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Psilocybin-Blunting Effects of SSRI’s and Antidepressants

Serotonergic medications like SSRIs have been on the market for treatment of depression and anxiety for several decades now, and they’ve largely maintained a steady public backing since their conception. More recently though, the cultural discussion surrounding these regimens have addressed a wide-reaching dissatisfaction with their often intolerable side effects.

It’s this longing for more deep-rooted and durable antidepressant treatments that have given our psychedelic ‘renaissance’ such impassioned communal reinforcement. Whether you’re someone looking to replace a current medication with psychedelic-assisted therapy, someone seeking to conjoin a longstanding treatment with more fast-acting and all-encompassing alternatives, or even perhaps an individual whose been on these pharmaceutical drugs and felt disillusioned by a lack-luster psychedelic trip–understanding the poly-therapeutic interactions between prescription medications and ‘magic’ mushrooms is vital for educing the full extent of psilocybin’s medicinal properties.

Our recent, western curiosity of psychedelic therapeutics 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 meta analysis and systematic review to date, on the topic—covering the chemico-biological interactions of these medicines in each of their respective drug classes, their most scientifically congruent mechanisms for reducing or amplifying the potency of a psychedelic trip, and the steps you can take to reduce the likelihood of confronting similar events. For your reading reference, the following chart offers some context on the pharmaceutical medications we’ll be relating these experiences/interactions to.

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 a psychedelic trip is key for having an experience that’s tailored to your body’s metabolic needs. 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 somatic mechanisms that scientists believe to be encouraging this mind-body discord. Please note, the infancy of the psychedelic medicine industry unfortunately limits the range of controlled research studies 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 subjective absorption-related deficiency.

What Does the Science Say About Antidepressants and Psychedelics?

In a 1999 study conducted by G K Aghajanian et al., from the Department of Psychiatry at the Yale School of Medicine, researchers deduced that the perceptual distortions experienced from hallucinogenic drugs are mainly hosted by 5-HT2ARs 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 receptors. 5-HT is serotonin. 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, researched the biological mechanisms of antidepressants. Their findings concluded that serotonergic medications 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. While psilocybin (an agonist) is trying to bind to and activate 5-HT2A receptors for creating the hallucinations famously experienced during psychedelic trips, serotonergic medications are attaching themselves to these same receptors, then blocking the sites to prevent further 5-HT (serotonin) binding. This dilutes our body’s biological response to 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. These mechanisms are intentionally done to allow for improved communication between neighboring nerve cells. By hindering reabsorption, our brains are given a larger supply of unoccupied serotonin to amplify transmission between its neurons.

A study by Kathryn G. Commons and colleagues from 2019 suggests that autoreceptor desensitization isn’t an effect of antidepressants. They contradict the hypothesis that long term use of antidepressants overstimulates serotonin receptors and consequently reduces their ability to continue emitting this autoinhibitory feedback, which would indicate that prolonged antidepressant use may completely desensitize our brain’s ability to detect and produce normal levels of serotonin, later down the road. Their research argues 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. Essentially, their analysis concludes that return to baseline doesn’t occur because unfortunate desentization has taken place, but rather as a positive product of the receptors that haven’t been desensitized and are working at above-average capacity.

A large number of studies partially agree with this perspective, but instead hypothesize that down-regulation is the culprit of our brain’s future inability to metabolize serotonin. One reputable 2013 study conducted by Dr. Neil A. Gray et al. from Columbia University, produced findings that supported this notion. Their research 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.

So the big question, how does this relate to the inability of experiencing normal levels of psychedelic hallucinations?

Very simply, while on an antidepressant our brains don’t allow psilocybin’s main chemical to attach itself to our serotonin receptors.

Since serotonin receptors are thought to be the main cause of the psychedelic sensations experienced by our abstract minds, an inability to permeate the serotonin reuptake pump means an inability to feel this fungus’s psychoactive properties. Conversely, someone who’s 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 conducted to investigate this phenomenon, a June 1996 investigation led by K. R. Bonson et al. recruited 32 volunteers to report on the intensity of their psychedelic experiences while on heavy use of antidepressants (fluoxetine, paroxetine, sertraline, trazodone). 88% of them experienced a significant reduction of LSD effects after more than 3 weeks of antidepressant dosing.

Another study from 2017, conducted by RL Carhart-Harris and DJ Nutt on the effects of serotonin on brain function, 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 from 1996 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, subjects on MAOIs experienced a significant reduction of subjective psychedelic effects. These two studies support our informed hypothesis that tryptamines reduce psychedelic subjectivities while adding strong anecdotal evidence of a correlation between chronic MAOI use and decreased psychedelic effects. A literary review conducted by Dr. Ken Gillman 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.

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 on the topic, conducted by Thomas Pokorny and colleagues, used a double blind, within-subject, counterbalanced design to analyze the effects of Buspirone on psilocybin hallucinations. They employed 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, never fear. There are steps we can take to ensure our bodies metabolize psilocybin to the best of their ability and we’ve detailed those, below.

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, 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 SSR’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.

Proactive Planning: 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.

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. 

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. Now let’s review what can be done to promote better somatic absorption of psilocybin to hopefully yield more adequately-weighted psychedelic experiences. 

  • 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.

Microdosing and Psychotropic Medication

Microdosing 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 (also known as serotonin 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 symptoms 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 the neuroplasticity of the brain. Although this effect can’t be felt, it allows 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 symptoms.

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.

Some Helpful Tips on Tapering

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 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 symptoms, 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.

A Gentle Reminder

Psychedelic therapeutics is a very fresh industry to American society, 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 meta analytical, systematic 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, 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. Safe journeying, friends!

nick and jimmy headshot, psychedelic passage co-founders

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