March 20, 2025 by Alex Brewer, PharmD, MBA
TL;DR
- There is concern for combining antidepressants and psychedelics due to similarities in how they work.
- A 50-year old with difficult-to-treat depression underwent psychedelic-assisted psychotherapy (PAP) while continuing treatment with two antidepressants.
- The patient did not experience serious side effects during PAP sessions. But he did develop antidepressant discontinuation symptoms, which may have worsened his depression symptoms.
Medical literature comprises a wide variety of different types of publications. Primary sources are articles that describe original research. There are different types of study designs. My writing at The Psychedelic Pulse mostly focuses on analytic, experimental clinical studies, which include groups of participants stratified into the “intervention” group (the people who receive the trial medication or substance) and the “control” group (which often, but not always, means they receive a placebo – a substance with no actual action, such as a sugar pill).
But today, I want to discuss a single case report, which is a type of descriptive or non-analytic study.
What is a Case Report?
Today’s study is a case report. A case report is “a detailed report of the symptoms, signs, diagnosis, treatment, and follow-up of an individual patient.” Unlike large clinical trials, case reports come from “real-life” patient cases in “real-life” medical practice. There’s no controlling of variables, and events typically happen over a few hours or days rather than weeks or months.
Case reports are useful because they can provide the spark for new ideas. Often, a case report details a novel or unusual happening. They may pose a question towards current theories or practice standards. They provide an avenue for busy clinicians who don’t have the time or resources for large-scale research to contribute to medical literature. Sometimes, they lead to larger studies years down the road.
Case reports also allow insight into complicated situations that aren’t frequently encountered, and are unlikely to occur in a clinical study. For example, a case report may describe the experience of an 85-year old (many clinical trials do not contain a single patient above 80) with 10+ chronic conditions (many clinical trials exclude participants with certain chronic conditions) taking 20+ medications (many clinical trials exclude participants who take certain medications). Other clinicians working with similar patient populations can use a case report as a guide when they encounter a similarly rare case.
They do have limitations, though. A case report details the experience of a single patient case. Scientists seek universal truths (for example, we’re all governed by the laws of gravity), and one person’s experience should not be assumed to universally apply to all people (a concept many people struggle or outright refuse to accept, but I digress).
So, now that you’re familiar with case reports, let’s discuss today’s study.
What Happened in This Study?
A 50-year old male experiencing difficult-to-treat depression for several years agreed to participate in a trial of psilocybin-assisted psychotherapy (PAP) through Health Canada’s Special Access Program, using 25-milligram (mg) psilocybin doses manufactured by Filament Health. He continued taking the antidepressants duloxetine (at a dose of 60 mg per day) and vortioxetine (20 mg per day dose).
About the Antidepressants
Duloxetine is an antidepressant medication. Specifically, it belongs to a medication class called serotonin and norepinephrine reuptake inhibitors, or SNRIs. It works by blocking reuptake of both serotonin and norepinephrine. “Blocking reuptake” simply means it stops nerve cells from reabsorbing serotonin and norepinephrine, increasing the amount of these neurotransmitters available in the brain.
Vortioxetine is a serotonin modulating antidepressant. Its mechanism of action (how a medication works) isn’t 100% understood. But we believe it boosts the actions of serotonin in the brain. It’s known to inhibit serotonin reuptake, and has other activities at certain serotonin receptors.
First Session
During the first PAP session (no, not a pap smear – quit snickering, I didn’t choose “PAP” as the abbreviation), the only side effect reported by the patient was a mild headache. His blood pressure did increase from 119/77 to 131/93 mm Hg, but this was transient. At his one-week follow-up, improvements were noted across domains rating depression and anxiety symptoms, as well as suicidality.
Second Session
Since he showed a partial response to PAP, he was offered a second session at the same dose. His treatment team also discussed stopping duloxetine and vortioxetine to see if this affected treatment outcomes. He did not want to stop vortioxetine but agreed to stop duloxetine two weeks prior to the session.
Stopping duloxetine led to antidepressant discontinuation symptoms, including fatigue, dizziness, and muscle pain. These continued into the second PAP session, where psilocybin was well-tolerated with no serious side effects (and a less notable blood pressure increase). However, at his one-week follow up, his depression, anxiety, and suicidality ratings all worsened.
Dicussion and Takeaways
Here we run into the issue faced by researchers trying to evaluate the effectiveness of psychedelics in treating depression. If we want to try and isolate the effects of a psychedelic, it’s preferred to have the patient stop using any antidepressant prior to the trial. There are also potential safety concerns to using these treatments together, based on how psychedelics and antidepressants work. Serotonin syndrome is a real concern when more than one serotonergic agent is used.
However, stopping most antidepressants isn’t easy. Antidepressant discontinuation syndrome (ADS) symptoms range from mild to serious. While they often last a few weeks at most, some persist for up to 12 months. In today’s case, the researchers posit that ADS may have contributed to the decline in the patient’s depression symptoms following the second PAP session.
Ideally, the patient in today’s case report would have slowly titrated (decreased) the dose over time until they stopped taking duloxetine entirely. This process can take several weeks, depending on the dose and duration of treatment. And when someone has experienced a mild or good, if not perfect, response to antidepressant treatment, there is risk to stopping treatment. Sometimes, the patient or primary care provider isn’t comfortable with doing so – a reasonable stance, given the risks.
So, how can today’s case report contribute to the literature on medical applications of psychedelics?
The lack of side effects, particularly lack of serious side effects, may encourage other clinicians to run trials allowing patients to continue antidepressants while also undergoing psychedelic-assisted psychotherapy. The results from a case study must be interpreted cautiously, but we’ll likely see studies allowing antidepressant use during psychedelic sessions. Another possibility is allowing patients to continue antidepressant use, but slowly decreasing the dose. This could lower the risk for serotonin syndrome while allowing for possible synergy between the actions of the antidepressant and the psychedelic.