Along with the rise of COVID-19 cases in America throughout 2020 and 2021, an increase in mental health struggles and depression for millions of Americans also occurred. These mental health struggles can be attributed to economic hardships, losing loved ones, and the severe effects of isolation and loneliness on the human psyche, amongst other factors. In 2018, an estimated 7.2% of American adults had a major depressive episode in the past year. 

Psychedelic drugs, such as psilocybin, have recently been looked at in clinical trials representing both academia and the pharmaceutical industry as possible treatments for mental health disorders. Following promising results of these trials, many states are taking notice of the benefits for some groups of patients.

In November 2020, Oregon passed Measure 109, which allows ”the manufacture, delivery, purchase, and consumption of psilocybin, a psychoactive component found in certain mushrooms, at licensed psilocybin service centers. A person would be allowed to consume and experience the effects of psilocybin only at a licensed psilocybin service center during a psilocybin administration session with a licensed psilocybin service facilitator.” This Measure would allow mental health patients the opportunity to legally go through psilocybin-assisted therapy with a licensed therapist in Oregon.  Although these practices will not begin until 2023 at the earliest, it is presumed that other U.S. states will follow Oregon’s lead. From 2015–2018, 13.2% of adults aged 18 and older had used antidepressant medications in the past 30 days. This statistic makes it imperative to address if there are drug interactions between psilocybin and antidepressants.

Antidepressants and Psilocybin

Many healthcare professionals might be concerned that when a patient takes a serotonergic drug, such as psilocybin, while already on a selective serotonin reuptake inhibitor (SSRI), Does this combination put someone at risk for serotonin syndrome?

Serotonin syndrome (SS) is a potentially life-threatening condition caused by the overactivation of serotonergic receptors in the brain. SS is commonly caused by an interaction between two different serotonergic drugs that both upregulate serotonin signaling in the body. Symptoms of SS can include hypomania, myoclonus, akathisia, diarrhea, fever, dilated pupils, shivering, and tachycardia, as well as other serious clinical symptoms. If left untreated, SS can be deadly. 

Since psilocybin also functions by a serotonergic mechanism, it is vital to consider the potential of SS when a patient is considering psychedelic therapy with psilocybin and is or has previously been on SSRIs. While SSRIs are the most commonly prescribed class of antidepressants in the U.S., it is important to note that there are also four other classes of antidepressants on the market. These include serotonin-norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), and atypical agents. 

Here is a list of some of the most commonly prescribed antidepressant medicines:

• SSRIs: block the reuptake of serotonin in the brain
  • Citalopram
  • Escitalopram
  • Fluoxetine
  • Fluvoxamine
  • Paroxetine
  • Sertraline
• SNRIs: block the reuptake of serotonin and norepinephrine
  • Duloxetine
  • Venlafaxine
  • Desvenlafaxine
• TCAs: block the reabsorption of serotonin, norepinephrine, muscarinic M1, histamine H1, and alpha-adrenergic receptors
  • Amitriptyline
  • Clomipramine
  • Desipramine
  • Doxepin
  • Imipramine
  • Nortriptyline
  • Protriptyline
  • Trimipramine
• MAOIs: block the activity of monoamine oxidase, an enzyme that breaks down norepinephrine, serotonin, and dopamine in the brain and other parts of the body
  • Isocarboxazid
  • Phenelzine
  • Selegiline
  • Tranylcypromine
• Atypical antidepressants: Each function by unique mechanisms of action and can affect levels of dopamine, serotonin, and norepinephrine in the brain
  • Bupropion
  • Trazodone
  • Mirtazapine

Relative Risk of Serotonin Syndrome

In July of 2021, Drs. Benjamin Malcolm and Kelan Thomas, both board-certified psychiatric pharmacists, reviewed the serotonin toxicity of serotonergic psychedelics.¹ This review analyzed the likelihood of serotonin syndrome due to interactions between the various classes of antidepressants and psychedelics such as psilocybin. 

Psilocin, the active metabolite of psilocybin, primarily exerts its effects by binding to the serotonin 2A receptor (5-HT_2AR). This activity is distinct from the mechanism of MAOIs, for example, which both exert their action and increase the risk of SS by preventing the body from breaking down serotonin in the synapse. MAOIs are known to increase the risk of SS when combined with other drugs that increase synaptic serotonin, like SSRIs. Because psilocybin does not directly increase serotonin levels, it is not likely to put a patient at increased risk of serotonin syndrome when combined with an MAOI. The review stated that combining psilocybin with acute MAOI use may increase the subjective effects’ duration and/or intensity. However, they further suggested that chronic MAOI use before psilocybin administration would reduce rather than increase the psychedelic effects. 

For the same reasons that combining an MAOI and psilocybin is not likely to increase the risk of SS, Malcolm and Thomas also stated that combining psilocybin and SSRIs present a very low risk of SS. In both cases, there is only one drug in the patient’s body to increase serotonin levels. Combining an MAOI with an SSRI, with or without a psychedelic, posed the most significant risk of SS. The authors did report that some other psychedelics, such as 5-MeO-DMT, lead to increased SS risk when combined with MAOIs. 

Overall, psilocybin was found not to lead to a higher risk of serotonin syndrome when combined with single antidepressants. Nonetheless, most modern clinical studies administering psilocybin ask patients to taper off SSRIs or simply exclude them.  

Tapering off SSRIs

Most psilocybin trials to date required participants to taper off their SSRIs before psilocybin administration. The decision to taper off SSRIs should ultimately be made under the guidance of a medical professional, as the abrupt cessation of SSRIs can result in discontinuation syndrome. Discontinuation syndrome is more profound in those that have used antidepressants long-term and can include flu-like symptoms, anxiety, sleep disturbances, and gastrointestinal pain. 

Tapering off an antidepressant involves slowly lowering the medication dosage in intervals down to half-minimum doses over weeks to months. It is worth noting that tapering schedules will differ between individuals and should be done under the guidance of a medical professional. 

Current trials have recommended discontinuing SSRIs at least two weeks before psilocybin-assisted therapy.² However, it remains unclear whether it is necessary to taper off SSRI medications before dosing psilocybin. 

The most apparent reason for tapering off SSRIs is that chronic SSRI use downregulates 5-HT_2A receptors. These receptor density changes may interfere with the efficacy of psilocybin-assisted therapy and might still be present weeks after discontinuation. It is also unclear whether two weeks is a long enough taper off the SSRI to restore the 5-HT_2A receptor density to baseline levels.

New Research on Interactions between SSRIs and Psilocybin

Emerging studies have further elucidated the details of whether or not to discontinue SSRIs, specifically escitalopram, when beginning psilocybin therapy.

A recent double-blind, randomized controlled trial (RCT) from Robin Cahart-Harris and colleagues compared escitalopram and psilocybin in patients with long-standing, moderate-to-severe major depressive disorder.² The RCT compared two groups: a psilocybin group and an escitalopram group. The psilocybin group received two separate 25 mg doses of psilocybin three weeks apart plus six weeks of daily placebo. The escitalopram group received two 1 mg doses of psilocybin (an active placebo) plus three weeks of 10 mg daily escitalopram followed by three weeks of 20 mg daily escitalopram. Both groups received psychological support during the trial.

Consistent with previous standards for psilocybin trials, patients taking SSRIs prior to the trial were tapered off and stopped at least two weeks before beginning study treatment. In correspondence about the study results, the authors referenced a post-hoc analysis regarding this SSRI discontinuation before psilocybin administration. Though all patients were required to taper off SSRIs before the trial, some had not taken an SSRI before enrollment. The analysis found that among patients in the psilocybin group, there was “greater improvement when there was no pretrial medication to discontinue[…]”^3,4

The conclusion revealed that people who were tapered off escitalopram over two weeks showed decreased efficacy responses to psilocybin therapy compared with patients who were not taking a pre-trial SSRI.² An inference can be made that patients would have a more favorable response to psilocybin if they were either never on SSRIs in the first place or if they were on SSRIs that the taper period was greater than two weeks. 

Concluding Remarks

As psilocybin therapy becomes available in Oregon and potentially in other parts of the United States, along with the possibility of FDA approval, it will be essential to note any interactions with currently approved mental health medications. Safe medication use and reduced risk of drug interactions will be a reason for the utilization of pharmacists as psychedelic-assisted therapy becomes more prominent in the United States. New research continues to arise on interactions between SSRIs and psilocybin. It will be important to consider these results if standardized guidelines are developed for psilocybin-assisted therapy.

References

1. Malcolm B, Thomas K. Serotonin toxicity of serotonergic psychedelics [published online ahead of print, 2021 Jul 12]. Psychopharmacology (Berl). 2021;10.1007/s00213-021-05876-x. https://doi.org/10.1007/s00213-021-05876-x 
2. Carhart-Harris R, Giribaldi B, Watts R, et al. Trial of Psilocybin versus Escitalopram for Depression. N Engl J Med. 2021;384(15):1402-1411. https://doi.org/10.1056/nejmoa2032994 
3. Carhart-Harris R, Blemings A, Nutt DJ. Psilocybin for Depression. Reply. N Engl J Med. 2021;385(9):863-864. https://doi.org/10.1056/nejmc2108082 
4. Carhart-Harris, R. (2021) [Twitter] Aug 27. Available at: https://mobile.twitter.com/RCarhartHarris/status/1431229150900244485 (Accessed: 15 December 2021)

Acknowledgements

Written by Melanie Flores, PharmD 2023 Candidate, OSU/OHSU for the Psychedelic Pharmacists Association with editing by The Psychedelic Pharmacists Association Board of Directors