Mixing antidepressants and psychedelics: 5 Questions for psychopharmacologist Kelan Thomas

Thomas discusses what we know — and don’t know — about potential interactions between psychedelics and SSRIs.

As a teenager in the 1990s, Kelan Thomas started reading Aldous Huxley. The novelist is credited with helping to coin the term “psychedelic,” and his books and essays asked big questions about mysticism, dystopia, and perception. Thomas went on to study pharmacogenetics, a field that investigates how genetics influence drug response. He’s now an associate professor of pharmacy sciences at Touro University in Vallejo, California. 

Selective serotonin reuptake inhibitors (SSRIs) are among the most popular prescription drugs in the U.S.; according to a survey conducted by the Centers for Disease Control and Prevention between 2015 and 2018, 13% of adults polled reported using an antidepressant in the last month. That amounts to roughly 43 million people taking antidepressants in the U.S. alone. Thomas’s early work looked at how genetic variation and SSRIs interacted. More recently, he’s turned his attention towards psychedelics: in 2021, Thomas and pharmacologist Benjamin Malcolm published a paper in the Psychopharmacology evaluating the potential risks of receiving psychedelic-assisted therapy while also taking SSRIs. The Microdose spoke with Thomas about what we know — and don’t know — about those potential interactions.

Many psychedelic clinical trials exclude participants who are taking SSRIs; others even taper participants off their SSRIs before letting them begin psychedelic treatment. Why is that?

These trials are geared towards understanding the efficacy and safety of a single drug for FDA approval. Stopping other medications — whether it’s an SSRI or any other drug — is necessary to isolate an individual drug’s effects. 

What do we know about the safety of mixing SSRIs and psychedelics?

The main risk is serotonin toxicity, which can occur when a drug that acts on the serotonin receptor — like SSRIs and many psychedelics — are mixed with a monoamine oxidase inhibitor (MAOI) that prevents the metabolism of serotonin. [Editor’s note: MAOIs, which include brands like Nardil and Marplan, were early generation antidepressants first developed in the 1950s. It is now common practice for medical professionals to prescribe SSRIs for depressive symptoms before recommending patients try MAOIs.) In healthy volunteers, there don’t seem to be big risks of serotonin toxicity when taking SSRIs and psychedelics. 

Does combining psychedelics and SSRIs lead to any difference in efficacy in treatment for conditions like depression or PTSD?

The Imperial College London group presented some preliminary data that isn’t published yet, and they’re working on answering this question. They looked at data from people who had to taper off an SSRI to get into a clinical trial, and people who didn’t. In trials using MDMA to treat PTSD and psilocybin to treat depression, people who were not taking SSRIs before the study tend to have a more robust response. 

The effect is more dramatic for MDMA, because there’s also an interaction at the transporter level itself; MDMA is essentially competing with the serotonin reuptake transporter for its intended effect. With psilocybin, the issue arises over a period of time, usually months — you’ll see receptor desensitization from SSRIs, and then the psilocybin doesn't seem to have as much of an effect. 

The big question that we don’t have an answer to yet: could you regain some of those effects if you just increase the psychedelic dose? 

How does tapering off SSRIs work, and are there risks to consider when doing that?

The obvious risk is that if people take antidepressants and are getting some benefit from them, then tapering off them could mean that their depression or anxiety symptoms will return. There’s also serotonin discontinuation syndrome, where people have flu-like symptoms after going off SSRIs. 

As for deprescribing or stopping medication, a safe taper depends on the half life of the drug. 

A drug like Prozac has a long half life, whereas with a drug like Effexor, people can start showing discontinuation syndromes within a day if they stop taking it abruptly. In clinical practice, the period over which we taper drugs depends on how long you've been taking it and the dose you’re on. It’s pretty typical to taper people over a month or more.

I’ve heard anecdotes and seen people posting in online forums about replacing their SSRIs with microdosing. What would you advise folks considering that kind of course of action?

I’ve heard that too, and the issue there for me is that we don’t know if microdosing is effective. There hasn’t been any clinical trial data to suggest it’s effective. That’s what we need to know first: is the microdose capable of actually treating depression on its own? 

The other piece is safety in the long term. If people keep microdosing every three days without breaks, it’s possible they could develop valvular heart disease, which can arise when serotonergic drugs like LSD or psilocybin thicken heart valve tissue. 

People should consider it on an individual, case by case basis. What benefits are you getting from your antidepressant? If you truly have treatment resistant depression, it could make sense to try something else. There are centers and plenty of clinical trials that are working on this issue that could provide some level of monitoring instead of doing it all yourself. 

In the long run, we know some people see benefits from making the switch, but we still need to study it. We need trials where we randomize people to either continue SSRIs or stop them, and see what differences we notice. That should also include an arm of the research where we use an increased psilocybin dose. If you’re seeing, say, a 30% decrease in subjective effects of the psilocybin in people on antidepressants, what if we increase their dose by 30%? Can we see the return of those benefits? We know taking SSRIs and psilocybin together is generally safe, but that still doesn't answer our question regarding whether doing so produces sufficient antidepressant benefits.

This interview has been edited and condensed for clarity and length.