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Many people who want to microdose are already on a prescription and want to know whether their medication is safe to combine with psychedelic substances.

Although psilocybin has effectively treated depression and several other mental health conditions, some prescription medications could have dangerous or undesirable interactions with the substance.

Fungal Friend always recommends checking in with your healthcare provider before mixing any psychedelics with your medications. However, below is a guide to what we know about some of the most common medications, and the risky combinations of psilocybin and antidepressants that you should avoid.

How Does Psilocybin Work?

Psilocybin is the main psychoactive component of psychedelic mushrooms, also known as “shrooms” or “magic mushrooms.” Since 1958, psilocybin has been used extensively in clinical research, with over 40,000 patients receiving this drug without serious adverse events. 

Psilocybin is converted in the stomach to psilocin, which crosses the blood-brain barrier, and then works by exerting partial agonist effects on brain 5-hydroxytryptamine (5-HT) 2A receptors, among others, and can alter normal waking consciousness. Common effects include unusual and colourful visuals with eyes open or shut, disintegration of ‘self’ or ‘ego’, unconstrained explorative thinking, cognitive, affective and perceptual changes, and a sense of connectedness to self, others and the world. Ingesting psilocybin, in the form of mushrooms or truffles, produces an intense psychedelic experience that lasts several hours.

By altering several different neurotransmitter systems in the brain, magic mushrooms or truffles activate serotonergic receptors on neurons, causing several brain systems to change significantly, and a wave of unique excitatory activity to spread throughout the main perceptual centers of the mind.

This has significant cognitive effects, including ego-dissolution, changes in external perception, alterations in the subjective experience of time, and even a full-blown hallucinogenic experience.

Psilocybin has been shown to significantly reduce symptoms in people suffering from severe depression, and these positive changes last longer than typical treatments, especially if skillful therapeutic integration programs support them.

However, most typical antidepressants also work on the serotonergic system, so there is a risk of overstimulating the body if you combine psilocybin with certain medications.

Can You Take Shrooms On An SSRI?

Selective Serotonin Reuptake Inhibitors (SSRIs) are the most commonly prescribed medications for depression, OCD, PTSD, and other anxiety disorders. Some of the most well-known SSRIs include:

SSRIs work by preventing the clearance of excess serotonin from the brain, meaning that serotonin levels are temporarily boosted. While in rare cases, it has been hypothesized that this can lead to serotonin syndrome, with proper guidance and supervision, such risks can be mitigated. We would say yes, it is safe to take microdoses on SSRIs, depending on medical history, and other factors. 

Can You Take Shrooms On An SNRI?

Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) are a class of antidepressant medications that boost both serotonin and norepinephrine levels in the brain. Similarly to SSRIs, their mechanism of action is largely unknown. Some typically prescribed SNRIs are:

Just like with SSRIs, we would expect SNRIs to overlap with the effects of psilocybin. However, there are no reports of serious adverse effects of combining the two. If anything, taking SNRIs appears to reduce the effects of mushrooms – but you should not use psilocybin unless you have professional guidance supporting you.

Can You Take Shrooms On A MAOI?

Monoamine Oxidase Inhibitors (MAOIs) are a class of substances sometimes used as antidepressants, or in treating anxiety disorders. They work by preventing the breakdown of monoamine neurotransmitters, including dopamine, serotonin, and norepinephrine. The result is a boost in the levels of these neurotransmitters in the brain.

Common MAOI medications include:

Since MAOIs affect the levels of serotonin in the brain and body, and psilocybin works through the serotonergic system, it is likely that combining the two will have additional unintended effects. There is a small possibility of serotonin syndrome if MAOIs are combined with psilocybin. As such, it is advised to avoid taking large doses of psilocybin if you take MAOIs. We do not recommend using “psilohuasca”, combining Hermaline and other MAOIs traditionally used in “ayahuasca” with psilocybin.

However, some people have reported that combining MAOIs with classic psychedelics reduces the psychedelic effect. As always, it is recommended to start with small doses.

Note: mixing MAOIs with MDMA has potentially fatal effects as the risk of serotonin syndrome is much higher. Do not ever mix MAOIs with MDMA.

Can You Take Shrooms On A TCA/TeCA?

Tricyclic Antidepressants (TCAs) and Tetracyclic Antidepressants (TeCAs) are medications that are less commonly seen in Western medicine due to the preference for so-called “third generation” antidepressants (SSRIs, SNRIs).

Some of the most well-known TCAs and TeCAs are:

TCAs and TeCAs work in a similar way to SNRIs, by boosting the levels of serotonin and norepinephrine in the brain. However, they also activate a wide range of additional receptors and block some ion channels, contributing to their dangerously diverse range of side effects.

Since TCAs and TeCAs have a less sophisticated effect on physiology and have been known to cause deaths by their effects on the heart, it is not recommended to mix these with psilocybin. In doubt, please contact your mental health care provider. The psychedelic experience is intense, and combining any substance that affects your heart or physiology with psilocybin is not wise.

Lithium is often given as a mediator in combination with TCAs. Numerous reports suggest that Lithium, when mixed with psychedelics, can cause fatal seizures or heart attacks. Do not mix psilocybin and Lithium.

Can You Take Shrooms On An NRI/NDRI?

Norepinephrine Reuptake Inhibitors (NRIs) and Norepinephrine-Dopamine Reuptake Inhibitors (NDRIs) are substances used to treat depression and anxiety disorders. They work by increasing the amount of norepinephrine (or norepinephrine and dopamine, in the case of NDRIs) available in the brain.

NRIs have mixed evidence of effectiveness, and it’s possible that some are less effective than placebo.

Some classic NRIs and NDRIs include:

It is unknown if psilocybin and NRIs/NDRIs interact. As far as we know, psilocybin does not significantly affect the norepinephrinergic or dopaminergic neurotransmitter systems. However, to be safe, do not combine psilocybin with an NDRI.

Can You Take Shrooms On An SMS/SARI?

Serotonin Modulators and Stimulators (SMSs) and Serotonin Antagonists and Reuptake Inhibitors (SARIs) are two classes of antidepressant medications that are similar to SSRIs, but in addition to boosting serotonin levels in the brain, also activate (or deactivate) several additional serotonin receptors.

As such, these medications have more complex effects on the serotonergic system. Medications include:

Since these substances will affect the serotonin system in a potentially less predictable way than SSRIs. To be safe, we do not recommend combining these with psilocybin.

Can You Take Microdoses On Lithium?

Lithium is often given as a mediator in combination with TCAs, but can also be prescribed on its own for the treatment of depression.

Its mode of action is unknown, but there are multiple reports of Lithium being a dangerous substance to combine with psychedelics. It has been reported to cause seizures, heart failure, and even death.

We advise staying away from psilocybin if you are taking Lithium.

What About Other Substances?

If your antidepressant isn’t listed here, or if you are curious about non-antidepressant interactions with psilocybin, we first recommend contacting your healthcare provider.

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