How Do Psychedelics Interact with Antidepressants?
If you’re considering using psychedelics for therapeutic reasons – in the form of psychedelic-assisted therapy or a psychedelic retreat – then it’s vital to know how these compounds can interact with any medications you might be on. For many people, psychedelics become an option they’re curious about after having tried other mental health treatments. Antidepressants are the most commonly used form of psychiatric medication, and it is common for many people interested in psychedelic medicine to already be taking an antidepressant, typically a serotonin selective reuptake inhibitor (SSRI).
As is standard practice in clinical trials on psilocybin therapy, participants who were taking an SSRI or serotonin-noradrenaline reuptake inhibitor (SNRI) at screening are required to discontinue use to join the study. In a 2024 paper published in the Journal of Psychopharmacology, a group of researchers at Imperial College London write, “This practice is due to some overlap in serotonergic pharmacology of SSRI/SNRIs and psilocybin (i.e. both cause elevated stimulation of 5-HT receptors) as well as an absence of established safety data for combined treatment”.
Psychedelic researchers want to see how psychedelics alone affect mental health outcomes, rather than psychedelics in combination with antidepressants. Moreover, as the 2024 paper highlights, there is some uncertainty around whether it is safe to combine the two types of substances. Outside of clinical trials, many people have used psychedelics while on an antidepressant and report no adverse effects, but this doesn’t mean there are no risks involved. Besides safety concerns, one of the main reasons people want to discontinue antidepressant use before a psychedelic experience is to ensure that the psychedelic effects aren’t blunted.
In this post, we’ll be delving into the most up-to-date science on how psychedelics interact with antidepressants and whether combining the two can lead to safe and therapeutic experiences.
Psychedelics and Antidepressants: Safety Considerations
The main safety concern about mixing psychedelics and antidepressants is serotonin syndrome. This is a potentially lethal drug reaction, involving high levels of serotonin in the body, that occurs when you combine two compounds that each increase the release of serotonin. This is why doctors, in most countries, avoid prescribing more than one serotonin medication at once. The severity of serotonin syndrome can range from mild to life-threatening.
While we know that both psychedelics and SSRIs increase serotonin neurotransmission, we still don’t know what these effects look like in combination. However, this doesn’t mean we shouldn’t exercise some caution. As Camile Bahi writes in a post for the MIND Foundation:
“There is no empirical data on the interaction between psychedelics and antidepressants, and whether this raises the risk of serotonin syndrome. Nevertheless, it is well-known that psychedelics have 5-HT2AR agonist properties, therefore increasing 5-HT2AR neurotransmission. Thus, from a pharmacological point of view, it seems likely that their co-administration with serotonergic antidepressants could induce serotonin syndrome.”
The main worry with mixing a psychedelic with an antidepressant is when a monoamine oxidase inhibitor (MAOI) is involved, the latter of which is contained in ayahuasca. MAOI inhibits the metabolism of serotonin. Because of this, the risk of serotonin syndrome is much higher if you were to drink ayahuasca (DMT + MAOI) when on an antidepressant than if taking a psychedelic without an MAOI added.
In conversation with Jane C. Hu for The Microdose, psychopharmacologist Kelan Thomas stresses that the involvement of an MAOI is the main safety concern people should have when it comes to mixing psychedelics and SSRIs. He clarifies, “In healthy volunteers, there don’t seem to be big risks of serotonin toxicity when taking SSRIs and psychedelics.” (He and fellow researcher Benjamin Malcolm published a study in 2021 on the relative risks of drug combinations involving psychedelics and serotonergic psychiatric drugs.)
However, since evidence on this drug interaction is lacking, you might want to be on the more cautious side and gradually taper off an antidepressant before participating in psychedelic therapy or a psychedelic retreat. (Before altering your antidepressant use, you should always follow guidance from a general physician or psychiatrist to prevent withdrawal symptoms.) Bahi points out that “since administration of serotonin agents within five weeks after the discontinuation of SSRIs has been shown to induce serotonin syndrome, it appears to be safer to wait for at least five weeks before using any psychedelic compound.”
Do Antidepressants Blunt Psychedelic Effects?
The Imperial College researchers add in their 2024 paper that “previous case reports have indicated that long-term administration of SSRI/SNRIs can reduce the therapeutically important subjective effects of psychedelics”. They cite 1992 research from Rick Strassman and 1996 research from Bonson et al. But what do more recent studies tell us?
A separate 2024 study by researchers at Imperial College explored the interaction between psychedelics and serotonin reuptake inhibitors (SRIs) in terms of therapeutic effects. They found that “‘SRI −’ participants [not on psychiatric medication] experience significantly more intense subjective effects compared to ‘SRI +’ participants [undergoing SRI treatment]”. They found that participants not on an antidepressant reported stronger mystical, challenging, and emotional breakthrough experiences.
Mystical and emotional breakthrough experiences are associated with the therapeutic benefits of psychedelics, and while less challenging experiences may be beneficial, avoiding them may not be essential for a psychedelic experience to produce significant benefits. However, despite the links between mystical and emotional breakthrough experiences and the benefits of psychedelics, the 2024 study just mentioned also notes, “Both groups exhibited similar improvements in well-being and depressive symptoms after the psychedelic experience.” Therefore, it appears that discontinuing antidepressant medication may not be necessary to enjoy the mental health benefits of psychedelics. The authors add, “No differences are observed in drug-induced visual effects.”
Based on this research, it seems that anecdotal claims about antidepressants reducing the intensity of psychedelic effects are partly true. Some types of effects can be dampened, but, according to the available evidence, it appears that the visual effects aren’t impacted much. Nonetheless, it is worth emphasising that the 2024 study on this drug interaction was survey-based. The authors note, “Further controlled research is needed to comprehend the interplay between serotonergic antidepressants and psychedelics.”
In terms of the mechanism behind antidepressant blunting of psychedelic effects, Bahi explains:
“Concerning SSRIs, a possible reason for this could be that the chronic administration of SSRIs causes downregulation of 5-HT2A receptors. This, in turn, may make someone less sensitive to substances affecting these receptors, such as psychedelics. Therefore, this decrease in subjective effects may result from 5-HT2AR downregulation.”
However, the precise mechanisms involved in this interaction are still unclear. Moreover, individual factors could influence the degree of the blunting involved, as well as how risky this drug interaction is in terms of serotonin syndrome. After all, there are genetic variations in the enzymes responsible for metabolising drugs. Further research could help answer these questions. If, as Kelan states, “taking SSRIs and psilocybin together is generally safe”, but people don’t want to lose the subjective intensity of psychedelic effects, which they find beneficial, then we also need research on whether simply increasing the dose is the solution. Kelan asks, “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?”
The gaps in our knowledge mean you should be cautious if you’re considering taking a psychedelic while on antidepressant medication. You should always know what psychedelic you’re taking and the dosage involved, and only enrol in psychedelic therapy or a psychedelic retreat if the practitioners involved are aware of all safety considerations involved.
