Depressive mood ratings are reduced by MDMA in female polydrug ecstasy users homozygous for the l-allele of the serotonin transporter

Altres ajuts: Dutch Organisation for Scientifc Research, 400-07-213, 400-05-096, 400-07-2013MDMA exerts its main effects via the serotonergic system and the serotonin transporter. The gene coding for this transporter determines the expression rate of the transporter. Previously it was shown that healthy individuals with the short allelic variant ('s-group') of the 5-HTTLPR-polymorphism displayed more anxiety and negative mood, and had a lower transcriptional efficiency compared to individuals who are homozygous for the l-allele ('l-group'). The present study aimed to investigate the role of the 5-HTTLPR polymorphism in MDMA-induced mood effects. Four placebo-controlled, within-subject studies were pooled, including in total 63 polydrug ecstasy users (N = 48; N = 15) receiving MDMA 75 mg and placebo on two test days, separated by minimally 7 days. Mood was assessed by means of the Profile of Mood States. Findings showed that MDMA induced -independent of sex- a positive mood state, and as a side effect also increased two negative affect states, anxiety and confusion. Anxiety ratings were higher in the l-group and independent of treatment or sex. Depression ratings were lowered by MDMA in the female l-group. Findings indicate that the MDMA-induced reduction in self-rated depressive feelings is sex- and genotype-dependent, with females homozygous for the l-allele showing this beneficial effect

Analysis of 4-fluoroamphetamine in cerumen after controlled oral application

Cerumen was found to be a promising alternative specimen for the detection of drugs. In a pilot study, drugs of abuse were identified at a higher detection rate and a longer detection window in cerumen than in urine. In this study, cerumen from subjects was analyzed after they ingested the designer stimulant 4-fluoroamphetamine (4-FA) in a controlled manner. Methods: Twelve subjects ingested placebo and 100 mg of 4-FA. Five of them were also given 150 mg of 4-FA in 150 mL Royal Club bitter lemon drink at least after 7 days. Cerumen was sampled using cotton swabs at baseline, 1 h after the ingestion of the drug and at the end of the study day (12 h). After extraction with ethyl acetate followed by solid-phase extraction, the extracts were analyzed using liquid chromatography coupled with tandem mass spectrometry (LC–MS/MS). Results and discussion: In the cerumen of all 12 subjects, 4-FA was detected 12 h after its ingestion; in most subjects, cerumen was detected after 1 h of ingestion, ranging from 0.06 to 13.90 (median 1.52) ng per swab. The detection of 4-FA in cerumen sampled 7 days or more after the first dose suggested a long detection window of cerumen. Conclusions: Cerumen can be successfully used to detect a single drug ingestion even immediately after the ingestion when a sufficient amount of cerumen is used

Safety profile and neurocognitive function following acute 4-fluoroamphetamine (4-fa) administration in humans

Availability of novel psychoactive substances (NPS) exponentially increased over the last years. Risk evaluations of NPS are hampered by the lack of pharmacological studies in humans on health parameters. The aim of the present study was to evaluate safety and neurocognitive function of healthy volunteers (N = 12) who received single doses of 100 and 150 mg 4-fluoroamphetamine (4-FA), a phenethylamine that has been associated with severe cardiovascular and cerebrovascular complications. The study was set-up as a placebo controlled, within subject, phase 1 trial as it was the first to administer 4-FA to humans under controlled conditions. Overall, 4-FA produced a strong elevation in blood pressure up until 4-5 h after administration that was followed by a sustained increase in heart rate. After an interim review of safety data from five participants, a decision was taken to cancel administration of 150 mg. We subsequently obtained complete datasets for placebo and 100 mg 4-FA treatments only. Effects of 4-FA on mood and neurocognitive function were most distinct at 1 h post drug and included significant elevations of vigor, friendliness, elation, arousal, positive mood, as well as improvements in attention and motor performance. Negative affect was also reported as time progressed in the acute phase and even more so during the subacute phase. Overall, the influence of 4-FA on vital signs, mood, and neurocognition was similar to that observed with other stimulants. Present findings confirm clinical observations of acute toxicity among 4-FA users and warrant warnings about potential health risks associated with 4-FA use

Verbal memory impairment in polydrug ecstasy users:A clinical perspective

Ecstasy use has been associated with short-term and long-term memory deficits on a standard Word Learning Task (WLT). The clinical relevance of this has been debated and is currently unknown. The present study aimed at evaluating the clinical relevance of verbal memory impairment in Ecstasy users. To that end, clinical memory impairment was defined as decrement in memory performance that exceeded the cut-off value of 1.5 times the standard deviation of the average score in the healthy control sample. The primary question was whether being an Ecstasy user (E-user) was predictive of having clinically deficient memory performance compared to a healthy control group. Conclusion: The combination of the acute and long-term findings demonstrates that, while clinically relevant memory impairment is present during intoxication, it is absent during abstinence. This suggests that use of Ecstasy/MDMA does not lead to clinically deficient memory performance in the long term. Additionally, it has to be investigated whether the current findings apply to more complex cognitive measures in diverse ‘user categories’ using a combination of genetics, imaging techniques and neuropsychological assessments

Brain reactivity to alcohol and cannabis marketing during sobriety and intoxication

Drugs of abuse stimulate striatal dopamine release and activate reward pathways. This study examined the impact of alcohol and cannabis marketing on the reward circuit in alcohol and cannabis users while sober and intoxicated. It was predicted that alcohol and cannabis marketing would increase striatal activation when sober and that reward sensitivity would be less during alcohol and cannabis intoxication. Heavy alcohol (n = 20) and regular cannabis users (n = 21) participated in a mixed factorial study involving administration of alcohol and placebo in the alcohol group and cannabis and placebo in the cannabis group. Non-drug users (n = 20) served as between group reference. Brain activation after exposure to alcohol and cannabis marketing movies was measured using functional magnetic resonance imaging and compared between groups while sober and compared with placebo while intoxicated. Implicit alcohol and cannabis cognitions were assessed by means of a single-category implicit association test. Alcohol and cannabis marketing significantly increased striatal BOLD activation across all groups while sober. Striatal activation however decreased during intoxication with alcohol and cannabis. Implicit associations with cannabis marketing cues were significantly more positive in alcohol and cannabis users as compared with non-drug using controls. Public advertising of alcohol or cannabis use elicits striatal activation in the brain's reward circuit. Reduction of marketing would reduce brain exposure to reward cues that motivate substance use. Conversely, elevated dopamine levels protect against the reinforcing potential of marketing

Safety Profile and Neurocognitive Function Following Acute 4-Fluoroamphetamine (4-FA) Administration in Humans

Availability of novel psychoactive substances (NPS) exponentially increased over the last years. Risk evaluations of NPS are hampered by the lack of pharmacological studies in humans on health parameters. The aim of the present study was to evaluate safety and neurocognitive function of healthy volunteers (N = 12) who received single doses of 100 and 150 mg 4-fluoroamphetamine (4-FA), a phenethylamine that has been associated with severe cardiovascular and cerebrovascular complications. The study was set-up as a placebo controlled, within subject, phase 1 trial as it was the first to administer 4-FA to humans under controlled conditions. Overall, 4-FA produced a strong elevation in blood pressure up until 4–5 h after administration that was followed by a sustained increase in heart rate. After an interim review of safety data from five participants, a decision was taken to cancel administration of 150 mg. We subsequently obtained complete datasets for placebo and 100 mg 4-FA treatments only. Effects of 4-FA on mood and neurocognitive function were most distinct at 1 h post drug and included significant elevations of vigor, friendliness, elation, arousal, positive mood, as well as improvements in attention and motor performance. Negative affect was also reported as time progressed in the acute phase and even more so during the subacute phase. Overall, the influence of 4-FA on vital signs, mood, and neurocognition was similar to that observed with other stimulants. Present findings confirm clinical observations of acute toxicity among 4-FA users and warrant warnings about potential health risks associated with 4-FA use