But Contraindications Don’t Have to Be the End.

 

Common misperception: “There aren’t many interactions with psilocybin—mainly antidepressants, lithium and antipsychotics.”

 

Unfortunately, this idea is not backed by evidence.

 

Nor the deep knowledge of pharmacists.

 

As psychedelic use grows—both through formal access programs and informal demand across populations—we need to broaden our lens on drug interactions. It makes sense that we started by looking at psychiatric and other psychotropic medications, given the demand by a population that commonly takes antidepressants or other psychotropic medications. But psilocybin is now being explored across broader populations with more chronic diseases, which means we need to think beyond just psychiatric meds.

 

After digging into the science on hundreds of medications and substances, we’ve found that non-psychotropic drugs may pose just as many, if not more, relevant interactions with psilocybin, such as those that impact:

 

  • UGT enzymes
  • Alkaline Phosphatase enzymes
  • Aldehyde Dehydrogenase enzymes
  • Blood pressure and heart rate or rhythm (see midodrine example below)
  • Potential for headache, nausea and other overlapping effects with psilocybin

 

Furthermore, with larger doses comes the journey context—or “setting”—which contributes an important piece of the interaction landscape. It’s not just about what drugs are in the system, but how they behave under specific conditions. For example, some medications, supplements and other substances:

 

  • Require fasting or require food
  • Delay gastric emptying – which is not a direct interaction with psilocybin, but a major safety consideration nonetheless
  • Cause severe photosensitivity – a significant risk if journeying outdoors in direct sunlight
  • Lead to adverse effects while lying down

 

These context-dependent factors can meaningfully shape the safety and effectiveness of a psychedelic experience.

 

 

The Good News: Interaction  ≠  Contraindication

 

The distinction between interaction and contraindication is crucial yet often misunderstood.

 

Despite our growing understanding of psilocybin and other psychedelic interactions, identifying an interaction doesn’t automatically mean someone can’t safely engage in psychedelic therapy. In other words, “interaction” does NOT mean “contraindication”.  Yet, all too often we fear that learning of an interaction will disqualify someone from psilocybin or other psychedelic therapy, when this most often is not the case. Discovering an interaction simply means further assessment is needed to determine the individualized risk and what to do about it.

 

Thus, when we identify a potential interaction with any medication or substance (not just with natural medicines and psychedelics), the critical questions to proceeding aren’t simply “yes or no?”. Instead, we need to ask:

 

How serious is the interaction?  Not all interactions carry equal weight. Some may cause mild, manageable effects, while others could pose life-threatening risks. The severity spectrum ranges from minor inconveniences to major safety concerns that require immediate attention. The latter represent relative or absolute contraindications.

 

Does this interaction require intervention?  Getting to a safe and effective “yes” or “no” answer requires deep understanding of pharmacology—not just drug interactions, relevant clinical practice, and having access to as much information about the individual, their risk factors, preferences and use context for the interacting medications, supplements and substances. As such, it is very common for one individual’s answer to this question be “yes” and another be “no” for the very same interaction. This is because an interaction’s overall risk impact heavily depends on context and individual risk factors.

 

For example:

 

Case where Lithium + Psilocybin Might Not = Contraindication: low-dose lithium prescribed off-label for cardiovascular wellness and to prevent cognitive decline1,2; all relevant labs regularly monitored and followed up by physician; patient using according to directions; no other interacting medications or health conditions. This interaction may not automatically require intervention.

 

Case where Lithium + Psilocybin = Contraindication: full dose lithium prescribed for bipolar disorder. In this case, an intervention is likely necessary – and the type of intervention depends on a deeper assessment. (However, even this ‘contraindication’ label is controversial, as it is based on weak and limited evidence linking seizure risk to this combination.3  While I would generally still avoid this combination given we don’t have evidence confirming it IS safe, I believe there could be cases where the risk of this combination may not outweigh the potential benefits—based on pharmacology understanding, evidence in those with bipolar II/bipolar depression, regular lab work showing normal values, close monitoring and oversight by physician, controlled setting, no other interacting medications or health conditions, and other risk reduction strategies. But those are a lot of factors that must align.)

 

If intervention is needed, what’s the best approach?  The answer to this question also requires the above-mentioned deep pharmacologic understanding, clinical practice and assessment information. Most interactions, including some contraindications, can be successfully managed (intervened upon) without stopping medications entirely. Sometimes we determine the most appropriate intervention is “do nothing” as the overall risk is low and acceptable. Other times the intervention is as simple as timing adjustments, dose modifications, or enhanced monitoring. Yet other interactions may require more substantial changes to the medication regimen or journey protocol. Entirely discontinuing or tapering off a medication the less often the best option—but it can be. It just depends. In summary, the scope of action steps might include:

 

        • No changes necessary
        • Adjusting dosing schedules to minimize overlap
        • Switching to alternative medications with fewer interaction risks
        • Implementing additional safety monitoring during the experience
        • Modifying the setting to account for interaction effects
        • Temporarily holding medications
        • Deprescribing (reducing, discontinuing or tapering off) medications
        • An alternative to natural medicines or psychedelics – sometimes staying on a medication that is contraindicated with psilocybin or other natural medicine/psychedelic may be the best option while other viable pharmacologic or non-pharmacologic options are explored

 

The answer to “what’s the best approach?” isn’t one-size-fits-all. It depends entirely on the person (their medical history, current health status, preferences, individual risk factors), the substance (specific medications and other OTCs or substances, doses, timing), and the context (journey setting, support available, monitoring capabilities).

 

 

More Good News: Even “Contraindications” Can Often Be Managed

 

As you might have taken away from the above information, even certain “contraindicated” medications can be simply managed to reduce the risks when combined with psilocybin or other natural and psychedelic medicines.

 

Midodrine is a compelling example. This medication, used to treat orthostatic hypotension, presents a clear contraindication with a psilocybin journey. The combination can potentially cause dangerously high blood pressures, especially when lying down4—a position commonly maintained during psychedelic journeys. This could lead to a hypertensive emergency requiring immediate medical intervention and significantly increased cardiovascular risks.

 

Yet even this seemingly absolute contraindication doesn’t have to mean permanent exclusion from healing. Rather than forcing someone to choose between their essential medication and potentially life-changing therapy, pharmaceutical expertise can identify relatively simple management strategies.

 

The alternative—automatically excluding someone from therapy based on a single medication—can cause profound psychological harm through loss of hope and loss of therapy, while the interaction or contraindication itself could be safely navigated with proper planning and expertise.

 

 

What Does This All Mean?

 

Psilocybin interactions, in other words, are more layered than they appear. Whether someone chooses to proceed with therapy or not, they deserve to understand their actual, individualized risks and options—not face blanket exclusions based on incomplete information. As psychedelic demand and use continue to grow, so must our pharmacological understanding. Nuance matters. Evidence matters. And we owe it to anyone considering psychedelic experiences to provide accurate, comprehensive safety information. Because the more we understand these risks, the better we can help people make informed decisions—whether for personal use, clinical trials, for formal therapy programs. With the right expertise, people can make truly informed decisions about their safety and wellbeing.

 

 

 

References:

  1. Hamstra SI, Roy BD, Tiidus P, et al. Beyond its Psychiatric Use: The Benefits of Low-dose Lithium Supplementation. Curr Neuropharmacol. 2023;21(4):891-910. doi:10.2174/1570159X20666220302151224
  2. Strawbridge R, Kerr-Gaffney J, Bessa G, et al. Identifying the neuropsychiatric health effects of low-dose lithium interventions: A systematic review. Neurosci Biobehav Rev. 2023;144:104975. doi:10.1016/j.neubiorev.2022.104975
  3. Nayak SM, Gukasyan N, Barrett FS, Erowid E, Erowid F, Griffiths RR. Classic Psychedelic Coadministration with Lithium, but Not Lamotrigine, is Associated with Seizures: An Analysis of Online Psychedelic Experience Reports. Pharmacopsychiatry. 2021;54(5):240-245. doi:10.1055/a-1524-2794
  4. Midodrine.com. Updated October 28, 2024. Accessed September 22, 2025. https://www.drugs.com/monograph/midodrine.html

 

 

If you would like to cite this article, copy the format you need:

 

AMA (11th ed.)
Speer K. Psychotropic interactions are just the beginning. PharmD Consult. Published September 22, 2025. Accessed [add current month, day, year, remove brackets]. https://psychedelicinteraction.com/pharmd-consult

 

APA (7th ed.)
Speer, K. (2025, September 22). Psychotropic interactions are just the beginning. PharmD Consult. https://psychedelicinteraction.com/pharmd-consult. Accessed [add current month, day, year, remove brackets].

 

Chicago (17th ed., author-date citation)
Speer, Kristin. 2025. “Psychotropic Interactions are Just the Beginning.” PharmD Consult, September 22, 2025. Accessed [add current month, day, year, remove brackets]. https://psychedelicinteraction.com/pharmd-consult.

 

MLA (9th ed.)
Speer, Kristin. Psychotropic Interactions are Just the Beginning. PharmD Consult, 22 Sept. 2025. Accessed [add current day, then month abbreviated, year, remove brackets]. https://psychedelicinteraction.com/pharmd-consult.

 

 

Disclaimer

The information provided on this page is for educational purposes only. It should not be used as medical advice. Always follow the advice and direction of your provider(s). Do not attempt to stop or make changes to your medications or care plans on your own, as this can be dangerous. Neither Dr. Speer nor PharmD Consult shall be held responsible or liable for any outcomes related to the use of this information.