The effect of methamphetamine and 3,4-methylenedioxymethamphetamine on peripheral endocannabinoid concentrations: a study in healthy adults.

We describe the use of hair roots as a matrix for detection of methamphetamine (MP) and 3,4-methylenedioxymethamphetamine (MDMA) abuse. The concentration of drugs was determined in rat hair roots, hair shafts, and plasma after a single administration of MP or MDMA, by use of an HPLC-peroxyoxalate chemiluminescence (PO-CL) method involving column switching. Plasma and hair roots and shafts were collected from male Wistar rats before and after administration of MP (10 mg kg(-1), i.p.). In addition, the roots and shafts of pigmented and non-pigmented hair of male Lister hooded rats were collected after administration of MDMA (10 mg kg(-1), i.p.). The concentrations of MP and MDMA in plasma and hair were determined by use of the HPLC-PO-CL method, with satisfactory sensitivity and reproducibility. The concentration of MP in hair roots 1-14 days after administration ranged from 0.038 to 0.115 ng mg(-1) (n = 3). By use of the HPLC-PO-CL method, MP could be detected in hair roots for longer (up to 14 days) than it could be detected in conventional biological specimens, for example plasma (~1 day), and MDMA was detected in hair roots from 1 to 10 days after administration. The AUC(1-10) (ng day mg(-1)) for MDMA in roots of non-pigmented and pigmented hair was comparable (4.93 ± 2.09 vs. 6.67 ± 1.28, n = 3), whereas AUC(1-14) for hair shafts differed significantly (1.86 ± 0.93 vs. 4.58 ± 0.63, P < 0.05, n = 3). The window for detecting MP (or MDMA) in hair roots under our conditions was 1-14 (or 1-10) days.

Do cosmetic treatments increase the incorporation of amphetamines into hair?

Methamphetamine and 3,4-methylenedioxymethamphetamine interact with central nicotinic receptors and induce their up-regulation

Methamphetamine (MA) and 3,4-methylenedioxymethamphetamine (MDMA) are empathogen (entactogen) psychoactive designer drugs which are mainly used for recreational purposes. Both MA and MDMA are central nervous system stimulants which are classified as monoamine neurotransmitter reuptake inhibitors. They have strong cytotoxic effects on dopaminergic and serotonergic neurons. Neurotoxicities of MA and MDMA by glial activation have been shown. The present work has investigated and measured cytotoxic, necrotic and apoptotic, and autophagic effects of MA and MDMA on U-87 MG (glial) and B104-1-1 (neuronal) cell lines by janus green, ethidium bromide/acridine orange, and monodansylcadaverine/propidium iodide staining to evaluate and compare their effects on glial and neuronal cells, respectively. The results of the present work showed that: (1) MDMA induced more potent mitochondrial toxicity, stronger necrotic and autophagic effects than MA in both B104-1-1 (neuronal) and U-87 MG (glial) cell lines; (2) although MDMA induced stronger apoptotic effect than MA on U-87 MG cell line, it had equal apoptotic effect on B104-1-1 cell line with MA; and (3) MDMA induced more potent mitochondrial toxicity, stronger necrotic, apoptotic, and autophagic effects than MA in B104-1-1 cell line than U-87 MG cell line.

Methamphetamine (METH) and 3,4-methylenedioxymethamphetamine (MDMA) are common drugs of abuse and driving under their influence may occur in 1million people yearly in the United States. This systematic review fills the currently unmet need in understanding the effects of METH and MDMA on motor vehicle driving performance (MVP) and provides insight into the forensic community. A PubMed search on September 24, 2020, for experimental and observational studies, which evaluated the impact of METH and MDMA on MVP was performed. After a review of 208 abstracts, 103 were considered potentially interesting and full texts were obtained. After the exclusion of non-English articles, review articles, single case reports, and articles which did not evaluate METH or MDMA on MVP, a total of nine experimental studies, 10 traditional observational studies, and 35 case series were included. The clinical rigor of experimental studies was evaluated using the Jadad scale. Experimental studies often demonstrated no significant MVP safety signals for METH or MDMA use, which was contrary to the overwhelming MVP safety risks found in observational studies. Common driving behaviors while using METH or MDMA include: errors in judgment, traveling at high speeds, failure to stop, merging inappropriately, lane weaving, and crashes. Limitations of experimental studies that led to dissimilar MVP outcomes from observational studies include: the common use of driving simulators, as opposed to actual driving examinations, and doses of METH or MDMA administered may not be representative of blood concentrations seen in observational studies. This systematic review has no funding source and was not registered.

Synthetic psychoactive cathinones: hypothermia and reduced lethality compared to methamphetamine and methylenedioxymethamphetamine

Neurotoxicity of amphetamine derivatives is mediated by caspase pathway activation in rat cerebellar granule cells

Repeated administration of beta-phenylalkylamines is known to produce neuronal changes in the central and peripheral nervous systems of mammals. It is suggested that various components of the cytoskeleton undergo profound alterations after amphetamine use and misuse, contributing to behavioral changes and neurotoxicity. Here we studied the expression of microtubule-associated protein 2 (MAP2) and beta-actin after repeated intraperitoneal applications with equimolar doses of p-chloroamphetamine (PCA), methamphetamine (METH) and 3,4-methylenedioxymethamphetamine (MDMA) in the brain of male Wistar rats. Effective (molecular) pharmacological doses (ED) were derived and used for the calculation of (molecular) pharmacological indices (PI). Besides clear but different dose-response curves on the toxicity of the drugs, in situ hybridization and Western blot analysis revealed that repeated administration of these compounds resulted in different substance- and dose-dependent changes in MAP2 gene expression, e.g. in the frontoparietal somatosensoric cortex. In contrast, the expression of beta-actin was not influenced by any of the compounds at the dose levels tested. Lethal doses were determined with 2.1 (PCA), >5.1 (METH) and 8.4 mg/kg/day (MDMA). Linear and non-linear repeat-dose lethality was observed for MDMA and PCA, respectively, whereas METH was non-lethal in the dose range used. Values for ED(MAP2) were 0.3, 0.52 and >16.8 mg/kg/day, and therefore those for PI(MAP2) were 20, 4, and 0.5 for METH, PCA and MDMA, respectively. Although the results on mortality did not reflect changes in MAP2 gene expression, they suggest a remarkable difference for those amphetamines without substituents or with a halogen atom at the paraposition of the benzene ring, such as METH or PCA, when compared with MDMA-like substances.

Despite their chemical similarities, methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA) produce differing neurochemical and behavioral responses in animals. In humans, individual studies of methamphetamine and MDMA indicate that the drugs engender overlapping and divergent effects; there are only limited data comparing the two drugs in the same individuals. This study examined the effects of methamphetamine and MDMA using a within-subject design. Eleven adult volunteers completed this 13-day residential laboratory study, which consisted of four 3-day blocks of sessions. On the first day of each block, participants received oral methamphetamine (20, 40 mg), MDMA (100 mg), or placebo. Drug plasma concentrations, cardiovascular, subjective, and cognitive/psychomotor performance effects were assessed before drug administration and after. Food intake and sleep were also assessed. On subsequent days of each block, placebo was administered and residual effects were assessed. Acutely, both drugs increased cardiovascular measures and "positive" subjective effects and decreased food intake. In addition, when asked to identify each drug, participants had difficulty distinguishing between the amphetamines. The drugs also produced divergent effects: methamphetamine improved performance and disrupted sleep, while MDMA increased "negative" subjective-effect ratings. Few residual drug effects were noted for either drug. It is possible that the differences observed could explain the differential public perception and abuse potential associated with these amphetamines. Alternatively, the route of administration by which the drugs are used recreationally might account for the many of the effects attributed to these drugs (i.e., MDMA is primarily used orally, whereas methamphetamine is used by routes associated with higher abuse potential).

BackgroundThe endocannabinoid (eCB) system is a neuromodulatory system that plays a significant role across a variety of behaviors critical to health and well-being, including stress reactivity, reward processing, and social interaction. While it is appreciated how exogenous cannabinoid administration (e.g., cannabis use) can impact this system, recent work has shown that the eCB system is impacted by acute and chronic use of other drug classes, as well. The eCB system has a rich pharmacology that allows for multiple methods of targeting, apart from direct receptor binding. Thus, understanding how acute and chronic drug exposure impacts eCB function and related behaviors may highlight novel pharmacotherapeutic opportunities.Aims & ObjectivesOur goal is to explore how acute and chronic opioid exposure impacts the eCB system and related behaviors.MethodIn a series of studies, we have collected blood samples to assess peripheral levels of eCB system ligands and will relate these to opioid exposure and stress sensitivity. First, we will highlight recently published data in healthy adults and chronic, non-medical opioid users, highlighting differences in circulating eCB levels that relate to feelings of social exclusion. Next, we will provide data from a double-blind, within-subject, placebo-controlled oxycodone administration study in healthy adults exposed to a social stressor, showing striking gender differences.ResultsBroadly, our result suggest a critical link between opioid-induced changes in eCB function and stress sensitivity. Chronic opioid exposure impacts concentrations of eCB ligands, which relates to feelings of social exclusion. Ongoing analyses are currently whether this relationship exists following acute opioid administration. Moreover, we will briefly compare these effects to recent work exploring similar impacts of alcohol and stimulant exposure in humans, profiling the shared and unique ways in which the eCB system is impacted by substance us and may subsequently contribute to long-term dysregulation of stress processing.Discussion & ConclusionsTogether, this work will highlight the eCB system as a critical target mediating stress and substance use in humans, suggesting novel therapeutic opportunities for substance use disorders, including opioid use disorder.

The long-term neurochemical effects produced by the repeated administration of methamphetamine (MA) and 3,4-methylenedioxymethamphetamine (MDMA) are well documented; however, the functional consequences have not been clearly defined. The present study was designed to investigate whether rats treated with a monoamine-depleting regimen of MA or MDMA exhibit disturbances in locomotor activity during the diurnal and nocturnal cycles. Rats were treated with the vehicle or a monoamine-depleting regimen of MA or MDMA (10 mg/kg, IP, every 2 h for four injections on a single day). One week after drug treatment, the rats were placed in residential activity chambers and their locomotor activity was monitored for the next 7-day/night cycles. MA-treated rats exhibited depletions of striatal dopamine and serotonin content of approximately 70%, whereas MDMA-treated rats showed depletions of striatal serotonin content of approximately 50%. Rats treated with MA demonstrated a significant reduction in diurnal, but not nocturnal, locomotor activity, whereas MDMA-treated rats exhibited significant reductions in both diurnal and nocturnal locomotor activity. Analysis of the difference in activity between the nocturnal and diurnal cycles revealed that MA-treated animals exhibited a significantly greater change in activity as compared to that observed in vehicle- and MDMA-treated rats. Although it is unknown whether the adaptations in locomotor activity observed in MA- and MDMA-treated rats are due to the loss of dopamine and/or serotonin, these data suggest that the administration of a monoamine-depleting regimen of MA or MDMA results in alterations in light-cycle-dependent locomotor activity.

Histamine H3 receptors inhibit the release of not only histamine itself, but also other neurotransmitters including dopamine. Previous papers have reported that histaminergic neurons inhibit psychostimulant-induced behavioral changes. To examine whether deficiency in histamine H3 receptors influences psychostimulant-induced behavioral sensitization and reward, we examined locomotor activity, conditioned place preference (CPP), and c-Fos expression in histamine H3 receptor–gene knockout mice (H3KO) and their wild-type (WT) counterparts before and after treatment with methamphetamine (METH) and 3,4-methylenedioxymethamphetamine (MDMA). The increase in locomotion induced by treatment with METH or MDMA was lower in histamine H3KO mice than in WT mice, while the locomotor sensitization was developed by METH or MDMA in both strains. However, no significant difference in METH- and MDMA-induced preference scores of CPP between histamine H3KO mice and WT mice was observed. Following treatment with METH, the number of c-Fos–positive neurons in the the caudate-putamen of histamine H3KO mice was lower than that in the caudate-putamen of WT mice. In contrast, there was no significant difference in the number of the psychostimulant-induced c-Fos–positive cells in the nucleus accumbens between the two strains of mice. These findings suggest that deficiency in histamine H3 receptors may have inhibitory effects on psychostimulant-induced increase in locomotion, but insignificant effects on the reward.

Simultaneous determination of methamphetamine, MDMA, and ketamine and their metabolites in urine using a rapid and simple HS-SPME-GC-MS method: A forensic study on drug abuse patterns in South Korea.

Most reports of the effects of methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA) on speech have been anecdotal. The current study used a within-participant design to assess the effects of methamphetamine and MDMA on speech. Eleven recreational users of amphetamines completed this inpatient, within-participant, double-blind study, during which they received placebo, methamphetamine (20, 40 mg), and MDMA (100 mg) on separate days. Following drug administration, study participants described movies viewed the previous evening and completed mood scales. Methamphetamine increased quantity of speech, fluency, and self-ratings of talkativeness and alertness, while it decreased the average duration of nonjuncture unfilled pauses. MDMA decreased fluency and increased self-ratings of inability to concentrate. To determine if methamphetamine- and MDMA-related effects were perceptible, undergraduates listened to the participants' movie descriptions and rated their coherence and the speaker's mood. Following methamphetamine, descriptions were judged to be more coherent and focused than they were following MDMA. Methamphetamine improved verbal fluency and MDMA adversely affected fluency. This pattern of effects is consistent with the effects of these drugs on functioning in other cognitive domains. In general, methamphetamine effects on speech were inconsistent with effects popularly attributed to this drug, while MDMA-related effects were in agreement with some anecdotal reports and discordant with others.

The amphetamines, including amphetamine (AMPH), methamphetamine (METH) and 3,4-methylenedioxymethamphetamine (MDMA), are among abused drugs in the US and throughout the world. Their abuse is associated with severe neurologic and psychiatric adverse events including the development of psychotic states. These neuropsychiatric complications might, in part, be related to drug-induced neurotoxic effects, which include damage to dopaminergic and serotonergic terminals, neuronal apoptosis, as well as activated astroglial and microglial cells in the brain. The purpose of the present review is to summarize the toxic effects of AMPH, METH and MDMA. The paper also presents some of the factors that are thought to underlie this toxicity. These include oxidative stress, hyperthermia, excitotoxicity and various apoptotic pathways. Better understanding of the cellular and molecular mechanisms involved in their toxicity should help to generate modern therapeutic approaches to prevent or attenuate the long-term consequences of amphetamine use disorders in humans.