Investigating sex differences and the effect of drug exposure order in the sensory reward-enhancing effects of nicotine and d-amphetamine alone and in combination.

Nicotine enhances the rewarding effects of other environmental stimuli; this reward-enhancement encourages and maintains nicotine consumption. Nicotine use precedes other psychostimulant use, but receiving a stimulant prescription also predicts future smoking. Previously, no study has investigated effects of drug exposure order in reward-enhancement, nor with nicotine and d-amphetamine. Thus, we aimed to investigate how drug exposure order impacted the reward-enhancing effects of nicotine and d-amphetamine, alone and in combination. We used 20 male and 20 female Sprague-Dawley rats. Enhancement was investigated within-subjects by examining responding maintained by a visual stimulus reinforcer following a pre-session injection of either d-amphetamine (Sal, 0.1, 0.3, or 0.6 mg/kg) or nicotine (Sal, 0.03, 0.06, 0.1, 0.3 mg/kg). Twenty rats (10 M, 10 F) completed enhancement testing with nicotine before d-amphetamine. The other 20 rats (10 M, 10 F) completed testing with d-amphetamine before nicotine. Following these phases, rats were then given two pre-session injections: one of d-amphetamine (Sal, 0.1, 0.3, or 0.6 mg/kg) and another of nicotine (Sal, 0.03, 0.06, 0.1, or 0.3 mg/kg). Experiencing amphetamine before nicotine increased reward-enhancing effects of nicotine. Females exhibited greater effects of d-amphetamine on reward-enhancement, with no effect of exposure order. During the interaction phase, receiving nicotine before amphetamine enhanced the interaction between nicotine and d-amphetamine for females whereas amphetamine before nicotine heightened this interaction for males. From this, prior and current amphetamine use, in addition to sex, should be considered when treating nicotine dependency and when examining factors driving poly-substance use involving nicotine and d-amphetamine. Keywords: Adderall, ADHD, Dexedrine, operant, smoking, polysubstance use.

Pharmacologic treatment of attention deficit hyperactivity disorder in adults: A systematic review and network meta-analysis.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) affects approximately 3% of adults globally. Many pharmacologic treatments options exist, yet the comparative benefits and harms of individual treatments are largely unknown. We performed a systematic review and network meta-analysis to assess the relative effects of individual pharmacologic treatments for adults with ADHD. METHODS: We searched English-language published and grey literature sources for randomized clinical trials (RCTs) involving pharmacologic treatment of ADHD in adults (December 2018). The primary outcome was clinical response; secondary outcomes were quality of life, executive function, driving behaviour, withdrawals due to adverse events, treatment discontinuation, serious adverse events, hospitalization, cardiovascular adverse events, and emergency department visits. Data were pooled via pair-wise meta-analyses and Bayesian network meta-analyses. Risk of bias was assessed by use of Cochrane's Risk of Bias tool, and the certainty of the evidence was assessed by use of the GRADE framework. RESULTS: Eighty-one unique trials that reported at least one outcome of interest were included, most of which were at high or unclear risk of at least one important source of bias. Notably, only 5 RCTs were deemed at overall low risk of bias. Included pharmacotherapies were methylphenidate, atomoxetine, dexamfetamine, lisdexamfetamine, guanfacine, bupropion, mixed amphetamine salts, and modafinil. As a class, ADHD pharmacotherapy improved patient- and clinician-reported clinical response compared with placebo (range: 4 to 15 RCTs per outcome); however, these findings were not conserved when the analyses were restricted to studies at low risk of bias, and the certainty of the finding is very low. There were few differences among individual medications, although atomoxetine was associated with improved patient-reported clinical response and quality of life compared with placebo. There was no significant difference in the risk of serious adverse events or treatment discontinuation between ADHD pharmacotherapies and placebo; however, the proportion of participants who withdrew due to adverse events was significantly higher among participants who received any ADHD pharmacotherapy. Few RCTs reported on the occurrence of adverse events over a long treatment duration. CONCLUSIONS: Overall, despite a class effect of improving clinical response relative to placebo, there were few differences among the individual ADHD pharmacotherapies, and most studies were at risk of at least one important source of bias. Furthermore, the certainty of the evidence was very low to low for all outcomes, and there was limited reporting of long-term adverse events. As such, the choice between ADHD pharmacotherapies may depend on individual patient considerations, and future studies should assess the long-term effects of individual pharmacotherapies on patient-important outcomes, including quality of life, in robust blinded RCTs. REGISTRATION: PROSPERO no. CRD 42015026049.

Pharmacokinetics of Sustained-Release Oral Dexamphetamine Sulfate in Cocaine and Heroin-Dependent Patients.

INTRODUCTION: Research has shown that sustained-release (SR) dexamphetamine is a promising agonist treatment for cocaine dependence. However, little is known about the pharmacokinetics (PKs) of SR oral dexamphetamine. This study examined the PKs of a new SR dexamphetamine formulation in cocaine plus heroin-dependent patients currently in heroin-assisted treatment. METHODS: The study was designed as an open-label PK study in 2 cohorts: n = 5 with once daily 60 mg and n = 7 with once daily 30 mg SR oral dexamphetamine. Five days of blood plasma dexamphetamine concentrations measured with liquid chromatography-mass spectrometry with PK parameter estimates using noncompartmental analysis. RESULTS: Twelve cocaine-dependent plus heroin-dependent patients in heroin-assisted treatment were included. The initial cohort 1 dose of 60 mg once daily was adjusted to 30 mg after mild to moderate adverse events. After oral administration, tmax values (coefficient of variation %) were 6.0 (17.0%) and 6.3 (16.3%) hours and t1/2 were 11 (24.6%) and 12 (25.4%) hours for 60 mg and 30 mg SR dexamphetamine, respectively. At steady state, CSSmax values were reached at 100 (27.5%) ng/mL and 58.4 (14.4%) ng/mL, whereas CSSmin values were 39.5 (38.9%) ng/mL and 21.8 (19.8%) ng/mL for 60 mg and 30 mg, respectively. CONCLUSIONS: The investigated SR formulation of dexamphetamine showed favorable slow-release characteristics in cocaine and heroin-dependent patients. A dose-proportional steady-state concentration was achieved within 3 days. These findings support the suitability of the SR formulation in the treatment of cocaine dependence.

Sustained-release dexamfetamine in the treatment of chronic cocaine-dependent patients on heroin-assisted treatment: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Heroin-assisted treatment is effective for methadone treatment-refractory heroin-dependent patients, but continued comorbid cocaine dependence remains problematic. Sustained-release dexamfetamine is a promising agonist pharmacotherapy for cocaine dependence and we aimed to assess its acceptance, efficacy, and safety. METHODS: In this multicentre, randomised, double-blind, placebo-controlled trial, patients who were treatment-refractory, as indicated by at least two earlier failed treatments aimed at reducing or abstaining from cocaine use, and who regularly (≥8 days/month) used crack-cocaine were enrolled from four heroin-assisted treatment centres in the Netherlands. Eligible patients were randomly assigned (1:1) to receive either 12 weeks of daily, supervised prescription of 60 mg/day oral sustained-release dexamfetamine or placebo in addition to co-prescribed methadone and diacetylmorphine. Randomisation was done by the collaborating pharmacist, using a computer-generated random number sequence with stratification by treatment centre in blocks of four per stratum. Randomisation was masked to patients, staff, and researchers throughout the study. The primary outcome was the number of self-reported days of cocaine use during study treatment, assessed every 4 weeks. Primary and safety analyses were done in the intention-to-treat population. The study was registered with the European Union Drug Regulating Authorities Clinical Trials (EUdraCT 2013-004024-11) and with The Netherlands Trial Register (NTR2576). FINDINGS: Between Aug 8, 2014, and Feb 27, 2015, 111 patients were assessed for eligibility, of whom 73 were enrolled and randomised; 38 patients were assigned to the sustained-release dexamfetamine group and 35 to the placebo group. Sustained-release dexamfetamine treatment resulted in significantly fewer days of cocaine use than placebo treatment (mean 44·9 days [SD 29·4] vs 60·6 days [24·3], respectively [95% CI of difference 3·1-28·4]; p=0·031; Cohen's standardised effect size d=0·58). One or more adverse events were reported by 28 (74%) patients in the dexamfetamine group and by 16 (46%) patients in the placebo group. Most adverse events were transient and well-tolerated. INTERPRETATION: Sustained-release dexamfetamine is a well accepted, effective, and safe agonist pharmacotherapy for comorbid treatment-refractory cocaine dependence in heroin-dependent patients in heroin-assisted treatment. Future research should aim to replicate these findings in chronic cocaine-dependent and other stimulant-dependent patients in more routine treatment settings, including strategies to optimise treatment adherence like medication management interventions and contingency management. FUNDING: Netherlands Organisation for Health Research and Development.

Influence of calcium channel antagonists on nonsomatic signs of nicotine and D-amphetamine withdrawal in mice.

BACKGROUND: Nonsomatic signs of psychostimulant withdrawal, difficult to demonstrate in animal paradigms, may appear to promote drug seeking and drug relapse in humans; thus, it is important to understand the mechanisms that mediate this kind of behaviors. The present study was undertaken to examine the calcium-dependent mechanism of negative nonsomatic and anhedonia-related symptoms of acute and protracted withdrawal of nicotine and D-amphetamine. METHODS: Mice were chronically treated with nicotine (seven days, three times daily, 3.35 mg/kg, sc) or D-amphetamine (14 days, once daily, 2.5mg/kg, ip). Then, at the first, seventh or 14th day of withdrawal, anxiety- or depression-related effects, as well as cognition or nociception were studied. RESULTS: Our results demonstrated that, at the seventh or 14th day of D-amphetamine or nicotine withdrawal, respectively, mice exhibited increased anxiety and depression-like effects, memory impairment and hyperalgesia. Further, major findings showed that calcium channel antagonists, i.e., nimodipine, verapamil and flunarizine (10 and 20mg/kg, ip), injected before the test, attenuated above-mentioned signs of drug withdrawal. CONCLUSIONS: As an outcome, these findings support the hypothesis that similar calcium-dependent mechanisms are involved in an aversive nonsomatic component, associated with nicotine or d-amphetamine withdrawal. We can suggest that calcium channel blockers have potential to alleviate drug withdrawal and may thus be beneficial as pharmacotherapy of drug cessation and relapse.

Lisdexamfetamine dimesylate in the treatment of attention-deficit/hyperactivity disorder: pharmacokinetics, efficacy and safety in children and adolescents / Dimesilato de lisdexanfetamina no tratamento do transtorno do déficit de atenção e hiperatividade: farmacocinética, eficácia e segurança em crianças e adolescentes

Background: Psychostimulants (methylphenidate and amphetamines) are considered first-line therapy for attention-deficit/hyperactivity disorder (ADHD). Lisdexamfetamine dimesylate (LDX) is a new psychostimulant approved for the treatment of ADHD in Brazil. The pharmacologically active fraction, d-amphetamine, is gradually released by hydrolysis of the LDX prodrug. Objectives: To perform a systematic review of the literature of the efficacy and safety of LDX in the treatment of ADHD in children and adolescents. Methods: Medline/PubMed searches for “d-amfetamine”, “lisdexamfetamine” and “lisdexamfetamine dimesylate” were conducted including articles available from January 2000 to November 2013. Additional references were identified using references listed in those articles. Further data on LDX were requested from its manufacturer. Results: Thirty-one papers were found related to ADHD treatment in children and adolescents. Discussion: The therapeutic benefits of LDX in children with ADHD are achieved as early as 1.5 hours after its administration and last for up to 13 hours, with efficacy comparable or superior to that of other available psychostimulants. The literature also reports efficacy in long-term treatment, with safety and tolerability profiles comparable to those of other stimulants used for the treatment of ADHD. Most of the adverse events associated with LDX are considered to be mild or moderate in severity, with the most common being loss of appetite and insomnia...

Contexto: Psicoestimulantes (metilfenidato e anfetaminas) são considerados como tratamento farmacológico de primeira linha no tratamento do transtorno do déficit de atenção e hiperatividade (TDAH). O dimesilato de anfetamina é um novo psicoestimulante aprovado para uso no Brasil, cuja fração farmacologicamente ativa, a d-anfetamina, é gradualmente liberada por hidrólise da pró-droga. Objetivos Realizar uma revisão sistemática de literatura sobre eficácia e segurança da LDX no tratamento de TDAH de crianças e adolescentes. Métodos: Busca na base Medline/PubMed com os termos “d-amfetamine”, “lisdexamfetamine” e “lisdexamfetamine dimesilate”, de janeiro de 2000 até novembro de 2013. Referências adicionais foram retiradas das referências dos artigos obtidos; dados também foram obtidos do fabricante. Resultados: Trinta e um artigos foram encontrados, relacionados ao tratamento de TDAH em crianças e adolescentes. Conclusões: Os benefícios terapêuticos da LDX são obtidos em até 1,5 hora após administração e se estendem até 13 horas, com eficácia comparável ou superior à dos demais psicoestimulantes disponíveis. A literatura também documenta eficácia em longo prazo, com perfis de segurança e tolerabilidade comparáveis aos dos demais estimulantes usados no tratamento do TDAH. A maioria dos eventos adversos associados à LDX é considerada leve ou moderada quanto à gravidade, sendo os eventos mais comuns perda de apetite e insônia...

A case of rhabdomyolysis in the presence of multiple risk factors and dextroamphetamine use.

A 44-year-old Caucasian woman presented to the emergency room with worsening low back pain and loss of cutaneous sensation over the paraspinal muscles from T10 to S1. The patient had ingested the attention-deficit disorder medication dextroamphetamine before engaging in intense physical exercise with subsequent consumption of 3 alcoholic beverages before developing symptoms. The patient's creatine kinase levels remained elevated for 8 days with constant severe pain under standard treatment for rhabdomyolysis. Despite stabilization of pain and laboratory values at discharge, the patient continues to experience low paraspinal back pain. In patients with risk factors for rhabdomyolysis, the use of dextroamphetamine should be monitored closely. Outside our findings, there is no literature linking dextroamphetamine with rhabdomyolysis at nontoxic concentrations or with use of the supplement caffeine containing weight loss supplement, Hydroxycut. The authors believe that further research into the potential role of dextroamphetamine use in the setting of other risk factors for rhabdomyolysis is warranted.

Ingestion of stimulant medications does not alter bispectral index or clinical depth of anesthesia at 1 MAC sevoflurane in children.

BACKGROUND/AIM: Children treated with stimulant medications for the behavioral management of attention deficit hyperactivity disorder (ADHD) may present for elective surgery. Stimulant medication is often continued until the morning of surgery to optimize perioperative behavior. It is unknown whether such stimulant drug ingestion can affect cerebral arousal and alter depth of anesthesia. A clinically relevant alteration in measured depth of anesthesia could form the basis for an evidence-based recommendation that children taking stimulant medications require a change in the amount of anesthetic delivered or that they require routine monitoring of depth of anesthesia. MATERIALS AND METHODS: Thirty-four ASA 1 and 2 children aged between 5 and 16, presenting for elective day case surgery, were recruited. Seventeen had a diagnosis of ADHD and had taken stimulant medication on the day of surgery, and 17 were controls. A standard inhalational induction of anesthesia using air, oxygen, and sevoflurane by facemask was performed and maintained for 10 min at 1 MAC endtidal sevoflurane. During this time, no other stimulus was applied to the patient. Bispectral index (BIS) and other markers of depth of anesthesia were recorded after 10 min. RESULTS: Children in both groups were of similar ages and weights. There were a higher percentage of boys in the stimulants group. Baseline physiological parameters were similar in both groups. After induction and equilibration for 10 min of anesthesia at 1 MAC endtidal sevoflurane, there was no significant difference in BIS or clinical markers of depth of anesthesia. CONCLUSIONS: Children taking stimulant medication for ADHD, and who ingest medication on the day of surgery, do not appear to have altered BIS or depth of anesthesia at 1 MAC of sevoflurane. These results do not support a recommendation for a change in anesthetic practice for children having ingested stimulants up to the day of surgery, either in terms of increasing the amount of anesthetic given or monitoring of depth.

Eosinophilic hepatitis in an adolescent during lisdexamfetamine dimesylate treatment for ADHD.

We describe here the case of an adolescent who developed eosinophilic hepatitis during treatment for attention-deficit/hyperactivity disorder with lisdexamfetamine dimesylate (Vyvanse [Shire US Inc, Wayne, PA]). A 14-year-old boy presented to his primary care provider with abdominal pain and worsening jaundice. A diagnosis of hepatitis was made with biochemical markers, but evaluation failed to provide an etiology. Worsening hepatitis prompted hospitalization and initiation of steroids for presumed autoimmune hepatitis. A subsequent liver biopsy showed evidence of eosinophilic hepatitis. Known causes of eosinophilic hepatitis were ruled out, and a presumptive diagnosis of reaction to lisdexamfetamine dimesylate was made. Discontinuation of the medication led to resolution of the hepatitis and normalization of the liver biopsy. To our knowledge, this is the first report of hepatic injury attributed to lisdexamfetamine dimesylate.

'Kiddie drugs' and controlled pleasure: recreational use of dexamphetamine in a social network of young Australians.

BACKGROUND: This article explores the recreational use of diverted dexamphetamine, a pharmaceutical stimulant, amongst a social network of young adults (aged 18-31 years) in Perth, Western Australia (WA). Prior epidemiological research indicates that there are high levels of dexamphetamine prescription, and use of diverted dexamphetamine, in this jurisdiction. Little research exists on the social contexts of diverted dexamphetamine use in Australia or overseas. METHODS: Ethnographic fieldwork was conducted over 18 months amongst a network of approximately 60 young adults who regularly used psychostimulants. Data collection involved participant observation conducted in natural settings including nightclubs and private parties. In-depth interviews were also conducted with 25 key contacts which explored drug use histories and themes emerging from fieldwork. RESULTS: The use of diverted dexamphetamine, or 'dexies', was prevalent amongst the social network and integrated into local drug practices. The paper explores the ways in which dexamphetamine use is rationalised, negotiated and represented in the context of the use of alcohol and other psychostimulants such as methamphetamine and ecstasy. Two key aspects are emphasised. First, dexamphetamine use is seen as insignificant by network members and is positioned as 'safer' in relation to the use of other drugs by virtue of its pharmaceutical status. Second, dexamphetamine plays an instrumental role in facilitating the pursuit of 'controlled pleasure' via the heavy consumption of alcohol and other drugs. CONCLUSION: The findings of the paper have implications for harm reduction policy. In particular, dexamphetamine use facilitates heavy drinking and polydrug use amongst young adults, which may increase the harms associated with such use. Further, current interventions targeting young psychostimulant users, which emphasise their adulterated and illegal nature, may inadvertently contribute to the cultural construction of dexamphetamine as a relatively 'safe' drug.

A randomized, double-blind, placebo-controlled trial assessing the impact of dexamphetamine on fatigue in patients with advanced cancer.

Fatigue is very common in patients with cancer. Current guidelines suggest that psychostimulants are "reasonable to consider for severe fatigue." This randomized, double-blind, placebo-controlled trial investigated the hypothesis that dexamphetamine in fatigued patients with advanced cancer would produce a clinically significant improvement with minimal side effects. Fifty patients with advanced cancer, who were receiving palliative care, were randomized to dexamphetamine 10mg twice daily or placebo for eight days. Effectiveness was assessed using the Brief Fatigue Inventory and the McGill Quality-of-Life Questionnaire. The side effects were recorded. The results were analyzed on an intention-to-treat basis. The baseline demographics, fatigue levels, and quality-of-life scores were similar between the two arms. Patients were elderly, had impaired performance status (Eastern Cooperative Oncology Group score=3), and were taking a range of neurologically active medications. Thirty-nine patients completed the trial. There was a transient improvement in the fatigue levels on day 2, but no significant difference in fatigue (P=0.267) or quality of life (P=0.579) by the end of the study. Statistical modeling did not reveal any significant predictors of response to dexamphetamine. These results suggest that dexamphetamine 20mg daily, although well tolerated, does not significantly improve fatigue or quality of life in patients with advanced cancer, as measured by the selected instruments.

Methylphenidate and dextroamphetamine-induced peripheral vasculopathy.

Methylphenidate and dextroamphetamine are central nervous system stimulants used in the treatment of attention deficit hyperactivity disorders in children. These medications have been associated with cerebral arteritis, renal necrotizing vasculitis, and systemic and pulmonary hypertension. We report 4 patients, 2 on methylphenidate and 2 on dextroamphetamine who presented with acral cyanosis, livedo reticularis, or Raynaud phenomenon. Two patients were found to have a positive ANA at low titers, 1 of whom had histopathologic evidence of stratum malgiphian necrosis with perivascular lymphocytic infiltration on skin biopsy. Two had positive antihistone antibodies. One patient improved after withdrawal of dextroamphetamine; others had worsening of their symptoms on higher doses of medications. These cases indicate the potential for development of acral cyanosis, livedo reticularis, or Raynaud symptoms with these medications and their potential contribution to a vasculopathy.

Interference with smoking-cessation effects of varenicline after administration of immediate-release amphetamine-dextroamphetamine.

An 18-year-old man with attention-deficit-hyperactivity disorder (ADHD) was prescribed varenicline for smoking cessation. He quit smoking after 1 week of therapy and remained smoke free for the next 17 days. During that time, he had also been taking amphetamine-dextroamphetamine (Adderall) on work days for his ADHD. Because his supply of amphetamine-dextroamphetamine was diminishing, he took only half (30 mg every morning) of his prescribed dosage from days 4-12 of varenicline therapy. He further reduced his dosage to 15 mg every morning on days 13 and 14 of varenicline therapy, and his supply of amphetamine-dextroamphetamine was depleted on day 15. On day 23 of varenicline therapy, he received and filled a new prescription for amphetamine-dextroamphetamine and resumed his prescribed dosage (30 mg twice/day). He began smoking again within 48 hours. Rechallenge with varenicline while the patient continued to receive amphetamine-dextroamphetamine yielded similar results. Data suggest that addition of amphetamine to varenicline may negate the partial agonism of varenicline, resulting in elimination of the smoking-cessation aid's benefits. Other potential mechanisms for the drug interaction may also exist. Thus, varenicline may not aid smoking cessation in patients undergoing treatment with amphetamine and amphetamine-like drugs.

Quantification of phosphorylated cAMP-response element-binding protein expression throughout the brain of amphetamine-sensitized rats: activation of hypothalamic orexin A-containing neurons.

In the present study, using rats, we have examined acute, contextual, and sensitized patterns of activated or phosphorylated cAMP response element-binding protein (pCREB) expression in parallel, assaying across multiple nuclei that have been implicated in addiction. The paradigm used included a comparison of pretreatment dose of amphetamine upon patterns of cellular activation, following rechallenge. Because efferent orexinergic projections synapse on many targets through the mammalian brain, including mesotelencephalic regions and limbic systems involved in drug reward and reinforcement, we examined for coexpression of pCREB or c-Fos double labeling within orexin A-immunopositive neurons following sensitization. Acute challenge with amphetamine (1.5 mg/kg i.p.) resulted in an increase in the number of pCREB-immunoreactive (-IR) cells within the substantia nigra but a decrease of pCREB-IR cells in the central and medial subnuclei of the amygdala. Contextual re-exposure to the drug treatment environment altered pCREB expression, particularly in the basal ganglia and hypothalamus, although these effects were dictated by pretreatment dose of amphetamine. Sensitization to amphetamine resulted in robust increases in pCREB-IR cell numbers in the basal ganglia and lateral septum of rats that had been pretreated with high-dose (10 mg/kg i.p.) but not low-dose (2 mg/kg i.p.) amphetamine, despite a similar behavioral response. Orexin A-containing cells in the hypothalamus of sensitized rats did not coexpress pCREB; however, these cells double-labeled for c-Fos and orexin A. These data suggest that orexinergic neurons are activated during the expression of behavioral sensitization, although in a heterogenous manner with regard to afferent topologies and functional roles in the nervous system.

Agonist-like or antagonist-like treatment for cocaine dependence with methadone for heroin dependence: two double-blind randomized clinical trials.

Concurrent abuse of cocaine and heroin is a common problem. Methadone is effective for opioid dependence. The question arises as to whether combining agonist-like or antagonist-like medication for cocaine with methadone for opioid dependence might be efficacious. Two parallel studies were conducted. One examined sustained release d-amphetamine and the other risperidone for cocaine dependence, each in combination with methadone. In total, 240 subjects (120/study) were recruited, who were both cocaine and heroin dependent and not currently receiving medication. All provided consent. Both studies were carried out for 26 weeks, randomized, double-blind and placebo controlled. Study I compared sustained release d-amphetamine (escalating 15-30 or 30-60 mg) and placebo. Study II examined risperidone (2 or 4 mg) and placebo. All subjects underwent methadone induction and were stabilized at 1.1 mg/kg. Subjects attended clinic twice/week, provided urine samples, obtained medication take-home doses for intervening days, and completed self-report measures. Each had one behavioral therapy session/week. In Study I, reduction in cocaine use was significant for the 30/60 mg dose compared to the 15/30 mg and placebo. Opioid use was reduced in all groups with a trend toward greater reduction in the 30/60 mg d-amphetamine group. In Study II, methadone reduced illicit opioid use but cocaine use did not change in the risperidone or placebo groups. There were no adverse medication interactions in either study. The results provide support for the agonist-like (d-amphetamine) model in cocaine dependence treatment but not for antagonist-like (risperidone) treatment. They coincide with our previous reports of amphetamine or risperidone administered singly in cocaine-dependent individuals.

Amphetamine withdrawal modulates FosB expression in mesolimbic dopaminergic target nuclei: effects of different schedules of administration.

Different patterns of psychostimulant intake can elicit widely varying behavioral and neurochemical consequences. Accordingly, rats were studied during withdrawal from either of two schedules of amphetamine administration, one consisting of 6 days of low-dose (1.5 mg/kg, i.p.) daily intermittent (INT) amphetamine (AMPH) injections, and the other of 6 days of moderately high-dose (1-5 mg/kg, i.p.) escalating (ESC) AMPH injections, for the effects of these treatments on numbers of FosB-positive nuclei and monoamine utilization in dopaminergic target areas. Withdrawal from AMPH pretreatment according to the ESC schedule markedly increased FosB expression in the nucleus accumbens shell and basolateral amygdala. In contrast, withdrawal from INT-AMPH administration did not increase FosB expression in any of the regions examined. Post-mortem neurochemical analyses of these same brain regions did not reveal effects of withdrawal from either INT or ESC administration of AMPH. These results suggest that withdrawal from a moderately high-dose AMPH regimen modifies patterns of gene expression in mesocorticolimbic dopaminergic target nuclei without significantly affecting basal monoamine levels. The strength of these effects in the nucleus accumbens shell and basolateral nucleus of the amygdala are consistent with behavioral and clinical data indicating the importance of these areas in the neuroadaptive changes which characterize addiction and withdrawal states.

Two unusual cases of toxic epidermal necrolysis.

Two cases of toxic epidermal necrolysis (TEN) are presented. A 27-year-old woman presented with peripherally located targetoid plaques, papules, blisters and lip erosions which began 9 days after 'recreational' use of 'speed' (dexamphetamine and ephedrine) consistent with erythema multiforme major. Three days later she developed widespread lesions with large areas of blistering affecting 40% of body surface area. The diagnosis was revised to TEN. Intravenous cyclosporin led to rapid prevention of new blister formation. A 71-year-old woman, 3 months after commencing amiodarone, developed extensive erythema, blistering and erosions affecting 50% of body surface area, with a maculopapular rash affecting the limbs and extremities consistent with a diagnosis of TEN. She developed septicaemia following bilateral pneumonia with pleural effusions and died 7 days after admission.

Psychostimulants in supportive care.

Psychostimulant medications have been used clinically and investigated in psychiatric populations, the medically ill, cancer patients and healthy people. This article discusses the pharmacology of dextroamphetamine, methylphenidate, pemoline (and other psychostimulants such as caffeine and ephedrine), their use in general medicine and cancer care, side effects, and abuse potential. Therapeutic use in children is addressed only insofar as it illustrates facets of their use in adults.

Acute effects of d-amphetamine during the early and late follicular phases of the menstrual cycle in women.

Recent preclinical evidence indicates that ovarian hormones, such as estrogen and progesterone, may influence the behavioral effects of psychoactive drugs by interacting directly with neurotransmitter systems in the central nervous system. However, few studies have examined the effects of ovarian hormones on subjective or behavioral responses to psychoactive drugs in humans. In the present study, we assessed the subjective and physiological effects of d-amphetamine during the early and late follicular phases of the menstrual cycle. Nineteen healthy, regularly-cycling women participated in four sessions receiving doses of d-amphetamine (AMPH; 15 mg oral) or placebo during the early and late follicular phases of two menstrual cycles. During the early follicular phase levels of both estrogen and progesterone are low, whereas during the late follicular phase estrogen levels are higher while progesterone remains low. Dependent measures included self-report questionnaires, physiological measures and plasma hormone levels. Most of the subjective and physiological effects of AMPH were not affected by menstrual cycle phase. However, subjects reported greater Unpleasant Stimulation after AMPH, and less Unpleasant Sedation, during the late follicular phase than during the early follicular phase. These results provide limited evidence that higher levels of estrogen during the late follicular phase alter the subjective effects of AMPH in normal, healthy women.