Is it Safe to Mix Magic Mushrooms With Antidepressants?

“If the results are confirmed in subsequent studies … antidepressants may no longer need to be stopped for psilocybin treatment,” says Dr. Miri Halperin Wernli.

Key takeaways.

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We get asked a lot of questions about whether or not it’s safe to mix magic mushrooms with antidepressants.

It's a valid question because those with depression often seek out alternative therapy through psychedelics. But because there’s more than one kind of antidepressant, and because many are known to have numerous interactions, the answer can be convoluted.

For example, SSRIs — the most common class of antidepressants — work through the human body’s serotonergic system.

Because many psychedelics and recreational drugs work on the very same system, there is some controversy around whether or not this would generate excessive levels of serotonin—which are associated with severe and sometimes fatal events. However, this is unlikely to be the case. Psilocybin and psilocin do not significantly block the reabsorption of monoamine neurotransmitters, and as a result, they don't cause a substantial increase in serotonin levels.

Are there clinical trials on psilocybin and antidepressants?

Recent clinical trials demonstrate that SSRIs, including the common SSRI escitalopram, may be safe to use alongside psilocybin therapy.

That isn't to say that all antidepressants react with magic mushrooms the same way, or that all SSRIs are compatible with magic mushrooms.

In this article, we're covering the available data on magic mushrooms and SSRIs, SNRIs, Lithium, and MAOIs.

If you’re taking antidepressants, but want to experiment with magic mushrooms, the most important thing to do is talk to the doctor who prescribes your antidepressants. If they aren’t friendly to the concept of alternatives, find one who is. You may be required to wean off antidepressants before using psychedelics, but this should only be under the supervision of the professional who prescribes them to you.

What makes a mushroom "magic"?

Magic mushrooms. Everybody's heard of them by now. They've played a rich part in our history and evolution, and today they are being lauded for their therapeutic potential. But how well do they know them, really?

At their core, magic mushrooms are special types of fungi that induce a psychedelic experience. But how do they do this? And which mushrooms are capable? And are all psychedelic mushrooms "magic" mushrooms?

Many species of mushrooms contain psychoactive compounds that cause some sort of expanded state of consciousness. But when talking about magic mushrooms, we're not necessarily talking about any mushroom with psychedelic effects. For instance, the famous Fly agaric mushroom from the Amanita muscaria species (which is a deliriant or hypnotic) is certainly psychotropic, but it doesn’t always fall into the traditional magic mushroom category.

That's because the term "magic mushrooms" traditionally refers to those that are widely circulated and studied. More specifically psilocybin mushrooms, which contain the active substances psilocybin, psilocin, and, to a lesser extent, baeocystin.

The active ingredients in magic mushrooms.

As mentioned earlier, there are three main psychoactive compounds in psilocybin mushrooms:

• Psilocybin, which is converted into psilocin by the liver
• Psilocin, the psychoactive compound that produces the actual psychedelic effects
• Baeocystin, a derivative of psilocybin that isn't well understood but is known to contribute to the overall effects

But other compounds in magic mushrooms can also alter the psychedelic journey.

For example, in addition to psilocybin, psilocin, and baeocystin, magic mushrooms contain MAOIs, compounds that inhibit an enzyme in the body responsible for the breakdown of certain neurotransmitters.

The ratio of these compounds is not the same across species, subspecies, or even within groups of the same mushroom. Together, they give every mushroom strain an entourage effect, much like cannabis strains have their own entourage effect.

And how they’re balanced influences the which influences the effects, nature, and intensity of the mushroom trip as a whole. Some can be more visual, while others can be more meditative.

Psilocybin.

Psilocybin, a precursor to psilocin, is a naturally occurring psychedelic compound found in certain species of mushrooms, often referred to as "magic mushrooms." When ingested, it undergoes a transformation within the body. Also known as a prodrug, psilocybin itself is inactive, but it's converted into its active form, psilocin, by enzymes in the liver. Psilocin is the real agent responsible for the mind-altering effects.

While this substance is ultimately responsible for initiating the high, it must first be metabolized in the body into psilocin before actually exerting hallucinogenic effects. This process can also be carried out artificially before consumption.

Think of psilocybin as a unique key, and your body as a lock. When you consume magic mushrooms, you're essentially inserting the key (psilocybin) into the lock (your body's enzymes). This action unlocks a door to altered perception and consciousness, much like how a key can open a door to a different room. Psilocin activates serotonin receptors in the brain, leading to changes in thought processes, mood, and sensory experiences. This cascade of serotonin receptor activation, particularly in the prefrontal cortex, is what's behind the vivid visuals, altered sense of time, and profound introspection that people often experience on psilocybin.

It's important to note that while this analogy simplifies the process, the effects of psilocybin are far-reaching, and its potential therapeutic applications and psychological impact continue to be a subject of scientific exploration.

Psilocin.

Once ingested, the body metabolizes psilocybin into psilocin.

Psilocin is found most abundantly in fresh mushrooms, or in lemon tek—a process whereby psilocybin is theoretically converted into psilocin using lemon juice. Psilocin is the substance in mushrooms that directly interacts with the body and causes the psychedelic trip.

Psilocin is structurally similar to serotonin, a neurotransmitter that plays a key role in regulating mood, perception, and various cognitive processes. When psilocin enters the brain, it interacts with serotonin receptors, particularly the 5-HT2A receptor. This interaction disrupts the usual patterns of serotonin transmission, resulting in changes in thought patterns, mood, and sensory perception. It's like a guest arriving at a party and shaking up the usual rhythm—everything begins to flow differently.

The presence of psilocin in the brain leads to the vivid visuals, emotional depth, and altered sense of self and reality that people often experience during a "trip." The exact mechanisms behind these effects are still under investigation, but it's clear that psilocin's interaction with serotonin receptors plays a pivotal role in the psychedelic experience.

Baeocystin.

A derivative of psilocybin, baeocystin is the lesser-known and studied sibling of psilocin and psilocybin. Exactly what role it plays, or what effect it has on the body, is unknown. During the few times baeocystin has been administered alone, it exerted comparable effects to an equivalent dose of psilocybin. However, a more recent study from 2019 saw no significant change in mouse behaviour when given baeocystin compared to saline solution.

However, it's generally accepted that baeocystin can produce psychedelic effects when ingested, although it is generally considered to be less potent compared to psilocybin and psilocin.

To draw an analogy, if psilocybin and psilocin are the lead actors in the psychedelic experience, baeocystin might be considered a supporting character. It's like a member of an ensemble cast, contributing to the overall experience but perhaps not taking center stage. Baeocystin's precise role and its effects on the brain's neurotransmitter systems are still being studied, but it's thought to have some influence on the overall character and duration of the trip, enhancing the nuances of the experience.

The interactions of baeocystin with serotonin receptors and its exact contributions to the psychedelic journey are areas of ongoing research, making it an intriguing and increasingly recognized component of the magic mushroom experience.

Mixing magic mushrooms with SSRIs.

SSRIs are one of the most commonly prescribed antidepressants because, as a class of antidepressants, they are considered to have the fewest drug interactions and side effects. SSRI stands for selective serotonin reuptake inhibitor, and as we mentioned, it works on the nervous system’s usage and production of serotonin. 

The most common ones include:

• Citalopram (Celexa, Cipramil)
• Escitalopram (Lexapro, Cipralex)
• Fluoxetine (Prozac, Sarafem)
• Fluvoxamine (Luvox, Faverin)
• Paroxetine (Paxil, Seroxat)
• Sertraline (Zoloft, Lustral)

Clinical studies on the interactions between psilocybin and SSRIs.

There are a couple of clinical trials that specifically address the interaction between magic mushrooms and antidepressants.

Biotechnology company MindMed has released new data from a 2021 study showing how the selective serotonin reuptake inhibitor (SSRI) escitalopram interacts with psilocybin in humans, providing preliminary evidence these drugs could be safely used together without impacting psilocybin’s effectiveness to tackle depression and anxiety.

SSRI drugs are the most commonly prescribed antidepressant that can relieve the symptoms of depression by increasing the level of serotonin—often referred to as the “feel-good hormone” because it is responsible for stabilizing our mood, feelings of well-being, and happiness—within a person’s brain.

Because psilocybin is being investigated as a treatment for depression and anxiety, it is vital to understand how this drug interacts with current antidepressant treatments. Before this study, it was unclear if antidepressant medicines would interact with psilocybin, with some case reports indicating that antidepressants may reduce a person’s response to psychedelics.

The MindMed-sponsored study, carried out by the University Hospital Basel Liechti Lab, showed that pre-treatment with the SSRI escitalopram had no relevant impact on the positive mood effects of psilocybin.

For the study, healthy human participants either received 10mg of escitalopram daily for seven days followed by 20mg daily for the next seven days, including the day of psilocybin administration, or 14 days of placebo pre-treatment before psilocybin administration.

“These results indicate that psilocybin may be dosed during escitalopram treatment without apparent impact on the effect of psilocybin,” explains the study’s Principal Investigator, Dr. Matthias Liechti.

Some researchers theorize that because psilocybin and SSRIs work on the serotonergic system in different ways, magic mushrooms and SSRIs might be complementary. The MindMed study illustrated that before taking psilocybin, pre-treatment with escitalopram significantly reduced negative effects such as anxiety and adverse cardiovascular reactions when compared with a placebo pre-treatment.

Positive results from 25mg COMP360 psilocybin therapy with SSRI antidepressants.

A groundbreaking open-label study in 2021 challenged the idea that SSRI medications interfere with psilocybin therapy, opening new avenues in depression treatment. This study demonstrated that psilocybin therapy can work alongside SSRI antidepressants or as a standalone treatment.

Key Points from the COMP360 Study:

• 19 patients from the US and Ireland participated.
• 42.1% of patients responded positively at week 3, achieving remission.
• The average reduction in the MADRS (Montgomery-Åsberg Depression Rating Scale) total score was 14.9 at week 3.
• Participants initially had moderate to severe depression.
• Patients showed improved anxiety, depressive symptoms, and positive/negative affect.
• The therapy was well-tolerated, with no serious adverse events."

Is it safe to take SSRIs with psilocybin?

In a 2020 study, researchers discovered that, in addition to psilocybin and psilocin, magic mushrooms contain an alkaloid called b-carboline. This alkaloid falls into a category of compounds called MAOIs (monoamine oxidase inhibitors), which are known to adversely interact with SSRIs. However, in this study, researchers concluded that MAOIs can be safely co-administered with SSRIs, as long as they aren't MAO-B inhibitors.

But for this to be safe, the SSRI dose has to be at the lower end of the therapeutic index and has to be monitored closely. 

So what does this mean for SSRI takers?

Given the results of the 2021 Mind Mend and Compass Pathways studies, coupled with the conclusions of the 2020 study, it means it's likely safe, but you should always talk to your doctor. It seems there is a safe way to co-administer magic mushrooms and SSRI but it should be done under supervision to ensure that your SSRI dose is safe with your psilocybin dose. 

Mixing magic mushrooms with SNRIs.

SNRIs are similar to SSRIs except that they also work on norepinephrine as well as serotonin. They are typically prescribed when SSRIs aren’t tolerated and might also be beneficial for people with anxiety.

SNRI drugs include:

• Desvenlafaxine (Pristiq, Khedezla)
• Duloxetine (Cymbalta)
• Levomilnacipran (Fetzima)
• Venlafaxine (Effexor XR)

Is it safe to take SNRIs with psilocybin?

Given that SNRIs work in a very similar way to SSRIs, the same assumptions can be made about SNRIs. There’s a possibility that magic mushrooms are safe to use with SNRIs depending on the dose of both, but again this should be supervised by the professional who prescribes the SNRI.

Mixing magic mushrooms with Lithium, MAOIs, and other antidepressants.

Though there are no clinical trials on the co-administration of lithium with magic mushrooms, this is not recommended. There are reports of people mixing lithium with LSD and psilocybin mushrooms and experiencing seizures and heart attacks.

Is it safe to take Lithium, MAOIs, and other antidepressants with psilocybin?

Because MAOI-type antidepressants are, in fact, MAOIs, it's not recommended to use them with psilocybin. Psilocybin mushrooms also contain an MAOI, so it might sound counterintuitive to avoid mixing, but it's not known to what degree MAOI antidepressants potentiate the effects of magic mushrooms or even dampen them.

For all other antidepressants, there is next to no information about interactions. For this reason, we recommend avoiding concomitant use unless you have been given the OK from your doctor, or until you can wean off them.

It is possible antidepressants might dampen the effects of magic mushroom treatment.

Tryptamines, such as psilocybin, are lovers of serotonin receptors, and like we just talked about, so are pharmaceutical antidepressants. Antidepressants like SSRIs don’t just affect serotonin levels but they also modulate and affect serotonin receptors.

Benjamin Malcolm, the owner of Spirit Pharmacist, hypothesizes that because of the way that SSRIs and SNRIs modulate serotonin receptors, antidepressants may actually dampen magic mushrooms' therapeutic potential.

He offers this chart for interactions between different kinds of antidepressants and psychedelic drugs.

You can find his full compilation of possible drug interactions here.

When you look through the chart, you’ll notice that most of the time Benjamin Malcolm recommends weaning off antidepressants and discontinuing their use at least two weeks before using magic mushrooms. He also says that prolonged, chronic antidepressant use can lead to an overall dampened effect of magic mushrooms.

However, as we've seen from the COMP360 and MindMed studies, SSRIs and psilocybin might work synergistically. Always speak with a healthcare provider or trained therapist.

Don’t try this at home, folks.

The overwhelming advice, in light of how little we know, is to wean off antidepressants before you take magic mushrooms in any kind of therapeutic fashion. Although it’s unlikely to walk yourself into any kind of fatal event, not knowing at which correct doses to co-administer the two is unsafe. Plus, you don’t know how much of a disservice you’re doing to your antidepressant treatment or your magic mushroom experience.

If you’re one of the many people who is seeking an alternative treatment for depression and wants to try psilocybin, we recommend talking to your doctor to wean off before you try magic mushrooms. It’s the safest way to dip your foot in this ocean and your overall treatment might be much better off not mixing the two.

Have you ever weaned off antidepressants to use magic mushrooms? We’d love to hear your story — drop it in the comments.

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