Lon R. Hays

The cytochrome P450 2D6 (CYP2D6) enzyme polymorphism: Screening costs and influence on clinical outcomes in psychiatry

This study examined factors that affect cost, reliability, and the value of determining the cytochrome P450 2D6 (CYP2D6) polymorphism in clinical practice.

A Profile of OxyContin Addiction

Abstract OxyContin is a controlled-released form of oxycodone indicated for the management of moderate to severe pain. OxyContin diversion and abuse has become a major problem in certain areas of the United States, particularly rural areas and Appalachia. This study undertakes an 18-month retrospective chart review at a private freestanding psychiatric facility to develop a profile of OxyContin addicts seeking treatment. There were 579 admissions to the Addictive Disease Unit of this facility from October 2000 to March 2002, with 298 of these admissions being for the treatment of opioid abuse or dependence. One hundred and eighty-seven of these individuals were dependent on OxyContin, using an average dose of 184 milligrams of OxyContin per day. The OxyContin-dependent individuals tended to show a progression from p.o. use to either snorting or i.v. use. The author concludes that a socio-cultural understanding is needed to better treat these addicts as is improved communication between the pain treatment community and the addiction treatment community.

Psychiatrie and Pain Characteristics of Prescription Drug Abusers Entering Drug Rehabilitation

There has been intense interest in the problem of prescription drug abuse on the parts of health professionals, law enforcement, the media, and the general public. Clinicians not only need to know how to assess risk but also what drugs are being diverted most in their region. We conducted a prospective survey of prescription drug abusers entering a treatment facility in central Kentucky. Participants (n = 109) were enrolled and completed a structured clinical interview and prescription drug abuse survey. The prescription drug abusers assessed in the study had a mean age of 30.95 years (SD = 10.21), were comprised of 75 men (69%) and 34 women (31%), and were mostly Caucasian (98%). The majority (84%) stated that they had legitimately been given a prescription for opioids for pain at some point from a physician and 61% reported chronic pain concerns. The most commonly abused drugs were hydrocodone-containing formulations (78%) and oxycodone-containing products (69%), while products containing methadone (23%) or fentanyl (7%) were abused much less frequently. Most respondents (91%) stated that they had purchased prescription opioids from a street dealer at least once and the majority (80%) had altered the delivery system of the prescription drug by chewing, snorting, or using IV administration. Implications for pain management are discussed, focusing on the need for clinicians treating chronic pain to more thoroughly assess patients for their risk of abuse and addiction before starting an opioid regimen.

Acute behavioral and physiological effects of modafinil in drug abusers

Modafinil, a novel stimulant, is effective in the treatment of excessive daytime sleepiness associated with narcolepsy. It is biochemically and pharmacologically distinct from prototypical stimulants such as D-amphetamine, cocaine, and methylphenidate. The present experiment was designed to assess the acute behavioral effects of oral modafinil, cocaine, and placebo in participants (n =9) with recent histories of cocaine use (i.e. positive urine for cocaine or benzoylecgonine during the initial screening interview). Drug effects were assessed with a battery of self-reported drug-effect questionnaires, performance measures, and physiological indices. Cocaine, but not modafinil, produced stimulant-like self-reported drug effects (e.g. increased ratings of High and Stimulated). Modafinil and cocaine dose-dependently increased heart rate and blood pressure. The results of the present study suggest that modafinil has minimal abuse potential, but should be viewed cautiously because of the relatively small sample size. Future studies should further characterize the abuse potential of modafinil using other behavioral arrangements, such as drug discrimination or drug self-administration. A full characterization of the abuse potential of modafinil will become important as the use of this drug increases.

Aripiprazole Attenuates the Discriminative-Stimulus and Subject-Rated Effects of D -Amphetamine in Humans

The results of animal research suggest that the use of partial agonists at dopamine (DA) D2 receptors may be an effective strategy for the treatment of stimulant dependence. Aripiprazole is an atypical antipsychotic that has partial agonist activity at D2 receptors. In this experiment, seven human participants with a history of nontherapeutic stimulant use learned to discriminate 15 mg oral D-amphetamine. After acquiring the discrimination (ie ⩾80% correct responding on four consecutive sessions), the effects of a range of doses of D-amphetamine (0, 2.5, 5, 10, and 15 mg), alone and in combination with aripiprazole (0 and 20 mg), were assessed. D-Amphetamine alone functioned as a discriminative stimulus, produced prototypical subject-rated drug effects (eg increased ratings of Active, Alert, Energetic) and elevated cardiovascular indices. These effects were generally a function of dose. Aripiprazole alone did not occasion D-amphetamine-appropriate responding or produce subject-rated effects, but modestly impaired performance. Administration of aripiprazole significantly attenuated the discriminative-stimulus and cardiovascular effects of D-amphetamine, as well as some of the subject-rated drug effects. These data are consistent with previous preclinical findings and suggest that DA partial agonists deserve further evaluation as potential pharmacotherapies in the management of stimulant dependence. Future studies should investigate the ability of aripiprazole or related compounds to attenuate the behavioral effects of stimulants associated with a greater degree of dependence, such as methamphetamine or cocaine, in dependent individuals.

Discriminative-stimulus effects of modafinil in cocaine-trained humans

Modafinil is a novel stimulant that is effective in the treatment of narcolepsy and excessive daytime sleepiness. In vitro and in vivo neuropharmacological data suggest that the mechanism of action of modafinil is distinct from that of prototypical abused stimulants like cocaine and d-amphetamine. In the present experiment, six human volunteers with recent histories of cocaine use learned to discriminate 150 mg oral cocaine HCL. After acquiring the discrimination (i.e. > or = 80% correct responding on 4 consecutive days), a range of doses of oral cocaine (50, 100, and 150 mg), modafinil (200, 400, and 600 mg), and placebo were tested to determine if they shared discriminative-stimulus and self-reported effects with 150 mg cocaine. Methylphenidate (60 mg) and triazolam (0.5 mg) were included as positive and negative controls, respectively. Cocaine and methylphenidate, but neither modafinil nor triazolam, produced cocaine-like discriminative-stimulus, subject-rated, and cardiovascular effects. The results of the present experiment suggest that cocaine discrimination in humans is pharmacologically specific within and across drug classes.

Accessing Drug-Abuse Treatment: Perceptions of Out-of-Treatment Injectors

The Presidential Commission on the Human Immunodeficiency Virus Epidemic (1988) developed a 10-year plan in 1987 that recommended: “Expanded drug abuse treatment programs sufficient to admit all IV drug users who desired services and, until that occurred, short-term detoxification and low-dose methadone for those on waiting lists.” This study presents data collected from a sample of 2,613 out-of-treatment and non-incarcerated injection drug users in 21 U.S. cities to examine their drug-treatment access during the past year. Analyses on injectors who tried but were unable to enter treatment revealed that program-based reasons (e.g., no room, too costly, or stringent admission criteria) are the most commonly given barriers to drug treatment (72%). However, a notable number of injectors (20%) also reported that individual-based reasons are important for not accessing drug treatment. Injectors giving program- and individual-based reasons for not entering treatment are profiled using logistic regression.

Cocaine Choice in Humans During D-Amphetamine Maintenance

The results of preclinical laboratory experiments and clinical trials indicate that agonist replacements such as d-amphetamine may be a viable option for managing cocaine dependence. This study determined the effects of d-amphetamine maintenance on cocaine choice behavior in human participants. We predicted that d-amphetamine maintenance would reduce cocaine choice. Nine cocaine-dependent participants completed the study. Two d-amphetamine maintenance conditions were completed in a counterbalanced order (0 and 40 mg/d). After 3 to 5 days of placebo or d-amphetamine maintenance, the participants completed 5 experimental sessions. During these sessions, the participants first sampled the placebo (ie, 4 mg of intranasal cocaine) identified as drug A. The participants then sampled a second intranasal drug dose (4, 10, 20, or 30 mg of cocaine) identified as drug B. The participants then made 6 discrete choices between drugs A and B. Drug choices were separated by 45 minutes. The primary outcome measure was the number of cocaine choices. All doses of cocaine were chosen significantly more than placebo during both maintenance conditions (ie, placebo and d-amphetamine). Choice of the 20-mg dose of cocaine was significantly lower during d-amphetamine maintenance relative to when this cocaine dose was tested during placebo-d-amphetamine maintenance. Cocaine produced prototypical subject-rated drug effects (eg, good effects, like drug, willing to take again). These effects were not altered to a significant degree by d-amphetamine maintenance. Cocaine was well tolerated during d-amphetamine maintenance, and no unexpected or serious adverse events occurred. These results are concordant with those of previous preclinical experiments, human laboratory studies, and clinical trials that suggest that agonist replacement therapy may be a viable strategy for managing cocaine dependence.

Discriminative Stimulus and Subject-Rated Effects of Methamphetamine, d-Amphetamine, Methylphenidate, and Triazolam in Methamphetamine-Trained Humans

Methamphetamine abuse is a significant public health concern. Although widely studied in laboratory animals, little is known about the abuse-related behavioral effects of methamphetamine relative to other abused stimulants in controlled laboratory settings in humans. The aim of this study was to examine the discriminative stimulus, subject-rated, performance, and cardiovascular effects of methamphetamine in humans. In the present study, subjects first learned to discriminate 10 mg of oral methamphetamine from placebo. After acquiring the discrimination (≥80% drug-appropriate responding on four consecutive sessions), a range of oral doses of methamphetamine (2.5-15 mg), d-amphetamine (2.5-15 mg), methylphenidate (5-30 mg), and triazolam (0.0625-0.375 mg) was tested. Methamphetamine functioned as a discriminative stimulus and produced prototypical stimulant-like subject-rated effects. d-Amphetamine and methylphenidate produced dose-related increases in methamphetamine-appropriate responding, whereas triazolam did not. d-Amphetamine and methylphenidate produced stimulant-like behavioral effects, whereas triazolam produced sedative-like effects. Methamphetamine, but no other drug, increased heart rate, systolic pressure, and diastolic pressure significantly above placebo levels. Performance in the Digit-Symbol Substitution Test was not affected by any of the drugs tested. Overall, these results demonstrate that the acute behavioral effects of methamphetamine, d-amphetamine, and methylphenidate overlap extensively in humans, which is concordant with findings from preclinical studies. Future studies should assess whether the similarity in the behavioral effects of methamphetamine and related stimulants can be extended to other behavioral assays, such as measures of reinforcement, in humans.

Alprazolam attenuates the behavioral effects of d-amphetamine in humans.

Abstract: The results of preclinical behavioral pharmacology studies suggest that γ-aminobutyric acidA (GABAA) receptor modulators attenuate the behavioral effects of commonly abused stimulants such as amphetamines and cocaine under a variety of behavioral arrangements including drug discrimination and self-administration. In the present experiment, 6 healthy humans learned to discriminate 15-mg oral d-amphetamine. After acquiring the discrimination (ie, ≥80% correct responding on 4 consecutive days), the effects of a range of doses of d-amphetamine (0, 2.5, 5, 10, and 15 mg), alone and following pretreatment with alprazolam (0 and 0.5 mg), a GABAA receptor modulator, were assessed. d-Amphetamine alone functioned as a discriminative stimulus and produced stimulant-like self-reported drug effects (eg, increased scores on a Stimulant-Sensitive Adjective-Rating Scale). These effects were generally a function of dose. Alprazolam alone did not occasion d-amphetamine-like discriminative stimulus effects, nor did it increase ratings of sedation or impair performance. Alprazolam pretreatment significantly attenuated the discriminative stimulus effects of d-amphetamine, and some of the self-reported drug effects. Future human laboratory experiments should compare the behavioral effects of d-amphetamine alone and following pretreatment with alprazolam using other behavioral arrangements such as drug self-administration. Future laboratory experiments with humans should also determine if benzodiazepines with lower abuse potential (eg, oxazepam) might also attenuate the behavioral effects of d-amphetamine.