alone (76% vs. 68%) or no treatment (14% vs. 6.5%). At ADHD visits, adjusting for gender, age, and US census geographic-region, psychiatric comorbidity (odds ratio [OR], 6.5, 95% confidence interval [Cl], 3.5–12.4, p < 0.05) and self-pay reimbursement-source (OR, 2.7, 95% Cl, 1.3–5.7, p < 0.05) significantly increased the likelihood of behavioral treatment. Insurance reimbursement-sources other than private and self-pay significantly decreased the likelihood of an ADHD-specific pharmacotherapy (OR, 0.4, 95% Cl, 0.2–0.7, p < 0.05) or any ADHD-treatment (OR, 0.2, 95% Cl, 0.1–0.5, p < 0.05).  Adult-ADHD visits have increased in recent years, with a census-adjusted visit rate of 0.3–0.4%. Psychiatric comorbidity and reimbursement-source were associated with ADHD-treatment. Limited treatment may be a significant problem in US-ambulatory care. It is important to continue validation studies, educate providers, examine the efficacy of multimodal-treatments, and study insurance-related barriers to adult ADHD-treatment.

title: Evidence, Interpretation, and Qualification From Multiple Reports of Long-Term Outcomes in the Multimodal Treatment Study of Children With ADHD (MTA)
abstract: To review and provide details about the primary and secondary findings from the Multimodal Treatment study of ADHD (MTA) published during the past decade as three sets of articles.  In the second of a two part article, we provide additional background and detail required by the complexity of the MTA to address confusion and controversy about the findings outlined in part I (the Executive Summary).  We present details about the gold standard used to produce scientific evidence, the randomized clinical trial (RCT), which we applied to evaluate the long-term effects of two well-established unimodal treatments, Medication Management (MedMGT) and behavior therapy (Beh), the multimodal combination (Comb), and treatment “as usual” in the community (CC). For each of the first three assessment points defined by RCT methods and included in intent-to-treat analyses, we discuss our definition of evidence from the MTA, interpretation of the serial presentations of findings at each assessment point with a different definition of long-term varying from weeks to years, and qualification of the interim conclusions about long-term effects of treatments for ADHD based on many exploratory analyses described in additional published articles.  Using a question and answer format, we discuss the possible clinical relevance of the MTA and present some practical suggestions based on current knowledge and uncertainties facing families, clinicians, and investigators regarding the long-term use of stimulant medication and behavioral therapy in the treatment of children with ADHD.

title: ‘ Cognitive Enhancement : Methods , Ethics , Regulatory Challenges ’ ’
abstract: In an age of scientific breakthroughs whose potential applications rival the most imaginative science fiction and are regularly sensationalized for entertainment profits or political gain, recurrent efforts to forbid various kinds of scientific inquiry do not surprise. Those efforts raise concerns for many observers. The concerns largely focus on interventions by national governments, though international regulation is also relevant (Bostrom and Sandberg 2009). One family of concerns is that any attempt to limit scientific inquiry would be fraught with errors of administration. The debate about which inquiries should be limited would be manipulated too easily to serve partisan political purposes so that the substantive issues would be buried beneath a morass of subterfuge and pretense. Further, whatever agreements might be reached would suffer bureaucratic inefficiencies as the parties tasked to monitor the agreement would inevitably misconstrue its terms and intentions and seriously hinder the work of those being monitored. It is a tale of many grey suits interfering with important work on the basis of ineptly devised regulations and caution-begging incentives. A more comprehensive response attacks the presumption of legitimacy for government intervention and refuses to concede that science ought to be managed by government. This response probably acknowledges exceptions in the egregious instances where threats to public health and safety are clear and convincing. This view likely recognizes the social dimension of science, i.e., that it is a function of the interests and perspectives of the human beings who do the work, and so acknowledges that governments will fund the inquiries that match their ideological interests. However, it posits the baseline view that scientific inquiry qua science presumptively should be free and that efforts to limit it must satisfy substantial burdens before they can be endorsed.

title: Neurocognitive enhancement: what can we do and what should we do?
abstract: Our growing ability to alter brain function can be used to enhance the mental processes of normal individuals as well as to treat mental dysfunction in people who are ill. The prospect of neurocognitive enhancement raises many issues about what is safe, fair and otherwise morally acceptable. This article resulted from a meeting on neurocognitive enhancement that was held by the authors. Our goal is to review the state of the art in neurocognitive enhancement, its attendant social and ethical problems, and the ways in which society can address these problems.

title: Cognition-enhancing drugs.
abstract: New drugs that enhance cognition in cognitively healthy individuals present difficult public policy challenges. While their use is not inherently unethical, steps must be taken to ensure that they are safe, that they are widely available to promote equality of opportunity, and that individuals are free to decide whether or not to use them.

title: Mechanism of action of agents used in attention-deficit/hyperactivity disorder.
abstract: Several medications have been demonstrated effective in treating individuals with attention-deficit/hyperactivity disorder (ADHD). There appears to be some commonality in the physiologic mechanisms of action of these agents relevant to the treatment of ADHD. Either direct or indirect attenuation of dopamine and norepinephrine neurotransmission appears related to both the stimulant and nonstimulant medications efficacious in ADHD. However, important differences exist both between and within the specific classes of agents. Elucidating the various mechanisms of action of ADHD medications may lead to better choices in matching potential response to the characteristics (e.g., genotype) of individuals.

title: Pharmacology of stimulants prohibited by the World Anti‐Doping Agency (WADA)
abstract: This review examines the pharmacology of stimulants prohibited by the World Anti‐Doping Agency (WADA). Stimulants that increase alertness/reduce fatigue or activate the cardiovascular system can include drugs like ephedrine available in many over‐the‐counter medicines. Others such as amphetamines, cocaine and hallucinogenic drugs, available on prescription or illegally, can modify mood. A total of 62 stimulants (61 chemical entities) are listed in the WADA List, prohibited in competition. Athletes may have stimulants in their body for one of three main reasons: inadvertent consumption in a propriety medicine; deliberate consumption for misuse as a recreational drug and deliberate consumption to enhance performance. The majority of stimulants on the list act on the monoaminergic systems: adrenergic (sympathetic, transmitter noradrenaline), dopaminergic (transmitter dopamine) and serotonergic (transmitter serotonin, 5‐HT). Sympathomimetic describes agents, which mimic sympathetic responses, and dopaminomimetic and serotoninomimetic can be used to describe actions on the dopamine and serotonin systems. However, many agents act to mimic more than one of these monoamines, so that a collective term of monoaminomimetic may be useful. Monoaminomimietic actions of stimulants can include blockade of re‐uptake of neurotransmitter, indirect release of neurotransmitter, direct activation of monoaminergic receptors. Many of the stimulants are amphetamines or amphetamine derivatives, including agents with abuse potential as recreational drugs. A number of agents are metabolized to amphetamine or metamphetamine. In addition to the monoaminomimetic agents, a small number of agents with different modes of action are on the list. A number of commonly used stimulants are not considered as Prohibited Substances.

title: Brain dopamine transporter levels in treatment and drug naïve adults with ADHD
abstract: Attention deficit hyperactivity disorder (ADHD) is the most frequent psychiatric disorder in children, yet data are sparse on its pathophysiology. Particularly relevant are the dopamine transporters since these are the main targets of stimulant medications used for ADHD treatment. Though some imaging studies have shown increases in dopamine transporters in ADHD others have not and their role in the neurobiology of ADHD remains unclear. Here we investigate dopamine transporters in ADHD subjects with control of potentially confounding factors (previous medication and/or drug histories, comorbidity) and their association with clinical symptoms. Positron emission tomography and [11C]cocaine were used to measure dopamine transporters in 20 never medicated adults with ADHD and 25 controls. Dopamine transporters were lower in left caudate (13%, p < 0.05) and in left nucleus accumbens (p < 0.005) in ADHD subjects than in controls. In putamen dopamine transporters did not differ between groups but were associated with scores of inattention (Conners Adult Attention Rating Scale) both in ADHD subjects (p < 0.005) and in controls (p < 0.005). Thus, for a given transporter level the scores for inattention were on average five times greater in ADHD subjects than in controls. These results do not corroborate increases in dopamine transporters in ADHD subjects and show that in some they are reduced. It also provides evidence that dopamine transporter levels modulate attention but suggest that additional pathology (e.g., prefrontal or cingulostriatal pathways, noradrenergic neurotransmission) is necessary to account for the large differences in inattention observed between controls and ADHD subjects.

title: The Neuropsychopharmacology of Attention-Deficit/Hyperactivity Disorder
abstract: More than three decades of research has attempted to elucidate the neuropsychopharmacology of attention-deficit/hyperactivity disorder (ADHD). Stimulants, a principle treatment for the disorder, act on the norepinephrine (NE) and dopamine (DA) systems; this has led to a long-standing hypothesis of catecholamine dysfunction in ADHD. Animal studies show a clear role for NE and DA in the modulation of executive functions, which are often disturbed in persons with ADHD. Nonstimulant agents that are effective in the treatment of ADHD tend to affect the NE system, whereas those affecting only DA, or those that affect neither catecholamine, are less potent in reducing ADHD symptoms. Studies of the effects of NE and DA peripheral metabolites by ADHD pharmacotherapies show acute increases in levels of these catecholamines; however, their long-term turnover may be reduced. Imaging studies suggest stimulants increases DA levels in the brain, whereas some animal models of ADHD are more consistent with excessive DA activation in the disorder. Ultimately, ADHD therapy may modify activity in the NE and DA systems to a more optimal level, thus improving responses to environmental stimuli and enhancing working memory and executive function.

title: Coming to terms with the nonmedical use of prescription medications
abstract: In this commentary we highlight limitations with the way nonmedical use of prescription medications has been measured in U.S. national studies. We also offer an alternative way of conceptualizing the nonmedical use of prescription medications for future study.

title: The nonmedical use of prescription ADHD medications: results from a national Internet panel
abstract: BackgroundEmerging evidence suggests that nonmedical use (NMU) of prescription attention deficit/hyperactivity disorder (ADHD) medications is rising, but many previous investigations have used clinical or regionally based samples or limited their investigations to stimulants rather than to medications specifically used to treat ADHD. Using an Internet-based epidemiological survey, this paper advances understanding of the prevalence and correlates of NMU of medications used to treat ADHD, sources of diverted medications, motivations for use, and consumption patterns.MethodsThe study used a self-administered Internet survey of civilian, noninstitutionalized adults (N = 4,297) aged 18 to 49 in the United States. National-level estimates were created using propensity scoring methods and weighting procedures using data from three nationally representative probability surveys: a random-digit dialed telephone survey, the current U.S. Census, and the National Survey on Drug Use and Health (NSDUH).ResultsPast-year prevalence of NMU of ADHD medications was approximately 2%, with 4.3% reported among those aged 18 to 25 and 1.3% among those aged 26 to 49. Most respondents reporting NMU used on multiple occasions. Receipt of medications for ADHD was a significant correlate of past-year NMU, though most nonmedical users never had a prescription. Among persons who had never been prescribed medication to treat ADHD, friends or family members were the most common source. Productivity was the most frequently endorsed reason for NMU. Alcohol was the substance most commonly used in combination with ADHD drugs.ConclusionBecause most prescription ADHD medications currently are highly regulated, policy options for supply-side reduction of nonmedical use may include identifying those medications with lower abuse liability for inclusion on insurance formularies. Patient and physician education programs also may be useful tools to heighten awareness of intentional and unintentional diversion of ADHD medications for nonmedical purposes.

title: Risk and protective factors for methamphetamine use and nonmedical use of prescription stimulants among young adults aged 18 to 25.
abstract: This article reports on correlates of past-year nonmedical use of prescription stimulants and methamphetamine among young adults aged 18 to 25. Data from the 2002 National Survey on Drug Use and Health (NSDUH) were used to conduct logistic regression analyses of the demographic, psychosocial, and behavioral correlates of nonmedical stimulant use. The sample size was 23,645. Multivariate analyses revealed that selling drugs and using marijuana and other illegal drugs were associated with increased odds of both methamphetamine and nonmedical prescription stimulant use. Females, individuals not enrolled in college, and those who had been arrested were more likely than their counterparts to have used methamphetamine, whereas black individuals and less religious individuals were less likely than their counterparts to have used methamphetamine. Psychological distress, sensation seeking, binge drinking, and college enrollment were associated with increased risks of nonmedical prescription stimulant use, whereas Hispanic and other ethnic identification were associated with decreased risks of nonmedical prescription stimulant use. Different intervention strategies are needed to prevent methamphetamine use versus nonmedical prescription stimulant use.

title: Adolescents' Motivations to Abuse Prescription Medications
abstract: Our goals were to (1) determine adolescents' motivations (reasons) for engaging in the nonmedical (illicit) use of 4 classes of prescription medications and (2) examine whether motivations were associated with a higher risk for substance abuse problems.  The 2005 sample (N = 1086) was derived from one ethnically diverse school district in southeastern Michigan and included 7th- through 12th-grade students.  Data were collected by using a self-administered, Web-based survey that included questions about drug use and the motivations to engage in nonmedical use of prescription medication.  Twelve percent of the respondents had engaged in nonmedical use of opioid pain medications in the past year: 3% for sleeping, 2% as a sedative and/or for anxiety, and 2% as stimulants. The reasons for engaging in the nonmedical use of prescription medications varied by drug classification. For opioid analgesics, when the number of motives increased, so too did the likelihood of a positive Drug Abuse Screening Test score. For every additional motive endorsed, the Drug Abuse Screening Test increased by a factor of 1.8. Two groups of students were compared (at-risk versus self-treatment); those who endorsed multiple motivations for nonmedical use of opioids (at-risk group) were significantly more likely to have elevated Drug Abuse Screening Test scores when compared with those who were in the self-treatment group. Those in the at-risk group also were significantly more likely to engage in marijuana and alcohol use.  The findings from this exploratory study warrant additional research because several motivations for the nonmedical use of prescription medications seem associated with a greater likelihood of substance abuse problems.

title: The Use, Misuse and Diversion of Prescription Stimulants Among Middle and High School Students
abstract: This present study investigated the prevalence and the factors associated with the use, misuse, and diversion of prescribed stimulant medication for attention-deficit hyperactivity disorder (ADHD) in a sample of middle and high school students. As part of a school-based, self-administered web survey in May 2002, students from a Midwestern public school district in the United States in grades six through eleven (n = 1536) reported on three aspects of prescription stimulants; they reported on their use, misuse, and diversion (e.g., trading, selling, offering) of stimulant medication for ADHD. The total student sample was 57% White, 40% African American, and 3% from other racial and ethnic groups. Gender and school level were approximately equally distributed in the student sample, and 81% of students had plans to attend college. The illicit use of stimulant medication was reported by 4.5% of the overall sample. Of the students who reported prescription stimulant use, 23.3% reported being approached to sell, give, or trade their prescription drugs. After adjusting for sociodemographic factors, the odds for illicit use of stimulant medication was lower among African American students and higher among those students with no plans for attending college. When compared with students who did not use stimulants or who did not misuse their own prescriptions, students who reported illicit use of stimulant medications also reported significantly higher rates of alcohol and other drug use. High schools students had the highest odds for being approached to divert their stimulant medications. Our findings suggest that community-based approaches are needed to reduce the illicit use and diversion of stimulant medications within middle and high school student populations.

title: Medical and nonmedical stimulant use among adolescents: from sanctioned to unsanctioned use.
abstract: The past decade has seen a generalized upward trend in the prevalence of adolescent use of substances, including stimulants. The purpose of this article was to determine the prevalence of and risk factors for the medical and nonmedical use of stimulants, and the diversion of prescribed stimulants among adolescent students, and to demonstrate links between medical use, nonmedical use and the diversion of stimulants.



A self-reported anonymous questionnaire was administered in 1998 to a random sample of students in grades 7, 9, 10 and 12 in New Brunswick, Nova Scotia, Prince Edward Island, and Newfoundland and Labrador about their medical and nonmedical use of stimulants (Benzedrine, Dexedrine, Ritalin, Cylert, diet pills, "speed," "uppers," "bennies" and "pep pills"). A total of 13,549 students completed the questionnaire, representing a 99% participation rate among the students present at school on the day of the survey.



Of the 5.3% of students who reported medical use of stimulants in the 12 months before the survey, 14.7% reported having given some of their medication, 7.3% having sold some of their medication, 4.3% having experienced theft and 3.0% having been forced to give up some of their medication. Nonmedical stimulant use by students who did not have a prescription for stimulants was significantly related to increased numbers of students who gave or sold some of their prescribed stimulants, at both the school class and individual student levels (p < 0.001).



Although the vast majority of adolescent students taking prescribed stimulants appeared to be using their medication as sanctioned, a link was found between medical and nonmedical stimulant use and the diversion of medication from sanctioned to unsanctioned use.

title: From attention-deficit/hyperactivity disorder to medical stimulant use to the diversion of prescribed stimulants to non-medical stimulant use: connecting the dots.
abstract: To describe the connections among the likelihood of attention deficit/hyperactivity disorder (ADHD), medical and non-medical methylphenidate and amphetamine use and the diversion of prescribed methylphenidate in the general adolescent population.



Cross-sectional self-reported anonymous data from the 2002 Student Drug Use Survey in the Atlantic Provinces.



The Atlantic provinces of Canada.



A total of 12,990 students participated.



The outcomes were a positive ADHD screening test, medical and non-medical use of methylphenidate, medical and non-medical use of amphetamine and the giving and selling of methylphenidate medication by students with a prescription. The Ontario Child Health Study Hyperactivity Scale was used to screen for ADHD.



The prevalence of a positive ADHD screening test was 6% with no significant gender difference. The prevalence of medical and non-medical methylphenidate use and medical and non-medical amphetamine use was 2.0%, 6.6%, 1.2% and 8.7%, respectively. A positive ADHD screening test was independently predictive of these four patterns of use. About 26% of students with prescribed methylphenidate gave or sold some of their medication. Students in a class where at least one student had given or sold some of their prescribed pills had a 1.52-fold increased risk of non-medical methylphenidate use than their counterparts in classes where no giving or selling had taken place.



Connections were demonstrated at the population level between ADHD, medical methylphenidate use, the diversion of prescribed methylphenidate and the non-medical use of methylphenidate. The appropriate assessment and management of ADHD are essential to minimize both the risk of diversion and of substance use associated with unrecognized or untreated ADHD.

title: Student Perceptions of Methylphenidate Abuse at a Public Liberal Arts College
abstract: With the ever-increasing diagnosis of attention deficit hyperactivity disorder, methylphenidate has become readily accessible in the college environment. Several properties of methylphenidate indicate abuse liability. A survey regarding the recreational use of methylphenidate was distributed to the student body at a public, liberal arts college. More than 16% of the students reported they had tried methylphenidate recreationally, and 12.7% reported they had taken the drug intranasally. Use of the drug was more common among traditional students than among nontraditional students. Among traditional-age students, reports of methylphenidate use were roughly equivalent to reports of cocaine and amphetamine use. Environmental conditions characteristic of college student life may influence the recreational use of the drug.

title: Illicit Use of Prescribed Stimulant Medication Among College Students
abstract: The authors investigated illicit use of stimulant medications at a midwestern university. They used a questionnaire to (a) examine the extent to which university students illicitly used stimulant medications prescribed for attention-deficit hyperactivity disorder; (b) determine why college students abused such drugs; and (c) identify the factors that predicted illicit use of prescribed stimulant medication. Findings revealed that 17% of 179 surveyed men and 11% of 202 women reported illicit use of prescribed stimulant medication. Forty-four percent of surveyed students stated that they knew students who used stimulant medication illicitly for both academic and recreational reasons. Students reported they experienced time pressures associated with college life and that stimulants were said to increase alertness and energy. Regression analysis revealed that the factor that predicted men's use was knowing where to get easily acquired stimulant medication, whereas the main predictor for women was whether another student had offered the prescribed stimulants.

title: Patterns and knowledge of nonmedical use of stimulants among college students.
abstract: To determine patterns and knowledge of nonmedical use of stimulants among a sample of college students.



Completion of an anonymous survey consisting of 23 questions designed to explore college student use of medications intended to treat attention-deficit/hyperactivity disorder.



A private liberal arts college in New England.



Three hundred forty-seven undergraduate students.



Nonmedical use of stimulants.



Thirty-one students (9.2%) reported nonmedical stimulant use. Two hundred forty students (71.4%) had peers who used nonprescribed stimulants, 149 (44.3%) knew of peers who made stimulant medication-seeking visits to a physician although they did not believe that they had attention-deficit/hyperactivity disorder, and 178 (53.0%) knew of people who sold stimulants to students. Nonprescription users were significantly more knowledgeable about the effects of stimulants than nonusers, and nonusers whose peers used nonprescribed stimulants were more knowledgeable about the effects of stimulants than nonusers whose peers did not use nonprescribed stimulants. After controlling for age, race, and sex, the variables that predicted nonmedical use of stimulants were beliefs that stimulants help individuals study better, stay awake, and lose weight.



A substantial proportion of college students in this sample were using nonprescribed stimulants. Among nonusers, those whose peers use nonprescribed stimulants were much more knowledgeable about the effects of stimulant use than those whose peers do not use stimulants. This knowledge may confer an increased risk of future nonmedical stimulant use if students become tempted to seek the beneficial effects experienced by their peers.

title: Illicit Methylphenidate Use in an Undergraduate Student Sample: Prevalence and Risk Factors
abstract: To assess the prevalence of illicit methylphenidate use among undergraduate college students at a large university, and to identify alcohol and other drug use behaviors, as well as the negative consequences and risk factors, associated with illicit methylphenidate use.

title: Nonmedical Prescription Stimulant Use Among a Sample of College Students
abstract: To further investigate use and potential misuse of prescription stimulants (e.g., Ritalin, Adderall, Concerta) among a sample of college students and to explore the relationship between psychological variables and nonmedical stimulant use.  The sample consisted of 390 college students (71.6% female, 28.4% male). Participants were asked to complete five questionnaires concerning demographic information, prescription stimulant use, internal restlessness, sensation seeking, and psychological distress.  The study findings revealed that, regarding nonprescribed stimulants, 7.5% reported use within the past 30 days; 60% reported knowing students who misused stimulants; and 50% agreed or strongly agreed that prescription stimulants were “easy to get on this campus.” Findings further revealed a relationship between stimulant use and degree of psychological distress and internal restlessness.  Continued research regarding psychological variables, specific group membership (e.g., fraternity, sorority, athletics), and stimulant acquisition is suggested. Effective prevention and education efforts are needed to help address the nonmedical use of prescription stimulants on college campuses.  284-296)

title: Illicit use of psychostimulants among college students: A preliminary study
abstract: There is little recent research on the illicit use of prescription stimulants such as methylphenidate on college campuses. Given the increasing number of amphetamine prescriptions for attention deficit-hyperactivity disorder in older adolescents, non-medical use seems likely to occur. The present study surveyed undergraduates at a small college in the USA on their use of both legal and illegal stimulants; 35.5% of undergraduates who were convenience-sampled had used prescription amphetamines illicitly (defined as use without a prescription), with men reporting more use than women. Motivations were primarily academic, but 19.3% of students reported using prescription stimulants in combination with alcohol for recreational reasons. In addition, 34% of the sample reported using either cocaine or MDMA in the previous year. Motivations for use of illegal stimulants were primarily recreational. Sensation seeking appears to be a correlate of both types of stimulant use; for abuse of prescription drugs, being both high in sensation seeking and more perfectionistic is associated with greater use. Abuse of prescription and illegal stimulants appears to be widespread in this college sample.

title: Stimulant Medication Use, Misuse, and Abuse in an Undergraduate and Graduate Student Sample
abstract: In this study, the authors investigated the characteristics of use, misuse, and abuse of stimulant medication (primarily methylphenidate and variants) among students at a northeastern US university. Researchers sent an invitation to take an Internet survey to student e-mail addresses and passed 150 paper surveys in undergraduate classes, analyzing 1,025 (975 electronically) returned surveys. Sixteen percent of respondents reported abusing or misusing stimulant medication. Ninety-six percent of respondents who specified a medication preferred to abuse or misuse Ritalin. Men and women reported similar use patterns. Most respondents who abused or misused stimulant medication swallowed pills; 40% used intranasally. Reasons for abusing or misusing stimulant medication included improving attention, partying, reducing hyperactivity, and improving grades. Consistent with previous studies, results suggest that abuse of stimulant medication is a concern on college campuses. The results point to various reasons for and methods of abusing and misusing stimulant medication that may direct future research, prevention, and intervention.

title: Illicit Use of Specific Prescription Stimulants Among College Students: Prevalence, Motives, and Routes of Administration
abstract: To explore the illicit use of specific prescription stimulants among college students and add to our understanding of reasons (motives) and routes of administration associated with illicit use of these drugs.

title: Illicit Use of Prescription ADHD Medications on a College Campus: A Multimethodological Approach
abstract: The authors used quantitative and qualitative methodologies to investigate college students' perceptions and use of illegal Attention Deficit Hyperactivity Disorder (ADHD) stimulants during spring and summer 2006.  From fall 2005 through fall 2006, the authors studied 1,811 undergraduates at a large, public, southeastern research university in the United States.  The authors administered surveys to these students and conducted 175 in-depth interviews.  Of the study participants, 34% reported the illegal use of ADHD stimulants. Most illegal users reported using ADHD stimulants primarily in periods of high academic stress and found them to reduce fatigue while increasing reading comprehension, interest, cognition, and memory. Furthermore, most had little information about the drug and found procurement to be both easy and stigmafree.  This study supplies a rich understanding of the growing national trend of illegal ADHD stimulant use. The authors discuss strategies for stemming the tide of ADHD stimulant use.

title: Nonmedical ADHD stimulant use in fraternities.
abstract: Quantitative methods were used to investigate the use of nonmedical attention-deficit/hyperactivity disorder (ADHD) stimulants by fraternity members.



Three hundred thirty-three fraternity members at a large, public southeastern research university in the United States were surveyed in classes and at other campus locations. Once those with legal prescriptions for ADHD stimulants were removed (n = 26), the sample size was 307.



Of the study participants, 55% (n = 170) reported the nonmedical use of ADHD stimulants. Use was significantly higher among upperclassmen, those living off campus, and those who regularly smoke marijuana. The vast majority of fraternity members (1) reported academic motives for use, (2) did not view ADHD stimulants as dangerous, and (3) procured stimulants from their friends.



These results demonstrate a high rate of use of these drugs in a campus population. More studies on nonmedical users (and suppliers of users) are needed, as are educational interventions on university campuses, especially among members of fraternities.

title: Prevalence of Illicit Use and Abuse of Prescription Stimulants, Alcohol, and Other Drugs Among College Students: Relationship with Age at Initiation of Prescription Stimulants
abstract: To examine associations between age at initiation of prescription stimulants and illicit use and abuse of prescription stimulants, alcohol, and other drugs among college students in the United States.

title: Motives and Perceived Consequences of Nonmedical ADHD Medication Use by College Students
abstract: This study examines why college students without a prescription take ADHD medication, what they perceive the consequences of this to be, and whether attention problems are associated with this behavior.  More than 3,400 undergraduates attending one public and one private university in the southeastern United States completed a Web-based survey.  Nonmedical ADHD medication use in the prior 6 months was reported by 5.4% of respondents and was positively associated with self-reported attention difficulties. Enhancing the ability to study was the most frequent motive reported; nonacademic motives were less common. Students perceived nonmedical use to be beneficial despite frequent reports of adverse reactions.  Students without prescriptions use ADHD medication primarily to enhance academic performance and may do so to ameliorate attention problems that they experience as undermining their academic success. The academic, social, and biomedical consequences of illicit ADHD medication use among college students should be researched further.

title: College Undergraduate Ritalin Abusers in Southwestern California: Protective and Risk Factors
abstract: During the past five years, a few studies have reported that college students are using stimulants such as Ritalin without a prescription. To date, studies on college Ritalin/Adderall use have been from samples in the eastern or midwestern U.S. This study was designed to examine risk and protective factors associated with Ritalin/Adderall use among a college sample in Southern California. Our findings indicate that 11.2% of students reported past year and over 4% reported past 30 day use of Ritalin/Adderall. In our final analysis, students with lower GPAs, in a fraternity/sorority, not in a committed relationship, and who smoke and use other drugs were more likely to report past year and past 30 day Ritalin/Adderall use. Implications for prevention programming of these findings are discussed.

title: Nonmedical Use of Prescription Stimulants and Analgesics: Associations with Social and Academic Behaviors among College Students
abstract: Nonmedical use of prescription stimulants and analgesics was assessed from personal interviews with a stratified random sample of 1,253 first-year college students ages 17 to 20 attending a large public university (86% response rate). Lifetime and past-year prevalence of nonmedical use of stimulants, analgesics, or both was 19.6%wt and 15.6%wt, respectively. Nonmedical users had significantly lower grade point averages (GPAs) in high school as compared with nonusers; in college they skipped classes more often, spent more time socializing, and spent less time studying. For example, nonmedical users of both stimulants and analgesics skipped 21 % of their college classes whereas nonusers skipped 9%. Controlling for high school GPA and other factors, past-year nonmedical use independently predicted lower college GPA by the end of the first year of college; this effect was partially mediated by skipping more classes. Nonmedical users of prescription drugs comprise a high-risk group for academic problems in college.

title: Characteristics of Methylphenidate Misuse in a University Student Sample
abstract: Methylphenidate (MPH) is a prescription stimulant drug with known abuse potential; however, little is known about its patterns of misuse or the characteristics of its abusers.  A sample of 50 university students reporting MPH misuse and 50 control subjects matched for age, sex, and ethnicity completed structured face-to-face interviews about their MPH and other drug use. For each substance ever used, they provided information regarding routes of administration and other substances ever coadministered, as well as details about the most recent administration. MPH users provided additional information about their reasons for use and, in 36 cases, about how they obtained the drug.  Relative to control subjects, those who misused MPH were more likely to have used various other prescription and nonprescription stimulant drugs over their lifetime, and most MPH users reported mixing the drug with other psychoactive substances. Of the MPH sample, 70% reported recreational use of the drug, while 30% reported that MPH was used exclusively for study purposes. Relative to those using it exclusively for study, recreational users were more likely to report using MPH intranasally, as well as coadministering MPH with other substances. Most of those who reported their source of MPH obtained it from an acquaintance with a prescription.  Those who misuse MPH are more likely than their peers to misuse various other substances, and MPH misuse frequently occurs in the context of simultaneous polydrug use. Because the primary supply of inappropriately used MPH appears to be prescribed users, efforts should be directed toward preventing its diversion.

title: Characteristics and motives of college students who engage in nonmedical use of methylphenidate.
abstract: Methylphenidate (MPH) has a long history of being an effective medication for attention deficit/hyperactivity disorder (ADHD). Recently, the nonmedical use of MPH has increased, particularly among college students. To investigate this, we surveyed 2,087 students regarding MPH misuse. Of 2,087 respondents, 110 (5.3%) used MPH nonmedically at least once. Most obtained MPH free from a friend, acquaintance, or family member. Misuse of Ritalin(R) occurred four times more frequently than Concerta. Among Ritalin abusers, Intranasal use was reported more often than oral. Students reported using MPH nonmedically for recreational reasons as well as to improve academic performance.

title: Illicit use of prescription stimulants among college students: Prescription status, motives, theory of planned behaviour, knowledge and self-diagnostic tendencies
abstract: Published studies have reported that illicit prescription stimulant use is increasingly common on college campuses in the United States. The present study investigates the relationship between prescription status, motives, theory of planned behaviour, knowledge of side effects and self-diagnostic tendencies and illicit use of prescription stimulants among undergraduates (N = 333). Prescription holders and non-holders responded to a self-administered online survey. Results revealed that dependent variables were significantly different between illicit users and non-illicit users. Specifically, prescription holders were more likely than non-holders to report illicit use. Illicit users, relative to non-illicit users, reported more motives to use, less concern with ethics and safety of use, greater perception of use as socially acceptable, less perceived control over their behaviour without stimulant aid, more knowledge, and, among non-prescription holders, were more likely to self-diagnosis having an attention disorder. This study provides additional insight into students’ attitudes, beliefs, knowledge and practices related to prescription stimulant use on campus. Implications for future research and the need for interventions to provide aid to students who are at risk for using stimulant medications illicitly are discussed.

title: Medical Use, Illicit Use and Diversion of Prescription Stimulant Medication
abstract: The objective of this study was to examine the prevalence and factors associated with the illicit use of prescription stimulants and to assess the relationship between the medical and illicit use of prescription stimulants among undergraduate college students. A Web survey was self-administered by a random sample of 9,161 undergraduate students attending a large public midwestern university in the spring of 2003. A total of 8.1% reported lifetime illicit use of prescription stimulants and 5.4% reported past year dlicit use. The number of undergraduate students who reported illicit use of prescription stimulants exceeded the number of students who reported medical use of prescription stimulants for ADHD. The leading sources of prescription stimulants for illicit use were friends and peers. Multivariate logistic regression analyses revealed several risk factors for illicit use of prescription stimulants such as being male, White, member of a social fraternity or sorority, Jewish religious affiliation, and lower grade point average. All of these characteristics were also related to medically prescribed use of prescription stimulants. Those who initiated medically prescribed use of prescription stimulants for ADHD in elementary school were generally not at increased risk for illicit use of prescription stimulants or other drugs during college as compared to those who were never prescribed stimulant medication. The present study provides evidence that the illicit use of prescription stimulants is a problem among undergraduate college students, and certain subgroups appear to be at heightened risk.

title: Prevalence and Motives for Illicit Use of Prescription Stimulants in an Undergraduate Student Sample
abstract: To assess the prevalence and motives for illicit use of prescription stimulants and alcohol and other drugs (AODs), associated with these motives, the authors distributed a self-administered Web survey TO a random sample of 9,161 undergraduate college students. Of the study participants, 8.1% reported iifetime and 5.4% reported past-year illicit use of prescription stimulants. The most prevalent motives given for illicit use of prescription stimulants were to (1) help with concentration, (2) increase alertness, and (3) provide a high. Although men were more likely than women were to report illicit use of prescription stimulants, the authors found no gender differences in motives. Regardless of motive, illicit use of prescription stimulants was associated with elevated rates of AOD use, and number of motives endorsed and AOD use were positively related. Students appear to be using these prescription drugs non-medically, mainly to enhance performance or get high.

title: The effects of amphetamines upon judgments and decisions
abstract: SummaryD-amphetamine sulfate, dl-amphetamine sulfate, and placebo were orally administered to 93 college student volunteers who served as their own controls in a Latin Square design. Dosages were adjusted to the two-thirds power of body weight with the proportionality constant set for 14 mg/70 kg with each drug. Effects were measured upon performances in a mathematical reasoning test, upon self-appraisals of these performances, and in a task which attached monetary payments to the accuracy of self-appraisals (“Decision Score”). The objectives of this research were (1) to reassess the biases in performance self-appraisals reported by Smith and Beecher (1964), and (2) to determine whether these biases represent mere verbal expansiveness or whether they are reflected by changes in decision behavior.
Smith and Beecher's effect upon self-appraisals was confirmed (at p<.02). Decision Score also was affected (at p<.01) in the predicted direction. Performance scores were not significantly affected.

title: How to calculate effect sizes from published research: A simplified methodology
abstract: Overview This article provides a simplified methodology for calculating Cohen's d effect sizes from published experiments that use t-tests and F-tests. Accompanying this article is a Microsoft Excel Spreadsheet to speed your calculations. Both the spreadsheet and this article are available as free downloads at www.work-learning.com/effect_sizes.htm. Why we use effect sizes Whereas statistical tests of significance tell us the likelihood that experimental results differ from chance expectations, effect-size measurements tell us the relative magnitude of the experimental treatment. They tell us the size of the experimental effect. Effect sizes are especially important because they allow us to compare the magnitude of experimental treatments from one experiment to another. Although percent improvements can be used to compare experimental treatments to control treatments, such calculations are often difficult to interpret and are almost always impossible to use in fair comparisons across experimental paradigms. Although extensive articles have been written detailing methods for calculating effect sizes from published research articles (e. at least some of us—the first author included—require a simpler approach. This article provides a method to calculate Cohen's d from both t-tests and some F-tests of significance. Accompanying this article is a Microsoft Excel Spreadsheet that can be used to compute Cohen's d from published data. Cohen's d has two advantages over other effect-size measurements. First, its burgeoning popularity is making it the standard. Thus, its calculation enables immediate comparison Effect Sizes Work-Learning Research 3  to increasingly larger numbers of published studies. Second, Cohen's (1992) suggestion that effect sizes of .20 are small, .50 are medium, and .80 are large enables us to compare an experiment's effect-size results to known benchmarks. The simple methodology offered below is not new but is drawn from previously published articles, most notably Rosnow and Rosenthal (1996) and Rosnow, Rosenthal, and Rubin (2000). We have simplified the methodology not by changing the formulas and calculations but by discarding as much as possible the jargon and computational rationales typically included in articles written for research audiences. This article is an attempt to provide a practical methodology to enable the calculation of effect sizes. What is an effect size? In essence, an effect size is the difference between two means (e.g., treatment minus control) divided by the standard deviation of the two conditions. It is the division by the standard deviation that enables us to compare effect sizes across experiments. Because t-tests and F-tests utilize different measures …

title: D-Amphetamine Boosts Language Learning Independent of its Cardiovascular and Motor Arousing Effects
abstract: D-Amphetamine (AMPH) was effective in a number of studies on motor and language recovery after stroke, but given safety concerns, its general use after stroke is still debated. Most stroke patients are excluded from treatment because of a significant risk of cardiovascular dysregulation. AMPH acts on multiple transmitter systems, and mainly the noradrenergic actions are related to the cardiovascular effects. If AMPH's cardiovascular and arousal effects were correlated with its plasticity-enhancing effects in humans, this would imply that desired and undesired effects are inevitably tied. If not, improved cerebral reorganization may not be mediated by AMPH's arousing effects and could be achieved with substances lacking the undesired cardiovascular effects. As a model for language recovery after stroke, we used a prospective, randomized, double-blind, placebo-controlled design and taught 40 healthy male subjects an artificial vocabulary of 50 concrete nouns over the course of five consecutive training days (high-frequency training). The associative learning principle involved higher co-occurrences of ‘correct’ picture-pseudoword pairings as compared to ‘incorrect’ pairings. Subjects received either AMPH (0.25 mg/kg) or placebo 90 min prior to training on each day. Novel word learning was significantly faster and better in the AMPH as compared to the placebo group. Increased learning success was maintained 1 month post-training. No correlation was found between training success and drug-induced increases in blood pressure, heart rate, or a facilitation of simple motor reaction time. Our data show that AMPH's plasticity-enhancing effect in humans is not related to its cardiovascular arousal. This suggests that the beneficial effects in stroke patients could also be obtained by less cardiovascular active drugs.

title: A shift of paradigm: From noradrenergic to dopaminergic modulation of learning?
abstract: d-Amphetamine coupled with behavioral training has been effective for improving functional recovery after stroke. d-amphetamine acts on multiple brain transmitter systems, but the recovery enhancing effect has been attributed to its noradrenergic actions. Another potent modulator of learning is dopamine, which may also enhance stroke recovery in humans. Based on data from previous studies of our group, we compared the learning enhancing effects of d-amphetamine with a more selective dopaminergic substance (levodopa) in identical protocols. Using a prospective, randomized, double-blind, placebo-controlled design, we had taught 60 male healthy subjects a miniature lexicon of 50 concrete nouns over the course of five consecutive training days using an associative learning principle. Subjects had received either d-amphetamine (0.25 mg/kg), levodopa/carbidopa (fixed dose of 100/25 mg), or placebo 90 min prior to training on each of the 5 days. Novel word learning was significantly enhanced in both the d-amphetamine and levodopa groups as compared to the placebo group. The learning superiority was maintained at the two re-assessments (1 week and 1 month post training). Both d-amphetamine and levodopa are thus potent drugs in enhancing learning in humans. We here discuss why the efficiency of both d-amphetamine and levodopa may be related to dopaminergic rather than noradrenergic actions.

title: Pharmacological manipulations of arousal and memory for emotional material: effects of a single dose of methylphenidate or lorazepam
abstract: Benzodiazepines produce robust impairments of memory alongside global decreases in physiological and subjective arousal. Recently one benzodiazepine (triazolam) has been found to disproportionately impair memory for emotionally arousing material (Buchanan et al., 2003). The extent to which this effect may be mediated by the drug's sedative action is unclear. The present study aimed to assess how pharmacologically decreasing physiological arousal with a benzodiazepine and increasing arousal with a stimulant impact on memory for emotional material. A double-blind placebo controlled trial with 48 volunteers was used to investigate the effects of methylphenidate (40 mg) and Lorazepam (1.5 mg) on incidental memory for emotional material in Cahill and McGaugh's (1995) slide-story task. The slide-story was presented to participants administered either active drug or placebo and retrieval was assessed one week later. Methylphenidate produced stimulant effects and Lorazepam produced sedative effects. Significantly enhanced memory for emotional material was observed in participants given placebo, but not in those given either methylphenidate or Lorazepam. Despite producing opposite effects upon arousal, both methylphenidate and Lorazepam lessen the impact of emotionally arousing material on memory. The effects of Lorazepam add to a growing literature that benzodiazepines may exert their clinical, anxiolytic effects in part via altering emotionaL cognitive function.

title: Methylphenidate's effects on paired-associate learning and event-related potentials of young adults.
abstract: The effects of methylphenidate (0.3 mg/kg) on young adults paired-associate learning (PAL) of consonant-vowel-consonant (CVC) pairs and concomitant event-related potentials were assessed. The stimulant elevated mood and heart rate but did not affect PAL performance. For the first CVC, there were amplitude increases with learning for P3b at Pz, P2 at midline sites, and for a negative slow wave at Cz. For the second CVC, P3b and positive slow wave amplitude declined with learning. Increases in P3b amplitude to the first CVC were attributed to increments in stimulus meaningfulness. Decreases in P3b amplitude to the second CVC were interpreted as resulting from fewer disconfirmed expectations of feedback. The negative slow wave following the first CVC was viewed as a contingent negative variation. Methylphenidate increased parietal P3b amplitude for CVC 2, averaged over learning phases.

title: Effects of Magnesium Pemoline and Dextroamphetamine on Human Learning
abstract: Two central nervous system stimulants, magnesium pemoline and dextroamphetamine, were tested to see if they facilitate learning in human subjects. Subjects under placebo learned faster than the subjects under any of the several doses of magnesium pemoline; however, none of these differences reached statistical significance. Subjects who received dextroamphetamine learned significantly more slowly than those who received placebo.

title: Cognitive effects of milacemide and methylphenidate in healthy young adults
abstract: Cognitive effects of the novel glycine prodrug milacemide (400 mg), the catecholaminergic agonist methylphenidate (20 mg), and placebo were evaluated in 48 healthy young adults. Throughout a 6-h drug treatment day, subjects repeatedly performed tests of target-detection vigilance, immediate and delayed verbal free recall, and Buschke Selective Reminding; total free recall and forced-choice recognition tests were administered at the end of the day. Significant improvement in both vigilance reaction time and Selective Reminding Sum Recall was observed in the methylphenidate group. Contrary to expectations, the milacemide group evidenced significantdeclines in both vigilance perceptual sensitivity and free-recall difference scores (delayed-immediate). Vigilance reaction times significantly decreased over repeat testing in all groups, but only the methylphenidate group differed from placebo. The reaction-time functions for milacemide and placebo were similar, suggesting arousal was not diminished under milacemide and could not account for the cognitive decrements. No significant drug effects obtained for total free recall or recognition performance. Although the glycine prodrug milacemide was ineffective as a cognitive enhancer, the involvement of the NMDA receptor in memory function reported in the literature supports continued exploration of other approaches for manipulating NMDA receptor activity.

title: Catechol O-methyltransferase val158-met genotype and individual variation in the brain response to amphetamine
abstract: Monamines subserve many critical roles in the brain, and monoaminergic drugs such as amphetamine have a long history in the treatment of neuropsychiatric disorders and also as a substance of abuse. The clinical effects of amphetamine are quite variable, from positive effects on mood and cognition in some individuals, to negative responses in others, perhaps related to individual variations in monaminergic function and monoamine system genes. We explored the effect of a functional polymorphism (val158-met) in the catechol O-methyltransferase gene, which has been shown to modulate prefrontal dopamine in animals and prefrontal cortical function in humans, on the modulatory actions of amphetamine on the prefrontal cortex. Amphetamine enhanced the efficiency of prefrontal cortex function assayed with functional MRI during a working memory task in subjects with the high enzyme activity val/val genotype, who presumably have relatively less prefrontal synaptic dopamine, at all levels of task difficulty. In contrast, in subjects with the low activity met/met genotype who tend to have superior baseline prefrontal function, the drug had no effect on cortical efficiency at low-to-moderate working memory load and caused deterioration at high working memory load. These data illustrate an application of functional neuroimaging in pharmacogenomics and extend basic evidence of an inverted-“U” functional-response curve to increasing dopamine signaling in the prefrontal cortex. Further, individuals with the met/met catechol O-methyltransferase genotype appear to be at increased risk for an adverse response to amphetamine.

title: Methylphenidate Enhances Working Memory by Modulating Discrete Frontal and Parietal Lobe Regions in the Human Brain
abstract: The indirect catecholamine agonist methylphenidate (Ritalin) is the drug treatment of choice in attention deficit/hyperactivity disorder (AD/HD), one of the most common behavioral disorders of childhood (DSM-IV), although symptoms may persist into adulthood. Methylphenidate can enhance cognitive performance in adults and children diagnosed with AD/HD (Kempton et al., 1999; Riordan et al., 1999) and also in normal human volunteers on tasks sensitive to frontal lobe damage, including aspects of spatial working memory (SWM) performance (Elliott et al., 1997). The present study investigated changes in regional cerebral blood flow (rCBF) induced by methylphenidate during performance of a self-ordered SWM task to define the neuroanatomical loci of the beneficial effect of the drug. The results show that the methylphenidate-induced improvements in working memory performance occur with task-related reductions in rCBF in the dorsolateral prefrontal cortex and posterior parietal cortex. The beneficial effects of methylphenidate on working memory were greatest in the subjects with lower baseline working memory capacity. This is to our knowledge the first demonstration of a localization of a drug-induced improvement in SWM performance in humans and has relevance for understanding the treatment of AD/HD.

title: A triazolam/amphetamine dose–effect interaction study: dissociation of effects on memory versus arousal
abstract: RationaleIn addition to producing robust memory impairment, benzodiazepines also induce marked sedation. Thus, it is possible that the observed amnestic effects are secondary to more global sedative effects and do not reflect a specific primary benzodiazepine effect on memory mechanisms.ObjectiveThe objective was to use the nonspecific stimulant d-amphetamine to dissociate the sedative and memory-impairing effects of the benzodiazepine triazolam.Materials and methodsSingle oral doses of placebo, triazolam alone (0.25, 0.50 mg/70 kg), d-amphetamine sulfate alone (20, 30 mg/70 kg), and triazolam (0.25, 0.50 mg/70 kg) and d-amphetamine sulfate (20, 30 mg/70 kg) conjointly (at all dose combinations) were administered to 18 healthy adult participants across nine sessions in a double-blind, staggered-dosing, crossover design. In addition to standard data analyses, analyses were also conducted on z-score standardized data, enabling effects to be directly compared across measures.ResultsRelative to the sedative measures, the memory measures generally exhibited a pattern of less reversal of triazolam’s effects by d-amphetamine. The memory measures ranged in degree of reversal such that the most reversal was observed for reaction time on the n-back working memory task, and the least reversal was observed for accuracy on the Sternberg working memory task, with most measures showing an overall pattern of partial reversal.ConclusionsBenzodiazepines have specific effects on memory that are not merely a by-product of the drugs’ sedative effects, and the degree to which sedative effects contribute to the amnestic effects varies as a function of the particular memory process being assessed.

title: Neuropsychological effects of amphetamine may correlate with personality characteristics.
abstract: Although the stimulant properties of amphetamine are well established, its effects on cognitive test performance in unfatigued normal adults are poorly documented. Seventeen healthy individuals received a single oral dose of dextroamphetamine (0.25 mg/kg) in a double-blind, placebo-controlled, crossover study. Neurocognitive tests, motor tests, and behavioral observations were performed. Personality information, based on the Tridimensional Personality Questionnaire (TPQ) was also gathered to explore a relationship between personality factors and response to the stimulant. With the exception of two measures of reaction time, there were no overall changes in performance on measures of memory or other cognitive functions. There was decreased reaction time on the continuous performance task (CPT) and increased accuracy of performance under minimal delay conditions in the spatial delay response task while subjects were receiving amphetamine. In addition, the novelty-seeking subscale was found to correlate with a measure of verbal memory. Individuals with higher scores on the novelty-seeking scale deteriorated under amphetamine, while those who had lower scores improved. These results suggest that some cognitive abilities of persons who may have relatively high dopaminergic tone are disrupted by amphetamine, while those with relatively low dopaminergic tone may have their performance enhanced.

title: Amphetamine enhances human-memory consolidation
abstract: Although it is generally accepted that CNS stimulants have enhancing effects on long-term storage processes in laboratory animals, little is known about their influence on human learning. We report a series of experiments with free recall of lists of unrelated words, demonstrating a significant enhancement on long-term retention after amphetamine administration. A gradual increase of recall was observed up to 1 h after learning, remaining stable for at least 3 days, after oral administration before learning as well as intramuscular injection after learning. The results show that research on humans with drug-induced memory-enhancement techniques is necessary to supplement the animal studies for the understanding of the mechanisms involved in information consolidation.

title: Verbal memory performance improved via an acute administration of D‐amphetamine
abstract: An improved long‐term retention of verbal memory was observed after an acute D‐amphetamine administration. It was proposed that D‐amphetamine modulates consolidation, but a possible drug effect on retrieval could not be rejected.

title: Effect of amphetamine on long-term retention of verbal material
abstract: A series of five experiments was conducted to investigate the temporal aspects of human memory consolidation of symbolic material through the administration of amphetamine. Subjects had to recall or recognise unrelated words from a previously presented list. The first experiments support the conjecture, based on animal studies, that amphetamine enhances long-term memory performance. Subsequently, enhancement is demonstrated with oral administration before learning, as well as with intramuscular injection after learning. It is shown that improved recall cannot be explained solely by general arousal or attentional processes, but must be due to consolidation. By introducing different test delays we show that consolidation of symbolic material can be modulated by amphetamine during the 1st hour after learning. In a final experiment we demonstrate that the memory enhancement applies to recall as well as to recognition. The implications of the present results are discussed in the context of recent research on LTP processes.

title: Selective reminding for analysis of memory and learning
abstract: A new and more appropriate paradigm for verbal learning is described and illustrated. Reminding a subject only of items not recalled on the immediately preceding trial, instead of presenting all items on each trial, shows retrieval from long-term storage when items are retrieved again without further presentation. This permits simultaneous analysis of long-term storage (LTS), retrieval from long-term storage (LTR), and recall from short-term storage (STR). Evaluating LTR in terms of items consistently retrieved on all subsequent trials (without further presentation) differentiates LTR into random and organized LTR, and also provides a measure of list learning for comparison with item learning. To illustrate the use of selective reminding for investigation of retrieval alone, an example is also presented of reminding only until first recall.

title: The Hopkins Verbal Learning Test: Development of a new memory test with six equivalent forms.
abstract: A new test of verbal learning and memory, the Hopkins Verbal Learning Test, was developed. The test consists of three trials of free-recall of a 12-item, semantically categorized list, followed by yes/no recognition. Six parallel forms yielded equivalent results in normals. The performance of patients with Alzheimer's disease and chronic amnesia is described. The test is likely to be useful in patients too impaired for more comprehensive memory assessments and where repeated testing is necessary.

title: MANIFEST ANXIETY, AMPHETAMINE, AND PERFORMANCE.
abstract: The major purpose of this research was to determine whether administration of amphetamine, a drug assumed to increase drive level, alters performance in ways consonant with drive theory. The results obtained support earlier findings that high the Taylor Manifest Anxiety Scale (MAS) subjects perform better than low MAS subjects on noncompetitive paired-associates lists, whereas the low MAS subjects are superior on competitive lists. High MAS subjects tended to be superior on the simple and inferior on the difficult coding test, but these effects were not statistically significant. Amphetamine significantly improved performance on the noncompetitive paired-associates list and the simple coding test. The failure of amphetamine to produce a significant effect on either the competitive pairedassociates list or the difficult coding test does not support expectations based on drive theory, but does add to the accumulating evidence that relatively high level intellectual functions are not influenced by amphetamine. The significant improvement in performance on the pursuit rotor test, due to amphetamine, and the progressively greater discrepancy between amphetamine and placebo performance, over time, are both consistent with earlier literature.

title: Dopaminergic modulation of brain systems subserving decision making under uncertainty: A study with fMRI and methylphenidate challenge
abstract: There is evidence that the dopaminergic system is involved in probabilistic reinforcement learning and reward‐related decision‐making. However, little is known about the effects of external dopaminergic challenges on processing of uncertainty in decision‐making tasks. Therefore, the present study examined changes in fMRI activation patterns in a natural sampling paradigm. Decision making under uncertainty was examined before and after administration of a single dose of 40 mg methylphenidate as an acute dopaminergic pharmacological challenge. We found that the level of uncertainty was positively correlated with activations in the prefrontal cortex. Conversely, negative correlations with uncertainty were found in the left hippocampus, right amygdale, and right middle temporal gyrus. The drug intervention with methylphenidate revealed a differential picture. Uncertain information processing was associated with higher activation in the parietal association cortex and posterior cingulate cortex after placebo relative to methylphenidate. The methylphenidate challenge relative to placebo was associated with higher left and right parahippocampal as well as cerebellar activation under uncertainty. Apparently, the pro‐dopaminergic pharmacological influence induces a relative shift towards recruitment of hippocampal areas under uncertainty, whereas under placebo conditions, higher levels of parietal cortex activations are involved in the task. The findings suggest a role of dopamine in uncertainty processing and shed light on the pharmacological mechanisms of methylphenidate. Synapse  2009.

title: Behavioral and subjective effects of d-amphetamine and modafinil in healthy adults.
abstract: Modafinil is indicated for the management of excessive daytime sleepiness; however, recent studies have examined a broad range of potential uses. Given that clinical uses of modafinil may be expanding, this study compared modafinil and d-amphetamine effects on subjective and performance measures. Across 11 sessions, 11 healthy adults were tested after oral doses of placebo (5 sessions), modafinil (1.75 mg/kg, 3.50 mg/kg, or 7.00 mg/kg), and d-amphetamine (0.035 mg/kg, 0.070 mg/kg, 0.140 mg/kg) under double-blind, randomized conditions. Assessments of cognitive performance and subjective effects were completed before drug administration, 30 min after drug administration, and at hourly intervals after drug administration for 5 hr. Modafinil increased ratings on the Amphetamine and Morphine Benzedrine Group scales of the Addiction Research Center Inventory (ARCI) and increased ratings on the Vigor and Total Positive scales of the Profile of Mood States. d-Amphetamine increased visual analog ratings of feeling stimulated and liking the drug and increased ratings on the Morphine Benzedrine Group scale of the ARCI. Both medications significantly reduced visual analog scale ratings of feeling sleepy, and modafinil decreased ratings on the ARCI Pentobarbital-Chlorpromazine-Alcohol Group scale. Both medications sustained performance that deteriorated across time on the Sternberg Number Recognition Test. Modafinil also enhanced performance rate on the Digit-Symbol Substitution Task above baseline levels and increased response rate on the Repeated Acquisition of Response Sequences Task. These results suggest that modafinil engenders alerting effects and increases performance in healthy non-sleep-deprived individuals comparable with that of d-amphetamine.

title: Effects of d-amphetamine on task performance and social behavior of humans in a residential laboratory.
abstract: Six healthy adult male volunteers lived for 11 days in a residential laboratory. Acute effects of d-amphetamine (0, 5, or 10 mg/70 kg) on performance of tasks, social interaction, and self-reports of drug effects were measured. Each day, participants engaged in a 6.5-hr work period and a 6.5-hr recreation period. Beverages containing d-amphetamine or placebo were consumed daily before the work period and before the recreation period. d-Amphetamine increased response rate without affecting accuracy on some tasks. d-Amphetamine increased the proportion of time spent engaging in verbal interaction during the first but not the second week of study. No changes in self-reported drug effects were observed. Thus, d-amphetamine improved performance in the absence of stimulant-like subjective effects. This differentiation between performance and subjective effects confirms the importance of determining the effects of drugs on a range of behaviors.

title: Not All Executive Functions Are Related to Intelligence
abstract: Accumulating evidence suggests that executive functions (EFs) are related to intelligence, despite neuropsychological results initially considered evidence of no such relation. However, findings that EFs are not unitary raise the issue of how intelligence relates to different EFs. This study examined the relations of fluid and crystallized intelligence and Wechsler Adult Intelligence Scale IQ to three separable EFs—inhibiting prepotent responses (inhibiting), shifting mental sets (shifting), and updating working memory (updating)—in young adults. Updating was highly correlated with the intelligence measures, but inhibiting and shifting were not. Furthermore, in structural equation models controlling for the inter-EF correlations, updating remained strongly related to intelligence, but the relations of inhibiting and shifting to intelligence were small and not significant. The results indicate that intelligence measures differentially relate to these three EFs, suggesting that current intelligence measures do not equally assess a wide range of executive control abilities likely required for many “intelligent” behaviors.

title: Prefrontal cortical contributions to working memory: evidence from event-related fMRI studies
abstract: Working memory refers to the short-term retention of information that is no longer accessible in the environment, and the manipulation of this information, for subsequent use in guiding behavior. In this review, we will present data from a series of event-related functional magnetic-resonance-imaging (fMRI) studies of delayed-response tasks that were designed to investigate the role of different regions of the prefrontal cortex (PFC) during different working-memory component processes. From these data, we conclude that: (1) lateral PFC is anatomically organized according to the types of cognitive operations that one performs when attempting to temporarily maintain and manipulate information; and (2) consistent with the picture that has emerged from the monkey electrophysiological literature, human lateral PFC is involved in several encoding- and response-related processes as well as mnemonic and nonmnemonic processes that are engaged during the temporary maintenance of information. Thus, lateral PFC activity cannot be ascribed to the function of a single, unitary cognitive operation.

title: High-Speed Scanning in Human Memory
abstract: When subjects judge whether a test symbol is contained in a short memorized sequence of symbols, their mean reaction-time increases linearly with the length of the sequence. The linearity and slope of the function imply the existence of an internal serial-comparison process whose average rate is between 25 and 30 symbols per second.

title: Differential effects of scopolamine and amphetamine on microcomputer-based performance tests.
abstract: Scopolamine (1.0 mg) and d-amphetamine (10 mg) were administered alone and in combination to 16 subjects (medical students), randomly assigned to testing sessions in a fully crossed-over (Latin square) within-subjects design. After being practiced to stability, 9 performance tests from a menu of portable microcomputer-based tests were administered double-blind over 4 weekly treatments (including a placebo). Differential effects of drugs on performance were found. Motor and perceptual speed tests appeared enhanced by d-amphetamine and not degraded by scopolamine. Two of the five cognitive tests showed reductions with scopolamine. The findings are discussed in connection with using a menu of performance tests that can have diagnostic significance for assessment of drug treatments. The effects of scopolamine in this study and others are considered in terms of a model which implies that magnitude of performance deficit depends on performance type (cognitive, motor, self-report) and dosage level. Applying the model, we offer the following summary: below 0.15 mg scopolamine is without any effect; below 0.50 mg, the effect is limited, but can be revealed by some sensitive, complex performance tests and self-report; above 1.0 mg, the effect is likely to impact on operational efficiency.

title: Processing efficiency of a verbal working memory system is modulated by amphetamine: an fMRI investigation
abstract: RationaleWorking memory performance may be improved or decreased by amphetamine, depending on baseline working memory capacity and amphetamine dosage. This variable effect suggests an optimal range of monaminergic activity for working memory, either below or above which it is compromised. We directly tested this possibility with human participants by varying amphetamine dosage and measuring the efficiency of cortical processing in brain regions associated with working memory.ObjectivesThe modulation of cortical processing in a verbal working memory network by dextroamphetamine (d-amph) was examined using BOLD functional magnetic resonance imaging (fMRI) with healthy participants. The goal of the study was to test the hypothesis of an inverted U-shaped relationship between d-amph dose and processing efficiency of a verbal working memory system.Methodsd-amph dosage was increased cumulatively every 2 h across four scanning sessions collected in a single day. The primary measure used for analyses in this study was the extent of activation in brain regions empirically defined as a working memory network.ResultsAn inverted U-shaped relationship was observed between the amount of d-amph administered and working memory processing efficiency. This relationship was specific to brain areas functionally defined as working memory regions and to the encoding/maintenance phase (as opposed to the response phase) of the task.ConclusionThe results are consistent with the hypothesis that the neurochemical effects of amphetamine modulate the efficiency of a verbal working memory system. The effect of amphetamine on working memory in healthy individuals may provide insight regarding the working memory deficits seen in schizophrenia, given the overlap between neurochemical systems affected by amphetamine, and those disordered in schizophrenia.

title: Effects of methylphenidate on stimulus evaluation and response processes: evidence from performance and event-related potentials.
abstract: This study investigated the effects of methylphenidate in a memory scanning task with two levels of high cognitive load (memory set sizes 2 and 4 presented in displays of size 4) and two response requirements (simple mapping or rotation). Twenty young adults were tested under placebo and methylphenidate (0.3 mg/Kg) in a double-blind protocol. As expected, memory load increased misses, false alarms, confusions, and failures to respond by the deadline. In turn, the rotation requirement increased confusions and nonresponses. Reaction time (RT) was slowed by both factors. P3b latency also was increased by memory load and, to some extent, by the rotation requirement. These results are consistent with the proposition that P3b latency reflects largely evaluation, rather than response processes. 
 
 
 
Misses and reaction time were decreased in response to targets presented in the center vs. the periphery of the display. Confusions, however, showed the opposite trend. The display position did not affect P3b latency. These results can be explained by assuming that the subject was focusing on the center of the display and that accuracy diminished when stimuli were presented toward the periphery of the display. 
 
 
 
The stimulant challenge speeded up reaction times overall and specifically reduced the slowing effect of rotation. However, P3b latency was not affected by methylphenidate, so that the speeding of reaction time by the stimulant can be attributed to post-evaluation processes.

title: The dose-dependent effect of methylphenidate on performance, cognition and psychophysiology.
abstract: The effects of methylphenidate (MPH) on 32 healthy human male volunteers (aged 18 to 25 years, mean age=22.26) were examined using a within-subject design. Each participant attended six testing periods, held once per week. Within each testing period, three repeat testing sessions were undertaken: pre-medication, on-medication and two hours post-medication. In these sessions, dose was manipulated (placebo, 5 mg, 15 mg or 45 mg) according a double-blind placebo design. In this report, we focus on behavioral, autonomic arousal (heart rate, skin conductance) and psychophysiological (ERP) data acquired during the working memory task. We found increased autonomic arousal (heart rate, skin conductance and blood pressure) with MPH. A linear reduction in reaction time, omission errors and target P3 latency, and a corresponding increase in background P3 amplitude was observed with increased MPH dose. The relationship between these measures supported an increase in performance and underlying brain function with MPH. To our knowledge, this is the first paper to use behavioral, arousal and electrophysiological measures in an integrative approach to study the effects of MPH on healthy adults.

title: Effects of Dextroamphetamine on Cognitive Performance and Cortical Activation
abstract: Monoaminergic neurotransmitters are known to have modulatory effects on cognition and on neurophysiological function in the cortex. The current study was performed with BOLD fMRI to examine physiological correlates of the effects of dextroamphetamine on working-memory performance in healthy controls. In a group analysis dextroamphetamine increased BOLD signal in the right prefrontal cortex during a task with increasing working-memory load that approached working-memory capacity. However, the effect of dextroamphetamine on performance and on signal change varied across individuals. Dextroamphetamine improved performance only in those subjects who had relatively low working-memory capacity at baseline, whereas in the subjects who had high working-memory capacity at baseline, it worsened performance. In subjects whose performance deteriorated, signal change was greater than that in subjects who had an improvement in performance, and these variations were correlated (Spearman rho = 0.89, P<0.02). These data shed light on the manner in which monoaminergic tone, working memory, and prefrontal function interact and, moreover, demonstrate that even in normal subjects the behavioral and neurophysiologic effects of dextroamphetamine are not homogeneous. These heterogeneic effects of dextroamphetamine may be explained by genetic variations that interact with the effects of dextroamphetamine.

title: Acute Administration of d-Amphetamine Decreases Impulsivity in Healthy Volunteers
abstract: This study investigated the acute behavioral effects of d-amphetamine on several behavioral indices of impulsivity. Impulsivity has been defined, variously, as difficulty in inhibiting inappropriate behaviors, inability to wait, insensitivity to delayed consequences or an alteration in the perception of time; standardized procedures have been developed to measure these behavioral dimensions. However, it is not known how drugs affect these measures, and few studies have examined more than one measure in a single study. In this study, 36 healthy men and women participated in three sessions, in which they received placebo, 10 mg, or 20 mg d-amphetamine in randomized order. On each session they performed the following five tasks: the Stop Task, which measures behavioral inhibition, a delay discounting task, which measures the relative value of immediate vs. delayed rewards, a delay of gratification task, a Go/No-Go task, and a time estimation task. Subjects also completed mood questionnaires. Amphetamine produced its expected subjective, mood-altering effects, including increases in POMS Friendliness and Elation scales, and ARCI Euphoria and Stimulant scales. On the measures of impulsivity, amphetamine decreased impulsive responding on three of the tasks: on the Stop Task it decreased Stop reaction times without affecting Go reaction time, on the Go/No-Go task, it decreased the number of false alarms, and on the delay discounting measure, amphetamine (20 mg) decreased k values indicating less discounting of delayed reward. Other measures of impulsive behavior were unaffected. These results suggest that acute doses of amphetamine decrease several forms of impulsive behavior. These findings extend and confirm previous findings in humans and laboratory animals.

title: Pharmacologically induced changes in arousal: effects on behavioral and electrophysiologic measures of alertness and attention.
abstract: The relationships between the diffuse subcortical neurotransmitter systems and behavioral and physiologic measures of alertness and attention are not well understood. This study was designed to further understand these relationships. In this double-blind experiment, 23 subjects ingested methylphenidate, diphenhydramine or placebo on 3 different days and performed behavioral and cognitive tasks including covert orienting of spatial attention and visual search tasks. Subjective and physiologic measures of alertness included EEG frequency analysis, EEG event-related desynchronization, and amount of sleep and sleep onset time in the unstimulated eyes closed state. Performance on the cognitive tasks improved with MP and worsened with DPHA, but there were no specific attentional effects. The best measures of alertness were based on self-rated scales and on EEG recorded in the unstimulated eyes closed state. These observations suggest that methylphenidate and diphenhydramine primarily affected overall state and that healthy humans were able to partially compensate for the pharmacologically induced alertness changes during cognitive task performance.

title: Effects of scopolamine and dextroamphetamine on human performance.
abstract: The effects of two drugs used to prevent symptoms of motion sickness in the operational environment were examined in this study of human performance as measured by computer-based tests of cognitive and psychomotor skills. Each subject was exposed repetitively to five tests: Symbol-Digit Substitution, Simple Reaction Time, Pattern Recognition, Digit Span Memory, and Pattern Memory. Although there have been previous reports of decreases in human performance in similar testing with higher dosages of scopolamine or dextroamphetamine, no significant decrements were observed with the operational-level combined dose used in this study (0.4 mg oral scopolamine and 5.0 mg oral dextroamphetamine.) The controversy over the use of combination drug therapy in this environment is discussed along with the indications for further research based on the findings.

title: The acute effects of d-amphetamine and methamphetamine on attention and psychomotor performance
abstract: RationaleIt is not clear how the deleterious effects of amphetamines on driving performance are mediated in terms of select cognitive processes. current three separate experiments assessed the acute effects of an oral dose of either 0.42-mg/kg d-amphetamine, d,l-methamphetamine and d-methamphetamine on driving-related cognitive functions in a total of 60 healthy non-fatigued adults.Materials and methodsThree separate repeated measures counterbalanced, double-blind, placebo-controlled designs were employed in which 20 volunteers completed two treatment conditions, either d-amphetamine, d,l-methamphetamine or d-methamphetamine and placebo. Performance was assessed on a range of attentional, psychomotor and perceptual speed tasks.ResultsMean blood concentrations at 120-, 170- and 240-min postdrug administration were 83, 98 and 96 ng/ml, respectively, for d-amphetamine, 90, 95 and 105 ng/ml, respectively, for d,l-methamphetamine and 72, 67 and 59 ng/ml, respectively, for d-methamphetamine. The amphetamines, in general, improved various aspects of attention (Digit Vigilance, Digit Symbol Substitution Test and Movement Estimation Performance) with some evidence to suggest possible enhancement in psychomotor functioning (Tracking ability) and perceptual speed (Inspection Time).ConclusionsThe current series of studies primarily provides evidence of low-level amphetamine-related enhancement of function; however, it also provides evidence of less conservative movement estimation that might contribute to amphetamine-related road fatalities.

title: Effects of methylphenidate on spatial working memory and planning in healthy young adults
abstract: Previous studies of the effects of the psychomotor stimulant, methylphenidate, have concentrated on vigilance and reaction time tasks. In this study, the effects of methylphenidate on more complex aspects of cognition were studied using tasks from the CANTAB battery and related tests which have been shown to be sensitive to frontal lobe dysfunction. Twenty-eight young healthy men participated in a counterbalanced, double-blind, placebo-controlled study of the effects of methylphenidate. Cognitive assessment included tests of spatial working memory, planning, verbal fluency, attentional set-shifting and sustained attention. Methylphenidate had significant effects on performance of the tests of spatial working memory and planning but not on the attentional and fluency tests. When the drug was taken on the first test session, performance on the spatial tests was enhanced by the drug compared to placebo. However, when the drug was taken second, performance accuracy was impaired whereas response latencies were decreased. These results are consistent with a hypothesis that methylphenidate influences performance in two conflicting ways; enhancing executive aspects of spatial function on novel tasks but impairing previously established performance. This pattern of effects is discussed within the framework of dual, interacting arousal mechanisms.

title: Computerized assessment in neuropsychiatry using CANTAB: discussion paper.
abstract: This paper illustrates how recent developments in computing technology can be exploited for the neuropsychological assessment ofneurodegenerative diseases. Computerizedtests have many advantages over traditional paper and pencil tests, including precision, speed an-d reliability. For example, it is possible to measure -response latencies to' millisecond accuracy, necessarfor reaction time studies. Furthermore, the 6iomputer can 'be used to give feedback to the subjet in a iystematic 'and objective fashion. These generl' desgir 'features have now been utilized extengiMvelf inis set of tests knownas the Cambridge Neuropsycho6gic1a Test Automated Battery (CANTAB). -Other iijortant design1features of these tests are: (1) They are designed to test different aspects of mental functioning so that a profile ofperormance can be constructed'for a particular patient group. (2) Where appropriate they are graded in difficulty in order to assess abroad range ofcognitive ability. (3) They employ non-verbal stimuli and require nonverbal responses. This, of course, is essential for patients with language impairment, but is also an important advantage for -cross national studies. (4) They are designed to be-visually attractive and interesting, using positive feedback which has a 'game-like' quality and maintains motivation. CANTAB consists ofthree separate batteries oftests measuring visual memory, attention and planning. They are designed to run on an Acorn BBC Master Microcomputer and more recently on IBM PC and compatible machines. In both cases the programs employ high resolution graphics and responses are made using a touch sensitive screen. The theoretical rationale of the tests is based on two main themes: (i) adapting those tests of animal neuropsychology that have proved useful in establishing the neural substrates" of certain types of cognitive function and; (ii)'.undertaking a componential analysis ofthe processes comprising particular forms of cognitive function; for example spatial planning may involve the ability to store and sequence particular spatial representations, as well as manipulate them in working memory. A patient could fail a planning test because of impairments in any one of these constituent functions. The tests are comprehensive in terms of the range of functions they assess, and have been shown' to be sensitive to deficits, as well as progressive decline, in patients early in the course of dentia of the

title: Dopamine Release in Dissociable Striatal Subregions Predicts the Different Effects of Oral Methylphenidate on Reversal Learning and Spatial Working Memory
abstract: Previous data suggest that methylphenidate can have variable effects on different cognitive tasks both within and between individuals. This is thought to be underpinned by inverted U-shaped relationships between cognitive performance and dopaminergic activity in relatively separate fronto-striatal circuits and reflected by individual differences in trait impulsivity. Direct evidence for this is currently lacking. In this study, we demonstrate for the first time that therapeutic doses of oral methylphenidate administered to young healthy subjects result in different sized changes in D2/D3 receptor availability in different regions of the human striatum and that the change in receptor availability within an individual subregion predicts cognitive performance on a particular task. Methylphenidate produced significantly different effects on reversal learning and spatial working memory tasks within individuals. Performance on the reversal learning task was predicted by the drug-induced change in D2/D3 receptor availability in postcommissural caudate, measured using [11C]-raclopride radioligand PET imaging, whereas performance on the spatial working memory task was predicted by changes in receptor availability in the ventral striatum. Reversal learning performance was also predicted by subjects' trait impulsivity, such that the most impulsive individuals benefited more from methylphenidate, consistent with this drug's beneficial effects on cognition in attention deficit hyperactivity disorder.

title: Amphetamine improves cognitive function in medicated individuals with schizophrenia and in healthy volunteers
abstract: Recent research on schizophrenia indicates that cognitive deficits in this illness are important predictors of functional outcome, highlighting the need for treatments that have a positive impact on cognitive function. Here we explore the hypothesis that acute administration of d-amphetamine can improve cognitive function in individuals with schizophrenia who are well-treated with typical antipsychotics, as well as in healthy controls performing under dual task conditions designed to elicit performance deficits analogous to those found in schizophrenia.



Ten individuals with schizophrenia taking haldol or prolixin and 22 healthy controls performed spatial working memory, language production, and Stroop tasks under both placebo and 0.25 mg/kg of D-amphetamine.



D-Amphetamine improved reactions times on the spatial working memory and Stroop tasks for both individuals with schizophrenia and controls, and improved working memory accuracy in schizophrenia. In addition, D-amphetamine improved language production for both individuals with schizophrenia and controls.



These results provide support for the hypothesis that the adjunctive administration of dopamine agonist can improve cognitive in individuals with schizophrenia taking typical antipsychotics. The results are discussed in terms of their implications for understanding the nature of working memory deficits in schizophrenia, and potential future avenues for cognitive enhancement in this illness.

title: Dextroamphetamine Enhances “Neural Network-Specific” Physiological Signals: A Positron-Emission Tomography rCBF Study
abstract: Previous studies in animals and humans suggest that monoamines enhance behavior-evoked neural activity relative to nonspecific background activity (i.e., increase signal-to-noise ratio). We studied the effects of dextroamphetamine, an indirect monoaminergic agonist, on cognitively evoked neural activity in eight healthy subjects using positron-emission tomography and the O15 water intravenous bolus method to measure regional cerebral blood flow (rCBF). Dextroamphetamine (0.25 mg/kg) or placebo was administered in a double-blind, counterbalanced design 2 hr before the rCBF study in sessions separated by 1–2 weeks. rCBF was measured while subjects performed four different tasks: two abstract reasoning tasks—the Wisconsin Card Sorting Task (WCST), a neuropsychological test linked to a cortical network involving dorsolateral prefrontal cortex and other association cortices, and Ravens Progressive Matrices (RPM), a nonverbal intelligence test linked to posterior cortical systems—and two corresponding sensorimotor control tasks. There were no significant drug or task effects on pCO2 or on global blood flow. However, the effect of dextroamphetamine (i.e., dextroamphetamine vs placebo) on task-dependent rCBF activation (i.e., task − control task) showed double dissociations with respect to task and region in the very brain areas that most distinctly differentiate the tasks. In the superior portion of the left inferior frontal gyrus, dextroamphetamine increased rCBF during WCST but decreased it during RPM (ANOVA F(1,7) = 16.72, p < 0.0046). In right hippocampus, blood flow decreased during WCST but increased during RPM (ANOVAF(1,7) = 18.7, p < 0.0035). These findings illustrate that dextroamphetamine tends to “focus” neural activity, to highlight the neural network that is specific for a particular cognitive task. This capacity of dextroamphetamine to induce cognitively specific signal augmentation may provide a neurobiological explanation for improved cognitive efficiency with dextroamphetamine.

title: Methylphenidate Has Differential Effects on Blood Oxygenation Level-Dependent Signal Related to Cognitive Subprocesses of Reversal Learning
abstract: Complete understanding of the neural mechanisms by which stimulants such as methylphenidate ameliorate attention deficit hyperactivity disorder is lacking. Theories of catecholamine function predict that the neural effects of stimulant drugs will vary according to task requirements. We used event-related, pharmacological functional magnetic resonance imaging to investigate the effects of 60 mg of methylphenidate, alone and in combination with 400 mg of sulpiride, on blood oxygenation level-dependent (BOLD) signal in a group of 20 healthy participants during probabilistic reversal learning, in a placebo-controlled design. In a whole-brain analysis, methylphenidate attenuated BOLD signal in the ventral striatum during response switching after negative feedback but modulated activity in the prefrontal cortex when subjects maintained their current response set. The results show that the precise neural site of modulation by methylphenidate depends on the nature of the cognitive subprocess recruited.

title: Methylphenidate affects strategic choice behavior in normal adult humans
abstract: The time course of serum concentration and performance on a concurrent probability matching task were evaluated in normal adults receiving 0.15 or 0.3 mg/kg of methylphenidate. The behavioral task, an arcade-like problem-solving game, revealed that drug-treated subjects improved their performance upon repeated testings during pharmacokinetic evaluation at a lower rate than did non-treated controls over the same time span. However, drug-treated subjects failed to adopt the adaptive problem-solving strategies selected by controls.

title: Tryptophan depletion impairs stimulus-reward learning while methylphenidate disrupts attentional control in healthy young adults: implications for the monoaminergic basis of impulsive behaviour
abstract: Altered serotonergic and dopaminergic function have been widely implicated in behavioural disorders associated with impulsivity and risk-taking. However, little research has addressed the specific cognitive consequences of changed monoaminergic function that might contribute to the production of impulsive behaviour.  We compared the effects of rapid plasma tryptophan depletion, acute doses of the mixed indirect catecholamine agonist, methylphenidate (40 mg), and acute doses of the α1/α2 agonist, clonidine (1.5 µg/kg), on aspects of visual discrimination learning involving either acquisition of altered stimulus-reward associations (i.e. updating the affective valence of exteroceptive stimuli) or the control of attention towards relevant as opposed to irrelevant stimulus dimensions.  Relative to subjects who received placebo, subjects with reduced tryptophan exhibited a deficit in the ability to learn changed stimulus-reward associations, but were still able to shift an acquired attentional set away from a now-irrelevant stimulus dimension towards a newly relevant dimension. By contrast, subjects who received methylphenidate were able to learn effectively about changing stimulus-reward associations, but showed an enhanced ability to shift an attentional bias, in combination with slowed response times. Subjects who received clonidine showed neither of these changes.  These results suggest that reduction in central serotonin leads to altered neuromodulation of the cortical and subcortical regions (e.g. orbitofrontal cortex, striatum and anterior temporal structures) that mediate important aspects of associative learning whereby exteroceptive stimuli acquire altered incentive motivational value. On the other hand, facilitation of catecholamine neurotransmitters may disrupt the allocation of attention between relevant and irrelevant features of the environment, perhaps through altered modulation of the dorsolateral prefrontal cortex. The implications of these results for understanding the differential neuromodulation of cognitive functions are discussed.

title: Intelligence and changes in regional cerebral glucose metabolic rate following learning
abstract: Positron emission tomography (PET) studies of brain glucose metabolic rate (GMR) in normal volunteers report inverse correlations between GMR and scores on the Raven's Advanced Progressive Matrices (RAPM) and verbal fluency. A new study in eight normal men reports widespread significant GMR decreases following learning a complex task (the computer game “Tetris”). The purpose of this study is to ascertain the correlations between GMR changes following learning “Tetris” and psychometric intelligence scores (RAPM and WAIS-R) to determine whether high-ability subjects show the largest GMR decreases, as predicted by a brain efficiency hypothesis. This hypothesis is supported with significant correlations between the magnitude of GMR change and intelligence scores in many brain areas that changed with learning. Some implications for the role of attention, memory, and speed of processing are discussed in view of the specific brain areas involved.

title: Catecholamine modulation of prefrontal cortical cognitive function
abstract: The prefrontal cortex (PFC) utilizes working memory to guide behavior and to release the organism from dependence on environmental cues and is commonly disrupted in neuropsychiatric disorders, normal aging, or exposure to uncontrollable stress. This review posits that the PFC is very sensitive to changes in the neuromodulatory inputs it receives from norepinephrine (NE) and dopamine (DA) systems and that this sensitivity can lead to marked changes in the working-memory functions of the PFC. While NE and DA have important beneficial influences on processing in this area, very high levels of catecholamine release, for example, during exposure to uncontrollable stress, disrupt the cognitive functions of the PFC. This fresh understanding of the neurochemical influences on PFC function has led to new treatments for cognitive disorders such as Attention Deficit Hyperactivity Disorder (ADHD), and may help to elucidate the prevalence of PFC dysfunction in other mental disorders.

title: Modifiers of Long-Term School Outcomes for Children with Attention-Deficit/Hyperactivity Disorder: Does Treatment with Stimulant Medication Make a Difference? Results from a Population-Based Study
abstract: The purpose of this study was to describe the significance of potential modifiers of long-term school outcomes among children with attention-deficit/hyperactivity disorder (AD/HD), including treatment with stimulant medication.  Subjects included 370 children with research-identified AD/HD from a 1976–1982 population-based birth cohort (N = 5718). In a companion study, the complete school record for each subject was reviewed to obtain information on reading achievement, absenteeism, grade retention, and school dropout. Data on type of stimulant, dose, age at initiation of treatment, and start/stop dates were collected from medical and school records, available for all subjects.  Treatment with stimulants was associated with decreased rates of absenteeism; longer duration of treatment was also associated with decreased absenteeism rates. There was a modest positive correlation (r = .15, p = .012) between average daily stimulant dose and last reading score. Cases treated with stimulants were 1.8 times less likely to subsequently be retained a grade (95% confidence interval: 1.01–3.2; p = .047). The proportion of school dropout was similar between treated and not treated cases (22.2% vs 25.8%, p = .54). Other potential modifiers of school outcomes (sociodemographic risk factors, presence of comorbid learning or psychiatric disorders, and receipt of special educational services) were also examined and found to be associated with poorer outcomes.  In this birth cohort, stimulant treatment of children with AD/HD was associated with improved reading achievement, decreased school absenteeism, and decreased grade retention. This study provides support for efforts to ensure that children with AD/HD receive appropriate long-term medical treatment.

title: Occupational Outcome in Adult ADHD: Impact of Symptom Profile, Comorbid Psychiatric Problems, and Treatment
abstract: To determine the effects of symptom profile, comorbid psychiatric problems, and treatment on occupational outcome in adult ADHD patients.  Adult ADHD patients (N = 414) responded to questionnaires rating past and present symptoms of ADHD, comorbid conditions, treatment history, and work status.  Of the patients, 24% reported being in work, compared to 79% in a population-based control group (N = 359). Combined subtype of ADHD, substance abuse, and a reported history of depression or anxiety were correlated with being out of work. Current and past medical treatment of ADHD was correlated with being in work. Logistic regression analyses showed that stimulant therapy during childhood was the strongest predictor for being in work as adults (odds ratio = 3.2, p = .014).  Early recognition and treatment of ADHD is a strong predictor of being in work as an adult, independently of comorbidity, substance abuse, and current treatment.

title: What are the cognitive effects of stimulant medications? Emphasis on adults with attention-deficit/hyperactivity disorder (ADHD)
abstract: The relevant literature concerning cognitive effects of amphetamine and methylphenidate, was reviewed, with an emphasis on research conducted in adults diagnosed with attention-deficit/hyperactivity disorder. As first-line treatment for ADHD, stimulant drugs are well-known to improve attention and concentration. Yet, there is increasing evidence that (as with children and adolescents), they do not promote learning and academic achievement in adult college students with ADHD. A review of neuropsychological studies indicates that, although response latencies are reduced, performance of ADHD adults on tests of 'distractibility' and 'planning' is also not consistently improved by stimulants. Studies in non-ADHD adults suggest that stimulants do not promote acquisition of new information, might improve retention of previously acquired information, and facilitate memory consolidation, but may actually impair performance of tasks that require adaptation, flexibility and planning. It is still not clear if improvement only occurs when there is a baseline deficit. Stimulants may influence cognition by their effects on physiological arousal. Regardless, the evidence does not support the conclusion that stimulants are cognitive 'enhancers.

title: Modafinil: A Review of Neurochemical Actions and Effects on Cognition
abstract: Modafinil (2-[(Diphenylmethyl) sulfinyl] acetamide, Provigil) is an FDA-approved medication with wake-promoting properties. Pre-clinical studies of modafinil suggest a complex profile of neurochemical and behavioral effects, distinct from those of amphetamine. In addition, modafinil shows initial promise for a variety of off-label indications in psychiatry, including treatment-resistant depression, attention-deficit/hyperactivity disorder, and schizophrenia. Cognitive dysfunction may be a particularly important emerging treatment target for modafinil, across these and other neuropsychiatric disorders. We aimed to comprehensively review the empirical literature on neurochemical actions of modafinil, and effects on cognition in animal models, healthy adult humans, and clinical populations. We searched PubMed with the search term ‘modafinil’ and reviewed all English-language articles for neurochemical, neurophysiological, cognitive, or information-processing experimental measures. We additionally summarized the pharmacokinetic profile of modafinil and clinical efficacy in psychiatric patients. Modafinil exhibits robust effects on catecholamines, serotonin, glutamate, gamma amino-butyric acid, orexin, and histamine systems in the brain. Many of these effects may be secondary to catecholamine effects, with some selectivity for cortical over subcortical sites of action. In addition, modafinil (at well-tolerated doses) improves function in several cognitive domains, including working memory and episodic memory, and other processes dependent on prefrontal cortex and cognitive control. These effects are observed in rodents, healthy adults, and across several psychiatric disorders. Furthermore, modafinil appears to be well-tolerated, with a low rate of adverse events and a low liability to abuse. Modafinil has a number of neurochemical actions in the brain, which may be related to primary effects on catecholaminergic systems. These effects are in general advantageous for cognitive processes. Overall, modafinil is an excellent candidate agent for remediation of cognitive dysfunction in neuropsychiatric disorders.

title: Enhancement of Phonological Memory Following Transcranial Magnetic Stimulation (TMS)
abstract: Phonologically similar items (mell, rell, gell) are more difficult to remember than dissimilar items (shen, floy, stap), likely because of mutual interference of the items in the phonological store. Low-frequency transcranial magnetic stimulation (TMS), guided by functional magnetic resonance imaging (fMRI) was used to disrupt this phonological confusion by stimulation of the left inferior parietal (LIP) lobule. Subjects received TMS or placebo stimulation while remembering sets of phonologically similar or dissimilar pseudo-words. Consistent with behavioral performance of patients with neurological damage, memory for phonologically similar, but not dissimilar, items was enhanced following TMS relative to placebo stimulation. Stimulation of a control region of the brain did not produce any changes in memory performance. These results provide new insights into how the brain processes verbal information by establishing the necessity of the inferior parietal region for optimal phonological storage. A mechanism is proposed for how TMS reduces phonological confusion and leads to facilitation of phonological memory.

title: Noninvasive Brain Stimulation Improves Language Learning
abstract: Anodal transcranial direct current stimulation (tDCS) is a reliable technique to improve motor learning. We here wanted to test its potential to enhance associative verbal learning, a skill crucial for both acquiring new languages in healthy individuals and for language reacquisition after stroke-induced aphasia. We applied tDCS (20 min, 1 mA) over the posterior part of the left peri-sylvian area of 19 young right-handed individuals while subjects acquired a miniature lexicon of 30 novel object names. Every subject participated in one session of anodal tDCS, one session of cathodal tDCS, and one sham session in a randomized and double-blinded design with three parallel versions of the miniature lexicon. Outcome measures were learning speed and learning success at the end of each session, and the transfer to the subjects' native language after the respective stimulation. With anodal stimulation, subjects showed faster and better associative learning as compared to sham stimulation. Mood ratings, reaction times, and response styles were comparable between stimulation conditions. Our results demonstrate that anodal tDCS is a promising technique to enhance language learning in healthy adults and may also have the potential to improve language reacquisition after stroke.

title: Nutrition and Brain Function: A Multidisciplinary Virtual Symposium
abstract: A few months ago, the Brazilian Society for Neuroscience and Behavior (SBNeC) promoted a "virtual symposium" (by Internet, under the coordination of R.C.A. Guedes) on "Nutrition and Brain Function". The discussions generated during that symposium originated the present text, which analyzes current topics on the theme, based on the multidisciplinary experience of the authors. The way the brain could be non-homogeneously affected by nutritional alterations, as well as questions like early malnutrition and the development of late obesity and hormone abnormalities were discussed. Also, topics like the role of essential fatty acids (EFAs) on brain development, increased seizure susceptibility and changes in different neurotransmitters and in cognitive performance in malnourished animals, as well as differences between overall changes in nutrient intake and excess or deficiency of specific nutrients (e.g. iodine deficiency) were analyzed. It was pointed out that different types of neurons, possibly in distinct brain structures, might be differently affected by nutritional manipulation, including not only lack-but also excess of nutrient intake. Such differences could help in explaining discrepancies between data on humans and in animals and so, could aid in determining the basic mechanisms underlying lesions or changes in brain function and behavior.

title: Effects of sleep deprivation on neural functioning: an integrative review
abstract: Sleep deprivation has a broad variety of effects on human performance and neural functioning that manifest themselves at different levels of description. On a macroscopic level, sleep deprivation mainly affects executive functions, especially in novel tasks. Macroscopic and mesoscopic effects of sleep deprivation on brain activity include reduced cortical responsiveness to incoming stimuli, reflecting reduced attention. On a microscopic level, sleep deprivation is associated with increased levels of adenosine, a neuromodulator that has a general inhibitory effect on neural activity. The inhibition of cholinergic nuclei appears particularly relevant, as the associated decrease in cortical acetylcholine seems to cause effects of sleep deprivation on macroscopic brain activity. In general, however, the relationships between the neural effects of sleep deprivation across observation scales are poorly understood and uncovering these relationships should be a primary target in future research.

title: Be smart, exercise your heart: exercise effects on brain and cognition
abstract: An emerging body of multidisciplinary literature has documented the beneficial influence of physical activity engendered through aerobic exercise on selective aspects of brain function. Human and non-human animal studies have shown that aerobic exercise can improve a number of aspects of cognition and performance. Lack of physical activity, particularly among children in the developed world, is one of the major causes of obesity. Exercise might not only help to improve their physical health, but might also improve their academic performance. This article examines the positive effects of aerobic physical activity on cognition and brain function, at the molecular, cellular, systems and behavioural levels. A growing number of studies support the idea that physical exercise is a lifestyle factor that might lead to increased physical and mental health throughout life.

title: Attention regulation and monitoring in meditation
abstract: Meditation can be conceptualized as a family of complex emotional and attentional regulatory training regimes developed for various ends, including the cultivation of well-being and emotional balance. Among these various practices, there are two styles that are commonly studied. One style, focused attention meditation, entails the voluntary focusing of attention on a chosen object. The other style, open monitoring meditation, involves nonreactive monitoring of the content of experience from moment to moment. The potential regulatory functions of these practices on attention and emotion processes could have a long-term impact on the brain and behavior.

title: The cumulative cost of additional wakefulness: dose-response effects on neurobehavioral functions and sleep physiology from chronic sleep restriction and total sleep deprivation.
abstract: To inform the debate over whether human sleep can be chronically reduced without consequences, we conducted a dose-response chronic sleep restriction experiment in which waking neurobehavioral and sleep physiological functions were monitored and compared to those for total sleep deprivation.



The chronic sleep restriction experiment involved randomization to one of three sleep doses (4 h, 6 h, or 8 h time in bed per night), which were maintained for 14 consecutive days. The total sleep deprivation experiment involved 3 nights without sleep (0 h time in bed). Each study also involved 3 baseline (pre-deprivation) days and 3 recovery days.



Both experiments were conducted under standardized laboratory conditions with continuous behavioral, physiological and medical monitoring.



A total of n = 48 healthy adults (ages 21-38) participated in the experiments.



Noctumal sleep periods were restricted to 8 h, 6 h or 4 h per day for 14 days, or to 0 h for 3 days. All other sleep was prohibited.



Chronic restriction of sleep periods to 4 h or 6 h per night over 14 consecutive days resulted in significant cumulative, dose-dependent deficits in cognitive performance on all tasks. Subjective sleepiness ratings showed an acute response to sleep restriction but only small further increases on subsequent days, and did not significantly differentiate the 6 h and 4 h conditions. Polysomnographic variables and delta power in the non-REM sleep EEG-a putative marker of sleep homeostasis--displayed an acute response to sleep restriction with negligible further changes across the 14 restricted nights. Comparison of chronic sleep restriction to total sleep deprivation showed that the latter resulted in disproportionately large waking neurobehavioral and sleep delta power responses relative to how much sleep was lost. A statistical model revealed that, regardless of the mode of sleep deprivation, lapses in behavioral alertness were near-linearly related to the cumulative duration of wakefulness in excess of 15.84 h (s.e. 0.73 h).



Since chronic restriction of sleep to 6 h or less per night produced cognitive performance deficits equivalent to up to 2 nights of total sleep deprivation, it appears that even relatively moderate sleep restriction can seriously impair waking neurobehavioral functions in healthy adults. Sleepiness ratings suggest that subjects were largely unaware of these increasing cognitive deficits, which may explain why the impact of chronic sleep restriction on waking cognitive functions is often assumed to be benign. Physiological sleep responses to chronic restriction did not mirror waking neurobehavioral responses, but cumulative wakefulness in excess of a 15.84 h predicted performance lapses across all four experimental conditions. This suggests that sleep debt is perhaps best understood as resulting in additional wakefulness that has a neurobiological "cost" which accumulates over time.