Hands holding shrooms and SSRIs

SSRI and LSD Interactions, Plus Shrooms and More: Why Taking Psychedelics While on Antidepressants Could Make Treatment Ineffective

Dr. Julie Holland talks to DoubleBlind about SSRI and LSD interactions, plus how psilocybin, MDMA, and ketamine are impacted by anti-depressants.

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Updated September 27, 2021

Similar to how cannabis legalization was galvanized by its ability to reduce suffering during the Eighties AIDS epidemic, medical professionals are starting to cast a more favorable eye upon psychedelics due to promising effects on those suffering from depression and other mental health conditions.

We’ve seen psilocybin spread its spores into state legislatures and clinical trials, MDMA demonstrating promising results for patients with PTSD, and a growing movement of people interested in microdosing LSD to boost their mood and productivity. But for those patients who are prescribed antidepressants, there could be a disadvantage when it comes to benefiting from the guiding force of psychedelics.   

Further research is needed to explore the interaction between certain selective serotonin reuptake inhibitors (SSRIs) and psychedelics such as psilocybin, LSD, MDMA, DMT, and ayahuasca, among others. However, preliminary evidence has presented a cruel irony of sorts. What if those who can benefit the most from psychedelic-assisted psychotherapy may be hindered by their present, and perhaps even their past use of SSRIs.  

Dr. Julie Holland, a New York-based psychiatrist specializing in psychopharmacology, certainly believes that the question mark surrounding SSRIs and psychedelics is the elephant in the room for early clinical trials. Without solid information on how a history of antidepressant use impacts the effects of psychedelics, there’s no way of knowing how effective psychedelic-assisted treatment is for depression and anxiety.

“Wouldn’t it be terrible if it turns out that the people who need psychedelics the most benefit from it the least?” Dr. Holland tells DoubleBlind. “I’m certainly not willing to say that at this point, but I am willing to say that this is something to look at. It’s concerning.”

While peer-reviewed research remains sparse, there’s a bevy of available data that provides insight into how antidepressants may blunt the effectiveness of psychedelic-assisted treatment. Here’s a breakdown of what we know about the interaction between SSRIs and psychedelics. 

Serotonin Receptors: Where SSRIs and Psychedelics Meet

Before we explore the sparse research regarding antidepressants and various types of psychedelics, we should establish a general understanding of how SSRIs interact with and even blunt the effects of certain substances. 

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According to the National Center for Health Statistics, in 2017, 12.7 percent of the U.S. population over the age of 12 were taking antidepressants. SSRIs are the most commonly prescribed type of antidepressant, accounting for approximately 80 percent of the antidepressant market.

The primary function of SSRIs is to inhibit the serotonin transporter (SERT), which increases levels of serotonin in the brain by preventing it from leaving synapse. Over time, as SSRIs inhibit the serotonin transporter, the system attempts to self-regulate and serotonin receptors like the 5HT2A receptor aren’t expressed as much.

These serotonin receptors are where tryptamines (LSD, psilocybin, and DMT), phenethylamines (MDMA), and MAOI-containing substances like ayahuasca work their magic and lead us to the type of profound experiences that have changed so many lives. But, when these receptors are reformed by SSRIs, the way the body interacts with certain psychedelics may change.

Trying to Avoid Mixing Prozac and LSD or Paxil and MDMA? Here’s What To Know About Tapering Off Medication

In a chart compiled by psychopharmacologist Benjamin Malcolm on his website Spirit Pharmacist, existing evidence on the interaction between antidepressants and psychedelics has been categorized and matched with as much readily available information as possible. The guide itself should not be the basis of medical decisions, but it does provide interesting guidance regarding how patients may need to taper off their antidepressants in order to benefit from the effects of psychedelics.   

According to the chart, for phenethylamines, tryptamines, and MAOI-containing psychedelics, subjects may be safer or have more potent experiences by tapering off of Paroxetine (Paxil), Sertraline (Zoloft), Citalopram (Celexa), Escitalopram (Lexapro), and Fluvoxamine (Luvox) for at least two weeks, while those on Fluoxetine (Prozac) should wean off for period of at least six weeks.

Tapering off SSRIs can be dangerous, however, and shouldn’t be done without consulting with your doctor beforehand. Suddenly reducing SSRI dosages can induce several harsh symptoms, including dizziness, fatigue, and insomnia, as well as less common symptoms like nausea, diarrhea, flu-like effects, irritability, and anxiety. Coming off of antidepressants could also stir up suicidal thoughts, so it may not be worth the potentially enhanced psychedelic experience.

SSRI and LSD Interactions

The SSRI LSD Connection

One of the earliest studies providing insight into the interaction between psychedelics and antidepressants came courtesy of Katherine Bonson, a pharmacologist with the U.S. Food and Drug Administration (FDA). In a 1996 study published in Neuropsychopharmacology, Bonson and her research team collected first-hand accounts from volunteers who self-administered LSD while also taking an antidepressant. 

When asked to describe the hallucinatory and psychological effects of the LSD, 88 percent of the subjects who had taken an SSRI over a three week period reported a significantly diminished or eliminated response to LSD. One of the 32 subjects, who had fluoxetine administered for one week, had an increased response to LSD. In a previous study, Bonson and her team noted increased responses to LSD in subjects taking lithium or tricyclic antidepressants, which are commonly used for patients who do not tolerate SSRIs. 

Take Findings About LSD SSRI Interactions With a Grain of Salt

These findings certainly provide some insight, but should be taken with a grain of salt. After all, the study consists of self-reported experiences from volunteers through a questionnaire—a far cry from a double-blind clinical trial. Anecdotal evidence scattered throughout the internet has followed a similar theme to Bonson’s research. 

Similarly, anecdotal accounts also claim that there’s a diminished response when people on antidepressants take DMT. There’s no major research on the interaction between DMT and SSRIs, but these claims make sense considering that DMT also takes action within the serotonin receptors. 

SSRI and Shrooms

Like LSD, psilocybin is also classified as a tryptamine. Thus, there’s a similar concern that antidepressants could also cause a blunted response in psilocybin-assisted treatment. 

Various psilocybin-assisted treatment retreats, such as the Amsterdam-based Synthesis, openly refuse to accept visitors on SSRIs, and do not accept guests who have been administered SSRIs and other prescription medication over the last 6 weeks (although, based on the huge need and potential to benefit, Synthesis is working with consultants and experts to determine how they can safely expand their support to this population and plan to announce something about this before the end of 2020). In Jamaica, the psilocybin-assisted retreat MycoMeditations requires applicants to thoroughly report medications and mental illness. At this retreat, the team starts with conservative psilocybin doses to account for factors such as SSRI interactions and anxiety. 

While most accounts suggest that someone currently on SSRIs will likely experience a blunted response to psilocybin, there’s still the question of whether tapering off will provide a clean slate for an effective experience. Dr. Holland expresses concern that even years after the fact, past use of SSRIs could potentially hinder the potency of psychedelic-assisted treatment. 

But not all experts have found that prior use of SSRIs will damper the effects of psilocybin. According to Dr. Matthew Johnson, professor of psychiatry and behavioral sciences at Johns Hopkins University, his team hasn’t seen a diminished response when psilocybin treatment is administered to subjects with a history of SSRI use.

“Anyone with that chronic use history would have had to go off for several weeks before having a session,” Dr. Johnson tells DoubleBlind. “In terms of someone still having a blunted response even after that period, we have not specifically analyzed this, but I doubt if there is anything substantial as we’ve seen many cases of powerful sessions with folks in that situation.” 

While studies show that SSRIs restrain the psychedelic experience sparked by shrooms and LSD, there’s no evidence suggesting that mixing the two is necessarily dangerous. In fact, a group of researchers have proposed that SSRIs and psychedelics modify the serotonergic system in two different ways, and therefore could still lead to therapeutic outcomes when taken in a complementary fashion. This 2017 study theorized that SSRIs and other antidepressants enhance the 5-HT1AR pathways, while 5-HT2AR-agonist psychedelics like shrooms enhance the 5-HT2AR pathways. 

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Although MDMA is not usually what comes to mind when you think about classical psychedelics, this stimulating hallucinogen has nonetheless emerged as a potentially effective treatment for both depression and PTSD. On top of that, there’s more clinical research on the interaction between MDMA (also referred to as ecstasy) and the serotonin system than with any other psychedelic.

In a 2007 study published in the Journal of Pharmacology and Experimental Therapeutics, researchers conducted a double-blind, placebo-controlled trial with 12 healthy male subjects. Over a three day period, they were either given 20 milligrams of paroxetine or a placebo before taking 100 milligrams of MDMA. Researchers found that subjects who had been given the three-day dose of antidepressants experienced a notable decrease in the physiological and subjective effects of MDMA, even though they showed a 30 percent increase in MDMA plasma concentrations, indicating a metabolic interaction between antidepressants and MDMA. They concluded that the “decrease in the effects of MDMA could lead users to take higher doses of MDMA and to produce potential life-threatening toxic effects.”

Another study found that lab rats pretreated with the SSRI citalopram did not experience reductions in aggressive and exploratory behavior when administered MDMA, suggesting that the SSRI appeared to render the MDMA treatment as less effective for certain behaviors. Furthermore, other lab studies discovered that the SSRI fluoxetine may enact certain neuroprotectant effects that reduce the neurotoxic effects of MDMA and also restore serotonin levels. Dr. Holland explains that this is why some people believe that taking an SSRI six to eight hours later may help prevent the rather unpleasant MDMA “crash.” However, there’s no solid evidence to suggest that this practice is effective in cushioning the come down.

Further studies looking at how SSRIs modulate the effects of MDMA are still ongoing. Dr. Holland has been working with the Multidisciplinary Association for Psychedelic Studies (MAPS) as a medical monitor on a study focused on MDMA treatment for PTSD patients. 

“For MDMA, there’s no question,” says Holland. “I can state with a good amount of confidence that if you want a full experience from MDMA you have to get off SSRIs to do that.”  

The multi-center clinical trials, which have yet to be published, found that people who had a history of being on SSRIs demonstrated a blunted response to MDMA. Not only could this cause someone to over-consume in an attempt to achieve an equally potent experience, but could potentially lead to the onset of serotonin syndrome.

Serotonin syndrome can happen when certain serotonergic medications or substances are combined, causing the body to over-produce serotonin. This leads to extreme nerve cell activity and symptoms that include confusion, restlessness, nausea, vomiting, loss of muscle control, rapid heart rate, and in some extreme cases, seizures and uneven heartbeat.     

Now, while evidence suggests a correlation between people who take SSRIs having a blunted response to psychedelics, that doesn’t necessarily mean that antidepressants are the culprit. Holland cautioned that it’s important not to conclude that SSRIs are causing the diminished effects, as there are numerous unknown factors at play. 

“You can’t definitively conclude because you don’t know what came first: the chicken or egg,” says Dr. Holland. “It may be that the kind of people who end up on SSRIs for years and years are the kind of people who are not going to have a robust response to MDMA for some reason, due to their pre-existing serotonergic state.”  

SSRI and Ayahuasca

Another mystical psychedelic that has shown promise in the treatment of depression is ayahuasca, a South American brew made from Psychotria viridis leaves and the stalks of the Banisteriopsis caapi vine. Historically used by Amazonian tribes for spiritual purposes, ayahuasca is now being looked at in the clinical setting. 

In 2018, Brazlian scientists conducted a double-blind, placebo-controlled trial involving 29 patients with treatment-resistant depression. After giving subjects a dose of ayahuasca or a placebo, researchers found significant evidence that ayahuasca was effective in lowering depression levels. 

Despite the increasing interest in ayahuasca, researchers have cautioned against combining this mystical plant-based brew with SSRIs due to the risk of serotonin syndrome. Still, there’s no concrete evidence that combining the two will cause serotonin syndrome. As the story often goes with psychedelics, more research is needed to fully understand the interaction.

Similar to most psilocybin retreats, organizations that run ayahuasca ceremonies also commonly turn down applicants who are prescribed SSRIs. The Peruvian ayahuasca retreat Lotus Vine Journey, for instance, advises that visitors stop taking SSRI medications (with the blessing of their doctor, of course) at least six weeks prior to their workshop.

The Silver Lining: Ketamine Treatment Shows Promise

You might be thinking about how a majority of these studies are highly discouraging for people using antidepressants and looking to incorporate psychedelics into the healing process. It’s important to reiterate that more research is needed to fully comprehend whether different psychedelics are effective in treating depression, as well as how antidepressants could stifle these apparent benefits.

One promising sign for those suffering from depression is the early success of ketamine treatment. A medication commonly used for starting and maintaining anesthesia, ketamine induces a trance-like state and is increasingly being used to treat depression and pain. 

Unlike studies involving most other psychedelics, studies involving ketamine have found it to be an effective replacement for traditional antidepressants. Moreover, evidence suggests that people on SSRIs can still reap the benefits of ketamine treatment without any diminished response. 

In 2019, the FDA approved the first ever ketamine-based antidepressant, a major milestone in the search for alternatives to SSRIs. While antidepressants often take months to be effective and must be taken regularly to work, a single dose of ketamine has proven to have lasting effects on subjects suffering from depression. 

Although ketamine has proven itself to be a viable tool in depression treatment, we still have a long way to go before we can assuredly say the same about psilocybin, LSD, MDMA, ayahuasca, and other psychedelics. 

“You can be on antidepressants and still have a full ketamine experience,” Dr. Holland says. “But what happens when you’re on antidepressants and you have psychedelics? It seems, from what I’m hearing from some people, that there’s a blunted response, but there’s no double-blind, placebo controlled randomized trial to back up what I’m hearing from people anecdotally.” 

Psychedelics & Addiction

A word about psychedelics and addiction: For the most part, psychedelics are non-addictive substances, with a low risk to the user of developing a psychological or physical dependence. That said, they don’t come without risks, and specifically substances like ketamine and MDMA carry physiological risks and may lead to problematic use patterns. The other side of the coin is the physiological dependence that a user may develop in regard to a prescription medication, causing it to be more difficult to ween off said medication, especially if someone is hoping to do a psychedelic. It is best to consult with a physician when deciding to go off a prescription medication and to heed caution when incorporating a psychedelic into the mix.

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DoubleBlind is a trusted resource for news, evidence-based education, and reporting on psychedelics. We work with leading medical professionals, scientific researchers, journalists, mycologists, indigenous stewards, and cultural pioneers. Read about our editorial policy and fact-checking process here.

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DoubleBlind Magazine does not encourage or condone any illegal activities, including but not limited to the use of illegal substances. We do not provide mental health, clinical, or medical services. We are not a substitute for medical, psychological, or psychiatric diagnosis, treatment, or advice. If you are in a crisis or if you or any other person may be in danger or experiencing a mental health emergency, immediately call 911 or your local emergency resources. If you are considering suicide, please call 988 to connect with the National Suicide Prevention Lifeline.


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