Psychostimulant Properties Research Articles

Task-specific oromandibular dystonia secondary to chewing Khat (Catha edulis)- A series of 35 cases

BackgroundThe leaves of “Khat” (Catha edulis), an indigenous shrub of Yemen and Arabian Peninsula are habitually chewed by the inhabitants for psychostimulant properties. ObjectiveTo describe a unique task specific Oro-mandibular dystonia (OMD) in Yemenese men, with a temporal association with chewing “Khat”. MethodsMulticentric, retrospective analysis (2009–2020) of patients with OMD associated with “Khat” chewing, evaluating clinical features and response to Onabotulinum toxin A. Results35 Yemenese men with a negative family history, normal neuroimaging mean age of 44.31(±3.21) years and prolonged (20.31 ± 3.27 years) history of chewing Khat, around 5.16(±0.80) hours/day presented with OMD-20 jaw opening, 13 jaw closing and 2 mixed affecting chewing (n = 6), speech (n = 3), or both (n = 26). Additional lingual dystonia was seen in five. ConclusionsChewing of khat is a repetitive task involving the jaw musculature and may be one of the causative factors of this task specific OMD. Recognition can prevent disability in these regions.

The inhibitory effect of cannabidiol on the rewarding properties of methamphetamine in part mediates by interacting with the hippocampal D1-like dopamine receptors

Cannabidiol (CBD) is a potential treatment to decrease the rewarding properties of psychostimulants. However, the exact mechanism and distinct neuroanatomical areas responsible for the CBD's effects remain unclear. Indicatively, the D1-like dopamine receptors (D1R) in the hippocampus (HIP) are essential for expressing and acquiring drug-associated conditioned place preference (CPP). Therefore, given that involving D1Rs in reward-related behaviors and the encouraging results of CBD in attenuating the psychostimulant's rewarding effects, the present study sought to investigate the role of D1Rs of the hippocampal dentate gyrus (DG) in the inhibitory effects of CBD on the acquisition and expression of METH-induced CPP. To this end, over a 5-day conditioning period by METH (1 mg/kg; sc), different groups of rats were given intra-DG SCH23390 (0.25, 1, or 4 μg/0.5 μl, saline) as a D1Rs antagonist before ICV administration of CBD (10 μg/5 μl, DMSO12%). In addition, a different set of animals, after the conditioning period, received a single dose of SCH23390 (0.25, 1, or 4 μg/0.5 μl) before CBD (50 μg/5 μl) administration on the expression day. The results showed that SCH23390 (1 and 4 μg) significantly reduced the suppressive effects of CBD on the acquisition of METH place preference (P < 0.05 and P < 0.001, respectively). Furthermore, the highest dose of SCH23390 (4 μg) in the expression phase remarkably abolished the preventive effects of CBD on the expression of METH-seeking behavior (P < 0.001). In conclusion, the current study revealed that CBD's inhibitory effect on rewarding properties of METH partially acts through D1Rs in the DG area of the HIP.

Investigating the electrochemical profile of methamphetamine to enable fast on-site detection in forensic analysis

Methamphetamine (MA) is a synthetic psychoactive drug which is consumed both licitly and illicitly. In some countries it is prescribed for attention-deficit and hyperactivity disorder, and short-term treatment of obesity. More often though, it is abused for its psychostimulant properties. Unfortunately, the spread and abuse of this synthetic drug have increased globally, being reported as the most widely consumed synthetic psychoactive drug in the world in 2019. Attempting to overcome the shortcomings of the currently used on-site methods for MA detection in suspected cargos, the present study explores the potential of electrochemical identification of MA by means of square wave voltammetry on disposable graphite screen-printed electrodes. Hence, the analytical characterization of the method was evaluated under optimal conditions exhibiting a linear range between 50 μM and 2.5 mM MA, a LOD of 16.7 μM, a LOQ of 50.0 μM and a sensitivity of 5.3 μA mM−1. Interestingly, two zones in the potential window were identified for the detection of MA, depending on its concentration in solution. Furthermore, the oxidative pathway of MA was elucidated employing liquid chromatography – mass spectrometry to understand the change in the electrochemical profile. Thereafter, the selectivity of the method towards MA in mixtures with other drugs of abuse as well as common adulterants/cutting agents was evaluated. Finally, the described method was employed for the analysis of MA in confiscated samples and compared with forensic methods, displaying its potential as a fast and easy-to-use method for on-site analysis.

Identification and quantitation of kratom in the hair of a regular user of substances purchased on the darkweb

Kratom is a natural substance with psychostimulant properties obtained from the Mitragyna speciosa species. Used today as a recreational drug, the leaves are either chewed, encapsulated, smoked or ingested as an infusion with lemon juice and sugar. Mitragynin, one of the 40 alkaloids identified in the plant, is found in 0.2% of the leaves and is considered a more potent analgesic than morphine. We present hair analysis of a 27-year-old man who self-reported daily consumption for five years of about 20 g of kratom, purchased on the darkweb, coupled with regular consumption of cannabis, GABAergic drugs and sporadically JWH-122. He donated voluntarily some hair samples. After receiving the procedure, he took himself a 3 cm long strand of brown hair, 2 months after his last consumption of JWH-122 and sent by postal way. Sample preparation was done using a published method (Fabresse et al. Drug Test Anal 2019;11:697–708). The hair strand was cut in two segments of around 1.5 cm. After decontamination, 50 mg of hair sample were incubated in phosphate buffer (pH 5.0). Liquid-liquid extraction (LLE) was performed using a mixture of heptane/ethyl acetate (v/v; 90/10) and carbonate buffer at pH 9.7. After agitation and centrifugation, a second LLE was performed by dichloromethane/isopropanol (v/v; 80/20). Organic phases were evaporated and of the dry residue was reconstituted in a mixture of water/ammonium formiate/formic acid. The screening method used an ultra-high performance liquid chromatography coupled to a benchtop Orbitrap (Q-Exactive, Thermo) operating in data-dependent acquisition mode (DDA). The same extract was then submitted to a targeted analysis by LC-MS/MS for quantitation (LCQ TSQ Vantage XP triple-quadrupole mass spectrometer, Thermo). The LC-HRMS method led to the identification of mitragynin and JWH-122. Mitragynin was quantified at 2235 pg/mg in the proximal part (A) and at 1717 pg/mg in the distal part (B). The metabolite of mitragynin, the 7-hydroxymitragynin was not identified. In parallel, using the same method, was positively quantified the JWH-122 in both hair segments (69 pg/mg in A; 103 pg/mg in B). The measured concentrations of kratom are compatible with the only concentrations described in the literature in a regular user (3 g/d) (Meier et al. Drug Test Anal 2020;12:280–4). In this case, mitragynin was measured in hair samples taken from different regions of the scalp with concentrations ranging from 1054 pg/mg to 2244 pg/mg. About the synthetic cannabinoid, the 27-year-old male self-reported a punctual JHW-122 consumption (20–40 mg/10 consecutive days). The values measured are also in accordance with the JWH-122 concentrations found in the literature based on eight hair samples from frequent users of THC-containing products or chronic abusers of classical drugs (range: 7–2800 pg/mg) (Salomone et al., Drug Test Anal 2014; 6(1–2), 126–134). Hair therefore appears to be a suitable biological matrix for the diagnosis and monitoring of kratom consumption.

Gambaran Caffeine Addiction Pada Ibu Rumah Tangga

Caffeine is still a popular processed food or drink among teenagers and adults, as well as housewives who still have the habit of consuming caffeine such as coffee or tea. Caffeine as an antagonist at the adenosine receptor will stimulate dopaminergic activity which will cause psychostimulant properties, namely providing a wakeful and arousing effect which can then lead to potential addiction or addiction to caffeine. Consuming caffeine in excess of the daily limit can cause side effects including anxiety, insomnia, increased heart rate, and gastrointestinal disturbances. Therefore, the purpose of this study was to determine the description of caffeine addiction in housewives. The research method using descriptive analysis with sampling using cross sectional technique obtained a sample of 33 people. The data was obtained from filling out questionnaires by respondents about caffeine addiction, then the questionnaire was tested for validity and reliability. The results obtained from the validity test of 9 questionnaire questions, namely r count &gt; r table (0.344), it can be concluded that the questionnaire is valid. Furthermore, the reliability test on the questionnaire obtained the results of the Cronbach alpha value of 0.933 which means &gt; 0.6 so it can be concluded that the questionnaire in this study is said to be reliable. To find out the description of caffeine addiction in respondents, univariate analysis with SPSS showed that most respondents experienced caffeine addiction in the moderate category, namely 29 respondents (87.9%), and 4 respondents (12.1%) experienced caffeine addiction in mild category. The conclusion of this study is that housewives experience caffeine addiction in the moderate category, namely 29 respondents. The importance of limiting daily caffeine intake to minimize the risk of addiction to caffeine and the side effects caused by caffeine.&#x0D;

Multiple Direct Effects of the Dietary Protoalkaloid N-Methyltyramine in Human Adipocytes.

Dietary amines have been the subject of a novel interest in nutrition since the discovery of trace amine-associated receptors (TAARs), especially TAAR-1, which recognizes tyramine, phenethylamine, tryptamine, octopamine, N-methyltyramine (NMT), synephrine, amphetamine and related derivatives. Alongside the psychostimulant properties of TAAR-1 ligands, it is their ephedrine-like action on weight loss that drives their current consumption via dietary supplements advertised for ‘fat-burning’ properties. Among these trace amines, tyramine has recently been described, at high doses, to exhibit an antilipolytic action and activation of glucose transport in human adipocytes, i.e., effects that are facilitating lipid storage rather than mobilization. Because of its close structural similarity to tyramine, NMT actions on human adipocytes therefore must to be reevaluated. To this aim, we studied the lipolytic and antilipolytic properties of NMT together with its interplay with insulin stimulation of glucose transport along with amine oxidase activities in adipose cells obtained from women undergoing abdominal surgery. NMT activated 2-deoxyglucose uptake when incubated with freshly isolated adipocytes at 0.01–1 mM, reaching one-third of the maximal stimulation by insulin. However, when combined with insulin, NMT limited by half the action of the lipogenic hormone on glucose transport. The NMT-induced stimulation of hexose uptake was sensitive to inhibitors of monoamine oxidases (MAO) and of semicarbazide-sensitive amine oxidase (SSAO), as was the case for tyramine and benzylamine. All three amines inhibited isoprenaline-induced lipolysis to a greater extent than insulin, while they were poorly lipolytic on their own. All three amines—but not isoprenaline—interacted with MAO or SSAO. Due to these multiple effects on human adipocytes, NMT cannot be considered as a direct lipolytic agent, potentially able to improve lipid mobilization and fat oxidation in consumers of NMT-containing dietary supplements.

Uncovering Functional Contributions of PMAT (Slc29a4) to Monoamine Clearance Using Pharmacobehavioral Tools

Plasma membrane monoamine transporter (PMAT, Slc29a4) transports monoamine neurotransmitters, including dopamine and serotonin, faster than more studied monoamine transporters, e.g., dopamine transporter (DAT), or serotonin transporter (SERT), but with ~400–600-fold less affinity. A considerable challenge in understanding PMAT’s monoamine clearance contributions is that no current drugs selectively inhibit PMAT. To advance knowledge about PMAT’s monoamine uptake role, and to circumvent this present challenge, we investigated how drugs that selectively block DAT/SERT influence behavioral readouts in PMAT wildtype, heterozygote, and knockout mice of both sexes. Drugs typically used as antidepressants (escitalopram, bupropion) were administered acutely for readouts in tail suspension and locomotor tests. Drugs with psychostimulant properties (cocaine, D-amphetamine) were administered repeatedly to assess initial locomotor responses plus psychostimulant-induced locomotor sensitization. Though we hypothesized that PMAT-deficient mice would exhibit augmented responses to antidepressant and psychostimulant drugs due to constitutively attenuated monoamine uptake, we instead observed sex-selective responses to antidepressant drugs in opposing directions, and subtle sex-specific reductions in psychostimulant-induced locomotor sensitization. These results suggest that PMAT functions differently across sexes, and support hypotheses that PMAT’s monoamine clearance contribution emerges when frontline transporters (e.g., DAT, SERT) are absent, saturated, and/or blocked. Thus, known human polymorphisms that reduce PMAT function could be worth investigating as contributors to varied antidepressant and psychostimulant responses.

Clinical effects of central antagonist of cholecystokinin-1 receptors GB-115 in patients with Generalized Anxiety Disorder

Introduction The pilot clinical study of GB-115, a new peptide antagonist of central cholecystokinin-1 receptors, revealed that drug was clinically effective in patients with generalized anxiety disorder (GAD) at dose 6 mg daily. Here, we provide results of post-hoc analysis of changes of anxiety and fatigue symptoms to give characterization of its clinical effects in clinically relevant doses.ObjectivesTo research the changes of anxiety- and fatigue-related symptoms during GB-115 treatment in patients with generalized anxiety disorder (GAD).Methods Patients with GAD without somatic diseases aged 18-55 years were eligible in the study. Patients were prescribed with GB-115 6 mg daily for 21 days. Anxiety and fatigue symptoms were assessed with Hamilton Anxiety Rating Scale (HARS) and Multidimensional Fatigue Inventory (MFI-20). Variables are described as medians and interquartile range (IQR). Pre-post comparisons were performed using the Friedman ANOVA at 2-side p-value &lt;0.05.Results25 patients diagnosed with GAD (8 males, 17 females; median [IQR] age: 34 [29.75, 43.0]) included in the analysis. Median [IQR] HARS total score decreased from 22 [20, 24.5] to 19 [16, 20], 13 [10.5, 15.5], 9 [5.5, 11] and 5 [3.5, 8] on the Day 3,7,14 and 21, respectively (χ2=95.07, df=4, p&lt;0.001). Median [IQR] MFI-20 score decreased from 70 [46, 75.5] to 59 [41, 74.5], 52 [37.5, 64.5], 37 [26.5, 63] and 28 [24, 48.5] on the Day 3, 7, 14 and 21, respectively (χ2= 55.41, df=4, p&lt;0.001). None of patients had stimulation-related side effects.ConclusionsGB-115 action in the treatment of GAD patients is characterized with anxiolytic action with mild psychostimulant properties.DisclosureNo significant relationships.

Repeated administration of N-ethyl-pentedrone induces increased aggression and impairs social exploration after withdrawal in mice

N-ethyl-pentedrone (NEPD, 2-(ethylamino)-1-phenyl-1-pentanone) is one of the latest synthetic cathinone derivatives that emerged into the illicit drug market. This drug has psychostimulant properties and has been related with several intoxications and even fatalities. However, information about the consequences of its acute and repeated consumption is lacking. Thus, the aim of our study was to investigate the behavioral effects after both acute and repeated NEPD exposure as well as the neurochemical changes. Male OF1 mice were treated with an acute dose (1, 3 or 10 mg/kg, i.p.) or received repeated injections of these doses (twice/day, 5 days) of NEPD. Shortly after drug-exposure or during drug-withdrawal, anxiety-like behavior, aggressiveness, social interaction, depressive-like symptoms, body weight and temperature were assessed. Also, monoamine synthesis enzymes, levels of neurotransmitters and their precursors and main metabolites, as well as ΔFosB, were determined in striatum and prefrontal cortex from post-mortem tissue. Acute administration of NEPD induced anxiolytic effects and reduced social exploration whereas during withdrawal after repeated administration the anxiolytic effect had vanished, and the reduced social exploration was still present and accompanied with increased aggressive behavior. Moreover, NEPD (10 mg/kg) induced slight hyperthermia and reduced weight gain during the repeated administration, whereas increased locomotor activity and lack of depressive symptoms were found during withdrawal. This was accompanied by increased plasma corticosterone and decrease in striatal dopamine. Finally, the long-lasting and robust increase in ΔFosB levels found in striatum after NEPD chronic exposure suggests a high risk of dependence. The increased aggressivity and locomotor activity, together with this potential of inducing dependence justify a warning about the risks of consumption of NEPD if translated to humans.

Neuroinflammatory Response in Reward-Associated Psychostimulants and Opioids: A Review.

Substance abuse is one of the significant problems in social and public health worldwide. Vast numbers of evidence illustrate that motivational and reinforcing impacts of addictive drugs are primarily attributed to their ability to change dopamine signaling in the reward circuit. However, the roles of classic neurotransmitters, especially dopamine and neuromodulators, monoamines, and neuropeptides, in reinforcing characteristics of abused drugs have been extensively investigated. It has recently been revealed that central immune signaling includes cascades of chemokines and proinflammatory cytokines released by neurons and glia via downstream intracellular signaling pathways that play a crucial role in mediating rewarding behavioral effects of drugs. More interestingly, inflammatory responses in the central nervous system modulate the mesolimbic dopamine signaling and glutamate-dependent currents induced by addictive drugs. This review summarized researches in the alterations of inflammatory responses accompanied by rewarding and reinforcing properties of addictive drugs, including cocaine, methamphetamine, and opioids that were evaluated by conditioned place preference and self-administration procedures as highly common behavioral tests to investigate the motivational and reinforcing impacts of addictive drugs. The neuroinflammatory responses affect the rewarding properties of psychostimulants and opioids.

Amphetamine Promotes Cortical Up State in Part Via Dopamine Receptors.

Cortical neurons oscillate between Up and Down states during slow wave sleep and general anesthesia. Recent studies show that Up/Down oscillations also occur during quiet wakefulness. Arousal eliminates Down states and transforms Up/Down oscillations to a persistent Up state. Further evidence suggests that Up/Down oscillations are crucial to memory consolidation, whereas their transition to a persistent Up state is essential for arousal and attention. We have shown that D-amphetamine promotes cortical Up state, and the effect depends on activation of central α1A adrenergic receptors. Here, we report that dopamine also plays a role in D-amphetamine’s effect. Thus, using local-field-potential recording in the prefrontal cortex in chloral hydrate-anesthetized rats, we showed that the Up-state promoting effect of D-amphetamine was attenuated by antagonists at either D1 or D2-like dopamine receptors. The effect was also partially mimicked by co-activation of D1 and D2-like receptors. These results are consistent with the fact that D-amphetamine increases the release of both norepinephrine and dopamine. They are also in agreement with studies showing that dopamine promotes wakefulness and mediates D-amphetamine-induced emergence from general anesthesia. The effect of D-amphetamine was not mimicked, however, by activation of either D1 or D2-like receptors alone, indicating an interdependence between D1 and D2-like receptors. The dopamine/norepinephrine precursor L-DOPA also failed to promote the Up state. While more studies are needed to understand the difference between L-DOPA and D-amphetamine, our finding may provide an explanation for why L-DOPA lacks significant psychostimulant properties and is ineffective in treating attention-deficit/hyperactivity disorder.

Use of methylphenidate by university students in the health area

Methylphenidate is the drug most frequently used in the treatment of attention deficit hyperactivity disorder. However, due to its psychostimulant properties, this substance has been used to stimulate productivity and increase intellectual capacity in several areas of study. In this work, the characteristics of the use of methylphenidate among pharmacy, nursing, and medical students of a university in the capital of Bahia were analyzed. In this cross-sectional study, 338 students from different semesters of the aforementioned courses were interviewed. The instrument used for data collection was a standardized self-completed questionnaire applied by the researchers. Altogether, 76% of respondents were female and the average age was 22 years old. The frequency of students who used or who had already used methylphenidate at some point in their academic life was higher among medical students (12%). The main justification for the use of this substance was the higher concentration to study (59%). Also, 92% of respondents claimed to use Methylphenidate without medical supervision and 80% indicated the time of the tests as the time of greatest use of this drug. These results show high non-prescribed use of methylphenidate among health care students.

An updated review on synthetic cathinones.

Cathinone, the main psychoactive compound found in the plant Catha edulis Forsk. (khat), is a β-keto analogue of amphetamine, sharing not only the phenethylamine structure, but also the amphetamine-like stimulant effects. Synthetic cathinones are derivatives of the naturally occurring cathinone that largely entered the recreational drug market at the end of 2000s. The former "legal status", impressive marketing strategies and their commercial availability, either in the so-called "smartshops" or via the Internet, prompted their large spread, contributing to their increasing popularity in thefollowing years. As their popularity increased, the risks posed for public health became clear, with several reports of intoxications and deaths involving these substances appearing both in the social media and scientific literature. The regulatory measures introduced thereafter to halt these trending drugs of abuse have proved to be of low impact, as a continuous emergence of new non-controlled derivatives keep appearing to replace those prohibited. Users resort to synthetic cathinones due to their psychostimulant properties but are often unaware of the dangers they may incur when using these substances. Therefore, studies aimed at unveiling the pharmacological and toxicological properties of these substances are imperative, as they will provide increased expertise to the clinicians that face this problem on a daily basis. The present work provides a comprehensive review on history and legal status, chemistry, pharmacokinetics, pharmacodynamics, adverse effects and lethality in humans, as well as on the current knowledge of the neurotoxic mechanisms of synthetic cathinones.

Khat use and perceived health problems among African migrants in Australia: an exploratory study.

The chronic use of khat, a plant with psychostimulant properties, has been associated with physical and mental health problems. Previous research found that non-khat users were more likely than khat users to perceive its use to be associated with poor health. We aimed to identify differences in the perception of specific khat-associated health problems between khat users and non-users. In 2012, 133 adults (≥ 18 years) from African migrant communities in 4 state capital cities in Australia completed questionnaires to ascertain their perception of whether specific health problems were associated with khat use. Multivariable log-linked Poisson regression was used to compare the perceptions of the 2 groups and identify differences, adjusting for sociodemographic factors, tobacco use and years living in Australia. Overall, 58 (44%) and 75 (56%) participants reported current khat use and no use respectively. Adjusted log-linked Poisson regression showed that people who use khat were less likely than non-users to perceive certain health and related problems were associated with khat use, including, poor health in general [prevalence risk ratio (PRR) = 0.86; 95% CI: 0.75, 1.00]; laziness (PRR = 0.86; 95% CI: 0.75, 0.99); stomach and throat problems (PRR = 0.83; 95% CI: 0.72, 0.96); and teeth, gum and mouth problems (PRR = 0.81; 95% CI: 0.67, 0.99). Khat users are less likely to perceive use being associated with health problems than non-users. Providing information on the health problems associated with khat use may be an important component of health promotion strategies and interventions aimed at minimising khat-related harm.

A cup of coffee, what else?

IntroductionCaffeine is the worldwide most frequently consumed psychostimulant. Its availability is nearly unlimited and in Europe it is not subject to state regulation. n the DSM-5 “caffeine use disorder” is categorized as a possible future disorder that currently needs further study.ObjectivesTo describe clinical evaluation, diagnosis, treatment and evolution of a 24 years old female patient.MethodsA 24-year-old woman admitted to the Dual Pathology Unit with a diagnosis of: unspecified psychotic disorder, mild intellectual disability and borderline disorder. In week 17 of admission, she decided to suspend the medication, with significant improvement. Therapeutic permits increase and Wais-III is repeated, resulting in having a limited intellectual capacity. Two months after being discharged, she was readmitted with manic symptoms. The nursing staff discover that she was drinkiing a large amount of caffeine (up to 4 liters / day). After gradually stopping caffeine intake, she was discharged without psychopharmacological treatment, being able to lead a normalized life, even studying a medium degree. No more incomes were need.ResultsCaffeine produces psychomotor-activating, reinforcing, and arousing effects.ConclusionsThe pattern of caffeine use of patients should be considered in the medical practice. The psychostimulant properties of caffeine are reviewed and compared with those of prototypical psychostimulants able to cause substance use disorders.

Cannabidiol efficiently suppressed the acquisition and expression of methamphetamine-induced conditioned place preference in the rat

Methamphetamine (MET) is one of the most prevalently abused psychostimulants in the world with drastic repercussions. Several studies emphasized the inhibitory effect of Cannabidiol (CBD) on the reward properties of psychostimulants. The current investigation utilized conditioned place preference (CPP) to assay CBD's impact on MET's reward characteristic, including acquisition and expression phases of MET-induced CPP. Like our prior researches, animals received MET (1 mg/kg; sc) in a five-day schedule to induce CPP. The rats were given intracerebroventricular (ICV) microinjection of CBD (2, 10, and 50 μg/5 μL DMSO) during the 5-day conditioning phase in the CPP paradigm to highlight the CBD's impact on the development (acquisition) of MET-induced place preference. Furthermore, animals were treated with CBD (2, 10 and 50 μg/5 μL) in the lateral ventricle on the post-conditioning day to elucidate the effect of ICV injection of CBD on the expression of MET-induced CPP. It was revealed that CBD (10 and 50 μg/5 μL) microinjection profoundly inhibited both phases of MET-induced CPP without any side effect on the locomotion in animals were treated by MET injection over conditioning phase. Also, CBD's inhibitory impact was more potent in the acquisition phase than the expression phase of MET-induced CPP. Ultimately, the current research reported that CBD could be a beneficial compound to treat drug abuse however more investigations are needed.

Acute Pharmacological Effects of Oral and Intranasal Mephedrone: An Observational Study in Humans.

Mephedrone (4-methylmethcathinone) is a synthetic cathinone with psychostimulant properties which remains one of the most popular new psychoactive substances (NPS). It is frequently used orally and/or intranasally. To date, no studies have evaluated the acute effects and pharmacokinetics after self-administration of mephedrone orally (ingestion) and intranasally (insufflation) in naturalistic conditions. An observational study was conducted to assess and compare the acute pharmacological effects, as well as the oral fluid (saliva) concentrations of mephedrone self-administered orally and intranasally. Ten healthy experienced drug users (4 females and 6 males) self-administered a single dose of mephedrone, orally (n = 5, 100–200 mg; mean 150 mg) or intranasally (n = 5, 50–100 mg, mean 70 mg). Vital signs (blood pressure, heart rate, and cutaneous temperature) were measured at baseline (0), 1, 2, and 4 h after self-administration. Each participant completed subjective effects questionnaires: A set of Visual Analogue Scales (VAS), the 49-item Addiction Research Centre Inventory (ARCI), and Evaluation of the Subjective Effects of Substances with Abuse Potential (VESSPA-SSE) at baseline, 1, 2, and 4 h after self-administration. Oral fluid and urine were collected during 4 h. Both routes of mephedrone self-administration enhanced ratings of euphoria and well-being effects and increased cardiovascular effects in humans. Although it was at times assessed that the oral route produced greater and larger effects than the intranasal one, concentrations of mephedrone in oral fluid and also the total amount of mephedrone and metabolites in urine showed that concentrations of mephedrone are considerably higher when self-administered intranasally in comparison to orally. Controlled clinical trials are needed to confirm our observational results.

Behavioral Effects of 4-CMC and 4-MeO-PVP in DBA/2J Mice After Acute and Intermittent Administration and Following Withdrawal from Intermittent 14-Day Treatment

Synthetic cathinones appeared on the market in the 2000s as new psychoactive substances and gained significant prevalence among drug abusers. Cathinones produce psychostimulant and empathogenic effects by enhancing dopaminergic, noradrenergic, and serotoninergic neurotransmission in the brain, and those which potently and selectively enhance dopaminergic transmission are considered to have higher abuse potential. The present study examines the behavioral effects related to psychostimulant properties, abuse potential, and addiction in DBA/2J mice of two cathinones with different profile of action on monoamine system, 4-chloromethcathinone (4-CMC), and 4-methoxy-pyrrolidinopentiophenone (4-MeO-PVP). 4-CMC and 4-MeO-PVP increase spontaneous locomotor activity after acute treatment and produce behavioral sensitization after 7-day intermittent treatment, which is a common feature of drugs of abuse. 4-MeO-PVP, but not 4-CMC, produces conditioned place preference after 4 days, indicating its rewarding properties. Finally, the ability of 4-CMC and 4-MeO-PVP to induce withdrawal symptoms after discontinuation from 14-day treatment was assessed using a battery of tests for behavioral markers of depression in mice: a tail suspension test, a forced swim test, measuring despair, and a sucrose preference test, measuring anhedonia. None of the three tests revealed increased depressive symptoms. Moreover, neither spontaneous locomotor activity nor motor performance on a rotarod was impaired after 14-day treatment with the tested compounds. These results indicate that 14-day treatment of mice with 4-CMC or 4-MeO-PVP does not induce significant withdrawal symptoms after cessation, nor significant impairment of dopaminergic circuitry resulting in motor impairment. The current study shows that 4-CMC and 4-MeO-PVP produce abuse-related behavioral changes in mice, which are more pronounced after more dopamine-selective 4-MeO-PVP.

Syntheses and analytical characterizations of novel (2-aminopropyl)benzo[b]thiophene (APBT) based stimulants.

Two groups of amphetamine-like drugs with psychostimulant properties that were first developed during the course of scientific studies and later emerged as new psychoactive substances (NPS) are based on the (2-aminopropyl)indole (API) and (2-aminopropyl)benzofuran (APB) structural scaffolds. However, sulfur-based analogs with a benzo[b]thiophene structure (resulting in (2-aminopropyl)benzo[b]thiophene (APBT) derivatives) have received little attention. In the present investigation, all six racemic APBT positional isomers were synthesized in an effort to understand their structure-activity relationships relative to API- and APB-based drugs. One lesson learned from the NPS phenomenon is that one cannot exclude the appearance of such substances on the market. Therefore, an in-depth analytical characterization was performed, including various single- and tandem mass spectrometry (MS) and ionization platforms coupled to gas chromatography (GC) and liquid chromatography (LC), nuclear magnetic resonance spectroscopy (NMR), and solid phase and GC condensed phase infrared spectroscopy (GC-sIR). Various derivatizations have also been explored; it was found that all six APBT isomers could be differentiated during GC analysis after derivatization with heptafluorobutyric anhydride and ethyl chloroformate (or heptafluorobutyric anhydride and acetic anhydride) under non-routine conditions. Discriminating analytical features can also be derived from NMR, GC-EI/CI- single- and tandem mass spectrometry, LC (pentafluorophenyl stationary phase), and various infrared spectroscopy approaches (including GC-sIR). Availability of detailed analytical data obtained from these novel APBT-type stimulants may be useful to researchers and scientists in cases where forensic and clinical investigations are warranted.

Psychoactive Bath Salts and Neurotoxicity Risk.

Synthetic cathinones are new designer drugs that possess hallucinogenic and psychostimulant properties, and are designed to mimic the effects of illegal substances such as cocaine, amphetamines, and 3.4-methylenedioxymethamphetamine (ecstasy) and to produce rewarding effects, circumventing existing laws and penalties. Synthetic cathinones, also referred to as 'bath salts', have become popular particularly among young people since the mid-2000s. Similar to other psychomotor stimulants, synthetic cathinones have the potential to increase monoamine concentration in the synaptic cleft by targeting the plasma membrane transporters of dopamine, norepinephrine, and serotonin. Because of their structural similarities to amphetamines, it has been suggested that synthetic cathinones may have a neurotoxicity profile similar to that of their amphetamine congeners. Therefore, it has been hypothesized that synthetic cathinones may induce neurotoxicity on monoamine nerve endings in the striatum, hippocampus, and cortex. To date, with regard to synthetic cathinone neurotoxicity, parameters such as monoamine depletion, biosynthetic enzyme inhibition, cytotoxicity, generation of reactive oxygen species, pro-oxidation status, and the ability to induce neuroinflammation were investigated in both in vitro and in vivo experimental studies. Compared with amphetamines, synthetic cathinones appear to have more moderate effects than their amphetamine congeners in terms of neurotoxic effects. However, many synthetic cathinone users take these substances simultaneously with other substances such as benzodiazepines, amphetamines, ecstasy, tetrahydrocannabinol, and ethanol and this abuse can modify their neurotoxic effects. Hence, it is important to understand the underlying mechanism of early neurotoxic effects in case of polysubstance use. In this review, we aimed to present up-to-date information on the abuse potential of synthetic cathinones, their legal status, mechanism of action, and particularly their neurotoxic effects.