Top 10 Psychedelics and SSRIs

Despite the underlying causes of many mental health disorders remaining open to debate, the drug-based paradigm of psychopharmacology has become the dominant lens through which we view and treat mental health disorders. Today, an array of pharmaceutical agents exist for treating mental health disorders like depression, anxiety and PTSD, disorders for which psychedelics hold promise.

Depression is one of the most well-researched disorders with psychedelics and numerous clinical trials involving psychedelic substances have yielded positive results. A range of psychiatric medications, commonly referred to as antidepressants, are currently available for the treatment of depressive disorders. One of the most common conventional treatments is selective serotonin reuptake inhibitors (SSRIs). As well as depression, SSRIs are often used to treat other mental health disorders like anxiety, obsessive-compulsive disorder (OCD) and even PTSD.

SSRIs work by increasing levels of the neurotransmitter serotonin in the brain. This neurotransmitter is believed to influence mood and emotion, among other things. Under normal conditions, when serotonin is released in the brain, it is quickly reabsorbed by neurons.

As the name suggests, SSRIs act by inhibiting the serotonin reuptake by neurons thereby increasing the rate of serotonin transmission in the brain. While these drugs don’t cure depression, they can improve symptoms for some, especially when used in tandem with different forms of psychotherapy. Common SSRIs include fluoxetine, paroxetine, escitalopram, and sertraline [1].

Many people benefit from SSRIs. However, possibly just as many people remain unresponsive to this type of treatment. In most cases, these drugs must be taken daily for an extended period of time before any effects are felt. Many SSRIs also come with unwanted side effects like nausea, drowsiness, and nervousness, to name a few. Moreover, the FDA requires that SSRIs carry a ‘black box’ warning, their most serious warning, given the accompanying risks of suicidal thoughts and behaviours, particularly in young adults [2].

In terms of psychedelics, substances like psilocybin, LSD, and MDMA also act by modulating levels of serotonin in the brain albeit through various mechanisms of action. Therefore, it is important that people partaking in clinical trials with psychedelics make researchers aware if they are currently using SSRIs or any other psychiatric medication for that matter. In some rare cases, excess levels of serotonin in the brain can lead to potentially fatal serotonin toxicity.

Most of the published clinical research with psychedelics allude to SSRIs, specifically, that participants were tapered off SSRI treatment prior to participating in the trial. However, despite the fact that psychedelics are poised to be a paradigm shift in how we view and treat mental illness, the research specifically exploring the effects of psychedelics and conventional treatments like SSRIs remains scarce. Nonetheless, here we present the top ten available articles exploring psychedelics, serotonin and SSRIs. If these ten articles don’t fully satisfy your curiosity, here’s an essay we previously published on SSRIs and psychedelics.

Top 10 Psychedelics and SSRIs Papers Walkthrough

1. Serotonin, psychedelics and psychiatry

In this brief review, Robin Carhart-Harris discusses how serotonin is affected quite differently by SSRIs and psychedelics. He proposes the ways in which psychedelics affect serotonin and why they may work to help someone look at their environment in a new, better, way as opposed to conventional chronic medication with SSRIs.

Interestingly, he notes that in spite of the prescription rates of SSRIs increasing year on year, widespread SSRI use has not noticeably impacted depression prevalence. He also questions the safety, efficacy, and general philosophy of psychopharmacotherapy.

2. Serotonin and brain function: a tale of two receptors

In this theory-building paper, Robin Carhart-Harris and David Nutt discuss the mechanism of action of both psychedelics and SSRIs. The authors argue that psychedelics act on the serotonin (5-HT) 2a receptor which is responsible for active coping (actively addressing a source of stress) of adversity and that this is mediated by increased neuroplasticity.

On the other hand, SSRIs act the 5-HT1a receptor which leads to passive coping (tolerating a source of stress). The theory offers an explanation for the different pathways and outcomes of psychedelics and more traditional medications/ways of coping.

3. Serotonin toxicity of serotonergic psychedelics

This comprehensive review assesses the safety of combining psychedelics and SSRIs. The researchers describe the signs, symptoms, and risk factors of serotonin toxicity, and outline potential management strategies.

Additionally, they identify the major risk stemming from psychotropics such as ayahuasca that contain monoamine oxidase inhibitors (MAOI) and the associated risk of neurotoxicity by increasing levels of serotonin at the synapse.

MAOIs are another class of antidepressants that are commonly prescribed to treat depression.

4. Trial of Psilocybin versus Escitalopram for Depression

This trial is one of the first studies to directly compare the effects of a psychedelic to that of an SSRI. The double-blind placebo-controlled trial (n=59) compared psilocybin (2x25mg; 3 weeks apart) to escitalopram (SSRI) over a six-week period.

Large improvements in depression scores for those suffering from depression in both groups were found. Noteworthily, on the main measure of depression, the Quick Inventory of Depressive Symptomology, there was no significant difference between both groups. The study did find significant differences, favouring psilocybin, on the Hamilton Depression Rating Scale, Montgomery-Asberg Depression Rating Scale, avoidance, flourishing, wellbeing, and suicidality.

5. Acute Effects of Psilocybin After Escitalopram or Placebo Pretreatment in a Randomized, Double-Blind, Placebo-Controlled, Crossover Study in Healthy Subjects

In this double-blind placebo-controlled trial, researchers at the University of Basel assessed the effects of psilocybin (25mg) in healthy volunteers who had been taking the antidepressant escitalopram or placebo before psilocybin treatment.

Pretreatment with escitalopram had no relevant effect on positive mood but significantly reduced bad drug effects adverse cardiovascular effects, and other adverse effects of psilocybin compared with placebo pretreatment.

Interestingly, this research speaks towards a possible positive effect of pre-treatment with SSRIs, whilst other studies show a reduced effect after long-term antidepressant use or reduced acute effects (see below) of psychedelics. A possible explanation for the difference is the much shorter (one week versus months or years) time the volunteers took the antidepressant in this study.

6. The serotonin uptake inhibitor citalopram reduces acute cardiovascular and vegetative effects of 3,4-methylenedioxymethamphetamine (‘Ecstasy’) in healthy volunteers

A separate study by Matthias Liechti and colleagues at University Hospital Basel explored the effects of the SSRI citalopram has on the effects of MDMA (105mg/70kg) in 16 healthy volunteers in a double-blind placebo-controlled study. MDMA was found to induce psychological effects including heightened mood, increased self-confidence, and extroversion, to name a few.

These psychological effects were markedly reduced by citalopram. These findings suggest that activity is associated with the 5-HT uptake site.

7. Discontinuation of medications classified as reuptake inhibitors affects treatment response of MDMA-assisted psychotherapy

MAPS have been making headwind with using MDMA to treat PTSD through various clinical trials which are now in Phase III. In this study, the researchers pooled the results of four Phase II trials (n=50) with MDMA-assisted therapy to explore the effect of tapering antidepressant medication has on treatment outcomes with MDMA.

It was found that recently tapering off SSRIs may reduce treatment response, as measured using the Clinician-Administered PTSD Scale.

8. Human hallucinogen research: guidelines for safety

In this seminal paper, Matthew Johnson and colleagues at Johns Hopkins set out the commonly used guidelines for safety when doing research with psychedelics. It urges researchers to check for (a family history of) psychotic disorders, the need for trust with the monitors, and the risk of an overwhelming trip.

In one section, the researchers discuss how certain medications may affect the psychedelic experience and recommend these individuals do not partake in psychedelic research. The authors state that SSRIs may attenuate the response to psychedelics and in some cases may lead to the development of serotonin syndrome (SS).

9. COMPASS Pathways announces positive outcome of 25mg COMP360 psilocybin therapy as an adjunct to SSRI antidepressants in open-label treatment-resistant depression study

As 2021 came to a close, COMPASS Pathways announced the results of their trial investigating COMP360 (psilocybin) administration in conjunction with SSRI antidepressants. 19 participants were administered a single dose of psilocybin (25mg) in tandem with their existing SSRI antidepressant regimen in this open-label study.

Psilocybin was well-tolerated and the mean reduction in MADRS scores was 14.9 indicating that psilocybin in conjunction with SSRI may be a viable treatment option. However, given that these results are published in a press release, no definitive conclusions can be drawn until the official publication of the results.

10. Chronic administration of serotonergic antidepressants attenuates the subjective effects of LSD in humans

Although science has come a long way since this publication in 1996, it is one of the few to report the effects antidepressants have on the LSD experience. Katherine Bonson and colleagues investigated the effects of the chronic administration of antidepressants on self-administered LSD through structured interviews using a standardized questionnaire in 32 participants.

28 participants who had been taking antidepressants, including SSRIs for over three weeks, reported a subjective decrease or virtual elimination of their responses to LSD. Even in these early stages of psychedelic research, the authors proposed interactions at the 5-HT2 and 5-HT1A receptors as a possible mechanism of action for the attenuated response.


1. Mayo Clinic. (n.d). Selective serotonin reuptake inhibitors. Mayo Clinic.

2. Bielefeldt, A., Danborg, P. B., & Gøtzsche, P. C. (2016). Precursors to suicidality and violence on antidepressants: systematic review of trials in adult healthy volunteers. Journal of the Royal Society of Medicine, 109(10), 381–392.

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