The Truth About Mushrooms & Meds: Are They Safe to Mix?

In this guide, we explore the potential interactions between psilocybin, the primary psychoactive compound in magic mushrooms, and various pharmaceutical medications.

Many people are wondering whether they can combine magic mushrooms with their prescription medicines, like antidepressants, or anxiolytics, or even antipsychotics. And it's no wonder—we've all heard of their seemingly miraculous ability to reset the brain. The promise of healing and transformation, of reclaiming ourselves with minimal side effects or addiction, is enticing, to say the least.

At the same time, you're likely here because you're not sure whether it's safe to combine your prescription meds with those nootropic microdose caps you saw an ad for.

In our mission to make access to plant medicines safer and more accessible, and to help reduce the potential for harm, we put together this systematic review of Randomized Clinical Trials (RCTs) studying the interactions between magic mushrooms and pharmaceutical medications.

This systematic review aims to bring together all the available data concerning the pharmacokinetic (how the body interacts with it), physiological, and subjective effects of drug interactions between psilocybin and medications prescribed in psychiatry. We shed light on how these fascinating fungi may interact with different types of medications, and how they might potentially affect each other.

While reviews of drug interactions with psilocybin have been published, none have been systematic, and this review serves as the first comprehensive exploration of drug interactions involving psilocybin.

Let's delve into the findings.

What is psilocybin?

Psilocybin is a naturally occurring compound and renowned psychoactive tryptamine found in over 200 species of mushrooms, particularly in the Psilocybe genus. Often referred to as a "classic psychedelic," psilocybin's effects on perception, emotion, and cognition primarily stem from its interaction with 5-HT2A receptors, although it also binds to other 5-HT receptor subtypes.

Psilocybin has long been enjoyed both medicinally and recreationally. In both spiritual and clinical settings. In its raw form, lemon juice extractions, or ground into capsules and combined with other functional foods. Foodies delight in their brownies and gummies.

Clinical trials have administered psilocybin in various doses, ranging from very low to high, with effects typically beginning within 20-40 minutes, peaking around 60-90 minutes, and lasting for approximately 6 hours.

The metabolism of psilocybin.

When you ingest magic mushrooms, the psilocybin hidden in their cell walls rapidly converts to its active form, psilocin, through enzymatic processes (your liver).

Unlike some substances, psilocybin and psilocin do not significantly inhibit monoamine reuptake pumps, reducing the risk of increased serotonin levels, and thus, serotonin toxicity.

Psilocybin's physiological and psychological effects.

Physiologically, psilocybin can cause mild increases in blood pressure and heart rate, with common adverse effects including headache, nausea, dizziness, and fatigue.

On a psychological level, psilocybin often induces mystical-type experiences, characterized by a heightened sense of unity, altered perception of time and space, and feelings of euphoria. These experiences are associated with decreased activity in specific brain circuits known as the default mode network (DMN) and long-term improvements in well-being.

It's worth noting that psilocybin lacks dopamine-mediated reinforcement and does not appear to lead to habituation or addiction.

However, psilocybin is not for everyone. It's likely a bad idea to trip if you're grieving. Some users may experience transient anxiety, dysphoria, impaired sleep, paranoia, grief, and preoccupation with death.

Speak to a trusted therapist who is trained in psilocybin-assisted therapy to make sure it's right for you. They can guide you through from preparation to integration, ensuring a safe and optimal journey to personal growth and healing.

How psilocybin works.

As you can see in the figure above, psilocin and serotonin are structurally similar.

Psilocin is psilocybin's active form. Because of its similarity to serotonin, it activates serotonin 5-hydroxytryptamine-2A (5-HT2A) receptors, creating an altered state of mind that can produce positive mood effects, including mystical experiences and feelings of bliss. These acute effects have been linked to long-term improvements in depression, anxiety, and addiction.

Psilocybin may also promote neuroplasticity and increase markers of neuroregeneration, such as brain-derived neurotrophic factor (BDNF).

However, it's important to note that psilocybin can also lead to short-term adverse effects like anxiety, headache, insomnia, and nausea.

Psilocybin's drug interaction potential.

The potential for drug interactions with psilocybin is an important consideration, especially when combined with medications that also affect the serotonin system, such as SSRIs, SNRIs, TCAs, MAOIs, mirtazapine, trazodone, lithium, buspirone, atypical antipsychotics, and others.

Some interactions may increase the risk of toxidromes like serotonin syndrome. Additionally, the effects of psilocybin can be attenuated by recent exposure to antidepressants. This requires careful consideration of washout periods.

Furthermore, there are potential interactions with drugs targeting neurotransmitter systems beyond serotonin, such as norepinephrine and dopamine, which can impact the effects of psilocybin. Benzodiazepines may be used to mitigate acute adverse effects related to psychedelics, and some medications can influence the metabolism of psilocybin through their impact on enzymes.

Antipsychotics and psilocybin.

There are three Randomized Controlled Trials (RCTs) where researchers combined psilocybin with three antipsychotics: chlorpromazine, haloperidol, and risperidone.

The first study paired chlorpromazine, a typical antipsychotic, with psilocybin, resulting in a reduction in psilocybin-induced eye dilation and visual perceptual changes.

In 1998, Vollenweider et al. conducted the two other studies, one investigating the effects of haloperidol and the other investigating risperidone, which antagonize D2 receptors. Haloperidol had no impact on psilocybin-induced perceptual changes but increased the sense of "dread of ego dissolution." On the other hand, risperidone reduced various aspects of altered consciousness induced by psilocybin, including the reduction of dread of ego dissolution. Working memory was tested, revealing that psilocybin alone delayed reaction time, but this delay was less pronounced when co-administered with risperidone.

Antidepressants and psilocybin.

Psilocybin is often studied for use in patients with psychiatric disorders, many of whom are already on antidepressant medications, particularly serotonin transporter inhibitors.

Previous case reports and clinical practices suggested that antidepressants might diminish the effects of psychedelics. Therefore, it has been a common practice to discontinue antidepressant treatment before administering psychedelics, raising concerns about withdrawal symptoms and potential relapses of depression.

Below, we investigate the 3 clinical studies to date on combining antidepressants with psilocybin.

Serotonin agonists and psilocybin.

A single RCT by Pokorny et al. in 2016 explored the combination of psilocybin with serotonin agonists.

Psilocybin binds to 5-HT1A and 5-HT2A receptors, and the researchers examined its effects when combined with buspirone and ergotamine, both of which have similar receptor affinities.

Buspirone reduced visionary restructuralization (the visual elements of the trip), suggesting that it reduced psilocybin-induced visual perceptual changes. Ergotamine, on the other hand, had no significant effect on psilocybin-induced subjective experiences, possibly due to differing receptor profiles.

Selective serotonin reuptake inhibitors (SSRIs) and psilocybin.

Conducted in 2021, Becker et al. combined psilocybin with the SSRI escitalopram in one of the only two RCT on SSRIs and psilocybin as of this writing.

Contrary to earlier reports stating that SSRIs reduced the effects of LSD, escitalopram did not significantly diminish the subjective effects of psilocybin. Instead, it was associated with reductions in negative experiences like fear, anxiety, and ineffability.

Physiologically, escitalopram reduced psilocybin-induced elevations in blood pressure and pupil dilation, without altering levels of psilocin.

Exploring escitalopram's impact on psilocybin.

In this double-blind, placebo-controlled, crossover study, healthy subjects underwent two experimental test sessions, each involving psilocybin (25 mg) after either escitalopram pretreatment or placebo. The order of treatment was randomized and counterbalanced.

Escitalopram pretreatment involved daily doses of 10 mg for 7 days, followed by 20 mg for another 7 days, including the day of psilocybin administration. In contrast, the placebo group received 14 days of pretreatment with a placebo before the psilocybin session.

The study assessed various outcome measures, including subjective effects, adverse effects, cardiovascular responses, plasma BDNF levels, gene expression, and pharmacokinetics.

Key findings and implications.

The results of the study indicated that escitalopram pretreatment did not have a significant effect on the positive mood effects of psilocybin. However, it did significantly reduce adverse effects, anxiety, adverse cardiovascular effects, and other negative effects associated with psilocybin when compared to placebo pretreatment.

Importantly, escitalopram did not alter the pharmacokinetics of psilocin, the psychoactive form of psilocybin.

This research sheds light on the potential safety of combining psilocybin with escitalopram treatment, offering an initial indication that such combinations may be viable. Further studies are needed, particularly with extended antidepressant pretreatment and with patients suffering from psychiatric disorders, to provide more comprehensive insights into the interactions between antidepressants and psilocybin.

COMPASS Pathways announces positive outcome of 25mg COMP360 psilocybin therapy as adjunct to SSRI antidepressants.

In 2021, an open-label study presented groundbreaking findings that challenged the widely-held belief that SSRI medications would interfere with the therapeutic effects of psilocybin, opening the door to new possibilities in depression treatment. This research paves the way for psilocybin therapy to be considered both as an adjunctive treatment to SSRI antidepressants and as a therapy on its own.

Breaking down the COMP360 study.

This open-label study involved 19 patients from clinical sites in Ireland and the United States. Most of the patients were female (68.4%), with an average age of 42 years. The primary objective was to assess the change in baseline MADRS (Montgomery-Åsberg Depression Rating Scale) total score at 3 weeks in patients receiving 25mg COMP360 psilocybin therapy alongside their existing SSRI antidepressant regimen.

The results were remarkable, with 42.1% of patients showing a positive response at week 3, and all of them achieving remission. The mean reduction in the MADRS total score at week 3 was 14.9, signifying a significant improvement. These findings were consistent with the phase IIb trial results and indicated a rapid response from day 2 to week 3 after COMP360 therapy.

The study participants initially had a baseline MADRS score of 31.7, indicating moderate to severe depression. In addition to MADRS scores, other measures also showed positive signals of improvement, including reduced anxiety, improved depressive symptoms (assessed by clinicians and self-rated), and enhanced positive and negative affect.

Safety and tolerability.

Importantly, the 25mg COMP360 psilocybin therapy was well-tolerated when administered alongside the patients' SSRI treatment. There were no serious treatment-emergent adverse events, and no adverse events related to suicidal ideation or self-injury.

Epidemiologic studies on psilocybin.

In 2021, Nayak et al. analyzed accounts of co-ingesting mood stabilizers (lithium and lamotrigine) with psychedelic substances, including psilocybin. Some reports involving lithium resulted in seizures, while those combining lamotrigine with psilocybin did not. Nevertheless, the evidence was considered low-quality due to a lack of standardization and clinical verification.

The researchers analyzed 96 accounts posted online, primarily on platforms like Erowid, the Shroomery, and Reddit. These accounts detailed experiences involving the concurrent use of mood stabilizers, including lithium, lamotrigine, valproic acid, carbamazepine, and oxcarbazepine, alongside various psychedelic substances. While the analysis covered a range of psychedelics, the majority of the reports centered around lysergic acid diethylamide (LSD), another well-known classic psychedelic.

In the context of mood stabilizers, the study focused on the combination of lamotrigine and lithium with psilocybin. Out of the six reports involving the combination of lithium and psilocybin, two cases resulted in seizures. Conversely, none of the ten reports involving lamotrigine and psilocybin reported seizures.

It's essential to note that the study authors acknowledged the evidence's low quality due to certain limitations, including a lack of standardization, potential selection bias, and the absence of clinical verification. These factors suggest that while the findings are valuable, further research with greater rigor and control is needed to draw more definitive conclusions about the potential interactions between psilocybin and mood stabilizers, particularly in the context of seizure risk.

The need for further exploration.

In the context of clinical research and the potential application of psilocybin in therapy, it is essential to explore these interactions to ensure safe and effective treatment protocols. These studies set the stage for more in-depth investigations and have the potential to reshape clinical practices, potentially eliminating the need to discontinue antidepressant treatment when administering psilocybin in clinical settings.

Always consult with a medical professional for personalized advice. While the effects of combining psilocybin with different types of medications can vary, it's important to consider these findings and exercise caution when combining these substances, especially if you are taking psychiatric medications.

If you are searching for professional support from a healthcare provider, please refer to our directory of psychedelic therapists in Canada, sorted by city.

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