Combining MDMA with SSRIs - Are there possible dangers? A review of recent literature

Note: This was originally published as a post on the /r/DrugNerds subreddit, and garnered a number of interesting comments there.

Does combining MDMA and Selective serotonin reuptake inhibitors (SSRIs) put you at a fatal risk of serotonin syndrome? This seems to be common knowledge in many parts of the internet, but where is the evidence? I had seen a number of papers to the contrary, which indicated that SSRIs would be neuroprotective against the harms of MDMA. However the "common knowledge" must have come from somewhere. Was I just missing some vital information? Luckily a quick google search brought up a relatively recent (2013) paper that seems to be trying to summarize the research about the interaction of MDMA and SSRIs, with a view of warning the world.

Dobry, Y., Rice, T., & Sher, L. (2013). Ecstasy use and serotonin syndrome: a neglected danger to adolescents and young adults prescribed selective serotonin reuptake inhibitors. International Journal of Adolescent Medicine and Health, 25(3). doi:10.1515/ijamh-2013-0052

Sci-Hub link for paper

Well the title certainly indicates that the authors think there is a risk. Lets give this a read. From the abstract:

MDMA, in combination with the widely prescribed SSRI antidepressant class, can lead to rapid, synergistic rise of serotonin (5-HT) concentration in the central nervous system, leading to the acute medical emergency known as serotonin syndrome.

Well that seems pretty definitive. Lets see how they came to that conclusion.

The paper starts by giving an overview of how SSRIs and MDMA work, and the mechanisms of serotonin syndrome. Lets skip that and get into the meat of it though.

Ecstasy in combination with SSRI increases the risk of serotonin syndrome

Now that's the title we've been looking for. Surely all the facts are in here.

Despite a clear need, basic and clinical science has done little to investigate a physiological interaction between SSRIs and MDMA This omission disregards the powerful potential of both drugs to tremendously raise synaptic cleft serotonin. Microdyalisis and measured lab data has shown that SSRIs are capable of very rapid, and large increases of serotonin (5-HT) concentration in animal brains (60–62), and that MDMA administration releases serotonin at various brain sites at a rate possibly above that produced by the SSRIs (63, 64).

That's in isolation though, what about when they are combined?

The combined pharmacokinetic drug-drug interaction additionally ensues when SSRIs that are also potent CYP450 2D6 inhibitors reduce MDMA metabolism (53, 65). MDMA can conversely exert metabolic effects upon SSRI metabolism. Paroxetine and fluoxetine administration, for example, has been shown to increase MDMA levels by as much as 30% (66)

Well, the amount of MDMA in the blood being elevated to that degree does sound alarming, especially if it's releasing all that serotonin. Lets look at the cited paper.

(66) Farre M, Abanades S, Roset PN, Peiró AM, Torrens M, et al. Pharmacological interaction between 3,4-methylenedioxy-methamphetamine (ecstasy) and paroxetine: pharmacological effects and pharmacokinetics. J Pharmacol Exp Ther 2007

PDF link for paper

Even though plasma concentrations of MDMA were increased, a boost in pharmacological and subjective effects was not observed. On the contrary, a clear decrease was observed, which indicates a pharmacodynamic interaction.

Hmm, it seems like this is more complicated than just blood levels.

In vitro studies have shown that fluoxetine inhibits MDMA-induced release of serotonin into the synaptic space (Gudelsky and Nash, 1996), and there is some evidence that pre-treatment with SSRIs reduces some MDMA-related effects (Liechti et al., 2000; Liechti and Vollenweider, 2000b; Tancer and Johanson, 2007). SSRIs, such as paroxetine, antagonize MDMA activity either by preventing its interaction with the 5-HT uptake site or alternatively by blocking the efflux of 5-HT through the carrier.

Oh. So even with more MDMA in the blood, less serotonin is being released. I'm not seeing where serotonin syndrome would come from. Maybe there are other sources? Lets get back to the main paper.

Moreover, increased body heat from muscle use during prolonged dancing and cooling dysregulation brought about by dehydration can significantly increase body temperature, leading to an excessive increase in the serotonin release rate through the amplified thermodynamic processes (70, 71).

Well I can't find fault with thermodynamics. This seems unrelated to SSRIs though, getting too hot is classic MDMA. What happens with SSRIs in the mix? Lets get back to citation 66.

During the paroxetine condition, the increase in temperature shown during the administration of MDMA alone decreased by approximately 50%.

So adding SSRIs to the MDMA would reduce the amount of serotonin released via thermodynamics, not increase it. Another dead end. I'm beginning to wonder how deeply the authors read the papers they cited.

Well the pharmacological dynamics seem to be a bust for causing serotonin syndrome, but those were all measured in sterile laboratories. The real world can be messier and throws in curveballs. Do they have any data about it happening in the real world?

A survey of 216 young adults from Sydney, Australia who had used Ecstasy at least once in the previous 6 months reported 19 cases of purposeful concomitant use of antidepressant medication with MDMA. A considerable number of these subjects took the SSRI either to enhance their Ecstasy high or to prevent neurotoxic effects. This sample was analyzed for neuropsychiatric symptoms and a large proportion has been shown to display symptoms consistent with serotonin syndrome of various severity (75)

This seems to show exactly what I was talking about, lets see the facts on the ground. The paper cited:

(75) Copland J, Dillon P, Gascoigne M. Ecstasy and the concomitant use of pharmaceuticals. Addict Behav 2005;31:367–70

Sci-Hub link for paper

Only four pages, extremely brief

SSRI and MAOI antidepressants were reported 19 times

The paper grouped SSRIs and MAOIs in a single category when reporting symptoms resulting from MDMA combined with antidepressants - Cited only as SSRIs. That's no good. We know that MAOIs can cause serotonin syndrome when combined with MDMA (and lots of other drugs). That's going to really skew the results.

However that paper was also concerned about this risks of MDMA and anti-depressants.

This is of concern, as some of these ecstasy-pharmaceutical combinations can have potentially serious health consequences (Singh & Catalan, 2000; Sternbach, 1991)

Lets keep going down the chain and read the papers they used to come to this conclusion.

Singh, A. N., & Catalan, J. (2000). Rave drug (ecstasy) and selective serotonin reuptake inhibitor anti-depressants. Indian Journal of Psychiatry,42(2), 195–197.

PDF link for paper

We report two cases of misuse of selective serotonin re-uptake inhibitors (SSRIs) antidepressants in combination with Ecstasy and their beneficial subjective effects experienced by misusers. We hypothesis the probable underlying pharmacological reasons and recommend its use in the treatment of neurotoxic effects of MDMA

Where is the harm? Not in this paper. They actually come to the opposite conclusion.

Sternbach, H. (1991). The serotonin syndrome [comment].American Journal of Psychiatry,148(6), 705–713.

Sci-Hub link for paper

A paper about the dangers of serotonin syndrome – Focused on MAOIs (don’t combine them with your lithium). Zero mention of MDMA, and only really mentions SSRIs in terms of them being combined with MAOIs (don't).

It seems like when you dig into the citations of harm there is almost zero evidence of the claims they are supposed to support. To really demonstrate that, lets finish up back at Dobry et al

One of the case reports even describes death from the combination of fluoxetine and MDMA (84)

Bold is mine.

Have we finally found the harm? A full case report showing the fatal combination of SSRIs and MDMA?

(84) Byard RW, Gilbert J, James R, Lokan RJ. Amphetamine derivative fatalities in South Australia-is “Ecstasy” the culprit? Am J Forensic Pathol 1998;19:261–5.

PDF link for paper (thanks MAPS)

A collection of six case reports of deaths related to "ecstasy", including a single case where fluoxetine was present.

Toxicologic analysis of blood revealed elevated, but apparently not lethal, levels of PMA, with therapeutic levels of fiuoxetine (Prozac). Ecstasy not detected.

Bolds are mine.

PMA and a SSRI, not MDMA and a SSRI. PMA can be fatal if a user mistakes it for MDMA, but if a scientific author makes the same mistake it can really fill in the gaps in their evidence.

Overall my confidence in peer-review has really taken a hit after going through this. Now I'm wonder how many other papers I've taken on faith can also be taken to pieces by actually checking the citations. I've actually been convinced that SSRIs can really help with protecting from some of the damage MDMA might cause, and I'm planning on popping some paroxetine on the comedown of my next roll.