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3,4-Methylenedioxymethamphetamine (MDMA) has shown efficacy as a medication adjunct for treating post-traumatic stress disorder (PTSD). However, MDMA is also used in nonmedical contexts that pose risk for cardiovascular and neurologic complications. It is well established that MDMA exerts its effects by stimulating transporter-mediated release of the monoamines 5-hydroxytryptamine (5-HT), norepinephrine, and dopamine. Current research efforts are aimed at developing MDMA-like monoamine releasers with better efficacy and safety profiles. To this end, we investigated neurochemical and behavioral effects of novel analogs of the designer drug 5-(2-methylaminopropyl)benzofuran (5-MAPB). We used in vitro transporter assays in rat brain synaptosomes to examine transmitter uptake inhibition and releasing properties for enantiomers of 5-(2-methylaminobutyl)benzofuran (5-MABB) and 6-(2-methylaminobutyl)benzofuran (6-MABB) compared with MDMA. We then tested these same compounds in male Sprague-Dawley rats trained to discriminate MDMA (1.5 mg/kg) from saline. In vitro results revealed that S isomers of 5- and 6-MABB are efficacious releasing agents at transporters for 5-HT (SERT), norepinephrine (NET), and dopamine (DAT). By contrast, R isomers are efficacious releasers at SERT and partial releasers at NET but lack releasing activity at DAT. In vivo results showed that all compounds produce dose-dependent increases in MDMA-lever responding and full substitution at the highest dose tested. The diminished NET and DAT releasing activities for R isomers of 5- and 6-MABB are associated with reduced potency for inducing behavioral effects. Collectively, these findings indicate that the aminoalkyl benzofuran scaffold may be a viable template for developing compounds with MDMA-like properties. SIGNIFICANCE STATEMENT: Despite the clinical utility of 3,4-methylenedioxymethamphetamine (MDMA), the drug is associated with certain cardiovascular risks and metabolic side effects. Developing a therapeutic alternative with MDMA-like monoamine releasing activity is of interest. Our in vitro and in vivo findings indicate that the aminoalkyl benzofuran scaffold may be useful for developing compounds with MDMA-like properties., (U.S. Government work not protected by U.S. copyright.)

The detection of changes in mental states such as those caused by psychoactive drugs relies on clinical assessments that are inherently subjective. Automated speech analysis may represent a novel method to detect objective markers, which could help improve the characterization of these mental states. In this study, we employed computer-extracted speech features from multiple domains (acoustic, semantic, and psycholinguistic) to assess mental states after controlled administration of 3,4-methylenedioxymethamphetamine (MDMA) and intranasal oxytocin. The training/validation set comprised within-participants data from 31 healthy adults who, over four sessions, were administered MDMA (0.75, 1.5 mg/kg), oxytocin (20 IU), and placebo in randomized, double-blind fashion. Participants completed two 5-min speech tasks during peak drug effects. Analyses included group-level comparisons of drug conditions and estimation of classification at the individual level within this dataset and on two independent datasets. Promising classification results were obtained to detect drug conditions, achieving cross-validated accuracies of up to 87% in training/validation and 92% in the independent datasets, suggesting that the detected patterns of speech variability are associated with drug consumption. Specifically, we found that oxytocin seems to be mostly driven by changes in emotion and prosody, which are mainly captured by acoustic features. In contrast, mental states driven by MDMA consumption appear to manifest in multiple domains of speech. Furthermore, we find that the experimental task has an effect on the speech response within these mental states, which can be attributed to presence or absence of an interaction with another individual. These results represent a proof-of-concept application of the potential of speech to provide an objective measurement of mental states elicited during intoxication.

±3,4-Methylenedioxymethamphetamine (MDMA) is a popular recreational drug that enhances sociability and feelings of closeness with others. These "prosocial" effects appear to motivate the recreational use of MDMA and may also form the basis of its potential as an adjunct to psychotherapy. However, the extent to which MDMA differs from prototypic stimulant drugs, such as dextroamphetamine, methamphetamine, and methylphenidate, in either its behavioral effects or mechanisms of action, is not fully known. The purpose of this review is to evaluate human laboratory findings of the social effects of MDMA compared to other stimulants, ranging from simple subjective ratings of sociability to more complex elements of social processing and behavior. We also review the neurochemical mechanisms by which these drugs may impact sociability. Together, the findings reviewed here lay the groundwork for better understanding the socially enhancing effects of MDMA that distinguish it from other stimulant drugs, especially as these effects relate to the reinforcing and potentially therapeutic effects of the drug., (© The Author(s) 2016.)

The drug 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy", "molly") is a widely used illicit drug and experimental adjunct to psychotherapy. MDMA has unusual, poorly understood socioemotional effects, including feelings of interpersonal closeness and sociability. To better understand these effects, we conducted a small (n=12) within-subjects double-blind placebo controlled study of the effects of 1.5 mg/kg oral MDMA on social emotions and autobiographical disclosure in a controlled setting. MDMA displayed both sedative- and stimulant-like effects, including increased self-report anxiety. At the same time, MDMA positively altered evaluation of the self (i.e. increasing feelings of authenticity) while decreasing concerns about negative evaluation by others (i.e. decreasing social anxiety). Consistent with these feelings, MDMA increased how comfortable participants felt describing emotional memories. Overall, MDMA produced a prosocial syndrome that seemed to facilitate emotional disclosure and that appears consistent with the suggestion that it represents a novel pharmacological class., (© The Author(s) 2016.)

Rationale: ±3,4-methylenedioxymethamphetamine (MDMA) is widely believed to increase sociability. The drug alters speech production and fluency, and may influence speech content. Here, we investigated the effect of MDMA on speech content, which may reveal how this drug affects social interactions., Method: Thirty-five healthy volunteers with prior MDMA experience completed this two-session, within-subjects, double-blind study during which they received 1.5 mg/kg oral MDMA and placebo. Participants completed a five-minute standardized talking task during which they discussed a close personal relationship (e.g. a friend or family member) with a research assistant. The conversations were analyzed for selected content categories (e.g. words pertaining to affect, social interaction, and cognition), using both a standard dictionary method (Pennebaker's Linguistic Inquiry and Word Count: LIWC) and a machine learning method using random forest classifiers., Results: Both analytic methods revealed that MDMA altered speech content relative to placebo. Using LIWC scores, the drug increased use of social and sexual words, consistent with reports that MDMA increases willingness to disclose. Using the machine learning algorithm, we found that MDMA increased use of social words and words relating to both positive and negative emotions., Conclusions: These findings are consistent with reports that MDMA acutely alters speech content, specifically increasing emotional and social content during a brief semistructured dyadic interaction. Studying effects of psychoactive drugs on speech content may offer new insights into drug effects on mental states, and on emotional and psychosocial interaction., (© The Author(s) 2015.)

Rationale: Several laboratories have conducted placebo-controlled drug challenge studies with 3,4-methylenedioxymethamphetamine (MDMA), providing a unique source of data to examine the reliability of the acute effects of the drug across subject samples and settings. We examined the subjective and physiological responses to the drug across three different laboratories and investigated the influence of prior MDMA use., Methods: Overall, 220 healthy volunteers with varying levels of previous MDMA experience participated in laboratory-based studies in which they received placebo or MDMA orally (1.5 mg/kg or 125-mg fixed dose) under double-blind conditions. Cardiovascular and subjective effects were assessed before and repeatedly after drug administration. The studies were conducted independently by investigators in Basel, San Francisco, and Chicago., Results: Despite methodological differences between the studies and differences in the subjects' drug use histories, MDMA produced very similar cardiovascular and subjective effects across the sites. The participants' prior use of MDMA was inversely related to feeling "Any Drug Effect" only at sites testing more experienced users., Conclusions: These data indicate that the pharmacological effects of MDMA are robust and highly reproducible across settings. There was also modest evidence for tolerance to the effects of MDMA in regular users.

Increasing use of 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") has been accompanied by concern about acute and possible long-term toxicity. This article discusses acute serious toxicity, chronic toxicity, and common problems associated with Ecstasy use, as well as the implications of these areas for prevention programs targeted at current Ecstasy users. The low incidence of serious adverse events in users creates difficulties for attempts to develop harm reduction recommendations. Many hypothesized risk factors for serious adverse events cannot be confirmed or denied and may not be associated with dramatic elevations in risk. Research on chronic toxicity in users provides strong evidence of neurophysiological changes and suggestive evidence of possible neurocognitive changes. Because these worrisome changes are clinically subtle, users may not be influenced by concerns of neurotoxicity. In contrast, common Ecstasy-related complaints are relatively well documented and have identified risk factors, including factors relating to extent of Ecstasy use (such as "binges"). Common complaints include modest acute and subacute adverse effects,some lasting several days, and problems in life. The apparent willingness of users to modify drug use and other behaviors to decrease these common problems could be used by harm reduction or other prevention programs to encourage users to decrease the extent of Ecstasy use.