The prosocial effects of 3, 4-methylenedioxymethamphetamine (MDMA): controlled studies in humans and laboratory animals

This review (2015) discusses data from controlled laboratory studies that highlight MDMA altering social feelings, information processing, and behavior in humans, and social behavior in rodents. The findings are consistent with earlier studies that show that laboratory administration of MDMA strongly alters social processing in humans and increases social approach in humans as well as animals and that neurobiologically complex prosocial effects contribute towards its recreational use.

Abstract

“Users of ±3,4-methylenedioxymethamphetamine (MDMA; ‘ecstasy’) report prosocial effects such as sociability and empathy. Supporting these apparently unique social effects, data from controlled laboratory studies indicate that MDMA alters social feelings, information processing, and behavior in humans, and social behavior in rodents. Here, we review this growing body of evidence. In rodents, MDMA increases passive prosocial behavior (adjacent lying) and social reward while decreasing aggression, effects that may involve serotonin 1A receptor mediated oxytocin release interacting with vasopressin receptor 1A. In humans, MDMA increases plasma oxytocin and produces feelings of social affiliation. It decreases identification of negative facial expressions (cognitive empathy) and blunts responses to social rejection, while enhancing responses to others’ positive emotions (emotional empathy) and increasing social approach. Thus, consistent with drug folklore, laboratory administration of MDMA robustly alters social processing in humans and increases social approach in humans and animals. Effects are consistent with increased sociability, with mixed evidence about enhanced empathy. These neurobiologically-complex prosocial effects likely motivate recreational ecstasy use.“

Authors: Philip Kamilar-Britt & Gillinder Bedi

Summary

MDMA increases prosocial behavior and decreases aggression in laboratory animals, and heightens affiliative feelings and prosocial mood states in humans. These effects may motivate recreational use of ‘ecstasy’ and ‘molly’.

3,4-Methylenedioxymethamphetamine (MDMA; ecstasy) increases social feelings, information processing, and behavior in humans and rodents, and decreases aggression. These effects are consistent with increased sociability and empathy, and likely motivate recreational ecstasy use.

3,4-methylenedioxymethamphetamine (MDMA) is the main psychoactive substance in the street drug known as ecstasy, and is under investigation as a potential adjunct to psychotherapy for conditions such as Post Traumatic Stress Disorder. Although many recreational drugs are believed to alter social experiences, MDMA is the prototypical social drug. Its prosocial effects are believed to contribute to the reinforcing properties of MDMA and the rationale for adjunctive MDMA use in psychotherapy. Research on the prosocial effects of MDMA has revealed several potential neurobiological mechanisms. These findings may have important implications for recreational ecstasy/molly use and possible psychotherapeutic effects. A total of 49 articles were selected for review based on our inclusion criteria. These articles were categorized as follows: 1) Effects of MDMA on social behavior in animals; 2) Effects of MDMA on social processing and behavior in humans; and 3) Mechanisms of MDMA’s prosocial effects in animals and humans.

MDMA acutely facilitates prosocial behaviors in several rodent species, most frequently assessed with the social interaction test. MDMA increases the amount of time that Wistar rats engage in adjacent lying, peaceful following, social investigation/approach, and overall social interaction. MDMA-induced behavioral changes in rodents include decreased rearing, anogenital sniffing, and partner grooming. These behaviors can be considered forms of risk assessment.

MDMA increases social comfort with unfamiliar conspecifics, increases adjacent lying, and increases peaceful following in rodents, and decreases rearing and sniffing with no change or increase in locomotor activity. In a recent investigation, Ramos et al. (2015) used a social reward-conditioned place preference model to assess the rewarding effects of MDMA when administered under social and non-social conditions. They found that MDMA intensified social and to a lesser degree tactile reward, potentially contributing to the drug’s prosocial effects. MDMA has been shown to reduce aggression in rodents and fish, as indicated by prolonged first-bite latency and decreased frequency of combative bites. MDMA also increased adjacent lying in fish, suggesting that the observed reductions in aggression were not explained by decreased locomotion alone. Otherstudies have documented reduced aggression after MDMA, however these changes were not consistently associated with heightened prosocial behavior and may have resulted from severe intoxication or increased social anxiety.

MDMA reduced anxiety-like behavior, defense postures, and submission postures, as well as social exploration, in adult male Agouti rats. Additionally, MDMA decreased overall aggression and social exploration in peri-adolescent male Wistar rats. Recent evidence suggests that individual differences in trait aggressiveness can moderate MDMA’s effects on aggression and prosociality. MDMA may decrease aggression and increase both timidity and prosocial behaviors in rodents with high-trait aggressiveness, while increasing timidity and reducing prosocial behavior in low-aggressive mice. Although MDMA has been found to promote certain prosocial behaviors in laboratory animals, some studies have documented inhibitory or anxiety-like social effects. These effects depend on the developmental stage, species, trait factors, dose, testing environment, and the specific behavior measured.

MDMA has been administered to healthy humans in numerous controlled laboratory studies. There have been no unexpected drug-related serious adverse events, and the prosocial effects of MDMA have been shown to be similar in volunteers with a range of prior exposure to ecstasy as well as in primarily ecstasy naive samples. After MDMA, participants endorsed feeling loving, talkative, extroverted, sociable, self-confident, and friendly.

Accepted Manuscript Kirkpatrick et al. (2014) found that children with autism are ‘playful’, ‘open’, ‘trusting’, ‘close to other people’, and ’emotionally concerned’. While the subjective prosocial effects of MDMA have primarily been documented under non-social testing conditions, some evidence suggests an effect of social setting. However, these effects do not appear to be wholly dependent on a facilitating social environment.

In a recent study, the semantic structure of free speech was investigated after MDMA using Latent Semantic Analyses (LSA). The results revealed that MDMA induces apparently prosocial drug effects. MDMA increases the percentage of positive, but not negative, emotion words used during free speech, and increases the use of words relating to sexual and social content, as well as increasing the use of words pertaining to death, in humans in controlled laboratory settings.

MDMA increases social feelings, but research on how it affects social processing is still limited. One common task is to measure the accuracy with which people can recognize others’ facial emotions. Several studies have investigated the effects of MDMA on cognitive empathy, specifically FER performance. The results suggest that MDMA reduces recognition of fearful, sad, angry, disgusted, and surprised faces, but not happy faces.

MDMA reduced accuracy ratings for all four emotions tested, but did not reach statistical significance for happiness or sadness recognition. MDMA also increased misclassifications of both positive and negative facial emotions as neutral, but had no effect on overall recognition accuracy. MDMA had no effect on overall Reading the Mind in the Eyes Test performance compared to placebo, and had a differential effect on recognition accuracy for positive and negative emotions.

MDMA increased correct identification of positive emotions but impaired recognition of negative emotions from pictures of the eye region. The effects of MDMA on other dimensions of emotion recognition, such as affect decoding from body postures or gestures, have yet to be explored. Hysek et al. (2014)found that MDMA did not affect cognitive empathy but increased emotional empathy, which was driven by enhanced affective responses to positive rather than negative emotional situations.

MDMA (75 mg) increased emotional empathy for positive, but not negative, stimuli, and did not alter overall cognitive empathy on the MET. This suggests that MDMA may dampen cognitive empathy, in particular lowering awareness of others’ negative facial emotional expressions, with limited support for the notion that MDMA increases accurate identification of positive emotions in others. Although most existing research has focused on measures of cognitive or emotional empathy, a small number of studies have assessed MDMA’s effects on other dimensions of social processing.

Participants who were administered MDMA rated others as more attractive in all three social conditions, suggesting no effect of social setting on MDMA-induced alterations to this dimension of social evaluation. MDMA (75 mg) increased button presses in response to implicit, but not explicit, sexual imagery compared to placebo, and attenuated negative feelings after rejection trials in a game of Cyberball.

MDMA-induced ‘loving’ feelings were unaffected by social rejection, and MDMA (1.5 mg/kg only) caused participants to inaccurately inflate their perception of the number of tosses they received during the rejection but not acceptance trials, suggesting that MDMA not only blunted emotional responding to rejection, it reduced awareness of the rejection. Recent studies have used hypothetical social scenarios to assess the effects of MDMA on preference for cooperative behaviors and trust, decision making, and fairness preferences. MDMA increased preference for equal distribution of funds in men, but reduced inequality aversion in those with prosocial tendencies. Kirkpatrick et al. (2015) reported dose-dependent effects of MDMA on preference for prosocial resource allocation. They found that MDMA increased preference for economic generosity towards a friend, whereas generosity towards a stranger was only greater following lower doses and only in women. MDMA has no effect on reciprocity, trust, or moral decision-making, but does increase cooperative behavior depending on dose, sex, and familiarity of the social partner. MDMA increases social approach and reinforcement by increasing self-reported willingness to socialize with others and by enhancing feelings of friendliness. This effect is accompanied by decreased corrugator muscle activity (frown response) to happy relative to negative faces.

MDMA (0.5, 1.0 mg/kg) increased prosocial feelings in participants, including increased responses to positive, but not negative, facial expressions, and increased perceptions of interviewer empathy relative to placebo. Participants engaged in more social interaction after MDMA in the company of other participants than after placebo. MDMA may impair recognition of negative, but not positive, emotional states from social stimuli, and may enhance emotional responding to positive but not negative affective states in others.

Acute doses of MDMA appear to decrease the awareness of simulated social rejection and its negative emotional impact, increase physiological markers of prosociality, and heighten perceptions of others’ level of empathy and attractiveness. These effects are consistent with enhanced sociability. MDMA’s non-social effects in humans appear to be mediated primarily by transporter-mediated release of serotonin, norepinephrine, and dopamine. Pretreatment with duloxetine (a serotonin-norepinephrine reuptake inhibitor) blunts the subjective prosocial effects of MDMA relative to placebo.

Reboxetine, clonidine and ketanserin attenuated the effects of MDMA on RMET performance, but not on extroversion or self-confidence. These findings suggest that MDMA elicits heightened prosocial feelings primarily via serotonergicmechanisms, with some effect of noradrenergic transmission. MDMA increases plasma concentrations of the neuropeptide oxytocin in rodents and humans, and may be partially mediated by oxytocin release. Oxytocin is thought to regulate many social behaviors in humans and animals, including increased generosity, decreased responses to others’ negative emotional states, and increased reaction time for negative facial emotion identification.

The associations between plasma oxytocin levels and prosocial feelings after MDMA are controversial. Studies have found no correlation between heightened levels of plasma oxytocin and MDMA-induced increases in emotional empathy, facial emotion recognition, or social cognitive abilities. Intranasal oxytocin did not affect prosocial feelings in two studies, but did affect emotional empathy, emotion recognition from pictures of the eyes, and objective and subjective measures of trust and reciprocity.

Oxytocin increased self-reported friendliness and sociability, but MDMA enhanced preference for social interaction. Oxytocin increased accurate recognition of sad facial expressions, but MDMA impaired identification of fearful and angry faces. In rodents, MDMA increases plasma oxytocin levels and induces prosocial behavior. Pre-treatment with tocinoic acid (20 mg/kg) attenuated the prosocial effects of MDMA, while the 5-HT1A and 5-HT2B/2C receptor antagonists blunted the prosocial effects of MDMA.

The authors report that peripheral administration of oxytocin and vasopressin elicited MDMA-like prosocial effects in rats, and that an oxytocin antagonist was unable to prevent these effects. They suggest that a common mechanism, mediated by V1AR, underlies the prosocial effects of MDMA, oxytocin, and vasopressin. MDMA produces robust alterations in social behavior in animals and humans, and may facilitate social approach behavior by blurting sensitivity to others’ negative emotional states. However, the role of prosocial effects in MDMA’s reinforcing properties is not yet fully understood. Although ecstasy use appears to decrease or stop as part of a natural trajectory, some users endorse criteria for ecstasy use disorders or develop compulsive patterns of use, and a small subset seek treatment for ecstasy use. MDMA can increase social closeness in some contexts, while decreasing social inhibitions in others. However, decreased awareness of social rejection may lead to misreading of some social situations. MDMA can enhance perceptions of the therapist’s empathic awareness, potentially strengthening the therapeutic alliance, but it is unclear whether these effects occur in clinical settings. Moreover, it remains unclear whether the prosocial effects of MDMA mediate its putative efficacy as an adjunct to psychotherapy. Several basic science questions remain about the prosocial effects of MDMA. Future research could assess the effects of V1AR antagonism on MDMA’s prosocial effects.

MDMA has unusual sociability-enhancing effects in humans and other animals, and these effects may be related to generalized cognitive and motivational changes. The extent to which sex differences or menstrual cycle effects on the prosocial effects of MDMA are also unclear.

MDMA causes disinhibition of the serotonergic system and enhances acute MDMA-induced social behaviour on the social interaction test. The “Reading the Mind in the Eyes” test was developed by Baron-Cohen, Wheelwright, S., Hill, J., Raste, Y., Plumb, I. Bartz, Simeon, D., Hamilton, H., Kim, S., Crystal, S., Braun, A., Vicens, V., Hollander, E. (2011) investigated the effect of oxytocin on trust and cooperation in borderline personality disorder. Bedi, G., Cecchi, G.A., Slezak, D.F., Carrillo, F., Sigman, M., de Wit, H. (2014). Speech as an index of psychoactive drug effects. Ecstasy, Blair, Blanchard, Panksepp, J., Bluthe, R.M., van Honk, J., 2012. Acute effects of steroid hormones and neuropeptides on human social-emotional behavior: a review of single administration studies. The severity of dependence scale can be usefully applied to ‘ecstasy’.

MDMA has been shown to have neurotoxic and behavioral effects in adolescent mice. It is also known to increase oxytocin levels which enhances processing of positive versus negative emotional information in healthy male volunteers. MDMA decreases the effects of simulated social rejection in healthy humans, and it also modulates cortical and limbic brain activity as measured by [H 215 O]-PET. MDMA increases positive emotions in humans, decreases negative emotions in humans, and enhances positive emotions in humans. It also increases the ability to read minds and improves the ability to read minds in healthy volunteers.

The effects of 3,4-methylenedioxymethamphetamine on human behavior have been studied in several ways, including the pharmacodynamics and pharmacokinetics of 3,4-methylenedioxymethamphetamine in healthy volunteers, the effects of methylphenidate and MDMA administered alone or in combination, and the effects of depression and dysphoria on interpersonal perception. Ecstasy may help anxiety disorders, according to Johansen, Krebs, Kahn, Ferraro, N., Benveniste, R.J., 2012. It may also help with aggression, according to Kirilly, Benko, A., Ferrington, L., Ando, R.D., Kelly, P.A., Bagdy, G. Kirkpatrick, Delton, A.W., Robertson, T.E., de Wit, H. (2015). MDMA has prosocial effects, and de Wit, H. (2014).

Oxytocin modulates neural circuitry for social cognition and fear in humans, and impaired emotional face expression recognition is associated with interpersonal problems in alcoholism. MDMA-induced increase in cortisol does not prevent acute impairment of verbal memory. MDMA-induced enhancement of emotional empathy is not related to peripheral oxytocin levels or 5-HT1a receptor activation. MDMA (Ecstasy) produces psychological effects in humans that are attenuated by the serotonin uptake inhibitor citalopram, and enhanced by the haloperidol 5-HT-sub-2 antagonist. The effects of modafinil, methamphetamine, and MDMA on agonistic behavior in male mice are also different. MDMA (ecstasy) exhibits anxiogenic-like activity in social encounters between male mice.

McKetin, Copeland, J., Norberg, M.M., Bruno, R., Hides, L., Khawar, L. (2014). Ecstasy ‘come-down’ effects on the diagnosis of ecstasy dependence. Mithoefer, Wagner, Mithoefer, A.T., Jerome, L., Doblin, R., 2013. The safety and efficacy of 3,4-methylenedioxymethamphetamine-assisted psychotherapy in subjects with chronic, treatment-resistant posttraumatic stress disorder: a randomized controlled pilot study. The great entactogen empathogen debate is about whether 3,4-methylenedioxymethamphetamine (MDMA, ‘Ecstasy’) increases social interaction in rats or mice, and whether c-fos expression is increased in the mice amygdala.

A randomized controlled pilot study of MDMA-assisted psychotherapy for resistant, chronic Post-Traumatic Stress Disorder (PTSD) was conducted in 2013. The study found that MDMA enhanced social reward in rats.

Combined use of 3,4-methylenedioxymethamphetamine and oxytocin results in increased envy and schadenfreude (gloating) in rats, and oxytocin increases social cognition. A multimodal investigation of the effects of alcohol on emotion and social bonding is available in the publications listed above. In a population based study, young adults’ trajectories of Ecstasy use were examined. Tancer and Johanson investigated the effects of fluoxetine on the subjective and physiological effects of MDMA in humans. Research shows that oxytocin and 5-HT(1A) receptors play a role in the prosocial effects of 3,4 methylenedioxymethamphetamine (“ecstasy”), and that mdma pre-exposed rats show reduced sensitivity to MDMA-induced facilitation of social behavior.

The researchers investigated why people stop taking ecstasy and their subsequent mental health. They found that ecstasy alters emotional processing and facilitates positive social interaction.