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Antidepressant and Psychedelic Combinations: A Guide to Risks & Discontinuation Times

After browsing through a few Reddit threads and Facebook forums about how to manage the antidepressant you’ve come across confusing and conflicting information.  You’re earnestly looking for information and get emotionally charged or even false responses like “Pharma poison and psychedelics always harm” or “It’s a myth that ayahuasca can cause serious drug interaction” or “Try asking a doctor instead of the internet”. You may have serious and valid reservations about discussing psychedelics with your prescriber as you know that if psychedelic drug use gets documented in your medical record, you may be treated differently by medical teams or shamed by your prescriber due to the stigma around psychedelic use. People that have combined psychedelics and antidepressants are saying that it didn’t really work for them, while people that haven’t are saying that you’ll die of serotonin syndrome if you do. Even when you think you’ve got it straight, some say to stop for a few days, others say to stop for 4 months prior to using a psychedelic.

So who is right?

It’s true that most psychedelics and most antidepressants don’t mix well, although why they don’t mix well and how dangerous it is depends on the antidepressant(s) you’re taking and the psychedelic drug you’re planning on using.

Click here to get my chart summarizing antidepressant and psychedelic drug interactions


A Note on Tapering, Discontinuation, and Antidepressant Free Periods

Before we get into the concerns and answering some of the questions surrounding antidepressant and psychedelic use, it is recommended to perform a thorough and thoughtful reflection on whether it’s truly a good time to try psychedelics and/or discontinue your antidepressant. If you are undergoing or are anticipating major life changes or are weathering a particularly rough patch at the moment, it may not be the right time. If you’re in a crisis, it’s almost certainly not the right time. If you’ve experienced extreme symptoms or suicidality in the past, please don’t make a hasty decision as changing doses of antidepressants and the associated discontinuation syndrome has been linked to suicidality [5]. If you do ultimately decide that discontinuation and psychedelic use is part of your healing path, then plan time to taper slowly as faster tapers or abrupt discontinuation lead to more severe discontinuation syndromes. It’s recommended to have your prescriber on board and in agreement for a plan to taper. They can help with prescribing any step down doses you may need and provide additional support to help you through the process. Tapering and discontinuation of antidepressants can lead to either discontinuation syndromes or return of your original symptoms so it’s reasonable to anticipate that it may be a difficult time. Beyond planning with your prescriber, it’s a good idea to have extra support in place from friends, family, community, a therapist, or a psychedelic integration coach. Be kind to yourself in the process, plan extra time to taper in case something emerges that slows you down, and attempt to approach any emotions that arise as practice or preparation for your ceremony or session.

While I present some data supporting minimum time frames to be antidepressant free before using psychedelics in this article, longer times may be considered. It may be a good idea to be off your antidepressant for an entire month before using a psychedelic, even if two weeks is the minimum time frame necessary, such that any discontinuation syndrome can fully run its course and you can accurately gauge your stability off antidepressants before engaging with powerful substances like psychedelics. Conversely, being off your antidepressants for excessively long periods before using psychedelics could also introduce risk of an unnecessary relapse or undue suffering.

Now that’s been said, there are two main concerns that we’ll walk through, the first is lack of psychedelic effects and the second is physical safety. Lastly, we’ll touch on ketamine as it is compatible with commonly used antidepressants.

Blunted Psychedelic Effects with MDMA, Mescaline, Psilocybin, and LSD

In general, when Selective Serotonin Reuptake Inhibitors (SSRI) and Serotonin Norepinephrine Reuptake Inhibitors (SNRI) antidepressants are mixed with tryptamine or phenylethylamine psychedelics such as MDMA, psilocybin, and LSD it has been reported that psychedelics lose their edge and don’t produce the intense subjective effects characterizing psychedelic experiences [6-13]. There are a few different mechanisms that may explain why this occurs. Although reviewing them in detail is beyond the scope of this guide, here is a poster summarizing the effect with MDMA. This effect has been best established with MDMA, although some data also exists for LSD. The other phenylethylamine (e.g. mescaline) or tryptamine (e.g. psilocybin) psychedelics mentioned have some anecdotal reports of experience blunting with antidepressants, although have not been conclusively demonstrated to interfere with psychedelic experiences.

There is no convincing evidence supporting that combinations of antidepressants with classic phenylethylamine or tryptamine psychedelics that do not contain a monoamine oxidase inhibitor (MAOI) present risks of severe physical toxidromes such as serotonin syndrome. These observations also extend to the lesser used tricyclic antidepressants (TCAs) since they work similarly to SSRIs and SNRIs. Other antidepressants such as trazodone (usually used for sleep) and mirtazapine may also produce blunted effects because they block 5HT2A receptors, which are necessary for psychedelic experiences to occur.  

There are many other novel psychoactive substances (NPS) with psychedelic effects in phenylethylamine (2Cx, DOx, NBOMe), tryptamine (5-MeO-DMT, 5-MeO-DiPT, DPT, AMT), and cathinone (methylone, 4-MMC, MDPV, mephedrone) classes that share similar pharmacology with classic psychedelics, however there may also exist significant differences between them. For example, some data suggests alpha-methyltryptamine (AMT) and its analogs have significant MAO inhibition as part of their pharmacology [14]. Therefore, the reader is cautioned against generalizing what’s known about classic psychedelics to NPS. 

So, if it’s not physically dangerous, why not just give it a try?

If you’re using a psychedelic with the intention of finding healing, gaining insight, or having a profound experience, then there’s a lower chance that you’ll have the subjective effect and subsequent experience you’re hoping for. On a related note, if you’re using a psychedelic because you have a refractory mental illness, then you may be at risk for ‘loss of hope’ if the experience is less than you thought you signed up for. Research has found an association between the degree of mystical experience and therapeutic outcomes, thus if you have a dud journey, you’re probably less likely to get an experience that meets your intention or mediates healing effects, which could lead to intensified feelings of hopelessness [15]. So, it seems at the least it could lead you to falsely believe that psychedelics don’t work and in extreme cases it could lead to severe consequences such as self-injurious behaviors. Not to mention you likely wasted some of your time and money.

There are some other, more theoretical, reasons that antidepressants and psychedelics may not be a good idea to combine. For example, in a neuroscientific model of antidepressant and psychedelic effects, it has been postulated that antidepressants work by repressing emotion and increasing tolerance to existing circumstances due to activation of ‘passive coping mechanisms’ [16]. Conversely, psychedelics have been postulated to work by increasing emotional processing and catalyzing change due to stimulation of ‘active coping mechanisms’. It is unknown if combining drugs with these differing mechanisms are complementary or counterproductive, however intuitively it seems it may not be advantageous to use drugs that repress emotion with drugs that bring up emotion simultaneously [16].

How long do I have to wait after stopping an antidepressant before a psychedelic will have an effect?

It is unknown the exact amount of time it takes and is probably dependent on the antidepressant used, the time it was used for, and perhaps the dose taken. The good news is that it’s probably not a long period of time. This is evidenced by existing trials of MDMA and psilocybin-assisted psychotherapies. Some of the clinical trials of MDMA and psilocybin enrolled persons with refractory illness, which was defined by trying and failing at least two antidepressants in the past. Persons taking antidepressants were required to taper and discontinue antidepressants for 5 half-lives (generally accepted time-frame for total elimination of drug from the body) plus an extra week to demonstrate stability. For most antidepressants this equates to discontinuation approximately two weeks prior to psychedelic use [17-20]. The table in this article has a list of times it takes to eliminate antidepressants from the body. Another useful resource for antidepressant elimination times can be found in table 6 on page 59 of this clinical trial protocol used by the Multidisciplinary Association of Psychedelic Studies (MAPS)[20].

In psychedelic trials to date, they’ve found significant therapeutic effects without a signal for loss of effect in persons that had stopped antidepressants. Thus for SSRI or SNRI antidepressants, literature supports an antidepressant-free period of two weeks being sufficient to restore full psychedelic effect. An exception to this general rule may be fluoxetine (Prozac), which tends to take a longer time to be completely eliminated from the body. For fluoxetine (Prozac) users the body may need 6 weeks of antidepressant-free time before a full effect is restored [20].

Can I just take a bigger dose of psychedelic to overcome issues with ‘lack of effect’?

This is a poor idea as it could lead to increased risks of physical toxicities or increased risks of psychological harms. It’s a better idea to taper and discontinue than try combining antidepressants with ‘heroic’ doses of psychedelics. If the blunting effect is actually less than anticipated you could end up biting off more than you can chew with this strategy and end up having a traumatic or difficult experience that doesn’t bring the healing effect you wanted.

What about bupropion, is it the same as SSRI and SNRIs?

Bupropion works by inhibiting dopamine and norepinephrine reuptake and has no appreciable affinity for serotonin receptors or the serotonin reuptake pump, therefore phenylethylamine and tryptamine psychedelics should still produce effects while taking bupropion [21]. In fact, one study found that bupropion actually boosted MDMA concentrations and prolonged its subjective effects without increasing cardiovascular effects [22]. This doesn’t necessarily mean that they should be combined or that there are no risks as bupropion can lower seizure thresholds and MDMA has some pharmacological effects that may increase seizure risk [23]. It does, however, mean that bupropion doesn’t carry the same risk of ‘loss of effect’ compared with SSRI or SNRIs. Bupropion was disallowed to be used in the 2 weeks prior to MDMA or psilocybin clinical studies. It may be a good idea to reflect on what your goals of psychedelic use are and what level of risk tolerance you have when trying to decide whether to stop bupropion or not before psychedelic use. It may also be reasonable, particularly with MDMA, to reduce the dose of MDMA used given it’s expected to have a longer experience with higher MDMA blood concentrations if taken concurrently with bupropion [22].

Are there any other concerns with using antidepressants and psychedelics?

Most certainly. Many psychedelics are metabolized by an enzyme in your liver called CYP2D6, while several antidepressants (fluoxetine, paroxetine, bupropion, duloxetine) are known to inhibit this enzyme [6, 11, 24]. This means that they could block the metabolism of some psychedelics and lead to higher blood concentrations. This is likely the mechanism by which bupropion boosts MDMA blood concentrations [22]. While this may not be the biggest problem with some psychedelics and antidepressants due to blunting of subjective and cardiovascular effects, others could be hazardous [25]. 

Physical Safety Issues with Ayahuasca or MAOI Containing Psychedelics

The combination of antidepressants with serotonin reuptake inhibition (as well as other commonly used drugs or substances) and MAOIs can lead to serious toxidromes such as serotonin-related toxicities, hypertensive crises, or even death [26-28]. The most commonly encountered psychedelic containing MAOIs is ayahuasca. Other MAOI containing psychedelic concoctions may contain Syrian rue or moclobemide and are collectively termed ‘pharmahuasca’. Dried plant or herbal materials can be laced with MAOIs and DMT, which are known as ‘enhanced leaf’ Changa [29].

While there are differences in the amount of time harmala alkaloids such as those found in ayahuasca inhibit MAO compared with pharmaceutical MAOIs, it is well established that the harmala alkaloids are potent MAOIs with the potential for serious drug interaction [26, 28, 30]. You may find people that insist ayahuasca is “not a complete MAOI” or that the risks are overstated, however please ignore them as they are not correct and spreading dangerous misinformation. It was first reported by Callaway that SSRIs and ayahuasca are capable of producing prolonged and serious toxidromes [26]. While it’s unknown and unclear what combinations of drugs were involved, poison control calls in the US related to ayahuasca have resulted in placement of breathing tubes, seizures, and death [27]. The signs, symptoms, and outcomes in these poison control cases are suggestive of unsafe drug combinations and severe serotonin toxicities.

Got it, I don’t want to experience toxicity, how long should I be off my SSRI or SNRI before using a MAOI?

Since MAOIs were the first antidepressants on the market, we actually have extensive research and data on how long you need to wait to safely be able to use a MAOI. For the SSRI and SNRI medications with the exception of fluoxetine (Prozac), the recommended and safe time frame is at least two weeks. For fluoxetine (Prozac), it’s at least six weeks [31].

What other drugs should I be off before using an MAOI?

Other drugs that are contraindicated with MAOIs involve those that increase serotonin release or block serotonin reuptake such as phenylethylamines (MDMA, 2Cx, DOx, NBOMe) and the tryptamine 5-MeO-DMT [32, 33]. Drugs that increase dopamine or norepinephrine levels (amphetamine, methylphenidate, cocaine, bupropion) may introduce risk of high blood pressures (hypertensive crisis) and associated risks like heart attack, stroke, or kidney failure. There are several other drug classes that are contraindicated or cautioned to be used only with expert oversight in conjunction with MAOIs including tramadol, methadone, trazodone, pseudoephedrine, dextromethorphan, anti-Parkinson’s medications among others.  Some herbal products or supplements are also contraindicated with MAOIs include St. John’s Wort, L-tryptophan, and 5-HTP. This is not an all-inclusive list and recommend seeking guidance if planning to use psychedelics containing MAOIs with existing medication, supplements, or herbal products.

Ketamine: The Antidepressant Friendly Psychedelic

Ketamine has not traditionally been considered a psychedelic and is usually categorized as a dissociative anesthetic [34]. However, ketamine can produce profound mind altering effects and classic psychedelic experiences such as the ‘mystical experience’ have been reported with ketamine use [35]. Furthermore, ketamine has been shown to produce neuroplasticity similar to class psychedelics such as DMT [36]. Whether you consider ketamine a psychedelic or categorize it as an anesthetic or analgesic is perhaps a semantic debate or a function of dose and route of administration. For the purposes of this discussion I’m considering it to be a psychedelic. Ketamine differs from most psychedelics in that its mechanism doesn’t directly affect serotonin neurotransmission and it appears that it works to modulate glutamate (and possibly opioid) systems instead [37]. Therefore, ketamine retains its mind-altering effects when combined with traditional antidepressant therapies without introducing risks of physical toxicity. Early trials of ketamine for depressive states required participants to be off their antidepressant medications for two weeks prior to use [38]. However, several studies from real-world clinics document retained benefits when combined with antidepressants [39]. Additionally, the newly approved intranasal form of ketamine is intended to be used in conjunction with antidepressants and contains language recommending concurrent use in its manufacturer produced drug information [40].

What advantages does ketamine offer compared to other psychedelics?

Probably the most significant advantage ketamine offers is that it’s regulated as a controlled substance instead of an illicit substance in the United States, meaning that it can be accessed through traditional medical providers and does not introduce risks associated with clandestine treatments or carry the same level of stigma that other psychedelics do. It is also a shorter acting drug than other psychedelics, which could be considered advantageous to some. Recently, an intranasal applicator for a form of ketamine (S-ketamine or esketamine) was approved for the treatment of refractory depression [40]. This approval sends a clear signal to the greater medical community that the use of ketamine for management of refractory depression is acceptable and within the ‘standard of care’ for refractory illness.  Another significant advantage of ketamine, is that it has been successfully used in the management of depression associated with bipolar illness, whereas bipolar disorder would be considered to be a contraindication to use of phenylethylamine or tryptamine psychedelics with serotonin based mechanisms of action [38]. For persons hoping to have a therapeutic experience with an altered state of consciousness that are not ready to taper antidepressants or have bipolar disorder, ketamine is perhaps the best existing option.

What are some disadvantages of ketamine compared to other psychedelics?

Ketamine produces significant, rapid, and robust antidepressant effects, although it tends to not produce the durability in results that have been observed with other psychedelic-assisted psychotherapies such as those with psilocybin or MDMA. Ketamine usually produces beneficial effects that last, on average, 5-7 days. It also it usually given as a series of treatments, perhaps 2-3x weekly for a few weeks. Therefore, if wanting to use ketamine therapeutically, you may need to get several treatments in a short period of time. While substance use disorders with ketamine have not developed from use in clinical studies, it is generally a higher risk drug for development of substance use disorders than serotonin based psychedelics, particularly tryptamines like psilocybin or LSD. The approved ketamine nasal applicator was also not studied within a wider framework that incorporates adjunctive psychotherapy and there is variability in provider perspectives of the utility of the altered state ketamine produces. There are some that are practicing ketamine assisted psychotherapy (KAP), while others simply administer the drug and monitor from a distance, without providing much support for the experience or integrative psychotherapy post-experience [35].  It is encouraged to seek a ketamine provider that is well-versed in drug-assisted psychotherapy modalities and provides support before, during, and after the experience.

Summary & Conclusions

There are many things to consider when taking antidepressants and considering psychedelic use. It appears with phenylethylamine and tryptamine psychedelics without an MAOI that there is a risk of loss of subjective psychedelic effects whereas with psychedelics that contain an MAOI there are risks of physical toxicity. Ketamine appears to be well tolerated and retains effectiveness in combination with antidepressants. I hope this guide helped to clarify some of the issues around psychedelics and antidepressants.

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