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RationaleAgonist-based pharmacologic intervention is an accepted approach in treatment of opioid and tobacco use disorders.ObjectivesWe conducted a systematic review and meta-analysis to evaluate usefulness of an agonist approach as treatment of (psycho)stimulant use disorder (PSUD).MethodsWe reviewed PubMed/Medline, LILACS, and ClinicalTrials.gov databases searching for randomized, double-blind, placebo-controlled, parallel-design studies evaluating outcomes of individuals treated for cocaine- or amphetamine-type substance use disorder. We combined results of all trials that included the following prescription psychostimulants (PPs): modafinil, methylphenidate, or amphetamines (mixed amphetamine salts, lisdexamphetamine, and dextroamphetamine). The combined sample consisted of 2889 patients. Outcomes of interest included the following: drug abstinence (defined as 2–3 weeks of sustained abstinence and the average maximum days of consecutive abstinence), percentage of drug-negative urine tests across trial, and retention in treatment. We conducted random-effects meta-analyses and assessed quality of evidence using the GRADE system.ResultsThirty-eight trials were included. Treatment with PPs increases rates of sustained abstinence [risk ratio (RR) = 1.45, 95% confidence interval (CI) = (1.10, 1.92)] and duration of abstinence [mean difference (MD) = 3.34, 95% CI = (1.06, 5.62)] in patients with PSUD, particularly those with cocaine use disorder (very low-quality evidence). Prescription amphetamines were particularly efficacious in promoting sustained abstinence in patients with cocaine use disorder [RR = 2.44, 95% CI = (1.66, 3.58)], and higher doses of PPs were particularly efficacious for treatment of cocaine use disorder [RR = 1.95, 95% CI = (1.38, 2.77)] (moderate-quality evidence). Treatment with prescription amphetamines also yielded more cocaine-negative urines [MD = 8.37%, 95% CI = (3.75, 12.98)]. There was no effect of PPs on the retention in treatment.ConclusionPrescription psychostimulants, particularly prescription amphetamines given in robust doses, have a clinically significant beneficial effect to promote abstinence in the treatment of individuals with PSUD, specifically the population with cocaine use disorder.

Abstract The opioid overdose epidemic is typically described as having occurred in 3 waves, with morbidity and mortality accruing over time principally from prescription opioids (1999–2010), heroin (2011–2013), and illicit fentanyl and other synthetic opioids (2014–present). However, the increasing presence of synthetic opioids mixed into the illicit drug supply, including with stimulants such as cocaine and methamphetamine, as well as rising stimulant-related deaths, reflects the rapidly evolving nature of the overdose epidemic, posing urgent and novel public health challenges. We synthesize the evidence underlying these trends, consider key questions such as where and how concomitant exposure to fentanyl and stimulants is occurring, and identify actions for key stakeholders regarding how these emerging threats, and continued evolution of the overdose epidemic, can best be addressed.

Background The psychostimulant properties of caffeine are reviewed and compared with those of prototypical psychostimulants able to cause substance use disorders (SUD). Caffeine produces psychomotor-activating, reinforcing, and arousing effects, which depend on its ability to disinhibit the brake that endogenous adenosine imposes on the ascending dopamine and arousal systems. Objectives A model that considers the striatal adenosine A 2A -dopamine D 2 receptor heteromer as a key modulator of dopamine-dependent striatal functions (reward-oriented behavior and learning of stimulus-reward and reward-response associations) is introduced, which should explain most of the psychomotor and reinforcing effects of caffeine. Highlights The model can explain the caffeine-induced rotational behavior in rats with unilateral striatal dopamine denervation and the ability of caffeine to reverse the adipsic-aphagic syndrome in dopamine-deficient rodents. The model can also explain the weaker reinforcing effects and low abuse liability of caffeine, compared with prototypical psychostimulants. Finally, the model can explain the actual major societal dangers of caffeine: the ability of caffeine to potentiate the addictive and toxic effects of drugs of abuse, with the particularly alarming associations of caffeine (as adulterant) with cocaine, amphetamine derivatives, synthetic cathinones, and energy drinks with alcohol, and the higher sensitivity of children and adolescents to the psychostimulant effects of caffeine and its potential to increase vulnerability to SUD. Conclusions The striatal A 2A -D 2 receptor heteromer constitutes an unequivocal main pharmacological target of caffeine and provides the main mechanisms by which caffeine potentiates the acute and long-term effects of prototypical psychostimulants.

RationaleNo drugs are currently validated to treat psychostimulant use disorder (PUD). Pathophysiological studies consistently highlight the contribution of cholinergic mechanisms in psychostimulant use, including the vulnerability to PUD, paving the way for potential therapeutic strategies.ObjectivesThe aim of this systematic review is to describe and discuss the efficacy of cholinergic agents in drug trials for patients with PUD.MethodsA systematic review was conducted on April 4, 2024 in MedLine, Embase and Cochrane Library databases on controlled clinical drug trial of cholinergic agents in humans with PUD, psychostimulant abuse or dependence and psychostimulant use in recent year.ResultsTwenty-eight articles were included, twenty-one on cocaine and seven on amphetamines. Cholinergic agents used in these studies were biperiden (a muscarinic antagonist), mecamylamine (a nicotinic antagonist), nicotinic agonists, acetylcholinesterase inhibitors (AChEI), or citicoline. Two types of trials were identified. There were seventeen randomized controlled clinical trials evaluating cholinergic agents on psychostimulant use reduction in outpatients seeking treatment. Additionally, we retrieved eleven short-term «proof-of-concept» laboratory trials mainly with supervised psychostimulant administration and/or triggered craving challenges. Outpatient trials were heterogeneous and for most, inconclusive. Only two studies on galantamine (AChEI) and citicoline, reported a significant reduction of cocaine consumption. «Proof-of-concept» laboratory trials showed no evidence of efficacy on the selected outcomes, notably on craving.ConclusionsThis review does not support the current prescription of cholinergic agents to treat PUD. Replication clinical trials notably on galantamine or other AChEI, and proof-of-concept trials on comedown symptoms will be necessary to identify a potential therapeutic indication for cholinergic agents in PUD.

[This corrects the article DOI: 10.3389/fnbeh.2023.1251144.].

RationalePsychostimulants, including methylphenidate (MPH), are the mainstay of pharmacotherapy for attention-deficit/hyperactivity disorder (ADHD) in adults. Even though MPH is the most commonly used medication for ADHD these days, there are relatively few resources available that provide comprehensive insight into the pharmacological and clinical features of the compound.ObjectiveThe aim of this paper is to provide an up-to-date outline of the pharmacology and clinical utility of MPH for ADHD in adult patients.MethodsWhile conducting the narrative review, we applied structured search strategies covering the two major online databases (MEDLINE and Cochrane Central Register of Controlled Trials). In addition, we performed handsearching of reference lists of relevant papers.ResultsMethylphenidate exhibits multimodal mechanism of action, working primarily as a dopamine and noradrenaline reuptake inhibitor. It also protects the dopaminergic system against the ongoing ‘wearing off’ (by securing a substantial reserve pool of the neurotransmitter, stored in the presynaptic vesicles). In placebo-controlled trials, MPH was shown to be moderately effective both against the core ADHD symptoms (standardized mean difference [SMD], 0.49; 95% confidence interval [CI], 0.35–0.64), and the accompanying emotion regulation deficits (SMD, 0.34; 95% CI, 0.23–0.45). The most common adverse events related to long-term treatment with MPH are decreased appetite (~ 20%), dry mouth (15%), heart palpitations (13%), gastrointestinal infections (~ 10%), and agitation/feeling restless (~ 10%).ConclusionsThere is substantial body of evidence to suggest that MPH is an effective and safe treatment option for adults with ADHD.

IntroductionWe present the case of a 65-year-old woman who was prescribed levodopa by the Neurology department due to motor symptoms that were not clearly suggestive of a diagnosis of Parkinson’s Disease (PD). Before that, the patient had never showed any hallucinations or delusions. After years of increasing doses of levodopa, the diagnosis of PD was withdrawn. However, during the treatment the patient developed severe psychosis with severe impairment of social functioning. Levodopa is the most effective treatment for motor symptoms in PD. However, it might involve difficulties in dose-control and may present with deletereous complications and adverse effects.ObjectivesTo analyse the incidence of pharmacological psychotic symptoms after levodopa treatment.MethodsA case report is presented alongside a review of the available literature regarding psychotic symptoms in patients treated with levodopa.ResultsHallucinations and delusions are prevalent symptoms of PD. Nonetheless, they could also be potential side-effects of levodopa treatment. When psychotic symptoms occur, they are commonly attributed to the natural course of the disease. Available evidence does not provide with clear guidelines to distinguish the iatrogenic syndrome from the one caused by the disease itself. Our patient, whose PD diagnosis was dismissed, presented extreme psychotic symptoms which disappeared after the discontinuation of levodopa treatment.ConclusionsLevodopa is an effective treatment with important risks which must not be overlooked. Adverse effects of the drug could have been minimized by making an accurate differential diagnosis of PD. Individualized benefit-risk balance previous to prescription and a close follow-up should be standardized.DisclosureNo significant relationships.

Psychostimulants interacting with the dopamine transporter (DAT) can be used illicitly or for the treatment of specific neuropsychiatric disorders. However, they can also produce severe and persistent adverse events. Often, their pharmacological properties in vitro do not fully correlate to their pharmacological profile in vivo. Here, we investigated the pharmacological effects of enantiomers of pyrovalerone, α-pyrrolidinovalerophenone, and 3,4-methylenedioxypyrovalerone as compared to the traditional psychostimulants cocaine and methylphenidate, using a variety of in vitro, computational, and in vivo approaches. We found that in vitro drug-binding kinetics at DAT correlate with the time-course of in vivo psychostimulant action in mice. In particular, a slow dissociation (i.e., slow koff ) of S-enantiomers of pyrovalerone analogs from DAT predicts their more persistent in vivo effects when compared to cocaine and methylphenidate. Overall, our findings highlight the critical importance of drug-binding kinetics at DAT for determining the in vivo profile of effects produced by psychostimulant drugs.

New psychoactive substances (NPS) are a heterogeneous and rapidly evolving class of molecules available on the global illicit drug market (e.g smart shops, internet, \"dark net\") as a substitute for controlled substances. The use of NPS, mainly consumed along with other drugs of abuse and/or alcohol, has resulted in a significantly growing number of mortality and emergency admissions for overdoses, as reported by several poison centers from all over the world. The fact that the number of NPS have more than doubled over the last 10 years, is a critical challenge to governments, the scientific community, and civil society [EMCDDA (European Drug Report), 2014; UNODC, 2014b; Trends and developments]. The chemical structure (phenethylamines, piperazines, cathinones, tryptamines, synthetic cannabinoids) of NPS and their pharmacological and clinical effects (hallucinogenic, anesthetic, dissociative, depressant) help classify them into different categories. In the recent past, 50% of newly identified NPS have been classified as synthetic cannabinoids followed by new phenethylamines (17%) (UNODC, 2014b). Besides peripheral toxicological effects, many NPS seem to have addictive properties. Behavioral, neurochemical, and electrophysiological evidence can help in detecting them. This manuscript will review existing literature about the addictive and rewarding properties of the most popular NPS classes: cannabimimetics (JWH, HU, CP series) and amphetamine-like stimulants (amphetamine, methamphetamine, methcathinone, and MDMA analogs). Moreover, the review will include recent data from our lab which links JWH-018, a CB1 and CB2 agonist more potent than Δ(9)-THC, to other cannabinoids with known abuse potential, and to other classes of abused drugs that increase dopamine signaling in the Nucleus Accumbens (NAc) shell. Thus the neurochemical mechanisms that produce the rewarding properties of JWH-018, which most likely contributes to the greater incidence of dependence associated with \"Spice\" use, will be described (De Luca et al., 2015a). Considering the growing evidence of a widespread use of NPS, this review will be useful to understand the new trends in the field of drug reward and drug addiction by revealing the rewarding properties of NPS, and will be helpful to gather reliable data regarding the abuse potential of these compounds.

Attention-deficit/hyperactivity disorder (ADHD), a common neurodevelopmental disorder in children, is associated with alterations in gut microbiota and short-chain fatty acids (SCFAs), which are metabolites influencing the gut-brain axis. Evidence suggests that psychostimulant medications, widely used to manage ADHD symptoms, may also impact gut microbiota composition and SCFA levels. This study explores these potential effects by examining gut microbiota profiles and SCFA concentrations in unmedicated and medicated children with ADHD, compared to healthy controls. Fecal samples from 30 children aged 6–12 years (10 unmedicated ADHD, 10 medicated ADHD, and 10 healthy controls) were analyzed using 16 S rRNA sequencing and targeted metabolomics. Unmedicated ADHD children show distinct gut microbiota profiles, with lower level of Tyzzerella , Prevotellaceae , and Coriobacteriaceae , compared to controls. Notably, propionic acid levels were negatively associated with ADHD symptom severity, suggesting a potential biomarker role. Medicated ADHD children showed lower gut microbial diversity, unique taxa, and lower SCFA levels, compared to unmedicated children with ADHD. These findings suggest that gut microbiota and SCFAs may be linked to ADHD symptomatology, underscoring the importance of gut-brain interactions in ADHD. This study highlights the potential of gut health monitoring as part of future ADHD management strategies.