There’s a lot of controversy within the psychedelic therapy community on psychedelic therapy and psychotropic medications. Some experts think SSRIs should be fully discontinued before therapy, while others believe patients can stay on their medications. As these medicines move closer to FDA approval, it’s essential for clinicians to understand how these substances interact. We sat down with Dr. Ben Malcolm to get more clear on psychedelic therapy and psychotropic medications.
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There’s a lot of emphasis on set and setting, mindset, and integration in psychedelic medicine. But psychedelics cause physiological changes in the body, as well as psychological changes in the mind. And the psychedelic experience may be affected by psychotropic medications.
Dr. Malcolm, (AKA the Spirit Pharmacist) got his PharmD and MPH from Touro University. After residency, he was board certified in psychiatric pharmacy. He’s an expert in how psychotropic medications interact with entheogenic substances, and he currently offers consulting and education for these interactions. Let’s get into his fascinating presentation by introducing these interactions of psychedelic therapy and psychotropic medications.
Introducing Drug-Drug Interactions
Dr. Malcolm started out by defining a few key principles of pharmacology. Here are some basic definitions to be clear on.
- Pharmacokinetics (PK) is “what the body does to the drug.” This is characterized by the process of absorption, distribution, metabolism, and elimination (ADME). It’s influenced by age, kidney and liver function, nutritional status, diseases, genetics, and other factors.
- Pharmacodynamics (PD) is “what the drug does to the body.” These are the biochemical, physiological, and neurobehavioral effects of the substance. These effects are influenced by concentration at receptors, permeability, receptor number, and binding characteristics.
When pharmacokinetics and pharmacodynamics overlap, drug-drug interactions can happen. One drug may block or increase the metabolism of another, or they may target the same receptor and interfere with each other’s actions.
When it comes to psychedelics and psychotropics, much of the interactions happen within the serotonergic system. Classic psychedelics and many psychiatric medications cause activation of serotonin receptors. Let’s talk about what these drug interactions mean.
Dr. Malcolm defined two separate categories for drug interactions:
- Drug-Drug Interactions (DD) are when two separate substances act differently when taken together. These can happen because of pharmacodynamics and pharmacokinetics:
- Pharmacodynamic drug-drug interactions can happen when drugs with similar mechanisms of action overlap
- These interactions aren’t necessarily one substance’s effect’s compiling on another. They can be synergistic, where the two substances work more strongly together. They can be additive, where one substance enhances the effect of the other. They can also be diminutive, where one substance inhibits the action of the other.
- Pharmacokinetic drug-drug interactions happen when the metabolism or transport of a substance is changed. For instance, CYP liver enzymes can inhibit or increase blood concentrations of substances. And these enzymes can be inhibited or induced by certain substances.
- Drug-Disease Interactions are when a drug exacerbates disease conditions, or when a disease interferes with a drug’s action
There are several ways that drugs can interact with each other, or with pathophysiological diseases. Dr. Malcolm pointed out that few drugs have been shown to have pharmacodynamic influences on psychedelics. But the underlying disease process that a person has may affect their safety in therapy.
For instance, blood thinners likely wouldn’t affect psychedelic metabolism. But a patient is likely on blood thinners because of a history of cardiovascular disease. They may have a history of clotting or arrhythmia. Patients with these conditions have not been studied in clinical trials, and may not be safe for psychedelic therapy.
While medications may not preclude patients from getting psychedelic therapy, their health history still can. This may mean that patients and therapists take on more risks in therapy. Medical history can be a significant factor for determining eligibility for psychedelic therapy. As clinical trials grow and we see patients with more diverse health histories in research studies, we’ll know more about specific disease risks.
Little research has been done on interactions between psychedelic therapy and psychotropic medications. But a review from this year has shed more light on DDIs between psychiatric medications, psilocybin, and MDMA . What we do know is that drug-drug interactions with psychedelics can have consequences on the safety and efficacy of psychedelic therapy. This is especially a conundrum because psychotropics are first-line treatments that may limit patients’ options down the line for psychedelic therarpy.
Overall, more research has been done on drug interactions with MDMA than on psilocybin. This is likely because MDMA’s mechanism of action is more complex, the majority being from serotonin release. We’ll talk more about MDMA pharmacology later on. But first, let’s define major players at the serotonin synapses.
Serotonin Synapses: Major Players
Medications that target the serotonin reuptake transporter (SERT) and serotonin (5-HT) receptors consistently change the subjective effects of psychedelics. These pharmacodynamic interactions can happen in two different ways:
- Direct DDIs, which occur in the acute drug period. Drugs like SSRIs diminish psychedelic effects by blocking receptors that the two substances compete for.
- Neuroadaptive DDIs, which are more long-term. This is when receptors are down-regulated over time, for example SSRIs, where there are fewer serotonin receptors available for psychedelics to act on. We’re still not sure how long receptors are down-regulated after medications like SSRIs are discontinued.
In the short and long term, psychotropics may affect the psychedelic experience. Now let’s talk about MDMA and what we know about its interactions.
MDMA Pharmacology & Drug Interactions
MDMA has a complex mechanism of action. Its effects are mostly induced by increasing serotonin release as well as binding to serotonin receptors themselves. Under MDMA, the flow of serotonin reverses from normal. This results in more serotonin at the synapse, which is why it’s possible to have complications on MDMA if certain other medications have been taken.
Certain drugs that interfere with SERT, VMAT2, 5HTRs, and MAO may interact with MDMA. MAOIs are potentially dangerous when combined with MDMA. On the other hand, SSRIs diminish the desired effects of MDMA.
Metabolism of MDMA
MDMA is primarily metabolized in the liver. It’s processed primarily by the cytochrome enzyme CYP2D6, and it also blocks this enzyme. Other medications, like HIV meds, also block CYP2D6, which has led to toxicity. Wellbutrin blocks CYP2D6, and may increase the risk of seizures.
These medications and others may need to be stopped before MDMA therapy. In many cases, patients won’t be able to stop their prescriptions (like in the case of HIV therapy) and will need to pursue other options.
A few trials have been done on people with antidepressants undergoing MDMA therapy. Antidepressants that block serotonin re-uptake transporters significantly inhibit MDMA’s positive effects, as can recently tapered antidepressants.
Duloxetine (Cymbalta) had the greatest change, with subjective MDMA effects decreased by 60-80%. Citalopram (Celexa) and Paroxetine (Paxil) decreased MDMA experiences by 60-70%. Dr. Malcolm said that these interactions could diminish the MDMA experience to the scale of a strong espresso, so the effects on the MDMA experience are significant.
On the other hand, some medications have increased effects. In one trial, Wellbutrin (Buproprion) actually increased physiologic effects of MDMA by 10-30%. This caused a longer duration and higher blood concentrations of MDMA. And inversely, MDMA increased concentrations of Wellbutrin. This another area to watch when it comes to psychedelic therapy and psychotropic medications.
SSRIs vs. MAOIs in Combination with MDMA
MDMA, SSRIs and MAOIs all work on the serotonin system, which is why interactions between them are a concern. But the effects of their interactions are actually quite different.
For instance, the effects of MDMA for a person on SSRIs will likely be very diminished. SNRIs and SSRIs block the serotonin reuptake pump, blocking MDMA’s primary mechanisms for serotonin release. This causes muted effects of MDMA.
On the other hand, MAOIs block monoamine oxidase, which increases intrasynaptic serotonin concentration. MAO can’t break down this serotonin, which has nowhere to go or be metabolized. This is the process that can lead to excessive intrasynaptic serotonin, and potentially life-threatening serotonin syndrome.
Some other drugs interact with MDMA, although we have even less research for them. Clonidine, Carvedilol, and others don’t have subjective effects but may alter the cardiovascular aspects of MDMA. This could lead to more cardiovascular risk in these patients. Dr. Malcolm posits that this risk may be mitigated by other medications, like a sympathomimetic, but we don’t yet have research on this subject.
Drug Interactions with MDMA: Check out Dr. Malcolm’s Chart
For review, here’s a chart on how certain medications may interact with MDMA:
|Pharmacodynamic Interactions with MDMA||Pharmacokinetic Interactions with MDMA|
|SSRIs mute MDMA’s effects, reducing efficacy. Acute and neuroadaptive interactions are also possible.||Ritonavir/cobicistat for HIV infection can cause potentially fatal serotonin toxicity.|
|MAOIs can cause serotonin toxicity, which is potentially fatal.||Buproprion boosts blood concentrations of MDMA, and vice versa. It also creates an increased risk for seizures and potentiated experiences.|
|Lithium increases intrasynaptic serotonin signaling. This causes a risk for seizures, decreases the quality of experiences, and can cause serotonin toxicity.||CYP2D6 inhibitors increase blood concentrations of MDMA (this includes fluconazole, fluoxetine, and bupropion).|
|Benzodiazepines cause muted effects and may reduce efficacy. We don’t yet have randomized trials yet, but anecdotal reports call benzodiazepines a “trip killer”.|
|MDMA + amphetamines/cathinones cause additive risks of stimulant toxicities and serotonin syndrome.|
It’s clear that several medications are contraindicated in MDMA therapy. Now let’s talk about psilocybin.
Psilocybin Pharmacology & Drug Interactions
Relative to MDMA, psilocybin’s mechanism of action is relatively simple. It doesn’t have significant effects on monoamine oxidase, the serotonin reuptake pump, or the vesicular transporter VMAT. The active metabolite of psilocybin is psilocin, which binds to serotonin receptors. It also is a partial agonist on serotonin receptors with the 5-HT 2A receptor indicated as the primary target underlying subjective effects.
Because it’s a partial agonist, there’s a ceiling on psilocybin’s effects on the receptor activity. Unlike MDmA, psilocybin doesn’t increase the intrasynaptic serotonin levels. This partial agonism is why there’s little risk for serotonin toxicity from eating too many psilocybin mushrooms. However, people may still have intense psychological experiences and get into unsafe situations during a psilocybin experience.
The psychedelic experience of mushrooms comes from the major metabolite of psilocybin, called psilocin, which is mostly metabolized by adding a sugar molecule. This is different from the CYP metabolism of other medications because there’s no known substance that mediates this sugar process. As a result, there are far fewer ways for psilocin toxicity to happen. About 20% of psilocin is metabolized by monoamine oxidase. This is much lower compared to other psychedelics like 5-MeO-DMT.
In terms of drug interactions, there are fewer medications that interact with psilocin compared with MDMA. And some of the research is quite old, so updates are needed. Check out the medications with the largest effect on psilocybin experiences:
- Buspirone was shown to decrease the subjective psilocybin experience by 30-50%.
- Risperidone also decreases subjective effects by 15-30%. This antipsychotic medication may be more aptly called an anti-psychedelic because it was originally designed to block LSD effects.
- Haloperidol caused about 27% more negative experiences associated with ego dissolution. Haldol blocks dopamine receptors and may increase the risk of anxiety while diminishing mystical experiences.
- Escitalopram may mitigate anxiety during psilocybin experiences, and physiological changes may be more blunted.
These substances may change the acute experience of psilocybin therapy. But research suggests that more drug-drug interactions with psilocybin happen due to adaptability in the long term. Let’s break down the drug interactions that are most concerning with psilocybin:
|Medication||Interaction with Psilocybin|
|Lithium||Increased risk of seizures|
|5HT2A receptor blocking antipsychotics (clozapine, risperidone), serotonin agonists (buspirone), and serotonin reuptake blocking antidepressants (citalopram, escitalopram, sertraline)||Diminished subjective effects|
|Benzodiazepines (valium, xanax, klonopin)||Diminished effects, dependent on dose|
|MAOIs (selegiline, phenelzine)||Diminished effects with chronic use, intensified effects with acute MAOI use|
|Typical antipsychotics (haldol, nozinan)||Increased anxious ego dissolution|
|Serotonin agonists (fluprazine)||Additive vasocontriction|
|UGTIA10, IA9 inhibitors (diclofenac, probenecid), and alkaline phosphatase inhibitors (cinacalcet||May decrease metabolism|
Psilocybin has fewer interactions with medications compared to MDMA. Now let’s talk about how to manage drug interactions.
Approaches to Management of Drug Interactions, Psychedelic Therapy, and Psychotropic Medications
Many medications may lessen or change the effects of psychedelics. Few may have dangerous effects when interacting with MDMA, psilocybin, and others. When Dr. Malcolm considers the most dangerous psychedelic drug interactions, he says he mostly thinks about ayahuasca and ibogaine. But at this point, we still don’t have enough research data to show how these medicines affect one another.
When working with patients, Dr. Malcolm uses best practices around medication tapering and shared decision-making. He asks, “what does this person want to do, and is that feasible and reasonable?” If he can come up with a plan that a patient desires and is reasonable, that patient has a much higher chance for success.
At this point, Dr. Malcolm says you can safely combine SSRIs with psilocybin therapy, but this may result in changed or diminished responses to the psychedelic. Many people he speaks with say they have unpleasant somatic experiences when combining them, such as nausea. He’s not sure if this is because of their mental health, the antidepressant, or something else. Patients may be better served by tapering their psychotropics before taking a psychedelic substance to best achieve the desired effects.
Psychotropic Drug Tapering
Tapering psychotropics presents its own challenges. Weaning patients off their medications can exacerbate symptoms, and cause withdrawal effects that may be hard or impossible to endure. Dr. Malcolm points out that, “a lot of times the most difficult step in a taper is someone going from some medication to no medications”. Neuroadaptive effects may necessitate “wash-out” periods of several weeks after medication is completely discontinued.
Patients need lots of support during this process. And the risk/benefit balance needs to be weighed for each patient. For instance, two weeks after stopping their SSRI, a patient may still have less experience from psilocybin or MDMA. But they may also be experiencing symptom exacerbation that makes treatment more urgent, like suicidal ideation.
A patient’s individual risk and goals need to be fully explored before a plan can be determined. When helping patients decide whether or not to taper, Dr. Malcolm asks these questions:
- What are the benefits and side effects of their current drug regimen? Do they like their current meds?
- What is their goal regarding their medications? Is it realistic?
- What is the compatibility between their current medication and psychedelic substances of interest?
- Have they tapered, stopped, or missed doses before? What were the responses?
- What is the balance of risks/benefits of stopping/continuing medications?
- Risks: withdrawal syndrome, worsening of underlying illness
- Benefits: increased effect of psychedelic and/or/potential for deeper healing
Tapering oversight should be supervised by a prescribing provider. Not all patients have providers or have ones that feel comfortable offering oversight. Tapering, meaning slowly decreasing the medication dose overtime, is a delicate process when it comes to psychotropics. Holding, on the other hand, is when use of a drug is suspended with the intention of starting it up again.
Holding may be appropriate with medications that have lower withdrawal risk, or lower interaction risk. Holding may be sufficient to allow for most psychedelic effects to be felt and can limit the danger of drug interactions. But it may still have limitations compared to fully tapering a medication. Some patients may want to skip their meds the day of therapy to better their chances of a full psychedelic experience.
Most held drugs can be resumed 24-72 hours after psychedelic use, but a longer time frame may be appropriate for ayahuasca and ibogaine.
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In Conclusion on Psychedelic Therapy and Psychotropic Medications
Dr. Malcolm rounded out his talk with this conclusion:
“There are clinically significant drug interactions between first-line psychiatric medications and psychedelic therapies. These interactions could pose major hurdles or increase the risks of psychedelic therapies. Further understanding of interactions and careful management of psychiatric medications in persons undergoing psychedelic therapies is likely critical to safe and beneficial experiences.”
Some patients opt to suddenly stop their medications to undergo a psychedelic experience. They may have great experiences in psychedelic therapy, but have a resurgence in symptoms in the months afterward. Psychedelics can’t be an immediate replacement for psychotropics.
“People ask me all the time, ‘do psychedelics help taper psychiatric medications?’ And I don’t know what the answer is, but my response is that you should think of them as two parallel processes.” A slow, careful taper can’t be replaced with psilocybin or anything else.
Dr. Malcolm believes that people need to have serious conversations about tapering for psychedelic therapy. We didn’t have to talk to patients about tapering their psychotropics before this, because these medications were the best we could offer them. But now that we’ve seen that psychedelics could work as well or even better, the two treatments seem to be in conflict for many.
“A whole new world of persons is going to need some program or system in transitioning modalities in a safe way, because that gap between psychiatric meds and starting psychedelics has a lot of room for misadventure,” he says.
You can learn more about antidepressants and psychedelic interactions by checking out Dr. Malcolm’s tapering guide. He also has guides on breakthrough psychedelics and bridging the gap between psychedelics and psychotropics. His courses include CE credits for clinicians. Now let’s go over a few questions from viewers.
Viewer Questions on Psychedelic Therapy and Psychotropic Medications
Can You Speak to How Mood Stabilizers May Interact with Psilocybin and MDMA?
Lithium is contraindicated with psilocybin and MDMA, but it is compatible with ketamine therapy. A person with bipolar depression taking lithium could benefit from ketamine, which is easily available and accessible and has shown good benefits. This is important to consider when thinking about psychedelic therapy and psychotropic medications.
Unfortunately, there isn’t much information about the other mood stabilizers out there and how they interact with psychedelics. Lamotrigine is sometimes used in bipolar II, however, it may be better defined as an atypical antidepressant than a mood stabilizer because it doesn’t prevent mania. Lamotrigine seems compatible with serotonergic psychedelics. But it may diminish the effects of ketamine.
Valproic acid, carbamazepine, and oxcarbazepine have little information about them in conjunction with psychedelics. Carbamazepine has a lot of drug-drug interaction potential, as well as side effects and adverse effects associated with hyponatremia. MDMA can also cause low sodium, so there may be a risk of additive hyponatremia, but this has not been researched in trials.
Antiepileptics almost universally have sedative effects. Benzodiazepines are also sedatives that we know diminish the psychedelic experiences. Both of these medications may be used to treat illnesses that may preclude a person from getting psychedelic therapy, like manic depressive, or seizure disorders. Ultimately we have to look at the whole patient and the reasons they are on medications, not just the medications themselves.
We talked a bit about diminished experiences from SSRIs, is there evidence for increasing the dose of psilocybin or MDMA to overcome diminished effects?
We don’t yet have data to support this practice, but there are anecdotal stories. Dr. Malcolm recommends that if you’re going to increase the dosage, psilocybin is a better choice because it doesn’t have a lethal threshold. People can get away with 5-10-fold overdoses, which may be psychologically intense, but won’t cause a physical overdose.
MDMA on the other hand may still cause “serious physical hot water” if you take too much. This could result in stimulant toxicity from extremely high blood concentrations. Drug-drug trials use small therapeutic doses, which are a small fraction of recreational doses. A person on SSRIs may take several MDMA doses seeking a psychedelic experience, only to find themselves in an overdose situation that is physically and psychologically dangerous. Dr. Malcolm does not recommend increasing doses of MDMA in conjunction with SSRIs.
We want to thank Dr. Malcolm for taking the time to sit down with us in our speaker series. We often refer to his work when designing our courses, and it’s a pleasure to hear him break down these complex concepts.
You can find Dr. Malcolm in the Psychedelic Support network, where you can book a consultation call with him. He’s a trusted resource within the psychedelic medicine community, and we look forward to learning more about psychedelic-psychotropic interactions from him in the future.
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