Microdosing and Antidepressants: Experts Examine the Risks and Rewards

As the first wave of SSRIs was marketed to Americans at the end of the twentieth century, antidepressants were deemed a miracle. Pharmacologists had been tweaking medication to treat depression since the 1950s, but the FDA approval of fluoxetine (better known as Prozac) in 1987 began a renaissance of sorts for depression treatment. Within two years of the first SSRI (selective serotonin reuptake inhibitor) hitting the market, 2.5 million prescriptions had been filled. 

Prozac’s debut garnered national attention with cover stories in New York Magazine and Newsweek. For many people with depression, these pills offered a light at the end of the tunnel. The medications helped patients cope with the everyday crush of living, and remain an important tool in modern psychiatry. That said, they have never worked for everyone, and even if a person’s depression is well-handled with medication, they might feel weighed down by the considerable side effects. 

If you’re concerned about your own mental health or searching for an alternative to your current treatment, you’ve probably noticed the recent onslaught of media about psilocybin (or “magic”) mushroom trials for depression. Many of those trials are focused on patients who were given large doses of psilocybin, experiencing a full-body psychedelic experience. At the same time, “microdosing” has been gaining hype online. The practice involves taking a very small dose of psychedelics regularly, but not enough to shift you out of this reality. Skip the hallucinations, and get the feel-good benefits. Microdosing is appealing in particular to those seeking improved mood and enhanced focus. 

If you’re starting to wonder whether you’ll soon be able to ditch your pills for ‘shrooms, you’re not alone. Emerging research on mental health benefits from microdosing has yielded cautiously excited conclusions and calls for more studies. However, mixing mushrooms and antidepressants can be very risky, and psychedelic therapy practitioners have long banned the two from overlapping.  

Though mixing medications should never be taken lightly, some experts are starting to shift the debate away from this microdosing vs. antidepressant framework. Meanwhile, many healers are utilizing microdosing as a tool to wean or taper individuals who want to get off of SSRIs.  The answer to “Can I microdose if I’m taking antidepressants?” is still complicated, but research is beginning to catch up. As the psychedelic mental health space expands, conversations are becoming more nuanced on what the real risks of overlapping the two treatments are. 

How do Psychedelics Treat Depression? 

“Is it really the ‘Wonder Drug’ for depression?’ a 1990 Washington Post headline reads. Only two years after Prozac’s splashy debut, intense side effects were beginning to catch people’s notice. Psychiatry has advanced since 1987 and there’s currently a huge variety of available antidepressants on the market, but to date, there hasn’t been a true “wonder drug” for depression. Nothing’s gained as much popular buzz as Prozac until … ‘shrooms. 

A 2022 study from Johns Hopkins attracted headlines for showing that a psilocybin psychedelic experience improved patients’ depression symptoms for up to a year after treatment. About one in 10 Americans over the age of 12 take an antidepressant medication. As exciting research continues to be published on psychedelics and microdosing for mental health, many people suffering from depression are intrigued by the potential for an alternative treatment. 

Dr. Erica Zelfand is a licensed family doctor and psychedelic facilitator in Oregon, where psilocybin mushrooms have been decriminalized and legally regulated for therapeutic work. She is an advocate for treating depression with psilocybin and believes the mental health community needs to examine its assumptions about mixing mushrooms and antidepressants. On a recent webinar with Psychedelic Support, Dr. Zelfand explained in detail the physical effects of psilocybin, and how it can help the body in a depressed state. Depression, she explained, is thought to be connected to the amount of inflammation in the body. In earlier times of history with less medical intervention available, inflammation was triggered by illness or injuries and played a key role in the healing process by mobilizing repair cells. Inflammation in the brain causes depressive symptoms, prompting an injured or sick person to isolate and rest. 

“Depression was actually something that helped us heal,” Dr. Zelfand said. “Nowadays we live a lifestyle that helps drive low-grade inflammation all the time, irritating our brains.” 

Dr. Zelfand also points to neuroplasticity as a hallmark of a healthy brain. Neuroplasticity is the brain’s ability to change itself and adapt to new thinking patterns by physically creating new neural pathways. Depression is associated with an atrophy of nervous system cells in the prefrontal cortex and decreased size and density of neurons in the brain. 

A 2022 study at University of California-San Francisco and Imperial College London compared brain scans of depressed patients treated with psilocybin against a placebo group. Those who had been treated with psilocybin were able to alter their longstanding depressive neural connections, the changes visible on their scans. Scientists could observe a physical transformation in old ways of thinking.  

Microdosing vs. Antidepressants 

The interesting thing about microdosing and antidepressants is that they work – on a physical level – very similarly. According to Dr. Zelfand, both reduce inflammation and promote neuroplasticity by binding to serotonin receptors. The major difference between them is that they attach to different types of serotonin receptors, resulting in different mental effects. 

SSRIs bind to the receptors that make it easier for a person to handle their continuing depressed feelings. These medications allow some space and perspective, for a depressed person to have an easier time with their day-to-day schedule and responsibilities. 

“They are tools for coping,” Dr. Zelfand said of antidepressants. “They typically don’t fix the root cause of somebody’s depression.” The doctor disputes the negative stereotype that antidepressants are a “crutch,” however. 

“Try breaking a leg and walking without a crutch,” she said, explaining that antidepressants can get her patients to a state of stability so they can begin the deeper inner work of understanding past trauma and thought patterns that have contributed to their depression. This inner work, Dr. Zelfand believes, can be revolutionized by psilocybin use. 

Psilocybin works on a slightly different set of receptors, the doctor explained, and instead of helping patients simply cope with their distress, it can help them learn and creatively problem-solve. 

Promising research in the New England Journal of Medicine placed psilocybin and the SSRI escitalopram in a head-to-head contest. The study included a placebo control group as well. The results showed the two treatments provided about the same levels of relief from depression symptoms, and psilocybin was rated slightly better for secondary effects. 

“No serious adverse events were observed in either trial group,” the authors wrote. “The percentage of patients reporting adverse events was similar in the two groups: 26 (87%) in the psilocybin group and 24 (83%) in the escitalopram group.” 

The most common adverse effect of microdosing psilocybin was a headache. 

What are the Risks of Mixing Mushrooms and Antidepressants?

Currently, psilocybin is decriminalized and/or cleared for therapeutic use in a handful of states, and legal internationally in Jamaica, the Bahamas, and Brazil. This means many people are interested in clinics or retreats that have a narrow window of opportunity. Since most facilitators disallow participants from using antidepressants, people choose to quit cold turkey when they have the rare chance to attend therapy or a retreat. Herein lies a lot of risk, Dr. Zelfand said. 

She describes the case of one of her patients, a 52-year-old woman struggling with childhood trauma and depression. The patient had been on three different psychiatric medications for over a decade and quit all three for ten days before her psilocybin retreat in Jamaica. 

The retreat was successful for the patient, and she described feelings of breakthrough. She was not bothered during the retreat by withdrawal symptoms and she was able to experience the positive effects of psilocybin. However, after about two weeks, withdrawal symptoms from those long-standing medications began to affect the patient with a vengeance, and she expressed to the doctor that she felt “all of (her) work in Jamaica was for nothing.” Dr. Zelfand instructed her to begin taking one of her previous antidepressant medications again.

Dr. Zelfand says this patient is now stable, progressing in therapy, and eager to try psilocybin therapy in the future if she can safely. It is cases like this patient that have  Dr. Zelfand and other experts interested in whether the overlap of psilocybin and antidepressants is as dangerous as presumed. 

What is Serotonin syndrome? 

The conventional wisdom behind warnings of mixing psychedelics and antidepressants is that it will cause a toxic overstimulation of serotonin receptors, or “serotonin syndrome.” Serotonin syndrome can be fatal, understandably the psychedelic therapy community has been so cautious when it comes to preventing it. 

Symptoms of serotonin syndrome include

• High body temperature
• Nausea
• Headache
• High blood pressure
• Shivering or twitching

Because the above symptoms are also common, relatively harmless symptoms of psychedelic use, Dr. Zelfand said to look for these key signs if you suspect someone is experiencing serotonin syndrome:

• Very high fever
• Seizure
• Confusion
• Loss of consciousness

How do I prevent serotonin syndrome?

There is evidence that serotonin toxicity is unlikely to occur when using psilocybin mushrooms, specifically. 

“Psilocybin, being a psychedelic partial agonist at the serotonin 5-HT2A receptor, seems to have the lowest risk of any type for serotonin syndrome,” SS. Kelan Thomas, Associate Professor at Touro University California College of Pharmacy, told PsychedlicsOne. He called evidence from case reports that it is dangerous “shaky.” 

Dr. Zelfand warns that the following antidepressants and psychedelics are all extremely risky to combine,since they all work specifically on the same serotonin receptors:

• SSRIs
• SNRIs 
• TCAs 
• MAOIs 
• tramadol, 
• 5-HTP supplements 
• MDMA
• Ayahuasca

Psilocybin is not included on the list because of the difference in the receptors it targets. A recent study has specifically found the combination of the SSRI escitalopram and psilocybin safe. Patients who were given both experienced positive mood effects from psilocybin, and were also less likely to experience negative side effects from the SSRI like anxiety and cardiovascular issues. 

Dr. Zelfand said this study is promising but has some limitations because its subjects were only taking the SSRI for two weeks before psilocybin was introduced. Although the blood levels of medication in a person who had been using an SSRI  for two weeks would be the same as someone who had been on the medication for many years, their brains would not necessarily be similar. Dr. Zelfand estimates that long-term users of SSRIs would need to take between 30-40% more psilocybin to see the same benefits.  

Can I Microdose if I’m Taking Antidepressants? 

The answer is … maybe! That can be disappointing to hear if you’ve been eager to jump on a health trend that seems to be helping people who struggle with the same mental health concerns you do. Taking into consideration your personal medical professional's recommendation is an important step to determining if psychedelic microdosing is right for you. Research on psilocybin microdosing is continuing at a quick pace by the scientific community’s standards, and if you live in a country or state where therapeutic use is legal, you might find a doctor willing to work with you on transitioning from antidepressants to microdosing with minimal risk. 

Dr. Zelfand stresses that a slow taper of antidepressants is much healthier and more effective than a quick taper and that quitting cold turkey will never be worth it, even if it allows you to go to an exciting ayahuasca retreat when you have  vacation time. 

What Can I do in the Meantime?

If you do not have access to professionals in the psychedelic field, trying to DIY a microdosing regimen that doesn’t interact with your current antidepressant is a dangerous path to take. But, there are other actions you can take safely to help reduce inflammation and promote neuroplasticity in your brain. It might sound like an impossible ask if you are struggling with depression, but Dr. Zelfand stresses the importance of physical activity. 

“It’s like a fire hydrant, the amount of data we have on how much physical exercise helps our nervous system and brain health,” she said.

Memory games, yoga, dance, sleep, creating artwork, and learning new skills also help you strengthen, build and change neural pathways. These everyday healthy actions aren’t as exciting as any “miracle drug,” but it is important to remember that with a disorder as complicated as depression, there might never be a clear-cut solution. We can only hope that research on microdosing continues to evolve, and that experts and patients together are free to find the right balance of treatment.