Mechanism of action
- See also: Serotonin releasing agent §Effects and comparisons, MDMA §Pharmacology, and Psychedelic drug §Mechanism of action
Entactogens like MDMA are serotonin releasing agents and hence are indirect agonists of serotonin receptors. They produce entactogenic effects in animals such as increased prosocial behavior like adjacent lying, enhanced empathy-like behavior, and antiaggressive effects. Likewise, MDMA increases sociability, prosociality, and emotional empathy in humans.
In animals, MDMA induced prosocial behavior and elevations in circulating oxytocin levels and these effects were abolished by pretreatment with the serotonin 5-HT1A receptor antagonist WAY-100635. Conversely, the serotonin 5-HT1A receptor agonist 8-OH-DPAT produced prosocial behavior and increased oxytocin levels similarly to MDMA. In addition, MDMA has been shown to activate oxytocinergic neurons in the hypothalamus and this too is reversed by serotonin 5-HT1A receptor antagonism. Subsequent research found that direct injection of the serotonin 5-HT1A receptor WAY-100635 locally into the basolateral amygdala (BLA) suppressed MDMA-induced prosocial behavior and that direct injection of MDMA locally into the BLA significantly increased sociability.
The serotonin 5-HT2B and 5-HT2C receptor antagonist SB-206553 has also been found to block MDMA-induced prosocial behavior, although it produced potentially confounding thigmotaxis (hyperactivity at periphery of testing chamber) as well. Conversely, the serotonin 5-HT1B receptor antagonist GR-55562 and the serotonin 5-HT2A receptor antagonist ketanserin were both ineffective. Likewise, another study found that selective antagonists of the serotonin 5-HT1B, 5-HT2A, 5-HT2C, and 5-HT4 receptors (SB-216641), volinanserin (MDL-100907), SB-242084, and SB-204070, respectively) were all ineffective in suppressing MDMA-induced prosocial activity. Other research has found that serotonin 5-HT2B receptor inactivation abolishes the serotonin release induced by MDMA and attenuates many of its effects. In addition to the preceding findings, induction of serotonin release by MDMA in the nucleus accumbens and consequent activation of serotonin 5-HT1B receptors in this area is implicated in its enhancement of prosocial behaviors, whereas consequent activation of yet-to-be-determined serotonin receptors in this area is implicated in its enhancement of empathy-like behaviors. Injection of the serotonin 5-HT1B receptor antagonist NAS-181 directly into the nucleus accumbens blocked the prosocial behaviors of MDMA.
On the basis of the serotonin 5-HT1A receptor-mediated oxytocin release with MDMA, it has been proposed that increased oxytocinergic signaling may mediate the prosocial effects of MDMA in animals. Accordingly, intracerebroventricular injection of the peptide oxytocin receptor antagonist tocinoic acid blocked MDMA- and 8-OH-DPAT-induced prosocial effects. However, in a subsequent study, systemically administered C25, a non-peptide oxytocin receptor antagonist, failed to affect MDMA-induced prosocial behavior, whereas the vasopressin V1A receptor antagonist relcovaptan (SR-49059) was able to block MDMA-induced prosocial activity. It might be that tocinoic acid is non-selective and also blocks the vasopressin V1A receptor or that C25 is peripherally selective and is unable to block oxytocin receptors in the brain. More research is needed to clarify this. In any case, in another study, the non-peptide and centrally active selective oxytocin receptor antagonist L-368899 abolished MDMA-induced prosocial behavior. Conversely, in other studies, different oxytocin receptor antagonists were ineffective.
As in animals, MDMA greatly increases circulating oxytocin levels in humans. Serotonin reuptake inhibitors and norepinephrine reuptake inhibitors reduced the subjective effects of MDMA in humans, for instance increased extroversion, self-confidence, closeness, openness, and talkativeness. The 5-HT2A receptor antagonist ketanserin reduced MDMA-induced increases in friendliness. MDMA-induced emotional empathy was not affected by the serotonin 5-HT1A receptor antagonist pindolol or by intranasal oxytocin. Similarly, MDMA-induced emotional empathy and prosocial behavior have not been associated with circulating oxytocin levels. As such, the role of oxytocin in the entactogenic effects of MDMA in humans is controversial.
Other serotonin releasing agents, like fenfluramine, show prosocial effects in animals similar to those of MDMA. Fenfluramine has likewise been reported to improve social deficits in children with autism. Selective agonists of the serotonin 5-HT1A and 5-HT1B receptors and of the oxytocin receptors have been or are being investigated for the potential treatment of social deficits and aggression. Examples include batoprazine, eltoprazine (DU-28853), fluprazine (DU-27716), F-15,599 (NLX-01), zolmitriptan (ML-004), and LIT-001. Serotonergic psychedelics, for instance lysergic acid diethylamide (LSD) and psilocybin, which act as non-selective serotonin receptor agonists including of the serotonin 5-HT1 and 5-HT2 receptors, have shown prosocial and empathy-enhancing effects in animals and/or humans as well, both acutely and long-term.
The serotonin release of MDMA appears to be the key pharmacological action mediating the entactogenic, prosocial, and empathy-enhancing effects of the drug. However, in addition to serotonin release, MDMA is also a potent releasing agent of norepinephrine and dopamine, and hence acts as a well-balanced serotonin–norepinephrine–dopamine releasing agent. Additionally, MDMA is a direct agonist of several serotonin receptors, including of the serotonin 5-HT2 receptors, with moderate affinity. These actions are thought to play an important role in the effects of MDMA, including in its psychostimulant, euphoriant, and mild psychedelic effects, as well as in its unique and difficult-to-replicate "magic". It has been said by Matthew Baggott that few to no MDMA analogues, including MBDB, methylone, 6-APDB, 5-APDB, 6-APB, 5-APB, MDAT, and MDAI among others, reproduce the full quality and "magic" of MDMA. Exceptions may anecdotally include 5-MAPB, particularly in specific enantiomer ratios, and the Borax combo. The unique properties of MDMA are believed to be dependent on a very specific mixture and ratio of pharmacological activities, including combined serotonin, norepinephrine, and dopamine release and direct serotonin receptor agonism.
Some entactogens, such as the benzofurans 5-MAPB, 6-MAPB, BK-5-MAPB, and BK-6-MAPB, have unexpectedly been found to be potent serotonin 5-HT1B receptor agonists. In addition to serotonin release and other actions, this property may be involved in their entactogenic effects. Conversely, MDMA is much less potent as an agonist of the serotonin 5-HT1B receptor.
Ariadne, the α-ethyl analogue of the serotonergic psychedelic DOM, fully substitutes for MDMA in rodent drug discrimination tests, suggesting that it may have entactogen-like effects. This property is unusual among psychedelics, and is in notable contrast to DOM, which at best partially substitutes for MDMA. Besides Ariadne, the NBOMe drugs such as 25I-NBOMe and 25B-NBOMe also partially to fully substitute for MDMA in rodents. Unlike conventional entactogens, Ariadne shows no activity at the monoamine transporters, and instead acts as a selective serotonin 5-HT2 receptor partial agonist, including as a lower-efficacy agonist of the serotonin 5-HT2A receptor. Certain other psychedelics and related compounds, like low doses of 2C-B, are also selective serotonin 5-HT2 receptor partial agonists that have likewise been implicated as having entactogenic effects. MDMA itself is notable in being a lower-efficacy partial agonist of the serotonin 5-HT2A receptor as well. The stimulus effects of MDMA in the drug discrimination paradigm are partially blocked by the selective serotonin 5-HT2A receptor antagonist volinanserin in rodents. Similarly, the psychoactive effects of MDMA are partially blocked by the relatively selective serotonin 5-HT2A receptor antagonist ketanserin in humans.
