Psychedelic medicines like psilocybin and LSD are increasingly being studied for their effects on treatment-resistant antidepressants and other psychiatric disorders. The jury is still out on whether they are a safe and effective treatment method, but early studies are extremely positive. (1)

It does beg one question, though—if psychedelics really can help people struggling with depression, is it safe to use them alongside antidepressants?

How Psychedelics Interact With Antidepressants and Other Psychiatric Medications

As a psychedelic coach, you need to understand the risks of guiding someone through a psychedelic experience when they are taking psychiatric medications or have recently finished a course of prescription medication.

Psilocybin, LSD, DMT, and Mescaline

Psilocybin is thought to work by stimulating serotonin 2A receptors (5-HT2ARs), impacting a brain chemical that plays a role in regulating sleep and mood, among other things. (2) (3)

LSD and mescaline—considered “classic psychedelics” alongside psilocybin—have a similar mechanism of action. (4) (5)

Many antidepressants fall into a category known as selective serotonin reuptake inhibitors (SSRIs). These medications increase serotonin and, theoretically, improve the user’s mood. (6)

Although research is scant concerning the combination of antidepressants and classic psychedelics, there have been concerns that the former could blunt the effects of the latter, as well as warnings that it may increase the risk of serotonin syndrome. (7)

A study on the effects of psilocybin after escitalopram (an SSRI) pretreatment found that the antidepressant didn’t impact the positive effects of psilocybin, but it did increase the risk of negative reactions and adverse experiences. (8)

We have heard many similar stories from people who have sat with psychedelics while taking SSRI antidepressants. It’s also worth noting that there are various different types of medications prescribed for depression, and some are more problematic than others.

Lithium, for instance, has been linked with seizures and other serious adverse reactions when taken with psychedelics. (9)

Caution is advised if you’re taking any kind of antidepressant, but it’s best to avoid psychedelics if you’re on lithium or tricyclics.

If you have recently finished a course of antidepressants, the medication could still be in your system, but the risk of adverse reactions will be a lot lower.

A 2024 study actually looked at the effects of discontinuing antidepressants on subjects given psilocybin during clinical trials. It found that pre-study cessation was “not related to worsening of depression severity”, suggesting that prior antidepressant use does not limit the feasibility of psilocybin trials. However, studying the direct effects of both substances is a little more complicated due to the increased risk and similar mechanism of action. (10)

MDMA

There is no shortage of anecdotal reports about the relationship between antidepressants and MDMA, with one Vice article highlighting stories of people who felt that the effects of the MDMA were greatly reduced and restrained, leading to a flat and disappointing experience. (11)

It’s not just about reducing efficacy, either. A 2021 study found that there was a significantly increased risk of death when MDMA was combined with antidepressants like venlafaxine and sertraline. (12)

Ayahuasca

As you may have guessed, there’s a lot that we don’t know about how psychedelics interact with antidepressants. It’s not an easy combination to trial, and that means we’re often left to trawl through anecdotal reports or rely on a few small clinical studies.

It‘s a different story with ayahuasca, though, and that’s because this sacred blend contains monoamine oxidase inhibitors (MAOIs). It’s a type of antidepressant that was once commonly prescribed but has since been phased out for safer alternatives. There are various foods and medications you need to avoid when taking MAOIs. Including other antidepressants, cold medicines, and some painkillers. (13)

People who take MAOIs also need to avoid foods that are high in an amino acid known as tyramine, which rules out many smoked meats, aged cheeses, and fermented/pickled foods.

Ayahuasca is definitely not a good idea for anyone taking antidepressants—a complete purge and a very careful and methodical approach are needed before even considering sitting with this psychedelic. (14)

Ibogaine

Ibogaine, like classic psychedelics, can increase levels of serotonin, which may put the individual more at risk of serotonin syndrome. For this reason, most experts recommend stopping all medication at least a few days before use, giving those medicines time to leave the body. (15)

Other Possible Contraindications with Psychedelic Medicines

If a client is using any prescription medication, it should be carefully assessed to determine if it will interact with their psychedelic experience. As noted above, some medications can lessen the experience, while others will increase the risk of adverse reactions.

The risks don’t stop at antidepressants, either.

Antipsychotic drugs work in similar areas of the brain as SSRI antidepressants and may hinder the experience. Benzodiazepines like diazepam are occasionally used in cases of “hallucinogenic crises”, whereby someone reacts badly to a psychedelic experience, but as these drugs can impact the respiratory system, caution is still advised. (16) (17)

How to Prepare as a Psychedelic Coach

The first step is to understand the current mindset of your client while also assessing their medical needs, preexisting illnesses, and prescribed medications. If there is anything that presents a serious risk, such as lithium and classic psychedelics or SSRIs and ayahuasca, they should not be encouraged to continue any further.

In cases where the risk is greater but not necessarily fatal, they should be fully informed of the dangers, provided with all the necessary information, and then guided carefully. It may be wise to reduce the dose or ask them to terminate their use of a specific medication before going any further. The latter should only be done after consulting their physician, though.

Finally, make sure they are well supported throughout their experience and that they learn how to integrate it effectively. If they have been battling with depression, guide them on how to use their psychedelic experience to improve their mood and push their life in the right direction.

Conclusion: Psychiatric Medications and Psychedelics

There are innumerable reports of people who have transitioned from psychiatric medication to psychedelics, including in our own community (this post from this member and this one from this member are prime examples). It can be a huge, life-affirming leap, but it’s not something to take lightly.

As a psychedelic coach, you should always analyze your client’s needs and their current situation before advising them on their path. Weigh up the risks, direct them, and remind them to seek advice from healthcare professionals if they need recommendations about their medication.