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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.

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

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. causing monoamines to
spill out of the presynaptic neuron into the synapse.

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 com-
mon antidepressants inhibit CYP2D6 like bupropion, paroxetine, and fluoxetine and have been shown to
slightly increase MDMA concentration.

AM: What about other drug interactions and MDMA?

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

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

“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 demon-
strated 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.

AM: 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?

KT: I think that dysphoric reactions after MDMA are far more likely to be in the context of 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.

As a psychiatrist, many of your patients are using psychedelics on their own and will come to
you with questions. 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 tra-
ditional and novel treatments.

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 psychopharma-
cology reading and discussion course covering articles related to pharmacokinetics, pharmacodynamics,

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NORTHERN CALIFORNIA PSYCHIATRIC SOCIETY Page 13 January / February 2023