Oxytocin not likely to be the cause for MDMA's empathogenic properties

BlueBull

Moderator: M&ED
Staff member
Joined
Nov 3, 2012
Messages
2,774
So I was reading some studies because I wanted to propose the oxytocin-theory to be added to the MDMA wiki as a note, stating that it is theorized to cause MDMA's empathogenic effects.

But now I came across this study published very recently (27th of june) that says there is no evidence to support this.

The study is titled "No Evidence that MDMA-Induced Enhancement of Emotional Empathy Is Related to Peripheral Oxytocin Levels or 5-HT1a Receptor Activation" and was done by Kim P. C. Kuypers and others

I've made a semi-short summary below.

Thoughts? This is actually kind of surprising to me. In other studies (here and here are examples) they found a strong corrolation between oxytocin blood levels and subjective empathogenic effects. This now seems to be unrelated, or so this recent study claims. This could be viewed as a good thing, as even though we do not yet know the mechanics behind MDMA's empathogenic properties it could narrow the list of possible causes further. Furthermore it seems they are actively researching this topic, which is always a good thing. I would like some input on this from people more knowledgeable. Mods if this thread is better suited for the NPD forums feel free to move it, I wasn't sure where to best put it, seemed more relevant in MED

Thanks in advance for any replies,

BlueBull

A semi-short summary:
The present study aimed at investigating the effect of MDMA on measures of empathy and social interaction, and the roles of oxytocin and the 5-HT1A receptor in these effects. The design was placebo-controlled within-subject with 4 treatment conditions: MDMA (75 mg), with or without pindolol (20 mg), oxytocin nasal spray (40 IU+16 IU) or placebo. Participants were 20 healthy poly-drug MDMA users, aged between 18–26 years. Cognitive and emotional empathy were assessed by means of the Reading the Mind in the Eyes Test and the Multifaceted Empathy Test. Social interaction, defined as trust and reciprocity, was assessed by means of a Trust Game and a Social Ball Tossing Game. Results showed that MDMA selectively affected emotional empathy and left cognitive empathy, trust and reciprocity unaffected. When combined with pindolol, these effects remained unchanged. Oxytocin did not affect measures of empathy and social interaction. Changes in emotional empathy were not related to oxytocin plasma levels. It was concluded that MDMA (75 mg) selectively enhances emotional empathy in humans. While the underlying neurobiological mechanism is still unknown, it is suggested that peripheral oxytocin does not seem to be the main actor in this; potential candidates are the serotonin 2A and the vasopressin 1A receptors.
Design
The study was conducted according to a 4-way placebo-controlled within-subject design.

Three treatments
pindolol capsules (20 mg) or placebo, MDMA capsules (75 mg) or placebo, and an oxytocin nasal spray (40 IU+2 booster doses of both 8 IU) or placebo spray, were combined to entail 4 Treatment Conditions. Every participant received 3 treatments (active or placebo) each test day in order to blind them for Treatment Condition (see Table 2): (1) pindolol capsule + MDMA capsule + placebo spray; (2) placebo capsule + MDMA capsule + placebo spray; (3) placebo capsule + placebo capsule + oxytocin spray; (4) placebo capsule + placebo capsule + placebo spray. Treatment Conditions were randomized.

Empathy tests and questionnaire
  • Multifaceted Empathy Test (MET)
    The MET [28] consists of 40 pictures of people conveying a complex emotional state which was positive in 50% of the pictures and negative in the other half. To assess cognitive empathy (CE)
  • Reading the Mind in the Eyes test (RMET)
    This task measures the ability to infer the mental state of others from social cues in the eye region or cognitive empathy and has been shown to be sensitive to the administration of oxytocin [25].
  • Interpersonal Reactivity Index (IRI)
    The IRI, originally designed as a trait measure, was used in the present study as a state measure. The questions refer to feelings and thoughts experienced in different situations.
Social interaction tests and questionnaire
  • Trust game
    The Trust Game aims to assess the ability to infer the mental state of another and to cooperate in order to make beneficial choices [30]. This measure has been shown to be sensitive to the effects of oxytocin i.e. it causes a substantial increase in trust in healthy males [31].
  • Social Ball Tossing Game
    The adapted version of the CyberBall task designed by Andari and collaegues (2010) [35] was used, i.e. the Social Ball Tossing Game. This is a social interaction task measuring the participants' choice of cooperative (good, bad, neutral) opponent player. This relatively new task has been used in oxytocin research with high functioning autism spectrum disorders showing improved social behavior in these participants
  • Social Ball Tossing Game Questionnaire (SBTGQ)
    At the end of the Social Ball Tossing Game participants were asked to estimate, using a subjective seven-point rating scale, their sentiments of ‘trust’ and ‘preference’ with respect to the fictitious players [35].
Intranasal Oxytocin Spray
Oxytocin is a neuropeptide which crosses the blood-brain barrier reliably after intranasal administration [21]. The spray was administered five times, 45 minutes before onset of tasks, with a delay of 45s between administrations. Each administration consisted of one insufflation of the spray into each nostril. Each inhalation contained approximately 4 international units (IU) (total: 40 IU) (procedure confer [22]). In between the three task blocks, participants received 2 ‘booster’ doses of oxytocin (each 8 IU) in order to keep steady state levels of oxytocin during testing. Oxytocin plasma levels peak after 15 minutes and decrease after 30–60 minutes (24–26 IU) (e.g. [21]). Behavioural testing is commonly conducted 45 minutes after administration [22]–[25].

Results relevant to oxytocin

Empathy tests and questionnaire
  • Oxytocin-Emotional Empathy (MET) correlations
    Spearman's rho did not reveal significant correlations between oxytocin concentrations and emotional empathy (i.e. EEE-negative (rs = −.037), EEE-positive (rs = .133), EEI-negative (rs = .015), EEI-positive (rs = .068 )) and no effect of Treatment Condition on Cognitive Empathy, nor a Treatment Condition by Valence interaction.
  • RMET
    There were no Treatment Condition effects on total number correct, percentage correct or corresponding response times
  • IRI
    Analysis revealed a main effect of Treatment Condition on scales assessing emotional empathy; i.e., Emotional Concern (p = .010) and Personal Distress (p = .005). Further analyses revealed that these effects were due to pindolol+ MDMA (pEC = .006; pPD = .012) and oxytocin (pEC = .048; pPD<.001), causing higher levels of emotional concern and personal distress. The effect of oxytocin on Emotional Concern was not significant after Helm's Bonferroni correction. There were no Treatment Condition effects on scales assessing cognitive empathy, i.e. Perspective-Taking and Fantasy
Social interaction tests and questionnaire
  • Trust Game
    Analysis revealed no main effects of Treatment Condition on Reciprocity or Trust.
    There was no interaction effect of Treatment Condition by Risk or Benefit on Trust.
  • Social Ball Tossing Game
    There was no main effect of Treatment Condition, or a Treatment Condition by Player interaction
  • Social Ball Tossing Game Questionnaire
    Further analyses revealed that, irrespective of Treatment Condition, there was more trust in, and preference for the ‘good’ player compared with the ‘neutral’ player. There was no main effect of Treatment Condition on items of the questionnaire
For a complete result table, see this link
 
Last edited:

neurotic

Bluelighter
Joined
Dec 26, 2011
Messages
1,585
Location
intravenous
Now thats interesting, def gonna read it later, im feelin lazy now.

I too would like to hear what some of the more knowledgeable dudes hers have to say, this subject intrigues me

Nice find man
 

JWills20

Bluelight Crew
Joined
Feb 16, 2012
Messages
2,510
Location
England
Sounds fair enough. Only consideration I'd have is that the dosage is rather low, especially considering they are not MDMA-naiive, and hasn't been adjusted to become equipotent for each participant (everyone was given a stock 75mg capsule, instead of say 1.5mg/kg). Perhaps higher doses would induce more downstream oxytocin which would modulate 'cognitive empathy'. Difficult to tell though, you'd expect the pindolol to increase the emotional empathy if it was oxytocin governed. However, we do know that the dose-response curve is pretty steep. Perhaps oxytocin is a small fish in a big sea.
 

BlueBull

Moderator: M&ED
Staff member
Joined
Nov 3, 2012
Messages
2,774
Yeah indeed, that something that caught my eye as well. I'm wondering what sort of an impact this would have on results.

Also this is yet again a study done on poly-drug users, which adds a whole plethora of extra factors to consider (long-term neurological changes from using other drugs, stimulant tolerance,...). I wonder if the number of applicants is so small they need to use poly-drug users. In which case they should contact me =D I'm not a poly-drug user (not regularly anyways) so would be more than happy to help out. Doin' my part for science!

Apart from these considerations they are very interesting results though. I have a feeling they are going to find out it's influenced by a lot of different factors, not just a single one (oxytocin for example). Small fish big sea indeed

*edit* Test days were also only 7 days apart (minimum). This is in my opinion not sufficient to rule out any tolerance issues which could skew results. The empathic effects are among the ones most influenced by tolerance I think...
 
Last edited:

Ezeon

Greenlighter
Joined
Jul 21, 2014
Messages
2
This is already well known for anyone who has taken both MDMA and Oxytocin. Oxytocin has very little effect on the social and emphatic qualities of MDMA.
 

endotropic

Bluelight Crew
Joined
Feb 14, 2012
Messages
1,144
If you really want to test whether MDMA produces social effects by increasing 5-HT1A and Oxytocin activity you need to give 5-HT1A and oxytocin antagonists not agonists. The MDMA might already produce the maximal 5-HT1A and oxytocin activity required for social effects, so what does adding more on top tell you?
 

BlueBull

Moderator: M&ED
Staff member
Joined
Nov 3, 2012
Messages
2,774
That is a very good point actually. However if you give non-MDMA-naive persons only 75mg of MDMA it seems to me it's unlikely the empathogenic effects would be in full swing. I know that for me and my mates, the empathogenic effects keep increasing up until around 160-180mg. I also know this doesn't mean it's like that for everyone but at 75mg in people not MDMA-naive I think it would be unlikely these effects would be at their peak. I was wondering why they chose such a low dose for this experiment, perhaps this is the reason?

Again that is a very good point. I wonder why they went with the opposite approach as what you are describing seems to be the most obvious and best way to test this...
 
Last edited:

endotropic

Bluelight Crew
Joined
Feb 14, 2012
Messages
1,144
That is a very good point actually. However if you give non-MDMA-naive persons only 75mg of MDMA it seems to me it's unlikely the empathogenic effects would be in full swing. I know that for me and my mates, the empathogenic effects keep increasing up until around 160-180mg. I also know this doesn't mean it's like that for everyone but at 75mg in people not MDMA-naive I think it would be unlikely these effects would be at their peak. I was wondering why they chose such a low dose for this experiment, perhaps this is the reason?

Again that is a very good point. I wonder why they went with the opposite approach as what you are describing seems to be the most obvious and best way to test this...
Oxytocin and pindolol are safe compounds approved for human use, antagonists at those receptors are mostly research compounds not approved for human use. My guess is the authors went the easy route with the approved drugs to avoid the regulatory hurdles that go along with using unapproved drugs in clinical trials.
 
Top