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The American Journal of Drug and... May 2021: Cocaine use disorder (CUD) is a substantial public health problem with no FDA-approved medication treatments. Psychostimulants have shown promise as pharmacotherapy... (Clinical Trial)
Clinical Trial
: Cocaine use disorder (CUD) is a substantial public health problem with no FDA-approved medication treatments. Psychostimulants have shown promise as pharmacotherapy for CUD. Lisdexamfetamine, a novel prodrug psychostimulant, is roughly 40-50% as potent as dextroamphetamine.: To evaluate the safety, tolerability, and optimal dosing of lisdexamfetamine for treating CUD.: Open-label, 8-week trial of 17 CUD adults. Participants were titrated to the maximum tolerated dose of 140 mg over 2-week period and maintained for 4 weeks, followed by a two-week taper period. The primary outcome measures were the maximum daily dose achieved during the study period and tolerability as measured by medication-related study drop-out.: Among the 16 participants with post-enrollment data, the mean dose of lisdexamfetamine achieved was 118.1 mg (standard deviation (SD) = 40.4), mean retention was 6.5 weeks (SD = 2.0), and no participants discontinued study medication due to adverse effects. Four participants had dose reductions due to adverse effects and continued in the trial. Six participants (37.5%) were abstinent for the last 3 weeks of their study participation. Mean dollars of cocaine spent per day significantly decreased from $19.72 at baseline to $7.57 during the last 3 weeks of study participation ( = 3.60, = .003). The mean percent of using days significantly decreased from 25% at baseline to 12% during the last 3 weeks of study participation ( = 3.33, = .005).: The use of lisdexamfetamine for CUD in doses ranging to 140 mg daily was safe and generally well tolerated.
Topics: Adolescent; Adult; Central Nervous System Stimulants; Cocaine; Cocaine-Related Disorders; Female; Humans; Lisdexamfetamine Dimesylate; Male; Middle Aged; Pilot Projects; Treatment Outcome; Young Adult
PubMed: 33797985
DOI: 10.1080/00952990.2021.1885677 -
Causal effects of psychostimulants on neural connectivity: a mechanistic, randomized clinical trial.Journal of Child Psychology and... Nov 2022Psychostimulants are frequently used to treat attention-deficit/hyperactivity disorder (ADHD), but side effects are common leading to many patients discontinuing... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Psychostimulants are frequently used to treat attention-deficit/hyperactivity disorder (ADHD), but side effects are common leading to many patients discontinuing treatment. Identifying neural mechanisms by which psychostimulants attenuate symptoms may guide the development of more refined and tolerable therapeutics.
METHODS
We conducted a 12-week, randomized, placebo-controlled trial (RCT) of a long-acting amphetamine, lisdexamfetamine (LDEX), in patients with ADHD, ages 6-25 years old. Of the 58 participants who participated in the RCT, 49 completed pre- and post-RCT magnetic resonance imaging scanning with adequate data quality. Healthy controls (HCs; n = 46) were included for comparison. Treatment effects on striatal and thalamic functional connectivity (FC) were identified using static (time-averaged) and dynamic (time-varying) measures and then correlated with symptom improvement. Analyses were repeated in independent samples from the Adolescent Brain Cognitive Development study (n = 103) and the ADHD-200 Consortium (n = 213).
RESULTS
In 49 participants (25 LDEX; 24 Placebo), LDEX increased static and decreased dynamic FC (DFC). However, only DFC was associated with the therapeutic effects of LDEX. Additionally, at baseline, DFC was elevated in unmedicated-ADHD participants relative to HCs. Independent samples yielded similar findings - ADHD was associated with increased DFC, and psychostimulants with reduced DFC. Static FC findings were inconsistent across samples.
CONCLUSIONS
Changes in dynamic, but not static, FC were associated with the therapeutic effects of psychostimulants. While prior research has focused on static FC, DFC may offer a more reliable target for new ADHD interventions aimed at stabilizing network dynamics, though this needs confirmation with subsequent investigations.
Topics: Adolescent; Humans; Child; Young Adult; Adult; Lisdexamfetamine Dimesylate; Central Nervous System Stimulants; Attention Deficit Disorder with Hyperactivity; Brain Mapping; Brain; Magnetic Resonance Imaging
PubMed: 35141898
DOI: 10.1111/jcpp.13585 -
Presynaptic dopamine deficit in minimally conscious state patients following traumatic brain injury.Brain : a Journal of Neurology Jul 2019Dopaminergic stimulation has been proposed as a treatment strategy for post-traumatic brain injured patients in minimally conscious state based on a clinical trial using...
Dopaminergic stimulation has been proposed as a treatment strategy for post-traumatic brain injured patients in minimally conscious state based on a clinical trial using amantadine, a weak dopamine transporter blocker. However, a specific contribution of dopaminergic neuromodulation in minimally conscious state is undemonstrated. In a phase 0 clinical trial, we evaluated 13 normal volunteers and seven post-traumatic minimally conscious state patients using 11C-raclopride PET to estimate dopamine 2-like receptors occupancy in the striatum and central thalamus before and after dopamine transporter blockade with dextroamphetamine. If a presynaptic deficit was observed, a third and a fourth 11C-raclopride PET were acquired to evaluate changes in dopamine release induced by l-DOPA and l-DOPA+dextroamphetamine. Permutation analysis showed a significant reduction of dopamine release in patients, demonstrating a presynaptic deficit in the striatum and central thalamus that could not be reversed by blocking the dopamine transporter. However, administration of the dopamine precursor l-DOPA reversed the presynaptic deficit by restoring the biosynthesis of dopamine from both ventral tegmentum and substantia nigra. The advantages of alternative pharmacodynamic approaches in post-traumatic minimally conscious state patients should be tested in clinical trials, as patients currently refractory to amantadine might benefit from them.
Topics: Adult; Brain Injuries, Traumatic; Corpus Striatum; Dextroamphetamine; Dopamine; Dopamine Plasma Membrane Transport Proteins; Female; Humans; Levodopa; Male; Persistent Vegetative State; Positron-Emission Tomography; Presynaptic Terminals; Raclopride; Receptors, Dopamine D2; Substantia Nigra; Tegmentum Mesencephali; Thalamus; Young Adult
PubMed: 31505542
DOI: 10.1093/brain/awz118 -
Lakartidningen Sep 2019Emerging evidence supports a prevalence overlap between ADHD and bulimia nervosa/binge eating disorder. A high degree of ADHD symptoms may have a negative impact on... (Review)
Review
Emerging evidence supports a prevalence overlap between ADHD and bulimia nervosa/binge eating disorder. A high degree of ADHD symptoms may have a negative impact on recovery in eating disorders with loss of control over the eating, bingeing and purging. Screening/diagnostic evaluation of ADHD in all persons with loss of control over the eating/bingeing/purging eating disorders is required. For patients diagnosed with ADHD, treatment with stimulants can be tested and evaluated for both eating disorders and ADHD symptoms. While there is evidence that lisdexamfetamine reduces symptoms of binge eating disorder, rigorous studies evaluating ADHD treatment, including medication, for bulimia nervosa are still missing.
Topics: Attention Deficit Disorder with Hyperactivity; Binge-Eating Disorder; Bulimia Nervosa; Central Nervous System Stimulants; Feeding and Eating Disorders; Humans; Lisdexamfetamine Dimesylate
PubMed: 31529419
DOI: No ID Found -
The Primary Care Companion For CNS... Sep 2018
Topics: Adolescent; Attention Deficit Disorder with Hyperactivity; Central Nervous System Stimulants; Humans; Lisdexamfetamine Dimesylate; Male; Raynaud Disease
PubMed: 30256542
DOI: 10.4088/PCC.17l02240 -
Journal of Psychiatry & Neuroscience :... 2023The pathophysiology of psychosis is complex, but a better understanding of stimulus binding windows (BWs) could help to improve our knowledge base. Previous studies have... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The pathophysiology of psychosis is complex, but a better understanding of stimulus binding windows (BWs) could help to improve our knowledge base. Previous studies have shown that dopamine release is associated with psychosis and widened BWs. We can probe BW mechanisms using drugs of specific interest to psychosis. Therefore, we were interested in understanding how manipulation of the dopamine or catecholamine systems affect psychosis and BWs. We aimed to investigate the effect of dexamphetamine, as a dopamine-releasing stimulant, on the BWs in a unimodal illusion: the tactile funneling illusion (TFI).
METHODS
We conducted a randomized, double-blind, counterbalanced placebo-controlled crossover study to investigate funnelling and errors of localization. We administered dexamphetamine (0.45 mg/kg) to 46 participants. We manipulated 5 spatial (5-1 cm) and 3 temporal (0, 500 and 750 ms) conditions in the TFI.
RESULTS
We found that dexamphetamine increased funnelling illusion ( = 0.009) and increased the error of localization in a delay-dependent manner ( = 0.03). We also found that dexamphetamine significantly increased the error of localization at 500 ms temporal separation and 4 cm spatial separation ( = 0.009; = 0.01).
LIMITATIONS
Although amphetamine-induced models of psychosis are a useful approach to understanding the physiology of psychosis related to dopamine hyperactivity, dexamphetamine is equally effective at releasing noradrenaline and dopamine, and, therefore, we were unable to tease apart the effects of the 2 systems on BWs in our study.
CONCLUSION
We found that dexamphetamine increases illusory perception on the unimodal TFI in healthy participants, which suggests that dopamine or other catecholamines have a role in increasing tactile spatial and temporal BWs.
Topics: Humans; Dextroamphetamine; Dopamine; Illusions; Cross-Over Studies; Healthy Volunteers; Catecholamines
PubMed: 36918195
DOI: 10.1503/jpn.220149 -
Frontiers in Neuroscience 2023Cocaine is a highly addictive drug that is abused due to its excitatory effect on the central nervous system. It is critical to reveal the mechanisms of cocaine...
INTRODUCTION
Cocaine is a highly addictive drug that is abused due to its excitatory effect on the central nervous system. It is critical to reveal the mechanisms of cocaine addiction and identify key genes that play an important role in addiction.
METHODS
In this study, we proposed a centrality algorithm integration strategy to identify key genes in a protein-protein interaction (PPI) network constructed by deferential genes from cocaine addiction-related datasets. In order to investigate potential therapeutic drugs for cocaine addiction, a network of targeted relationships between nervous system drugs and key genes was established.
RESULTS
Four key genes (JUN, FOS, EGR1, and IL6) were identified and well validated using CTD database correlation analysis, text mining, independent dataset analysis, and enrichment analysis methods, and they might serve as biomarkers of cocaine addiction. A total of seventeen drugs have been identified from the network of targeted relationships between nervous system drugs and key genes, of which five (disulfiram, cannabidiol, dextroamphetamine, diazepam, and melatonin) have been shown in the literature to play a role in the treatment of cocaine addiction.
DISCUSSION
This study identified key genes and potential therapeutic drugs for cocaine addiction, which provided new ideas for the research of the mechanism of cocaine addiction.
PubMed: 37469839
DOI: 10.3389/fnins.2023.1201897 -
Psychiatric Annals Aug 2016
PubMed: 27667864
DOI: 10.3928/00485713-20160624-01 -
British Journal of Pharmacology Sep 2021Quercetin is a well-known plant flavonoid with neuroprotective properties. Earlier work suggested it may relieve psychiatric disorders, cognition deficits and memory...
BACKGROUND AND PURPOSE
Quercetin is a well-known plant flavonoid with neuroprotective properties. Earlier work suggested it may relieve psychiatric disorders, cognition deficits and memory dysfunction through anti-oxidant and/or radical scavenging mechanisms. In addition, quercetin modulated the physiological function of some ion channels. However, the detailed ionic mechanisms of the bioeffects of quercetin remain unknown.
EXPERIMENTAL APPROACH
Effects of quercetin on neuronal activities in the prefrontal cortex (PFC) and its ionic mechanisms were analysed by calcium imaging using mice bearing a green fluorescent protein, calmodulin, and M13 fusion protein and patch clamp in acute brain slices from C57BL/6 J mice and in HEK 293 cells. The possible ionic mechanism of action of quercetin on D-amphetamine-induced manic-like effects in mice was explored with c-fos staining and the open field behaviour test.
KEY RESULTS
Quercetin reduced calcium influx triggered by PFC pyramidal neuronal activity. This effect involved increasing the rheobase of neuronal firing through decreasing membrane resistance following quercetin treatment. Spadin, a blocker of TREK-1 potassium channels, also blocked the effect of quercetin on the membrane resistance and neuronal firing. Further, spadin blocked the neuroprotective effects of quercetin. The effects of quercetin on TREK-1 channels could be mimicked by GF109203X, a protein kinase C inhibitor. In vivo, injection of quercetin relieved the manic hyperlocomotion in mice, induced by D-amphetamine. This action was partly alleviated by spadin.
CONCLUSION AND IMPLICATIONS
TREK-1 channels are a novel target for quercetin, by inhibiting PKC. This action could contribute to both the neuroprotective and anti-manic-like effects.
Topics: Animals; Dextroamphetamine; HEK293 Cells; Humans; Mice; Mice, Inbred C57BL; Potassium Channels, Tandem Pore Domain; Quercetin
PubMed: 33908633
DOI: 10.1111/bph.15510 -
Neuroscience Feb 2023Psychostimulant drugs, such as cocaine, d-amphetamine and methylphenidate, alter a wide range of behaviors including locomotor activity and somatosensory perception....
Psychostimulant drugs, such as cocaine, d-amphetamine and methylphenidate, alter a wide range of behaviors including locomotor activity and somatosensory perception. These altered behaviors are accompanied by the activation of specific neuronal populations within reward-, emotion- and locomotion-related circuits. However, whether such regulation occurs at the level of the spinal cord, a key node for neural circuits integrating and coordinating sensory and motor functions has never been addressed. By evaluating the temporal and spatial expression pattern of the phosphorylated form of the immediate early gene cFos at Ser32 (pS32-cFos), used as a proxy of neuronal activation, we demonstrate that, in adult male mice, d-amphetamine increases pS32-cFos expression in both inhibitory and excitatory neurons in dorsal and ventral horns at the lumbar spinal cord level. Interestingly, a fraction of neurons activated by a first exposure to d-amphetamine can be re-activated following d-amphetamine re-exposure. Similar expression patterns were observed in response to cocaine and methylphenidate, but not following morphine and dozilcipine administration. Finally, the blockade of dopamine reuptake was sufficient to recapitulate the increase in pS32-cFos expression induced by psychostimulant drugs. Our work provides evidence that cFos expression can be activated in lumbar spinal cord in response to acute psychostimulants administration.
Topics: Male; Mice; Animals; Amphetamine; Pharmaceutical Preparations; Central Nervous System Stimulants; Cocaine; Methylphenidate; Spinal Cord; Dextroamphetamine
PubMed: 36502959
DOI: 10.1016/j.neuroscience.2022.12.005