Ground breaking systematic review of drug-drug interactions between psychiatric medications and psilocybin or MDMA

Researchers just published the first review of research on how MDMA and psilocybin interact with other drugs. This is very important work as these drugs begin to have more and more use by the public and as they are likely to soon begin to be part of legal clinical practice. Here’s a link to the paper if you want to read through all the details.

What’s the takeaway? The big one is that there isn’t a lot of good research, especially with people other than young, healthy adults.

So, perhaps the biggest takeaway is that mixing MDMA and psilocybin with other drugs usually involves, at best, educated guesses based on understanding mechanisms of action. This paper reviews those mechanisms of action in detail and is a must read for prescribers working in this space. It’s a dense read and must have taken a ton of time.

The other major takeaway is that this is all very complicated and the possible interactions are many.

Thus, without diving into the actual article, there aren’t a lot of firm conclusions that can be drawn, but here are a few.

One is that MDMA’s mechanism of action is complex and therefore it probably interacts with a lot more drugs than psilcobyin. For example, many drugs have significant inhibitory effects on CYP2D6, meaning that many of them will change how MDMA affects users. For example, fluoxetine and paroxetine are strong inhibitors of CYP2D6 and thus plasma levels of MDMA might be increased even as the subjective effects of MDMA might be inhibited.

Another conclusion was that psilocybin, in general, will result in fewer drug-drug interactions at the pharmacokinetic level:

Compared to MDMA, psilocybin is less likely to contribute to pharmacokinetic drug-drug interactions given that its metabolic pathway predominantly involves UGT1A10 and UGT1A9

They also suggest that drugs that block 5HT2A receptors will attenuate psilocybin’s effects.

They also conclude:

There are clear acute pharmacokinetic and pharmacodynamic interactions between many common psychiatric medications and MDMA or psilocybin which affect their physiological and subjective effects and help us better understand the mechanisms of action of these substances. However, the existing body of literature is not readily applicable to the clinical setting, prompting the need for additional research on the topic of drug-drug interactions with MDMA or psilocybin

I’ve only covered a few things they discussed in their lit review, so I refer you to the article to read more. This should not be taken as advice on how to mix drugs, as this is all very complicated and there are tons of unknowns on how MDMA and psilocybin will interact with other drugs.

Authors: Jason Luoma, Ph.D.