SSRIs and psilocybin both work on serotonin receptors. It’s common practice to tell patients to wean off their SSRIs before beginning psychedelic therapy. This interruption in medication therapy is considered standard practice, but is it necessary?
On May 13th, 2022 we sat down (virtually) with Dr. Erica Zelfand, a family medicine doctor, psychedelic facilitator, and ketamine provider. Dr. Zelfand specializes in functional medicine and integrative mental health, and has been active in our network for several years.
In her early experiences as a primary care provider, Dr. Zelfand noticed that her patients needed more mental health support. She saw that psilocybin could improve mental health outcomes, but that pharmaceutical treatment plans seemed to oppose psychedelic interventions. She wondered if the two could work together to bring patients the best outcomes.
It’s important to note that psychedelics are still illegal in much of the world. We’re in the midst of research that is helping us understand the interactions between medications and psychedelics. While Psychedelic Support is hopeful for the future of psychedelic therapy, we do not encourage people to do anything illegal.
Avenues like psilocybin retreats have made it possible for people to access psychedelic experiences outside of the United States. Dr. Zelfand began with a case study of a patient named Jennifer who attended one of these events.
Psilocybin and Antidepressants: Case Study #1
At 52, Jennifer had battled chronic depression, sleep problems, and anxiety all of her life. With a father in the military, she moved often as a kid. She’d been on a combination of psychiatric medications for more than a decade, but abruptly stopped them in preparation for a psychedelic retreat. These included Aripiprazole (Abilify), Vortioxetine (Trintellix), and Buproprion (Wellbutrin).
Jennifer had profound positive experiences during her psilocybin retreat. She tolerated the mushrooms well and found little to no symptoms of SSRI withdrawal. During her experience, she discovered a repressed memory of being molested as a young child. Yet she left feeling optimistic and healed.
But when she got home, Jennifer found herself in crisis. Despite the positive changes she’d experienced with psilocybin, she was anxious and sad. Her brain felt foggy, and she couldn’t focus. Physically, she couldn’t track with her eyes to read. “I feel like everything that happened in Jamaica was for nothing,” she said.
Dr. Zelfand knew that Jennifer was in a physical crisis as well as a mental one. She was going through an Antidepressant Withdrawal Reaction (AWR). After being on powerful medications for so long, her body was craving antidepressants.
Dr. Zelfand advised Jennifer to go back on her Abilify, and to stabilize on her medication for six months or more before tapering. Within that time, Dr. Zelfand would focus on optimizing her hormonal levels, nutrition, and gut health. They’d consider more psilocybin therapy after four to six weeks after she’d stabilized.
Take a 2-hour online microdosing course with Dr. Zelfand.
What is Serotonin (5-HT)?
Serotonin is a chemical signal that carries information between nerve cells. It’s the basis for how both psychedelics and antidepressants treat mental health problems. Sometimes called 5-HT (for 5-hydroxytryptamine), serotonin is often associated with mood and happiness.
Serotonin also has physiological effects on other cognitive processes, like:
- Memory. People on MDMA and psilocybin may recover memories that had been forgotten.
- Neuroplasticity. This is how the brain repairs and re-wires connections, and depression has a negative effect on these processes over time.
- Sleep. Many people with depression struggle with sleeping too much or too little.
- Cognition. Depression affects people’s ability to pay attention and learn.
- Eating. People with depression may over-eat, or lose their appetite. Certain antidepressants will also increase appetite because of serotonin’s effect on hunger.
- Temperature Regulation. Body temperature normally fluctuates across the day.
- Stress. Mental and physical strain affects our health and can negatively impact us if chronic.
90-95% of the serotonin our bodies produce is made in the gut. This is why nutrition matters in mental health. Probiotics can improve gut health, while antibiotics harm it by killing off good bacteria. Reflux drugs and GI infections also have detrimental effects on gut health, and serotonin.
The neuron is the fundamental unit of the nervous system. Neurons take chemical and electrical impulses to send messages throughout the body. Communication between nerve cells happens at the synapse, a finger-like projection from the neuron. Serotonin is received at the synapse, and the sending neuron can re-uptake, or re-absorb it so that it doesn’t over-stimulate the nerve cell.
Dr. Zelfand spoke about these medication classes for treating depression:
- SSRIs (Selective Serotonin Reuptake Inhibitors) work to partially stop serotonin from being re-uptaken, allowing it to circulate for longer. SSRIs are the most common antidepressants.
- SNRIs (Serotonin-Norepinephrine Reuptake Inhibitors) also work on norepinephrine, which is a stimulating neurotransmitter.
- SPARIs (Serotonin Partial Agonists & Reuptake Inhibitors) prevent reuptake while activating serotonin receptors.
- DNRIs (Dopamine Norepinephrine Reuptake Inhibitors), like Wellbutrin, don’t work on serotonin, but on dopamine and norepinephrine receptors. These help stimulate the nervous system.
Serotonin and SSRIs
Dr. Zelfand explained that in an unmedicated brain, the serotonin is “sucked back up” by the serotonin reuptake channel. SSRIs block this reuptake channel, “like rolling a rock in front of a doorway.” These blockers allow more serotonin to be available for the post-synaptic neuron. SSRIs also work on other neurotransmitter systems indirectly through serotonin.
Inflammation and Depression
Depression and inflammation have been shown to be associated in studies. It’s not clear whether one causes the other, but we believe that the two have evolutionary advantages.
In the acute phase, inflammation helps us heal from broken bones and infections. It helps us repair cells, and mount an immune response to viruses. Inflammation also works on the brain, making us feel less inclined to go out and be social, preventing us from spreading infection. It forces injured people to rest, letting broken limbs heal.
In this way, depression is helpful. But in modern life, depression isn’t in our interest as a species. Unchecked inflammation is associated with mental health conditions like depression, schizophrenia, and Alzheimer’s disease. It’s also associated with physical conditions, like atherosclerosis, rheumatoid arthritis, psoriasis, and type II diabetes.1
SSRIs not only work on serotonin, but inflammation. Psilocybin also has anti-inflammatory effects, which may explain why microdosing helps with depression.
This is the brain’s ability to “rewire” itself. It’s how our brains adapt, change, and compensate in response to new experiences. Physiologically, this looks like growing new neural networks, sprouting healthy nerve endings, reorganizing, and forming new connections. Especially early in life, neuroplasticity is modulated by serotonin.
Depression is the opposite of neuroplasticity. Instead of growing neurons, people with depression may have shrinkage, or atrophy, in the neurons of the prefrontal cortex. Depression is associated with reduced gray matter, as well as neuron size and density. The hippocampus, an area associated with emotion and memory, is smaller in patients with depression.
SSRIs can reverse the changes in gray matter that are associated with depression. They also support neuroplasticity. “People’s brains can really work better on SSRIs and other antidepressant medications.” Dr. Zelfand said.
Psilocybin also has positive effects on neuroplasticity, both in living and lab studies. And there are other ways to support neuroplasticity. Dr. Zelfand emphasizes physical exercise, “the best studied, cheapest medicine”. Other ways to promote neuroplasticity include sleep, intermittent fasting, making artwork, learning, botanical medicine, and ketamine.
Learn the foundations of “trip sitting” with Dr. Zelfand in a 1-hour online course.
Comparing SSRIs and Psilocybin at Serotonin Receptors
5-HT1a receptors are modulated by SSRIs. 5-HT2a receptors are targeted by psilocybin.2
5-HT1a receptors are in the limbic system, which is associated with stress. Stimulation helps us with coping. This means resilience, patience, emotional blunting, and stress tolerance. Basically, it lets us “put up with more”, says Dr. Zelfand.
5-HT2a receptor agonism helps us cope, change and adapt. “Not just bear it, but work through it”, Dr. Zelfand says. This is the change that psilocybin causes, with receptors located not only in the limbic system but throughout the cortex.
Depending on what a person’s goals are, either SSRIs or psilocybin may make more sense.
In the context of treatment, SSRIs alone are tools for coping. They can improve a patient’s tolerance for challenging conditions, but they won’t fix the underlying root cause of stress. SSRIs can protect patients from emotional crises and extreme states of consciousness.
SSRIs may be the best option for patients who are at risk of harm. They can help with sleep problems, and allow people to function in their responsibilities like child care and employment.
Are antidepressant medications “just a crutch?”
Dr. Zelfand answers this stigmatizing question with a comparison: patients who break their leg are often given crutches. In this instance, the patient needs physiological support to let the injured area rest, and spare the leg from repeated injury. This rest period is an essential part of healing and recovery. SSRIs can have this function for patients who are struggling with their mental health.
SSRIs help patients cope with life. Dr. Zelfand emphasized how important it is not to “pill shame” patients who are on SSRIs.
The Window of Tolerance
This idea was developed by Dr. Dan Siegel, Clinical Psychiatry professor. He described this as the zone of arousal where we can function most effectively. In this zone, we can readily receive, process, and integrate information. We can meet the demands of everyday life, and relate to others and ourselves.
People who are struggling with mental and emotional health have a very narrow window of tolerance. Their nervous system may make them feel anxious, angry, out-of-control. On the other hand, people may get spacy, feel numb, or freeze. These are not voluntary responses. They come from the nervous system, and they come from adaptation to stress.3
Therapy, SSRIs, psychedelics, and other healing methods can help patients expand their window of tolerance. These treatments help people expand the amount of stress they can handle in their life.
In some instances, certain antidepressants (like Wellbutrin) can push people into a hyper-aroused state. Microdosing can also cause this. Dr. Zelfand recommends telling someone close to you if you are microdosing. Be sure someone knows what medications you are on, and what substances you are taking.
Are Antidepressants a form of exposure therapy?
One hypothesis is that by mitigating emotional intensity, SSRIs can allow people to tolerate working through challenging emotions. Once patients stabilize from acute crisis, they can then work towards healing. “Healing often happens at the edge of the window”, where patients are safe. In this zone, patients can talk about shame, memories, and emotions.
Psilocybin and Antidepressants: Case Study #2
Sheila was a 72-year-old woman of Ashkenazi Jewish descent, who had struggled with chronic depression. Both her father and brother had struggled with depression. She’d been on Venlafaxine (Effexor) for the past several years before discontinuing. Then her brother died tragically by suicide.
She resumed her medication, then reached out to a psilocybin retreat. Leaders told her that she couldn’t come while on her medication, so she stopped taking her Venlafaxine.
Sheila described her psilocybin experience as challenging. She realized that her depression was “just anger that is so old it has curdled into sadness . . . It won’t let me go.” In her psilocybin experience, she couldn’t break through this sadness. She felt hopeless after her sessions.
In her integration session with Dr. Zelfand, Sheila could work through her anger. Through talk therapy, and physically smashing objects, she said her sadness felt lighter. She didn’t want to get back on her medication and decided to try microdosing next.
Unfortunately, Sheila experienced a major depressive relapse. She experienced suicidality and needed to be hospitalized for treatment. She was put back on her Venlafaxine, and is now stabilizing on her medication. She wants to try another psilocybin experience after stabilizing.
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Psilocybin vs. Escitalopram
In a study published by the New England Journal of Medicine, we got to see a common antidepressant compared with psilocybin. Patients in both groups did well. But in secondary outcomes, psilocybin did better than escitalopram.4
To Dr. Zelfand, this begs the question; must we choose just one medicine?
Another study combined psilocybin and escitalopram. Both placebo and medicated groups went through psilocybin experiences. Afterward, researchers tracked multiple data points including self-ratings, autonomic effects, adverse effects, and more.
They found that escitalopram had no effect on the positive mood benefits of psilocybin. Yet with escitalopram, patients saw fewer adverse reactions like bad drug effects, anxiety, heart events, and more. Escitalopram did not alter psilocybin’s pharmacokinetics. At the end of the study, researchers concluded that “stopping escitalopram before psilocybin administration may not be warranted.”5
This small study can’t be applied to all SSRIs, and escitalopram is only one psychiatric drug. Many patients are on more than one medication. Another fault of this study is that patients are typically on escitalopram long-term, which changes the brain over time. These changes can affect how our brains respond to psilocybin.
SSRIs work to block serotonin reuptake at the synapse. With chronic use, SSRIs change brain chemistry. Serotonin receptors are downregulated, so they aren’t as sensitive and there aren’t as many of them. This downregulation doesn’t just happen with 5-HT1A receptors, but with others as well. In response to SSRIs, our brains adapt and change.
This is why patients may need an increase in SSRI dosage after a few weeks or months of starting an SSRI medication, and these brain adaptations are also why withdrawal happens after discontinuation. The brain needs a chance to make receptors available again. Abruptly stopping SSRIs is “like pulling the rug out from under somebody,” says Dr. Zelfand.
Medicated brains respond differently to psilocybin. Someone who is chronically prescribed SSRIs may not experience the same level of profound effects. They may need more mushrooms to achieve a therapeutic dose. In Dr. Zelfand’s experience, chronic SSRI users require 30-50% higher dosage of psilocybin to achieve a similar effect.
This is a serious drug reaction caused by a build-up of serotonin. This can happen when someone gets too much of one serotonin-affecting medication. It can also happen when a patient is receiving combined medications that affect serotonin. Symptoms resemble infection, and can also mimic the symptoms of psilocybin experiences. These include:
- Increased temperature
- Nausea, vomiting
- Increased heart rate
- High blood pressure
- Twitching or shivering
Serotonin Syndrome is dangerous if it progresses. Watch out for:
- Very high fevers (>40C or 104F)
- Spasmodic jerking, or myoclonus
- Extreme agitation and confusion
- Loss of consciousness and coma
- Arrhythmias, or abnormal heart rhythms
- Any symptoms that last longer than the duration of an average trip
To avoid serotonin syndrome, avoid combining substances that affect serotonin. Here are a few substances that work on 5-HT receptors:
- Certain antidepressants, like SSRIs, SNRIs, TCAs, and MAOIs
- 5-Hydroxytryptophan (5-HTP)
- MDMA (Ecstasy, Molly)
Notice that psilocybin is not on this list. Psilocybin is a classic tryptamine, which means that it only partially stimulates serotonin receptors. They don’t increase serotonin in the synaptic cleft, and don’t activate secondary pathways which are associated with serotonin syndrome.
Serotonin toxicity is very rare with psilocybin . It’s primarily seen in patients taking MAOIs (which are quite rare), and patients who are taking more than one serotonin-affecting medication.
Discontinuing Antidepressants: Case Study #3
Roger was a 38-year-old man with a history of depression, anxiety, and panic attacks. He was going through a divorce, and was currently medicated on Fluoxetine and Buproprion.
Roger attended a psilocybin retreat that Dr. Zelfand was present for. In preparation, his doctor had taken him off of his SSRI and doubled his Wellbutrin dose. During the retreat, Dr. Zelfand noticed that Roger was angry, argumentative, and very agitated. He was eager to heal, and engaged in group therapy, but it was hard for his care team to know how to help him.
Most commonly, patients taper off of their psychiatric medications too quickly. Tapering over a few months is more associated with success than tapering over a few weeks. Dr. Zelfand says that patients taper too quickly, then take ayahuasca and experience a crisis after their ceremony. This makes the ayahuasca ceremony a traumatic event, rather than a therapeutic experience.
Guidelines for Tapering Psychiatric Medications
Dr. Zelfand advises tapering one medication at a time if you are on several. Aim for about 10% in dose reduction every 2-3 weeks. Here are a few more of her tips on tapering:
- SSRIs typically require at least 2-4 months for tapering.
- If you’re noticing more dream recall and more vivid dreams, you can taper more quickly.
- If you notice withdrawal symptoms, you’re tapering too quickly.
- You might consider switching to a similar drug with a longer half-life.
- Even if you’re on a dose smaller than the therapeutic minimum, continue weaning off in small amounts.
Tapering will be more successful if you have a care team, are in supportive housing, and have good support. Dr. Zelfand also recommends tapering patients in the summer, when there’s more sun.
Patients also need balanced blood sugar before tapering, and dietary changes that support gut health. Neither psilocybin or SSRIs can change the whole picture of health. It takes a good lifestyle, nutrition, and support for patients to really get better.
Case Study #4
Judy was a 53-year-old woman with chronic depression and very negative self-talk. She faced challenges with emotional abuse in her childhood. She’s been on citalopram for a few years, and tolerated it well. She chose to stay on her medication for her psilocybin experience.
In Judy’s psilocybin sessions, she needed an increased dosage to experience effects. She had weekly therapy before, during, and after her experiences.
After psilocybin therapy, she can now communicate with her family without getting triggered. She even could reduce the dose of her citalopram.
Summing Up SSRIs and Psilocybin
Dr. Zelfand closed her presentation with these take-aways:
- Anecdotal evidence, along with one recent clinical trial, suggests that it’s safe to combine psilocybin with SSRIs.
- Patients on SSRIs may need 30-50% higher doses of psilocybin for optimal effects.
- From what we know, there is no lethal dose of psilocybin.
- Positive influences on the Window of Tolerance should be leveraged for the best healing outcomes.
- When considering medication discontinuation, we need to consider the risks and benefits.
- Tapering should be done slowly and carefully.
- We should use all the tools at our disposal to meet people’s mental health needs.
Dr. Erica Zelfand is based in Oregon, and you can visit her at DrZelfand.com. She’s also on faculty at InnerTrek, which will be one of the first Oregon-approved facilitators for psilocybin education in the US.
Can patients use microdosing to augment withdrawal symptoms from medications?
Patients who are on medications that affect norepinephrine or dopamine (buproprion, duloxetine) may find that combining these medications with microdosing can be over-stimulating. Dr. Zelfand has had patients find microdosing really helpful. But we don’t yet have clinical evidence that microdosing can help with withdrawal symptoms.
It’s important to note that every psychedelic works differently on the brain. This talk focused on psilocybin, but other substances may interact differently with medications.
Dr. Zelfand encouraged patients to report their personal stories. Even without clinical trials and large research, we can gain understanding through people’s stories.
“If you’re experimenting on yourself, please share your findings. That’s going to help raise the tide for all of the boats. We want your data.” Citizen science will have a large role in psychedelic learning.
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- Miller AH, Raison CL. The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat Rev Immunol. 2016 Jan;16(1):22-34. doi: 10.1038/nri.2015.5. PMID: 26711676; PMCID: PMC5542678.
- Carhart-Harris RL, Nutt DJ. Serotonin and brain function: a tale of two receptors. J Psychopharmacol. 2017 Sep;31(9):1091-1120. doi: 10.1177/0269881117725915. Epub 2017 Aug 31. PMID: 28858536; PMCID: PMC5606297.
- Corrigan FM, Fisher JJ, Nutt DJ. Autonomic dysregulation and the Window of Tolerance model of the effects of complex emotional trauma. J Psychopharmacol. 2011 Jan;25(1):17-25. doi: 10.1177/0269881109354930. Epub 2010 Jan 21. PMID: 20093318.
- Nichols, D. (2021). Faculty opinions recommendation of trial of psilocybin versus escitalopram for depression. Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature. https://doi.org/10.3410/f.739937798.793584706
- Becker, A. M., Holze, F., Grandinetti, T., Klaiber, A., Toedtli, V. E., Kolaczynska, K. E., Duthaler, U., Varghese, N., Eckert, A., Grünblatt, E., & Liechti, M. E. (2021). Acute effects of Psilocybin after escitalopram or placebo pretreatment in a randomized, double‐blind, placebo‐controlled, crossover study in healthy subjects. Clinical Pharmacology & Therapeutics, 111(4), 886–895. https://doi.org/10.1002/cpt.2487
- Sarparast, A., Thomas, K., Malcolm, B. et al. Drug-drug interactions between psychiatric medications and MDMA or psilocybin: a systematic review. Psychopharmacology 239, 1945–1976 (2022). https://doi.org/10.1007/s00213-022-06083-y