You likely have patients on traditional antidepressants coming to you with questions about psychedelics. Or perhaps you're interested in incorporating psychedelics into your practice as they're reclassified.

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Either way, understanding the drug interactions between common antidepressants and psychedelics is crucial in preparing for the coming wave in mental healthcare.

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The following is an interview with psychiatric pharmacist Kelan Thomas, Associate Professor at Touro University California College of Pharmacy. ‍

‍He shares a practical guide to drug interactions between common antidepressants and psychedelics focusing on MDMA and psilocybin. 

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What you'll learn:

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• Separate fact from fiction regarding the acute adverse effects of MDMA and psilocybin.
• Understand how these drugs are metabolized.
• Learn about interactions between traditional antidepressants and psychedelics.
• Assess the safety and effectiveness of combining these treatments.
• Walk away with practical takeaways for your private practice.

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Let’s start with psilocybin.  How does it work, how is it metabolized, and what potential drug interactions might occur for persons on antidepressants?

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Kelan Thomas (KT): Psilocybin, which is rapidly dephosphorylated to psilocin, is a partial agonist at the 5-HT2A receptor. We think this activity leads to downstream effects on glutamatergic neurotransmission, resulting in enhanced neuroplasticity and changes in neural network connectivity that have been related to improvements in anxiety and depression symptoms.

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Psilocin is then mostly metabolized via glucuronidation enzymes, but there may also be other relevant enzymes involved, like MAO-A and CYP2D6, similar to metabolism of other tryptamines like DMT and LSD. The good news is that there aren’t a lot of psychiatric medications that seem to have clinically significant pharmacokinetic drug interactions with psilocybin. 

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Let's say that psilocin levels were increased by inhibition of CYP2D6. ‍Other than a more potent, psychedelic experience is there anything else we should be concerned about for our patients?

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KT: Well, I want to point out that there may be more than tenfold variation in the actual concentration of psilocybin in mushrooms people are obtaining, so it has been tricky to estimate doses for underground experiences. Regardless, in terms of adverse effects and subjective experience, higher levels of psilocin just lead to more intense effects.

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I've heard that psilocin could cause heart valve damage by agonizing the 5-HT2B receptor. Could you speak to that?

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KT: This is something that I have been very focused on.

Multiple drugs have been removed from the market with that 5-HT2B agonist effect. Even at low doses and low plasma concentrations, these drugs seem to have a cumulative exposure effect. 

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We don’t think single doses here and there are an issue. Our concern is if people start taking psilocybin every day, or even every couple days for months or years at a time, it could be a real problem—due to constant receptor stimulation and the possible mitogenic effect. We need to investigate this further as public use increases.

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Robin Carhart-Harris has said publicly that the risk of serotonin toxicity if one ingests psilocybin while taking SSRIs is very low. Do you agree with this as a pharmacist?

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KT: From a safety perspective, I completely agree. My colleague Ben Malcolm and I published a review of the literature and there is a very low risk for toxicity with psilocybin and SSRIs or SNRIs, or really for most drug combinations out there. 

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However, a retrospective analysis of data from online forums for classic psychedelic users showed that 47% of 62 lithium plus psychedelic users involved seizures (while none of the 34 lamotrigine reports did).  Furthermore, 39% of the lithium reports involved medical attention. Careful attention needs to be paid to real-world data to explore the full range of potential harms patients may encounter. 

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Let’s switch gears to discuss MDMA. How is its mechanism of action different from that of psilocybin?

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KT: The pharmacology between the two is quite different. Psilocybin is acting at the post-synaptic 5-HT2A receptor very specifically. Whereas MDMA acts on the vesicular monoamine transporter proteins, along with transporters SERT, NET and DAT located on pre-synaptic terminals. This action causes monoamines to spill out of the presynaptic neuron into the synapse.

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Moreover, MDMA is metabolized by CYP2D6 and is actually an auto inhibitor, so it eventually inhibits its own metabolism. CYP2D6 inhibitors are likely more relevant for MDMA than for psilocybin. Several common antidepressants inhibit CYP2D6 like bupropion, paroxetine, and fluoxetine and have been shown to slightly increase MDMA concentration.

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What about other drug interactions and MDMA? 

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KT: One should not combine MDMA with an MAOI because you could get a hypertensive crisis or serotonin toxicity with excessive elevations of monoamines.

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SSRIs/SNRIs actually reduce the subjective effects of MDMA and psilocybin. 

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 “Studies have demonstrated that when MDMA is co-administered with a SSRI/SNRI the subjective and physiological effects are markedly attenuated.” An article by Feduccia and colleagues 2021 also demonstrated that even participants who recently tapered off SSRIs don’t have as robust of a reduction in PTSD symptoms. Another NEJM correspondence by Carhart-Harris and colleagues also demonstrated that participants who had recently tapered off SSRI’s also had a less robust psilocybin antidepressant response. 

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In popular lore, there's this idea that if you take MDMA, there might be a dysphoric reaction afterward, presumably because of a possible depletion of monoamines. For example, college students will take a dose of an SSRI the day after to prevent that. What do you think about this practice?

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KT: I think that dysphoric reactions after MDMA are far more likely to be in the context of adverse effects related to drug ingestion, such as lack of hydration and sleep deprivation, which can come with taking stimulating drugs like MDMA. Controlled clinical trials have shown there should be a low risk of feeling dysphoric the next day after taking MDMA. 

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As a psychiatrist, many of your patients will come to you with questions about psychedelics. We hope this interview serves as a reference guide to help you dispel myths and prepare you for the emerging psychedelic paradigm, where we can expect the mixing of traditional and novel treatments.

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The article was originally published in the Northern California Psychiatric Society magazine.

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Dr Kelan Thomas is also a lead trainer with Fluence, a company providing a psilocybin-assisted therapy certificate program that is now approved by the Oregon Health Authority for people who would like to become psilocybin facilitators. It will be enrolling monthly. He also offers a psychedelic psychopharmacology reading and discussion course covering articles related to pharmacokinetics, pharmacodynamics, and neuroscience. Dr. KT wanted readers to know that his colleague Ben Malcolm has a website called Spirit Pharmacist where he does consultations for folks who would like help navigating an underground experience.