The options included placebo, benzodiazepine e. The VAS were administered at: min baseline , 0. The pharmacological class identification questionnaire was given at 8 h following initial drug administration. Blood samples for the determination of mephedrone were collected during each experimental session at -5 min 0 h, baseline , 0.
Urine was collected until 24 h data not shown. Mephedrone plasma concentrations were quantified by gas chromatography-mass spectrometry GC-MS. A liquid—liquid extraction was performed with tert-butyl methyl etherm and the silylation reagent [N-methyl-N- trimethylsilyl trifluoroacetamide] was used for the derivatization of mephedrone Papaseit et al. Blood samples for the determination of alcohol were collected during each experimental session at -5 min 0 h, baseline , 0. Blood samples for the determination of cortisol were collected during each experimental session at -5 min 0 h, baseline , 1, 2, 4, 6, and 8 h following drug administration.
Values from physiological and subjective effects were transformed to differences from baseline. The peak effects in the first 6 h after first drug administration maximum absolute change from baseline values, E max , and the 6-h area under the curve AUC of effects versus time were calculated by the trapezoidal rule for each variable.
Area under the concentration-time curve from mephedrone, alcohol and cortisol AUC , mephedrone AUC , and alcohol AUC were calculated by the linear trapezoidal rule. Firstly, these transformations were analyzed using a two-way analysis of variance ANOVA test to study the influence of some participant factors as age, body mass index, weight, smoking and alcohol use in the different parameters calculated. Subsequently, the statistical analysis presented was performed without considering those factors.
Then, these transformations were analyzed by means of one-way repeated-measures analysis of variance ANOVA with drug condition as factor.
In case of significant differences among treatment conditions in ANOVA, post-hoc multiple comparisons were performed using the Tukey test. The difference in time to reach peak effects T max values among conditions was assessed with the nonparametric Friedman test. Table 1 shows the summary of physiological and subjective effects where at least one statistical difference peak, AUC was found in the ANOVA and multiple comparison post-hoc test analyses.
The T-C differences from baseline for the most relevant physiological, psychomotor, and subjective effects are shown in Figures 1 and 2 , respectively. Concentrations over time and pharmacokinetic parameters of mephedrone and alcohol in plasma are presented in Figure 3 and Table 3 , respectively. No serious adverse events were observed.
No hallucinations, psychotic episodes, or any other psychiatric symptoms were experienced during the sessions. None of the participants required specific therapy or special care during the study. All 11 subjects completed the study.
Regarding physiological effects, the two conditions including mephedrone combination condition and mephedrone condition produced an increase in SBP, DBP, HR, and PD as compared with the placebo condition when considering both peak effects and AUC.
The more relevant differences for HR increase appeared between the combination and mephedrone conditions. In statistical terms, only significant differences were detected for AUC Esophoria induced by the combination condition was approximately two to three-fold lower The combination condition scored approximately midway between the mephedrone and alcohol conditions.
In general terms, the combination condition produced higher and more prolonged scores with statistically significant differences in AUC and several T-C points compared with mephedrone alone. As expected, statistically significant differences were detected in drunkenness rating scores between conditions AUC, peak, T max , and T-C, Tables 1 and 2.
For the other subscales only significant differences were detected at several T-C points. Conversely, for the LSD subscale no significant differences were detected between both conditions. Alcohol produced a statistically significant increase in the PCAG-sedation subscale in comparison to placebo.
Compared with the alcohol condition, the combination with mephedrone reduced the sedation induced by alcohol peak effect 6. In contrast, MBG peak difference scores were lower for alcohol compared to the combination condition 2.
The combination condition, in comparison to the mephedrone one, presented statistical differences in peak effects for ACT activity and energy and ANX psychosomatic anxiety subscales and in several T-C points for all the subscales Tables 1 and 2. For the mephedrone condition mephedrone plus placebo , mephedrone was identified by eight subjects as a designer drug All the active conditions mephedrone, alcohol, and the combination were well tolerated and no mania, hallucinations or psychotic reactions were observed or reported during the study.
The pharmacokinetic parameters for mephedrone and alcohol are summarized in Table 3 and Figure 3. When the two conditions containing mephedrone were compared, no significant differences were found in the pharmacokinetic parameters Table 3.
In the combination condition, mephedrone concentrations peaked at 1. In the mephedrone condition, mephedrone concentrations peaked at 1. In both conditions, at 10 h following first drug administration, mephedrone concentrations declined to mean values of Regarding alcohol, significant differences in pharmacokinetics were detected. Alcohol concentrations peaked at 2 h in the combination condition and at 1. Significant differences in AUC were detected between alcohol and combination conditions.
Kinetic parameters for cortisol are summarized in Tables 1 and 2. Plasma cortisol concentrations were significantly higher peak and AUC after the administration of the combination and mephedrone conditions as compared with placebo. Cortisol concentrations peaked at 2 h with a mean peak of The combination condition also showed significant differences in comparison to alcohol, cortisol concentrations peaked at 2 h with a mean peak of AUC for combination, mephedrone and alcohol conditions were Significant differences in peak, AUC and several T-C points 1 and 2 h were observed between the combination and mephedrone conditions in comparison to placebo, and also between alcohol and the combination conditions in comparison to mephedrone.
To the best of our knowledge, this study provides the first data in humans about the pharmacodynamics and pharmacokinetics of mephedrone and alcohol interactions and completes previous results on neurocognitive performance effects de Sousa Fernandes Perna et al. Our findings demonstrate the increased pharmacological effects of the co-administration of mephedrone and alcohol compared to single drug administration.
The mg oral administration of mephedrone reproduced pharmacological effects which concurred with the sole experimental study performed to date in humans Papaseit et al, It also induced stimulant-like effects euphoria, well-being, feelings of pleasure and mild changes in perceptions.
All these physiological and subjective effects were of rapid onset and short duration. Moreover, its faster and shorter duration confirmed results obtained in the previous human investigation Papaseit et al. The administration of an oral dose of 0. The co-administration of mephedrone and alcohol amplified cardiovascular effects, producing a more marked increase in HR in comparison with mephedrone alone.
In turn, these results are consistent with a previous description of cardiovascular toxicity associated with mephedrone and alcohol co-ingestion McGaw and Kankam, In addition, the combination of mephedrone and alcohol produced mydriasis and esophoria, an indicator of extraocular muscle tension, two specific acute psychostimulant-like effects, although slighter in comparison to mephedrone alone.
These results are in line with those observed after other psycho-stimulant drugs and alcohol co-administration Mas et al. Alcohol, as expected from the extrapolation of results obtained from other psychostimulant-alcohol interaction studies, attenuated the rise in PD and extraocular musculature contraction induced by mephedrone. Furthermore, the addition of alcohol to mephedrone increased the maximal psychostimulant effects, maintaining higher measures for euphoria and well-being for a longer period of time in comparison to mephedrone alone, which maximal effects are faster Papaseit et al.
Among conditions, the most remarkable difference was in the mephedrone-alcohol combination. It produced during 4 h relevant increases in subjective scores which were intense during the three first hours compared with 1—2 h following mephedrone alone.
Alcohol administration, equivalent four to six alcoholic beverages, in combination with mephedrone resulted in decreased drunkenness and reduced sedative effects producing mixed scores ARCI-PCAG and VAS drowsiness between the mephedrone and alcohol alone conditions.
Overall, the combination of mephedrone and alcohol slightly delayed peak effects and increased maximal effects which remained high with no changes in their total duration.
Cardiovascular and subjective effects after mephedrone-alcohol co-administration started at 0. In general terms, mephedrone induced lower effects than the combination and almost overlapped with our own observations in a previous study in which the same dose of mephedrone was administered Papaseit et al. Mephedrone effects were observed between 0. With respect to the pharmacokinetics of the mephedrone-alcohol combination, the most relevant finding was that alcohol did not modify the plasma levels of mephedrone.
The maximal concentrations of mephedrone after the combination administration were within the range of those obtained after mephedrone alone and concurred with previously published data Papaseit et al. This finding suggests that the pharmacokinetics of mephedrone is not altered when alcohol is concurrently administered. With reference to alcohol pharmacokinetics, statistically significant differences were detected in C max , AUC, and T max.
In the case of mephedrone, initial results suggest a similar kinetic scenario. An adequate pharmacological effect in relation to pharmacokinetics was thus observed despite the biological variability among subjects.
It should be emphasized that the short mephedrone half-life and T max following its co-administration with alcohol could partially explain the mephedrone-alcohol binge pattern among regular users.
Higher increases in cortisol plasma concentrations were found after the mephedrone-alcohol co-administration and mephedrone alone in comparison to the rest of conditions. As far as we know, the precise mechanism of this effect is poorly understood. Although the role of cortisol in the acute effects of mephedrone has as yet to be described, it could be extrapolated to MDMA and related-amphetamines Mas et al. The serotonergic effects of mephedrone might stimulate the hypothalamo-pituitary-adrenal axis, leading to an increase in cortisol plasma concentrations as previously described by other psychostimulants as MDMA Seibert et al.
Integrating the results of the present study and the previous one on psychomotor performance de Sousa Fernandes Perna et al. This dissociation between subjective and objective sedation measures is of interest. Subjects may feel less sedated by alcohol and psychomotor abilities remain impaired or unchanged. The potential impact of this dissociation in terms of driving safety is unknown, but it may be plausible that subjects would consider they are driving better when actual performance continues to be impaired by the effect of alcohol.
Similar dissociation has been reported when other psychostimulants e. The present study has several limitations which are mainly associated with its experimental design. Firstly, the moderate sample size. Secondly, a non-representative sample that not allows to generalize the results across gender absence of women due to unknown and potential seriously fetal risk. Thirdly, the evaluation of only one dose level of mephedrone and alcohol users usually are subjected to repeated drug consumption in a single session.
Fourthly, the alcohol blind was potentially insufficient. Nonetheless, we conducted a placebo controlled study, randomized, within-subjects, various control conditions combination condition, mephedrone condition, alcohol condition, and placebo condition. The results provide novel data on pharmacodynamics and pharmacokinetics of mephedrone-alcohol combination.
In summary, the concomitant administration of mephedrone and alcohol produced a significant increase in cardiovascular effects and induced more intense and prolonged feelings of euphoria and well-being, in comparison to mephedrone alone. Mephedrone reduced the drunkenness and sedation produced by alcohol. For example, they move a small part of the molecule, or replace it with another part. Or they add an extra chemical group to the molecule, like a chlorine, bromine or fluorine atom or a methyl group -CH3.
The starting point for the synthesis of an NPS is frequently the basic molecular structure of known and popular drugs, such as amphetamine, fentanyl or tryptamine. Some new psychoactive substances are developed by the pharmaceutical industry in its search for new medicines, while others are developed by clandestine laboratories. The figures below, taken from the EMCDDA annual report, show that tens of new, unique substances appear on the market every year, and that the total number of NPSs on the European market currently exceeds Source: Dec.
Regulatory bodies inevitably lag behind in imposing a possible prohibition on an NPS. The moment a new substance is forbidden, the designer can synthesize another one that is a lot like it. In some countries, the legislation is such that an NPS whose structure is derived from, or is very similar to, that of a prohibited substance, is itself also prohibited. In other countries, including the Netherlands, this is not the case. The new Opium Act is only expected to enter into force in However, because of the chemical differences, there are often no legislative restrictions on their manufacture and distribution.
As mephedrone is relatively new to the market, there is little existing research into its effects, pharmacology and toxicity. SMART teams work with Governments to develop, assess and report data and information on synthetic drugs, assisting countries in planning their prevention and law enforcement responses.
United Nations.
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