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amphetamine mixtures [keywords]
- Analysis of amphetamine-type substances and piperazine analogues using desorption electrospray ionisation mass spectrometry. [Journal Article]
- Rapid Commun Mass Spectrom 2014 Apr 15; 28(7):731-40.
Although amphetamine-type substances (ATS) have been investigated extensively in recent years, scarce data is available on screening tests for piperazine analogues. The need for a universal technique capable of detecting an extensive range of drug compounds becomes increasingly important with the continued emergence of novel drug analogues.Desorption electrospray ionisation mass spectrometry (DESI-MS) is a technique that allows examination of compounds in drug materials directly from ambient surfaces. In this study, DESI-MS was utilised in the analysis of ATS including amphetamine (AP), methylamphetamine (MA), 3,4-methylenedioxymethylamphetamine (MDMA), N,N-dimethylamphetamine (DMA), 4-methoxyamphetamine (PMA) and 4-methoxymethylamphetamine (PMMA), and piperazine analogues including 1-benzylpiperazine (BZP), 1-[3-(trifluoromethyl)phenyl]piperazine (TFMPP), 1-(3-chlorophenyl)piperazine (mCPP) and 1-(4-methoxyphenyl)piperazine (MeOPP). Semi-porous polytetrafluoroethylene (PTFE or Teflon) sheets welled with a 3 mm hole punch were used to contain the 2 μL liquid sample (spot size 7 mm(2) ).The limits of detection (LODs) of these compounds using DESI-MS were determined to be in the range 0.02-2.80 µg/mm(2) . The intra-day and inter-day precision of the technique were <25% and <33%, respectively. DESI-MS was successful in determining the compound of interest and reaction by-products and impurities in the samples tested (such as 1,4-dibenzylpiperazine in BZP samples) with the exception of those present in trace amounts. The effects of common adulterants on the detectability of MA were evaluated. The addition of magnesium stearate to MA significantly enhanced the signal response.This work has demonstrated the applicability of DESI-MS in the screening and profiling of MDMA, PMMA, BZP, TFMPP, mCPP, MeOPP as well as other complex mixtures. Copyright © 2014 John Wiley & Sons, Ltd.
- ["Legal highs" from the German internet--"bath salt drugs" on the rise]. [English Abstract, Journal Article]
- Arch Kriminol 2013 Sep-Oct; 232(3-4):91-103.
The appearance of dangerous and insufficiently studied designer drugs has increased substantially within the last few years. Mixtures containing centrally active compounds are often declared as "bath salt", "incense", "plant food", "bong cleaners" and are marketed in head shops and on the Internet. As the majority of the ingredients of such products are not subject to regulations of the German Narcotics Law (Betäubungsmittelgesetz, BtMG), the vendors and consumers mistake the sale of such products for legal. An alternative possibility to prosecute the distribution of so-called "legal highs" arises from the regulations of the German Medicinal Products Act (Arzneimittelgesetz, AMG). Indicating a private address, several products were purchased via the Internet. The products were analyzed by gas chromatography- mass spectrometry using computer-assisted database search and potential hits were checked for plausibility. The analysis of 100 samples revealed centrally acting compounds (including caffeine) in 98 % (75 % of all samples positive for caffeine). In 16 % of the samples, drugs subject to the BtMG at the time of purchase (end of 2011) were found including 2,5-dimethoxy-4-methylamphetamine, amphetamine, etilamphetamine, N-benzylpiperazine, mephedrone, methcathinone, and phenobarbital. In 55 % of the samples, drugs subject to the current BtMG were found (after its amendment on 20 July 2012). In 37 % of the samples, substances subject to the AMG were found (e.g. ephedrine). In 35 % of the samples, drugs with a potential psychotropic effect were found. In 57.3 % of the positive samples, more than one active ingredient was determined and in some cases up to five active components were found. Other interesting pharmacologically active ingredients found were 4-methylcathinone (n=13), flephedrone (n=8), trifluoromethylphenyl-piperazine (n=7), methylone (n=5), butylone (n=2), hordenine (n=2), and harmane (n=2). Most of the substances not covered by the BtMG can be classified as "unsafe" drugs. The distribution of unsafe drugs is illegal in Germany. However, the easy availability of real or potential drugs has to be seen critically. Little is known about the toxicological and pharmacological effects of those single substances, let alone of interactions in mixtures of such substances. In chat rooms, users advertise such drugs and blaze abroad their own experiences.
- Combination effects of amphetamines under hyperthermia - the role played by oxidative stress. [JOURNAL ARTICLE]
- J Appl Toxicol 2013 Jun 13.
Rise in body temperature is a life-threatening consequence of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) abuse. We evaluated the impact of hyperthermia on the cytotoxicity of combinations of MDMA and three other amphetamines, often co-ingested. For this, Hep G2 cells were exposed to MDMA, d-amphetamine, methamphetamine and 4-methylthioamphetamine, individually or combined, at 40.5 °C. The results were compared with normothermia data (37.0 °C). Mixture additivity expectations were calculated by independent action and concentration addition (CA) models. To delineate the mechanism(s) underlying the elicited effects, a range of stress endpoints was evaluated, including quantification of reactive oxygen/nitrogen species (ROS/RNS), lipid peroxidation, reduced/oxidized glutathione (GSH/GSSG), ATP and mitochondrial membrane potential (Δψm) changes. Our data show that, in hyperthermia, amphetamines acted additively and mixture effects were accurately predicted by CA. At 40.5 °C, even slight increases in the concentrations of each drug/mixture promoted significant rises in cytotoxicity, which quickly shifted from roughly undetectable to maximal mortality. Additionally, the increase of RNS/ROS production, decrease of GSH, ATP depletion and mitochondrial impairment were exacerbated under hyperthermia. Importantly, when equieffective cytotoxic concentrations of the mixture and individual amphetamines were compared for all tested stress endpoints, mixture effects did not deviate from those elicited by individual treatments, suggesting that these amphetamines have a similar mode of action, which is not altered in combination. Concluding, our data indicate that amphetamine mixtures produce deleterious effects, even when individual drugs are combined at negligible concentrations. These effects are strongly exacerbated in hyperthermia, emphasizing the potential increased risks of ecstasy intake, especially when hyperthermia occurs concurrently with polydrug abuse. Copyright © 2013 John Wiley & Sons, Ltd.
- Cytotoxic effects of amphetamine mixtures in primary hepatocytes are severely aggravated under hyperthermic conditions. [Journal Article, Research Support, Non-U.S. Gov't]
- Toxicol In Vitro 2013 Sep; 27(6):1670-8.
Amphetamine consumers are often, deliberately or not, polydrug abusers. Predicting combination effects based on concentration-response analysis of individual components is a valid strategy for accurate toxicological assessment of mixtures. We previously reported that joint effects of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) and three other often co-ingested amphetamines (methamphetamine, 4-methylthyoamphetamine and D-amphetamine) could be predicted by the concentration addition (CA) model in HepG2 cells. We sought to further evaluate the relevance of these findings by extending these studies to a cell model that more closely mimics the in vivo situation. Detailed cytotoxic information of the four individual amphetamines on primary rat hepatocytes was recorded by the MTT assay, at 37°C and 40.5°C, simulating the rise in body temperature that could be induced following amphetamine intake. Mixture expectations were calculated using CA and independent action (IA) models. At 37°C, concentration-dependent cytotoxicity occurred for the drugs individually and combined. Mixture effects were accurately predicted by the CA model, while the IA model underestimated cytotoxicity. At 40.5°C these cytotoxic effects were aggravated. Our findings provide evidence of the increased risks associated with the abuse of amphetamine mixtures, especially during hyperthermia, emphasising the need to increase awareness of misinformed users who believe these drugs are safe.
- Additive inhibition of human α1β2γ2 GABAA receptors by mixtures of commonly used drugs of abuse. [Journal Article, Research Support, Non-U.S. Gov't]
- Neurotoxicology 2013 Mar.:23-9.
Yearly, exposure to drugs of abuse results in ∼1 million emergency department visits in the US. In ∼50% of the visits, stimulant drugs like cocaine and amphetamine-like substances (e.g. 3,4-methylenedioxymethamphetamine (MDMA, the main active ingredient of ecstasy)) are involved, whereas in ∼60% multiple drugs are involved. These drugs induce higher dopamine and serotonin levels resulting in drug-induced toxicity. Since GABA receptors (GABA-R) provide the main inhibitory input on dopaminergic and serotonergic neurons, drug-induced inhibition of GABA-R could contribute to higher neurotransmitter levels and thus toxicity. We therefore investigated the effects of combinations of commonly abused stimulant drugs (cocaine, MDMA, 3,4-methylenedioxyamphetamine (MDA) and meta-chlorophenylpiperazine (mCPP)) on the function of the human α1β2γ2 GABAA receptor (hGABAA-R), expressed in Xenopus oocytes, using the two-electrode voltage-clamp technique. These drugs concentration-dependently inhibited the GABA-evoked current (mCPP>cocaine>MDMA>MDA). Most drug combinations decreased the GABA-evoked current stronger than the single drug. Additivity was observed during combined exposure to low concentrations of cocaine and mCPP as well as during combined exposure to MDA with cocaine or mCPP. However, combinations containing MDMA mainly resulted in sub-additivity or no additivity. At drug concentrations relevant for clinical toxicology, co-exposure to ≥2 drugs can decrease the GABA-evoked current in an additive manner. Thus, in patients exposed to multiple drugs, inhibitory GABA-ergic input is reduced more prominently, likely resulting in higher brain dopamine levels. As this will increase the risk for drug-induced toxicity, treatment of drug-intoxicated patients with drugs that enhance GABA-ergic input should be further optimized.
- Concentration ratios of methamphetamine to amphetamine in blood can help to distinguish use of methamphetamine from various mixtures of the two stimulants. [Journal Article]
- J Anal Toxicol 2012 Nov-Dec; 36(9):634-7.
Using a forensic toxicology database, the authors investigated cases of driving under the influence of drugs (DUID) if methamphetamine (MA) was identified in the blood samples (N = 9,310). The concentrations of MA and amphetamine (AM) in blood were determined after liquid-liquid extraction by gas chromatography-mass spectrometry at limits of quantitation of 0.03 mg/L for both stimulants. In 814 cases, AM was negative in blood and MA was positive at mean (median) and highest concentrations of 0.19 mg/L (0.11 mg/L) and 3.4 mg/L, respectively. Both amines were present in blood in 8,496 cases at concentrations of 0.54 mg/L (0.35 mg/L) and 10.4 mg/L for AM and 0.41 mg/L (0.22 mg/L) and 5.6 mg/L for MA. However, the correlation between AM and MA was low and insignificant (r = -0.13) in the whole material. The coefficient of correlation increased to r = 0.41 (P < 0.001) when the MA/AM concentration ratio was >1. When MA/AM ratios were selected at intervals of 1.0 (e.g., >3.0 and <4.0 up to >9.0 and <10.0), the correlation between AM and MA was r = 0.99 (P < 0.001). Such cases represent the use of MA without contamination from AM, and the mean (median) and highest concentrations of this secondary amine in blood of DUID suspects were 0.72 mg/L (0.56 mg/L) and 4.2 mg/L, respectively.
- The risky cocktail: what combination effects can we expect between ecstasy and other amphetamines? [Journal Article, Research Support, Non-U.S. Gov't]
- Arch Toxicol 2013 Jan; 87(1):111-22.
The recreational and illicit use of amphetaminic designer compounds, specially 3,4-methylenedioxymethamphetamine (MDMA; Ecstasy), is of concern worldwide. Such psychostimulating drugs are frequently present as complex mixtures in 'rave' pills, making concomitant polysubstance use a common trend. However, the understanding of possible combination effects with these substances is still scarce. The present study was aimed at predicting the cytotoxic effects of mixtures of four amphetaminic derivatives: MDMA, methamphetamine, 4-methylthioamphetamine and d-amphetamine in a human hepatoma cell line. Concentration-response curves for all single-mixture components were recorded by the MTT assay. Data obtained for individual agents were then used to compute the additivity expectations for mixtures of definite composition, using the pharmacological models of concentration addition (CA) and independent action. By comparing the predicted calculations with the experimentally observed effects, we concluded that CA accurately predicts the combination of amphetamines, which act together to generate additive effects over a large range of concentrations. Notably, we observed substantial mixture effects even when each drug was present at low concentrations, which individually produced unnoticeable effects. Nonetheless, for all tested mixtures, a small deviation from additivity was observed towards higher concentrations, particularly at high effect levels. A possible metabolic interaction, which could explain such deviation, was investigated, and it was observed that at higher mixture concentrations increased MDMA metabolism could be contributing to divergences from additivity. In conclusion, the present work clearly demonstrates that potentially harmful interactions among amphetaminic drugs are expected when these drugs are taken concomitantly.
- Use of intracranial self-stimulation to evaluate abuse-related and abuse-limiting effects of monoamine releasers in rats. [Journal Article, Research Support, N.I.H., Extramural]
- Br J Pharmacol 2013 Feb; 168(4):850-62.
Monoamine releasers constitute a class of drugs that promote the release of dopamine (DA), serotonin (5-HT) and/or norepinephrine. Although some drugs in this class are well-known drugs of abuse (amphetamine, methamphetamine), others are thought to have reduced (3,4-methylenedioxy-N-methylamphetamine [MDMA]) or no (fenfluramine) abuse potential. The purpose of this study was to further elucidate the role of dopamine versus serotonin selectivity on expression of abuse-related effects produced by monoamine releasers in an assay of intracranial self-stimulation (ICSS) in rats.This study evaluated effects produced in a frequency-rate ICSS procedure by 11 monoamine releasers that vary in selectivity to release DA versus 5-HT.Efficacy of monoamine releasers to facilitate ICSS correlated with DA-selectivity, such that DA-selective releasers exclusively facilitated ICSS, a 5-HT-selective releaser exclusively depressed ICSS, and mixed-action releasers both facilitated low ICSS rates and depressed high ICSS rates. Fixed-proportion mixtures of a DA-selective releaser and a 5-HT-selective releaser recapitulated effects of mixed-action releasers. Efficacy of monoamine releasers to facilitate ICSS also correlated with previously published data on efficacy to maintain self-administration in rhesus monkeys responding under a progressive-ratio schedule of reinforcement.These data support the importance of selectivity for DA versus 5-HT in determining abuse potential of monoamine releasers and demonstrate a novel correlation between rat ICSS and nonhuman primate self-administration measures of abuse-related effects. Taken together, these results support the use of ICSS in rats as an experimental tool to study the expression and pharmacological determinants of abuse-related effects of monoamine releasers.
- Illicit drugs and the environment--a review. [Journal Article, Research Support, Non-U.S. Gov't]
- Sci Total Environ 2013 Oct 1.:1079-92.
Illicit drugs and their metabolites are the latest group of emerging pollutants. Determination of their concentration in environment (such as water bodies, soil, sediment, air) is an indirect tool to estimate the community level consumption of illicit drug and to evaluate potential ecotoxicological impacts from chronic low level exposure. They enter the wastewater network as unaltered drugs and/or their active metabolites by human excretion after illegal consumption or by accidental or deliberate disposal from clandestine drug laboratories. This article critically reviews the occurrence and concentration levels of illicit drugs and their metabolites in different environmental compartments (e.g., wastewater, surface waters, groundwater, drinking water, and ambient air) and their potential impact on the ecosystem. There is limited published information available on the presence of illicit drugs in the environment, reports are available mainly from European countries, UK, USA, and Canada but there is a lack of information from the remainder of the world. Although the environmental concentrations are not very high, they can potentially impact the human health and ecosystem functioning. Cocaine, morphine, amphetamine, and MDMA have potent pharmacological activities and their presence as complex mixtures in water may cause adverse effect on aquatic organisms and human health. However, there is no current regulation demanding the determination of occurrence of these emerging pollutants in treated wastewater, surface water, drinking water, or atmosphere. Thus, critical investigation on distribution pattern of this new group of emerging contaminant and their potential harmful impact on our environment needs immediate attention.
- The amphetamine-chlordiazepoxide mixture, a pharmacological screen for mood stabilizers, does not enhance amphetamine-induced disruption of prepulse inhibition. [Journal Article]
- Behav Brain Res 2011 Nov 20; 225(1):377-81.
In rodents, administration of a mixture of the psychostimulant d-amphetamine and the benzodiazepine chlordiazepoxide results in supra-additive hyperlocomotion, a phenomenon used to identify mood stabilizers. In an attempt to determine whether the d-amphetamine/chlordiazepoxide assay could extend to other behaviors that are affected in mania, we evaluated the effects of the mixture on prepulse inhibition. In addition, we combined chlordiazepoxide with the selective dopamine reuptake inhibitor GBR 12909 or the noradrenergic stimulant (-) ephedrine, and tested these alternative mixtures in locomotor activity and prepulse inhibition tests. Chlordiazepoxide (3mg/kg) robustly potentiated amphetamine-induced hyperactivity, but did not change the amphetamine-induced disruption of prepulse inhibition. This indicates that the d-amphetamine-chlordiazepoxide-induced hyperlocomotion does not extend to other dopamine-driven behaviors. GBR 12909 (16mg/kg) and (-) ephedrine (50mg/kg) both enhanced locomotor activity and disrupted PPI, but combined treatment of either of these compounds with chlordiazepoxide had no significant additive effect on locomotor activity or prepulse inhibition. These findings suggest that the effect of the d-amphetamine/chlordiazepoxide mixture cannot be accounted for by the dopamine enhancing properties of amphetamine alone. Last, valproic acid (120-240mg/kg) did not reduce the GBR-induced hyperactivity. Therefore, further pharmacological evaluation of GBR 12909-induced hyperactivity is warranted to determine its pharmacological potential to model mania-like behavior. Based on the current results, it is concluded that the utility of the pharmacological d-amphetamine/chlordiazepoxide assay as a tool to study brain mechanisms relevant to mania is limited.