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The Psilocybin-Blunting Effects of SSRIs and Antidepressants

Erika Perez
Erika, Head of Content at Psychedelic Passage, plucks the natural chord of human curiosity to initiate dialogue that meets readers wherever they are in their life’s journey. She reminds you that inquisition is always a reliable road to self development, and that bringing more light to your own truth helps others to awaken to theirs.

Serotonergic medications like SSRIs have been on the market for treatment of mental health conditions like depression and anxiety for several decades now, and they’ve maintained a steady public backing since their conception. 

More recently though, the cultural discussion surrounding these regimens has addressed a wide-reaching dissatisfaction with their often intolerable side effects. It’s this longing for more deep-rooted and durable antidepressant and integrative mental health treatments that have given our psychedelic renaissance such impassioned communal reinforcement. 

Whether you’re looking to replace a current medication with psilocybin therapy, seeking to combine traditional talk therapy with psychedelic therapy,  or if you’re looking into reasons why you might not trip, even on a high dose of psychedelics, this discussion on the psychedelic drug interactions will undoubtedly inform your next steps.

Our recent, western curiosity of psilocybin therapy has begun to shed a much needed light on a scarcely-covered, but fairly prevalent phenomena that’s been affecting psychedelic journeyers for an immeasurable amount of time. 

Surfacing research has finally introduced plausible answers to the confounding experiences some of our clients have even encountered.

To the best of our knowledge, this may be the most comprehensive analysis and review to date, on the chemico-biological interactions of these medicines in each of their respective drug classes. 

We explore the mechanisms by which antidepressants can reducing or amplifying the potency of a psychedelic trip, and the safety-first steps you can take to reduce negative interactions.

Antidepressants That Interact With Psychedelic Medicine

Selective serotonin reuptake inhibitors (SSRIs)

  • Citalopram (Celexa)
  • Escitalopram (Lexapro)
  • Fluoxetine (Prozac)
  • Fluvoxamine (Luvox)
  • Fluvoxamine CR (Luvox CR)
  • Paroxetine (Paxil)
  • Paroxetine CR (Paxil CR)
  • Sertraline (Zoloft)

Serotonin-norepinephrine reuptake inhibitors (SNRIs)

  • Desvenlafaxine (Pristiq)
  • Duloxetine (Cymbalta)
  • Venlafaxine (Effexor)
  • Venlafaxine XR (Effexor XR)
  • Milnacipran (Savella)
  • Levomilnacipran (Fetzima)

Serotonin partial agonist/reuptake inhibitor (SPARIs)

  • Vilazodone (Viibryd)
  • Vortioxetine (Trintellix)

Tricyclic antidepressants (TCAs)

  • Amitriptyline (Elavil)
  • Desipramine (Norpramin)
  • Doxepin (Sinequan)
  • Imipramine (Tofranil)
  • Nortriptyline (Pamelor)
  • Amoxapine
  • Clomipramine (Anafranil)
  • Maprotiline (Ludiomil)
  • Trimipramine (Surmontil)
  • Protriptyline (Vivactil)

Monoamine oxidase inhibitors (MAOIs)

  • Phenelzine (Nardil)
  • Selegiline (Emsam)
  • Tranylcypromine (Marplan)
  • Isocarboxazid (Parnate)
  • Moclobemide

Norepinephrine-dopamine reuptake inhibitors (NDRIs)

  • Bupropion (Wellbutrin, Aplenzin)

Atypical agents

  • Mirtazapine (Remeron)
  • Nefazodone (Serzone)
  • Trazodone (Desyrel, Oleptro)
  • Buspirone (Buspar)

Expectation Management

Assuming well informed expectations for psilocybin therapy is key for having an experience that’s tailored to your body’s metabolic needs and to your present mental health conditions. 

While some studies on the matter have yielded contradicting findings, a substantial number of anecdotal reports draw a significant, negative correlation between prolonged use of serotonergic medications and the degree to which a psychedelic trip can be inwardly experienced.

In other words, people who are prescribed these pharmaceutical drugs and take them routinely, have reported experiencing little to no hallucinogenic effects on a standard dose of tryptamines, like psilocybin mushrooms and LSD.

Though this phenomena seems to expand its presence into a plethora of other psychedelic drugs, like Phenethylamines (MDMA, mescaline), today we’ll be settling our attention on the trip-suppressing effects of antidepressant pharmaceuticals.

Let’s begin by discussing the mechanisms that scientists believe are encouraging this mind-body discord. Please note, the infancy of the psychedelic medicine industry unfortunately limits the range of controlled research studies and clinical trials that have investigated less-discussed, sometimes case-specific nuances of our highly variant body of psychedelics.

Though that’s caused most of our current research to rely largely on anecdotal reports, it’s important to recognize the high and widespread frequency of these discouraging interactions. 

For the purpose of offering a comprehensive analysis, we’ll be piecing together the findings of several observational studies, to paint a more conclusive scientific explanation for this absorption-related dysfunction.

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Current Research Studies on Antidepressants and Psychedelics

In a 1999 study, researchers deduced that the perceptual distortions experienced from hallucinogenic drugs are mainly hosted by 5-HT2A (serotonin) receptors through glutamatergic transmissions occurring in the cerebral cortex. Substances like LSD and psilocybin are bicylicly structured into an indole-shaped ring. 

This form allows them to perfectly attach themselves to our brain’s 5-HT2A (serotonin) receptors. Picture this as the communion of a particular key with its corresponding lock, like the perfect piece to a complex puzzle. Now that we understand a small part of psilocybin’s cerebral route, let’s take a look at the mechanisms of antidepressants.

A study led by Pau Celada and colleagues in 2004, investigated the biological mechanisms of antidepressants. Their findings concluded that antidepressants act as antagonists at the 5-HT2A receptors. What does this mean? Well, first and foremost, it tells us that compounds like LSD and psilocybin target the same receptors as antidepressants. 

It also suggests a conflict of chemical interest, where two drugs are attempting to act on serotonin receptors to alter brain function. While psilocybin is trying to bind to and activate 5-HT2A receptors (in order to elicit hallucinogenic effects), antidepressants are attaching themselves to these same receptors, then blocking the sites to prevent further 5-HTR binding. 

This obstructs our body’s biological response to psychedelic drugs that act on 5-HT2AR, since their serotonin chemicals cannot be freely absorbed by the clogged receptor. 

Essentially, antidepressants increase extracellular serotonin levels in order to inhibit nerve cells from reabsorbing serotonin that was previously produced by it. By hindering reabsorption, our brains are given a larger supply of unoccupied serotonin to amplify transmission between its neurons.

A large number of studies hypothesize that down-regulation is the culprit of our brain’s inability to metabolize serotonin, after prolonged antidepressant use. One study conducted in 2013, produced findings that supported this notion. 

The study recruited 19 unmedicated subjects with major depressive disorder and compared the binding function of their 5-HT receptors before and after a 5-9 week period of self medication with SSRIs. Results showed an 18% downregulation of binding functions to 5-HT autoreceptors, congruous with previously conducted animal studies. 

This initial reduction is thought to increase the firing rate of serotonergic neurons in later stages of treatment, magnifying this communication by releasing more serotonin. However, post-treatment results indicate that this surge is not durably maintained without the anti-depressant and instead, causes our brains to have more trouble producing serotonin than it did pre-treatment.

antidepressant ssri blunts psilocybin

So the big question–how does these findings communicate the brain’s inability to experience normal levels of psychedelic hallucinations, during and after antidepressant use? Very simply, while on an antidepressant and in the weeks to months after discontinuation, our brains don’t allow psilocybin’s main chemical (serotonin) to attach itself to our serotonin receptors.

Since 5HT receptors are thought to be the main cause of psychedelic effects, an inability to permeate the serotonin reuptake pump means an inability to feel this fungus’ psychoactive properties. 

Also, someone who’s only recently stopped prolonged use of antidepressants, may not feel a standard psychedelic dose as potently as someone who’s never been on a serotonergic medication.

Of the very few observational studies directly investigating this phenomenon, a 1996 study recruited 32 volunteers to report on the intensity of their psychedelic experiences while on heavy use of antidepressants (fluoxetine, paroxetine, sertraline, trazodone). 88% experienced a significant reduction of LSD effects after more than 3 weeks of antidepressant dosing.

A study from 2017 agreed on much of what we’ve already discussed, coming to the conclusion that antidepressants evoke 5HT2AR downregulation, consequently blunting the effects of psychedelic drugs. 

One of their earlier studies examined the effects of tricyclic antidepressants on the LSD experience. After seeking out 10 subjects who had been on TCAs or MAOIs for at least 3 weeks, they gathered their reports on the LSD experience. 

A standardized questionnaire revealed a significant correlation between chronic use of TCAs and amplified hallucinatory distortions on LSD. Conversely, participants on MAOIs experienced a significant reduction of subjective LSD effects. 

However, a 2017 study came to much different conclusion. This study found that MAOIs increased the accumulation of 5-MeO-DMT in the central nervous system and enhanced its interaction with 5-HT2A receptors. This suggests that MAOIs may increase the effects of 5-MeO-DMT and other tryptamine hallucinogens, rather than decreasing their effects.

We should note though, the study primarily focused on the alteration of the pharmacodynamics of 5-MeO-DMT by MAOIs and did not directly investigate the subjective effects of the combination of MAOIs and tryptamine hallucinogens in humans.

A literary review conducted in 2016 also concluded that MAOIs should not be taken with drugs intended to release serotonin as their interaction could potentially cause serotonin syndrome– a bodily reaction caused by an excessive amount of amassed serotonin, which could be fatal. He also agreed that this combination could reduce the effects of psychedelics like MDMA and ecstasy.

To be clear, combining psychedelics with any drug that inhibits serotonin reuptake will increase the chances of serotonin sydrome, also known as serotonin toxicity. If serotonin is not able to be metabolized, it can overaccumilate in the brain, leading to potentially fatal outcomes.

Buspirone’s blunting effects on psychedelics are not caused by inhibition of reuptake, but by their partial agonist properties that may compete with the psychedelic attempts to enter those same serotonin receptors. 

A 2016 study used a double blind, within-subject design to analyze the effects of Buspirone on psilocybin hallucinations. The placebo group was given a small dose of ergotamine, an anti-migraine medication, to compare interactions against larger, regular doses of Buspirone. 

The Altered State of Consciousness rating scale was used to detail the subjects’ experiences which produced very strong evidence (p<0.001) for a significant decrease in visual hallucinations and a significant decrease in derealisation and depersonalisation (p=0.062), compared to main scale scores. 

Ergotamine did not produce any suppressing effects. These results conclude that Buspirone inhibits hallucinatory effects of psychedelic drugs.  To those who’ve found themselves in this colorless situation, unable to experience the therapeutic effects of psychedelic medicine–never fear. There are steps we can take to ensure our bodies metabolize psilocybin as they can.

Restoring The Serotonin System After Antidepressant Use 

A study by Kathryn G. Commons and colleagues from 2019 suggests that autoreceptor desensitization isn’t an effect of antidepressants. They argue against the hypothesis that long term use of antidepressant medications overstimulates serotonin receptors and permanently reduces their ability to continue emitting this autoinhibitory feedback. 

Their research suggests that although desentization may occur, the unaffected receptors do continue inhibiting reuptake, returning our brain to baseline levels of serotonin production using the compensatory feedback inhibitors that remain. 

These findings illustrate a positive outcome that has seems in line with many of our client’s experiences: After tapering off antidepressants, the brain’s serotonin system returns close-enough to baseline for journeyers to feel the effects of psychedelic medicine.

What Have We Seen Anecdotally With Our Clients?

As a company who facilitates psychedelic journeys professionally, we’ve worked with both clients who are on antidepressants and those who are not. Our take is that antidepressants don’t pose a safety concern when combined with psilocybin treatment, but they do tend to interfere with client expectations.

Chances are if you’re exploring an intentional psychedelic experience, you’re seeking some sort of change. The challenge is this—what happens if you put all the time, energy, and money towards preparing for a psychedelic experience only have nothing happen? For most people, the answer is disappointment. This is why we typically discourage combining serotonergic medications with psilocybin.

The interesting thing is that we’ve had clients send us this study which shows the SSRI’s don’t interfere with the psychedelic experience—but we’ve found that doesn’t hold true–at least not with all medications. While the study is a great data point, it’s also important to consider the results we’ve seen anecdotally working with clients first-hand over the last several years.

We’ve sat with some clients who are taking SSRI’s and are able to have psychedelic experiences—they typically just need a higher dose of psilocybin. Alternatively, we’ve sat with clients who are taking SSRI’s who eat 10+ grams of mushrooms and experience no effects at all.

So, it’s not that this study is ‘wrong’—just that it doesn’t paint the full picture. At this point in time, we don’t have enough information to accurately predict whether a client will have a significant psychedelic experience while taking SSRI’s—some will and some won’t. The question is, is that a risk you’re willing to take as a journeyer? Only you know the answer to that question.

How Long Do I Need to Discontinue Use?

Understanding what should be naturally expected from our body’s present conditions is step number one. Conscious and safe preparation for the psychedelic experience in step number two for ensuring you preserve your physical and mental health. 

Before diving into some relevant and typically effective options for getting the most out of your magic mushrooms, please be advised that cessation of any medical treatment like antidepressants, should always be discussed with your psychiatrist beforehand. 

Antidepressant dosage reduction or termination should always be done under the supervised care and direction of a medical professional and should never be abruptly withdrawn. Abrupt discontinuation of antidepressant medications can worsen mental health conditions and cause emotional instability and volatility.

Having said that, we understand it can be intimidating to approach your doctor with psychedelic-related concerns. If you need some guidance, check out our article on how to speak with your doctor about psilocybin therapy. Now, let’s review what can be done to promote better absorption of psilocybin to hopefully yield more adequately-weighted therapeutic psychedelic effects. 

  • If you’re taking any of the SSRIs or SNRIs referenced in the first chart, including SPARI drugs like Vibryyd (Vilazodone) or Trintellix (Vortioxetine), with the exception of fluoxetine, consider tapering off of your meds no less than 2 weeks before your psychedelic journey. If you’re on fluoxetine, discontinuation of medication should occur at least 6 weeks prior to your journey. By the time you’re ready to embark on the trip, you should have ceased consumption of any SSRI drug.
  • Fortunately, there are no reports of reduced psychedelic effects on Wellbutrin, but some would advise tapering medication as a precaution, correlating the length of premeditated discontinuation to the potency of desired effects.
  • On a Mirtazapine medication, tapering should also allow for a 2 week period of discontinued use, prior to your trip. Mirtazapine could dull psychedelic experiences, similar to SSRIs and SNRIs, but its blunting mechanisms lie in a blockage of the 5HT2A receptor, rather than blocking the 5HT reuptake pump.
  • This same 2 week tapering regimen should be applied for those on Tricyclic antidepressants. Discontinuation before a psychedelic trip is advised due to the potential for experiencing intensified psychedelic effects and serotonin syndrome.
  • If on Trazodone, tapering and discontinuation should be in effect a minimum of 5 days before a trip to prevent blunting effects.
  • Buspirone consumers should also follow this 5-day minimum to avoid the same events.
  • MAOIs should be discontinued through tapering 2 weeks before a trip for these same reasons.

How Microdosing & Psychotropic Medication Can Help

Microdosing psilocybin mushrooms can potentially be helpful for those looking to taper off of psychotropic medications such as antidepressants, anti-anxiety medications, stimulants, antipsychotics, and mood stabilizers. 

This is because psilocybin binds to the 5-HT receptors which are linked to mood, social behavior, sexual desire, memory, sleep, appetite and digestion among many other things. In other words, the benefit to including microdoses of psilocybin while tapering off of pharmaceuticals is that it provides a natural supplement to the systems influenced by psychotropic medications.

This effect lessens or even eliminates the pharmaceutical withdrawal side effects altogether (things like brain zaps, fatigue, irritability, etc.). Many people report feeling lighter and more alive while taking microdoses with their psychotropic medications, even while tapering.

The other benefit to microdosing during the tapering process is that it increases neuroplasticity in the brain. Although microdosing effects are sub-perceptual, they allow for the brain to form and reorganize synaptic connections. 

In other words, a microdosing protocol allows the brain to be re-wired in a way such that it is not dependent on pharmaceutical medications. In summary, microdosing psilocybin potentially allows one to taper off of their psychotropic medications faster and with far fewer withdrawal side effects.

Important Note: Because many psychotropic medications also work through the serotonin pathways, it will likely require a higher dose of psilocybin for the effects to be felt. This is normal, simply adjust your dosage as necessary.

Now that there is a basic understanding of the relationship between microdosing psilocybin and tapering down or off of psychotropic medications, the next logical question is how to actually taper off of pharmaceuticals.

How to Determine Psychedelic Dose

In a groundbreaking development for harm reduction practices, Dr. Felix Blei, based in Jena, Germany, has pioneered QTests—the world’s first quantitative reagent test kits specifically designed for psychedelics. 

Unlike traditional reagent kits that merely identify the presence of a substance, QTests go a step further by revealing the potency of psychoactive compounds in milligrams or as a percentage. The introduction of QTests revolutionizes the way individuals approach harm reduction in the realm of psychedelics. 

By providing quantitative data on the potency of psychoactive substances, these kits enable users to accurately determine the exact dosage of the most popular psychedelic drugs. Qtests offers an MDMA test kit, LSD test kit, psilocybin mushroom test kit, and even a cannabis test kit

QTest Potency of Psychedelics

QTests offer a scientifically validated method for determining the concentration of unregulated substances, granting both journeyers and healthcare providers greater control over treatment processes and enhancing the potential benefits of psychedelic therapies. The following is a brief overview of the fascinating and simple process behind QTest use.  

Helpful Tips on Tapering Off of Antidepressants

The best way to taper off, adjust, or eliminate any medication is with the supervision and guidance of your prescribing doctor or psychiatrist. However, we also recognize that many doctors are better at prescribing medications than they are at helping people taper. This often results in them recommending tapering regimens that are far too aggressive and lead to significant withdrawal symptoms.

For most people, these withdrawal symptoms are so disruptive and debilitating that it seems easier to continue to use a particular pharmaceutical drug in order to avoid the return of depressive symptoms. In an effort provide you with some general guidelines, we’ve outlined a tapering protocol established by Adele Framer, the founder of

Since 2011, has advocated a conservative 10% reduction per month of the most recent dose – an exponential taper, the size of each reduction becoming progressively smaller, approximating the hyperbolic method endorsed by recent research.40,72,73,98 These gradual tapers to minimize withdrawal symptoms typically require the creation of customized dosages and take many months to several years, depending on individual tolerance for dosage reduction.

Why reductions at monthly intervals? Although diagnostic criteria require withdrawal to appear within a week of dosage reduction, our members report it can take several weeks (or more) for them to appear.4,16,83 People may not recognize incipient symptoms themselves or it may take some time for symptoms to culminate. Pharmacokinetically, enough residual drug may be active to forestall withdrawal symptoms through the washout period.57,72,73,106,107 

If the taper proceeds without significant problems, for most drugs, people generally reduce to less than 2.5% of the original dosage before stopping completely.72,73 Given the potential lag time in emergence of withdrawal side effects, the person should be monitored for at least 3 months after discontinuation, with low-dose reinstatement at the ready should subsequent withdrawal symptoms appear.

To reiterate, taper slowly and listen to your body at all times. It is common for withdrawal side effects to have a delayed onset up to 2 weeks. Often times a more conservative tapering process will be faster in the long run than forcing things and ending up in the start/stop cycle.

What About Medications Other Than Antidepressants?

When it comes to other psychotropic medications like benzodiazepines, stimulants, and opioids we suggest being free and clear of the medication prior to ceremony. However, unlike serotonergic medications, these drugs can be stopped in the immediate 1-7 days prior to the journey given their minimal halflife and lack of significant withdrawl symptoms.

In order to determine when use should be cessated, look up the halflife of the medication in question via Google. From there, you can plug your dosage into this handy drug half life calculator to determine how long it will take for the drug to be eliminated from your system.

Closing Off

Psychedelic therapeutics is a very fresh space in the American mental health industry, but the niche work of research enthusiasts dating back over 25 years, are now serving a large population of interested supporters. 

That’s to say, although the drug interactions discussed in this analysis may precipitate feelings of angst, it’s this prefatory scientific research that has led to the admittedly rapid development of effective resolutions.

Of course, we cannot leave you without once again stating our firm advice against ceasing the use of any psychiatric medications without first getting explicit approval from your doctor. Embarking on a psychedelic journey can be a deeply life-changing experience, but this excitement should never shepherd impulsive decision-making that could lead to dangerous health complications.

It is truly our hope that this review will provide sufficient, educational information to motivate the safe and satisfying consumption of psilocybin mushrooms and of tryptamine drugs, as a whole. 

If there’s any more information you’d like to explore relating to all things psychedelic, including more education on ssris and mushrooms, check out our resources page for an abundant library of insight and perspective.

And if you’d like to speak to a us about the specifics of your medication, you’re welcome to book a consult with us today. Our psychedelic concierges can help you get connected to our pre-vetted network of experienced psychedelic guides who are located around the country. Well, that’s all for now, friends. Safe and mindful!

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At Psychedelic Passage, we offer professional 1-on-1 guidance and companionship on your journey of healing. We simply can't sit back and let Americans continue to sit in silent suffering trying to battle mental health issues within a broken health care system, all while knowing that effective alternatives exist. We stand for the sacred, at-home, ceremonial use of psychedelics for consciousness exploration, which we believe to be a fundamental human right.

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