-
Journal of Psychopharmacology (Oxford,... Feb 2023Fatigue remains an important factor in major aviation accidents. Stimulants may counteract fatigue's adverse effects, with modafinil as a promising alternative to... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Fatigue remains an important factor in major aviation accidents. Stimulants may counteract fatigue's adverse effects, with modafinil as a promising alternative to caffeine. However, the effect of a single dose of modafinil after a limited period of sleep deprivation remains unknown.
AIMS
This study aims to determine the effect of 200 mg modafinil on vigilance during a limited period of sleep deprivation compared to 300 mg caffeine and placebo.
METHODS
Thirty-two volunteers of the Royal Netherlands Air Force (RNLAF) were double-blindly administered modafinil, caffeine, and placebo on three non-consecutive trial days after being awake for median 17 h. Afterwards, subjects completed six series of the Vigilance and Tracking test (VigTrack), psychomotor vigilance task (PVT), and Stanford Sleepiness Scale (SSS), yielding six primary endpoints.
RESULTS
This study revealed statistically significant effects of caffeine and modafinil compared with placebo on all endpoints, except for VigTrack mean tracking error. PVT results were less impaired 2 h after administration, followed by VigTrack parameters and SSS scores 2 h thereafter. Compared with caffeine, modafinil significantly improved PVT and SSS scores at 8 h after administration.
CONCLUSIONS
The present study demonstrates that 200 mg modafinil and 300 mg caffeine significantly decrease the effects of a limited period of sleep deprivation on vigilance compared with placebo. Although PVT parameters already improved 2 h after administration, the most notable effects occurred 2-4 h later. Modafinil seems to be effective longer than caffeine, which is consistent with its longer half-life.
Topics: Humans; Modafinil; Caffeine; Wakefulness; Sleep Deprivation; Benzhydryl Compounds; Psychomotor Performance; Central Nervous System Stimulants; Fatigue; Sleepiness; Double-Blind Method
PubMed: 36515156
DOI: 10.1177/02698811221142568 -
The Journal of Pharmacology and... Mar 2023Although there are no Food and Drug Administration-approved treatments for cocaine use disorder, several modafinil analogs have demonstrated promise in reducing cocaine...
Although there are no Food and Drug Administration-approved treatments for cocaine use disorder, several modafinil analogs have demonstrated promise in reducing cocaine self-administration and reinstatement in rats. Furthermore, the range of dopamine transporter (DAT) compounds provides an opportunity to develop pharmacotherapeutics without abuse liability. This study extended the comparison of JJC8-088 and JJC8-091, the former compound having higher DAT affinity and predicted abuse liability, to rhesus monkeys using a concurrent cocaine versus food schedule of reinforcement. First, binding to striatal DAT was examined in cocaine-naïve monkey tissue. Next, intravenous pharmacokinetics of both JJC compounds were evaluated in cocaine-experienced male monkeys ( = 3/drug). In behavioral studies, acute and chronic administration of both compounds were evaluated in these same monkeys responding under a concurrent food versus cocaine (0 and 0.003-0.1 mg/kg per injection) schedule of reinforcement. In nonhuman primate striatum, JJC8-088 had higher DAT affinity compared with JJC8-091 (14.4 ± 9 versus 2730 ± 1270 nM, respectively). Both JJC compounds had favorable plasma pharmacokinetics for behavioral assessments, with half-lives of 1.1 hours and 3.5 hours for JJC8-088 (0.7 mg/kg, i.v.) and JJC8-091 (1.9 mg/kg, i.v.), respectively. Acute treatment with both compounds shifted the cocaine dose-response curve to the left. Chronic treatment with JJC8-088 decreased cocaine choice in two of the three monkeys, whereas JJC8-091 only modestly reduced cocaine allocation in one monkey. Differences in affinities of JJC8-091 DAT binding in monkeys compared with rats may account for the poor rodent-to-monkey translation. Future studies should evaluate atypical DAT blockers in combination with behavioral interventions that may further decrease cocaine choice. SIGNIFICANCE STATEMENT: Cocaine use disorder (CUD) remains a significant public health problem with no Food and Drug Administration-approved treatments. The ability of drugs that act in the brain in a similar manner to cocaine, but with lower abuse liability, has clinical implications for a treatment of CUD.
Topics: Male; Rats; Animals; Cocaine; Dopamine Plasma Membrane Transport Proteins; Macaca mulatta; Dopamine Uptake Inhibitors; Self Administration; Dose-Response Relationship, Drug
PubMed: 36507847
DOI: 10.1124/jpet.122.001363 -
The Cochrane Database of Systematic... Nov 2022Cognitive deficits are common in people who have received cranial irradiation and have a serious impact on daily functioning and quality of life. The benefit of... (Review)
Review
BACKGROUND
Cognitive deficits are common in people who have received cranial irradiation and have a serious impact on daily functioning and quality of life. The benefit of pharmacological and non-pharmacological treatment of cognitive deficits in this population is unclear. This is an updated version of the original Cochrane Review published in Issue 12, 2014.
OBJECTIVES
To assess the effectiveness of interventions for preventing or ameliorating cognitive deficits in adults treated with cranial irradiation.
SEARCH METHODS
For this review update we searched the Cochrane Register of Controlled Trials (CENTRAL), MEDLINE via Ovid, Embase via Ovid, and PsycInfo via Ovid to 12 September 2022.
SELECTION CRITERIA
We included randomised controlled (RCTs) trials that evaluated pharmacological or non-pharmacological interventions in cranial irradiated adults, with objective cognitive functioning as a primary or secondary outcome measure.
DATA COLLECTION AND ANALYSIS
Two review authors (MK, JD) independently extracted data from selected studies and carried out a risk of bias assessment. Cognitive function, fatigue and mood outcomes were reported. No data were pooled.
MAIN RESULTS
Eight studies met the inclusion criteria and were included in this updated review. Six were from the original version of the review, and two more were added when the search was updated. Nineteen further studies were assessed as part of this update but did not fulfil the inclusion criteria. Of the eight included studies, four studies investigated "prevention" of cognitive problems (during radiotherapy and follow-up) and four studies investigated "amelioration" (interventions to treat cognitive impairment as a late complication of radiotherapy). There were five pharmacological studies (two studies on prevention and three in amelioration) and three non-pharmacological studies (two on prevention and one in amelioration). Due to differences between studies in the interventions being evaluated, a meta-analysis was not possible. Studies in early radiotherapy treatment phase (five studies) Pharmacological studies in the "early radiotherapy treatment phase" were designed to prevent or ameliorate cognitive deficits and included drugs used in dementia (memantine) and fatigue (d-threo-methylphenidate hydrochloride). Non-pharmacological studies in the "early radiotherapy treatment phase" included a ketogenic diet and a two-week cognitive rehabilitation and problem-solving programme. In the memantine study, the primary cognitive outcome of memory at six months did not reach significance, but there was significant improvement in overall cognitive function compared to placebo, with similar adverse events across groups. The d-threo-methylphenidate hydrochloride study found no statistically significant difference between arms, with few adverse events. The study of a calorie-restricted ketogenic diet found no effect, although a lower than expected calorie intake in the control group complicates interpretation of the results. The study investigating the utility of a rehabilitation program did not carry out a statistical comparison of cognitive performance between groups. Studies in delayed radiation or late effect phase (four studies) The "amelioration" pharmacological studies to treat cognitive complications of radiotherapy included drugs used in dementia (donepezil) or psychostimulants (methylphenidate and modafinil). Non-pharmacological measures included cognitive rehabilitation and problem solving (Goal Management Training). These studies included patients with cognitive problems at entry who had "stable" brain cancer. The donepezil study did not find an improvement in the primary cognitive outcome of overall cognitive performance, but did find improvement in an individual test of memory, compared to placebo; adverse events were not reported. A study comparing methylphenidate with modafinil found improvements in cognitive function in both the methylphenidate and modafinil arms; few adverse events were reported. Another study comparing two different doses of modafinil combined treatment arms and found improvements across all cognitive tests, however, a number of adverse events were reported. Both studies were limited by a small sample size. The Goal Management Training study suggested a benefit of the intervention, a behavioural intervention that combined mindfulness and strategy training, on executive function and processing speed. There were a number of limitations across studies and few were without high risks of bias.
AUTHORS' CONCLUSIONS
In this update, limited additional evidence was found for the treatment or amelioration of cognitive deficits in adults treated with cranial irradiation. As concluded in the original review, there is supportive evidence that memantine may help prevent cognitive deficits for adults with brain metastases receiving cranial irradiation. There is supportive evidence that donepezil, methylphenidate and modafinil may have a role in treating cognitive deficits in adults with brain tumours who have been treated with cranial irradiation; patient withdrawal affected the statistical power of these studies. Further research that tries to minimise the withdrawal of consent, and subsequently reduce the requirement for imputation procedures, may offer a higher certainty of evidence. There is evidence from only a single small study to support non-pharmacological interventions in the amelioration of cognitive deficits. Further research is required.
Topics: Adult; Humans; Modafinil; Donepezil; Memantine; Quality of Life; Cognitive Dysfunction; Cranial Irradiation; Cognition; Methylphenidate; Brain Neoplasms; Fatigue; Dementia
PubMed: 36427235
DOI: 10.1002/14651858.CD011335.pub3 -
Brain Sciences Nov 2022cocaine craving is a core feature of cocaine use disorder and remains a critical challenge for abstinence and relapse prevention. This review summarizes the anti-craving... (Review)
Review
BACKGROUND
cocaine craving is a core feature of cocaine use disorder and remains a critical challenge for abstinence and relapse prevention. This review summarizes the anti-craving efficacy of pharmacotherapies tested for cocaine use disorder, in the context of randomized-controlled clinical trials.
OBJECTIVES
we assessed the databases of the U.S. National Library of Medicine, Google Scholar, and PsycINFO, without date restrictions up to August 2022, to identify relevant studies.
STUDY ELIGIBILITY CRITERIA, PARTICIPANTS, AND INTERVENTIONS
we included double-blinded randomized-controlled trials investigating pharmacotherapies for cocaine craving and/or cocaine use disorder whose outcomes included cocaine craving.
STUDY APPRAISAL AND SYNTHESIS METHODS
Two authors screened studies' titles and abstracts for inclusion, and both read all the included studies. We systematically gathered information on the following aspects of each study: title; author(s); year of publication; sample size; mean age; sample characteristics; study set-ting; whether participants were treatment-seeking; study design; craving measures; study interventions; drop-out rates; and other relevant outcomes.
RESULTS
Overall, we appraised 130 clinical trials, including 8137 participants. We further considered the drugs from the studies that scored equal to or greater than six points in the quality assessment. There was a correlation between craving and cocaine use outcomes (self-reports, timeline follow-back or urinary benzoylecgonine) in the vast majority of studies. In the short-term treatment, acute phenylalanine-tyrosine depletion, clonidine, fenfluramine, meta-chlorophenylpiperazine (m-CPP) and mecamylamine presented promising effects. In the long term, amphetamine, biperiden, carbamazepine, lisdexamfetamine, lorcaserin, methamphetamine, mirtazapine, pioglitazone, progesterone, guanfacine, levodopa, nefazodone presented promising anti-craving effects. Unfortunately, the highly tested medications were not successful in most of the trials, as follows: propranolol in the short term; amantadine, aripiprazole, bromocriptine, citicoline, ketamine, modafinil, olanzapine, topiramate in the long term. The remaining 52 medications had no positive anti-craving outcomes.
LIMITATIONS
Our review was limited by high heterogeneity of craving assessments across the studies and by a great range of pharmacotherapies. Further, the majority of the studies considered abstinence and retention in treatment as the main outcomes, whereas craving was a secondary outcome and some of the studies evaluated patients with cocaine use disorder with comorbidities such as opioid or alcohol use disorder, schizophrenia, bipolar disorder or attention deficit hyperactivity. Lastly, most of the studies also included non-pharmacological treatments, such as counseling or psychotherapy.
CONCLUSIONS
There is a direct association between craving and cocaine use, underscoring craving as an important treatment target for promoting abstinence among persons with cocaine use disorder. Clonidine, fenfluramine and m-CPP showed to be promising medications for cocaine craving in the short-term treatment, and amphetamine, biperiden, carbamazepine, lisdexamfetamine, lorcaserin, methamphetamine, mirtazapine, pioglitazone, progesterone, guanfacine, levodopa, nefazodone in the long-term treatment.
PubMed: 36421870
DOI: 10.3390/brainsci12111546 -
Frontiers in Public Health 2022Pharmacological neuroenhancement (PN) describes the use of divergent psychoactive substances to enhance mental performance (cognition) without medical need. This kind of...
Pharmacological neuroenhancement (PN) describes the use of divergent psychoactive substances to enhance mental performance (cognition) without medical need. This kind of substance abuse takes place predominantly in stressful situations. Users implicitly-or even explicitly-describe this kind of drug abuse to be a coping strategy. Regarding the decision making process whether to use PN drugs or not, users indicate that legal aspects to be decisive. However, the legal situation has been neglected so far. To elucidate the German legal situation, PN substances have to be divided into over-the-counter drugs, prescription drugs and illegal drugs. Amphetamines have the highest cognition-enhancing potential, followed by modafinil and caffeine-containing substances. It is pointed out that the use of both freely available and prescription PN substances and narcotics without medical indication have so far been largely exempt from punishment under German law. However, individuals (physicians, bus and truck drivers, etc.) taking PN substances may expose others at risk due to wrong decisions (driving or treatment), errors based on side effects of the used substances. Therefore, the protection of life and health of others could legitimize criminal regulation.
Topics: Humans; Criminals; Substance-Related Disorders; Illicit Drugs; Amphetamines; Adaptation, Psychological
PubMed: 36388290
DOI: 10.3389/fpubh.2022.1028654 -
Journal of Clinical Medicine Oct 2022Narcolepsy is a neurological disease characterized by a core symptom of excessive daytime sleepiness (EDS). Although effective pharmacological interventions for...
Narcolepsy is a neurological disease characterized by a core symptom of excessive daytime sleepiness (EDS). Although effective pharmacological interventions for narcolepsy have been developed, a lack of comparative evidence supporting the relative efficacy among these medications leads to clinical treatment challenge. Therefore, we performed a network meta-analysis to overcome this lack of head-to-head comparisons. Databases were searched systematically for randomized controlled trials that compared pharmacological interventions for narcolepsy. The primary outcomes were changes in the Epworth Sleepiness Scale (ESS) and the Maintenance of Wakefulness Test (MWT). A random-effects frequentist network meta-analysis was conducted. A total of 19 RCTs involving 2504 patients were included. Solriamfetol achieved the highest ranking based on the P-scores, and was superior to pitolisant (MD -2.88, 95% CI -4.89--0.88) and sodium oxybate (MD -2.56, 95% CI -4.62--0.51) for ESS change. Consistently, solriamfetol achieved the highest ranking according to MWT change, and was superior to pitolisant (SMD 0.45, 95% CI 0.02-0.88) and modafinil (SMD 0.42, 95% CI 0.05-0.79). Although solriamfetol demonstrated superior efficacy in EDS improvement, evidence from the clustered ranking plot supported that efficacy-safety profiles of pitolisant, sodium oxybate, and modafinil are more balanced than solriamfetol. Therefore, the choice of medication for EDS in narcolepsy should be made on an individual basis.
PubMed: 36362535
DOI: 10.3390/jcm11216302 -
Drug and Alcohol Dependence Reports Mar 2022There are no approved medications for the treatment of cocaine use disorder (CUD). Modafinil, a cognitive-enhancer with weak stimulant-like effects, has shown promise in...
INTRODUCTION
There are no approved medications for the treatment of cocaine use disorder (CUD). Modafinil, a cognitive-enhancer with weak stimulant-like effects, has shown promise in initial studies as a treatment for CUD. Its potential efficacy has not been examined in individuals dually dependent on cocaine and opioids.
METHODS
This study examined the efficacy of modafinil, in combination with contingency management (CM), for reducing cocaine and opioid use and improving cognitive function in methadone-stabilized individuals with opioid and cocaine dependence. We conducted a 17-week, double-blind, randomized controlled trial in which participants were randomized to one of four conditions: 1) modafinil + CM; 2) modafinil + yoked-control (YC); 3) placebo +CM; or 4) placebo + YC. Additionally, all subjects received platform treatments of cognitive behavioral therapy (CBT) and methadone. While the original planned sample size was N=160, a total of 91 participants were randomized. The two primary cocaine use outcomes were percentage of urine specimens positive for cocaine and percent of days of self-reported abstinence from cocaine during treatment. Cognitive function, opioid use, and secondary cocaine use outcomes were also considered.
RESULTS
Modafinil was well-tolerated with minimal reports of adverse effects. Modafinil was no more effective than placebo in reducing cocaine or opioid use or improving cognitive performance.
CONCLUSIONS
In the context of a trial with robust control conditions and platform treatments, findings did not provide support for the efficacy of modafinil treatment for the treatment of CUD in methadone-stabilized individuals with dual opioid and cocaine dependence.
PubMed: 36310662
DOI: 10.1016/j.dadr.2022.100032 -
Journal of Clinical Medicine Oct 2022Attention deficit hyperactivity disorder (ADHD) affects 6.4 million children in the United States of America. Children and adolescents, the main consumers of ADHD...
Attention deficit hyperactivity disorder (ADHD) affects 6.4 million children in the United States of America. Children and adolescents, the main consumers of ADHD medication, are in the bone growth phase, which extends over a period of up to two decades. Thus, impaired proliferation and maturation of chondrocytes and osteoblasts can result in impaired bone formation. The aim of this study is to investigate, for the first time, the effects of the ADHD-medication modafinil, atomoxetine and guanfacine on bone growth and repair in vitro. Using two-dimensional and three-dimensional cell models, we investigated the chondrogenic/osteogenic differentiation, proliferation and viability of human mesenchymal progenitor cells. Real-time cell proliferation was measured by xCELLigence. Live/dead staining and size measurement of hMSC- and MG63 monolayer and spheroids were performed after administration of therapeutic plasma concentrations of modafinil, atomoxetine and guanfacine. Chondrogenic differentiation was quantified by RTqPCR. The chondrogenic and osteogenic differentiation was evaluated by histological cryo-sections. Modafinil, atomoxetine and guanfacine reduced chondrogenic and osteogenic differentiation terms of transcript expression and at the histological level. Cell viability of the MG63- and hMSC monolayer was not impeded by ADHD-medication. Our in vitro results indicate that modafinil, atomoxetine and guanfacine may impair chondrogenic and osteogenic differentiation in a 3D model reflecting the in vivo physiologic condition.
PubMed: 36294540
DOI: 10.3390/jcm11206218 -
BMC Chemistry Oct 2022Modafinil (MDF) is one of the neurostimulants with a potential effect in the COVID-19 ICU ventilated patients and post-COVID neurological syndrome treatment. Four rapid,...
Modafinil (MDF) is one of the neurostimulants with a potential effect in the COVID-19 ICU ventilated patients and post-COVID neurological syndrome treatment. Four rapid, simple and cost-effective stability indicating spectrophotometric methods were used for estimation of MDF in the presence of its acidic degradation product, namely; ratio difference (RD), first derivative of the ratio spectra (DD), mean centering (MCR) and ratio subtraction method (RS). These methods were validated according to ICH guidelines and all methods revealed a good linearity in concentration range of (5-30 µg/mL) in addition to a good accuracy and precision with mean percentage recovery of 99.97 ± 0.305 for (RD), 100.10 ± 0.560 for (DD), 100.02 ± 0.483 for (MCR) & 99.18 ± 1.145 for (RS) method. Specificity of the proposed methods was assessed and MDF was determined in the presence of up to 80% of its acidic degradation product for RD, DD, MCR and RS methods. The proposed methods were successfully applied for the determination of MDF in bulk powder and its tablet dosage form with mean percentage recovery of 100.33 ± 0.915 for (RD), 100.62 ± 0.985 for (DD), 99.70 ± 0.379 for (MCR) and 100.21 ± 0.313 for (RS) method. The results obtained were statistically compared with those of official HPLC method and showed no significant difference with relevance accuracy and precision.
PubMed: 36271411
DOI: 10.1186/s13065-022-00869-z