Taking Psychedelics While on Antidepressants [Explained]

The following is for informational purposes only. WayofLeaf does NOT advocate the illegal sale, use, or possession of any psychedelics. Be sure to research, understand, and follow all laws and regulations relating to the use and possession of psychedelics in the state or region you live.

Recent research suggests psychedelics could benefit people living with mood disorders, including anxiety and depression. However, these drugs’ illegal status means that some are choosing to self-medicate rather than seeking a doctor’s advice. Many of these people are already receiving treatment and wondering about the safety of taking psychedelics while on antidepressants.

While we do not recommend using any substance, illegal or otherwise, without medical supervision, we do accept that it happens. Therefore, our goal is to provide up-to-date information to help our readers make a safe and informed decision.

So, do antidepressants and psychedelics interact? Let’s take a look.

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Antidepressants and Psychedelics: A Brief Overview

Many psychedelics and antidepressants work by altering the body’s serotonin system. Serotonin is a neurotransmitter that influences brain development, mental processing, perception, and mood. Many experts believe that serotonin deficits contribute to the development of depression, although its precise role is still unclear.


The majority of antidepressants work by increasing serotonin levels in the brain. However, there are many different types of antidepressants and how they do this varies depending on the drug. Some antidepressants also influence other neurotransmitters, such as norepinephrine.

Classic psychedelics, including psilocybin mushrooms, lysergic acid diethylamide (LSD), and N, N-dimethyltryptamine (DMT), also act upon the serotonin system.

However, rather than increasing neurochemical levels, they bind with serotonin receptors (specifically 5HT2A) to induce an altered state of consciousness.

Interestingly, there are some parallels between psychedelics and the evolution of antidepressants. Researchers discovered LSD and serotonin just ten years apart, in 1943 and 1953, respectively. Both were the subject of numerous research studies throughout the 1950s and 60s.

At that time, scientists were just starting to understand the complexities of the human brain and mental health disorders. Psychedelics played a significant role and were the subject of many clinical papers before they became illegal in the 1970s.

The impact of psychedelics on psychiatry was such that Czech psychiatrist Stanislov Grof compared it to the impact of the microscope on biology.

Below is a brief timeline of how antidepressants have evolved since the discovery of LSD:




Albert Hofman accidentally discovers LSD’s psychedelic effects.


Researchers Twarog and Page detect serotonin in the mammalian brain.

1950s – 1960s

The monoamine hypothesis of depression emerges. It suggests that depression results from depleted serotonin, norepinephrine, and dopamine levels in the brain.


Clinical trials investigate the treatment of depression with monoamine oxidase inhibitors (MAOIs). These drugs work by inhibiting the enzymes that break down amine neurotransmitters, including serotonin, norepinephrine, and dopamine. However, safety concerns limit their use.


Imipramine, the first tricyclic antidepressant, receives FDA approval. Tricyclics have a highly complex mechanism of action. In brief, they inhibit serotonin and norepinephrine reuptake by influencing several different receptors and transporters in the brain.


Researchers emphasize the role of serotonin in depression.


The Controlled Substances Act lists psychedelics as Class 1 Substances, seriously hindering research into their potential antidepressant effects.


Scientists develop fluoxetine, the first selective-serotonin reuptake inhibitor (SSRI) antidepressant. SSRIs inhibit the reuptake of serotonin by nerve cells, thus increasing its levels in the brain.


Fluoxetine receives FDA approval. Following this, there is a rapid rise in prescriptions for SSRI antidepressants.


Venlafaxine, a selective serotonin-norepinephrine inhibitor (SNRI) antidepressant, receives FDA approval. SNRIs work similarly to SSRIs but increase norepinephrine as well as serotonin levels.

1990s – present

Scientists review the monoamine hypothesis in an attempt to explain why some patients do not respond to antidepressants. Research into psychedelics for depression resumes, albeit in a limited capacity.

Use of Psychedelics with SSRI Antidepressants

Unfortunately, the answer to the question, “can you take psychedelics on antidepressants?” is not straightforward.

Firstly, there has been little research specifically into combining psychedelics with antidepressants. Therefore, much of what we know relies on anecdotal reports and has no scientific basis.

Secondly, there are many different types of antidepressants and many different psychedelics. Therefore, each combination is likely to interact very differently within the human body.

use of psychedelics with ssri antidepressants

Let’s look at SSRIs as an example, since they are among the most commonly prescribed antidepressants. SSRI antidepressants include:

  • Fluoxetine (Prozac)
  • Sertraline (Zoloft)
  • Citalopram (Celexa)
  • Escitalopram (Lexapro)
  • Paroxetine (Paxil)

First, let’s look at the classic psychedelics: psilocybin, LSD, and DMT. Anecdotal reports suggest that SSRI antidepressants weaken the effects of these substances. Some users state they experience the cerebral effects of the psychedelics but without any visual distortion.

Then there are the phenethylamines, including MDMA and mescaline. When taken with SSRIs, these drugs may have diminished effects.

Since SSRIs appear to dampen psychedelics’ effects, some people might be tempted to use more to compensate. However, this is strongly advised against.

It is also advised against consuming ayahuasca or ibogaine while taking any antidepressants, including SSRIs. Ayahuasca contains natural MAOI substances, making it highly likely to interact with antidepressants. Taking ayahuasca with SSRIs can cause serotonin syndrome. Meanwhile, ibogaine is potentially toxic and dangerous to consume alongside other drugs.

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Other Antidepressant Drugs and Psychedelics

Taking psychedelics with other antidepressant drugs could cause more severe interactions. For example, taking certain psychedelics with lithium or tricyclic antidepressants could cause serious side effects, including seizures.

Furthermore, using MDMA with MAOI antidepressants could cause serotonin syndrome, a potentially fatal disorder. Ayahuasca also carries a high risk of serotonin syndrome if taken with other drugs.

other antidepressant drugs and psychedelics

The symptoms of serotonin syndrome are highly variable, and can include:

  • Agitation
  • Anxiety
  • Restlessness or excitement
  • Disorientation
  • Tremors
  • Muscle spasms or twitching
  • Altered reflexes
  • High blood pressure
  • Rapid or irregular heart rate
  • Rapid breathing
  • High body temperature
  • Flushed skin
  • Sweating
  • Dilated pupils
  • Vomiting
  • Diarrhea

If these symptoms occur after taking psychedelics with antidepressants, seek medical attention immediately. If possible, bring samples of both substances to help medical staff provide the appropriate treatment as quickly as possible.

In short, for any readers wondering, “can I take psychedelics while on antidepressants?,” we urge extreme caution.

The only psychedelic in which concurrent use of antidepressant medication is recommended is ketamine. The FDA-approved prescription drug Spravato (esketamine) is a nasal spray designed for adults with long-term treatment-resistant depression. The spray, which must be prescribed by a doctor, is commonly used in conjunction with an oral antidepressant.

Antidepressants and Psychedelics: Final Thoughts

There is currently no way to be sure whether taking psychedelics with antidepressants is safe. There are many possible combinations of drugs that could all interact in different ways.


Additionally, every individual has unique brain chemistry. Therefore, one person may use psychedelics and antidepressants together without any ill effects. But another individual combining the same drugs might have an extreme adverse reaction.

Anyone determined to try using antidepressants and psychedelics together should seek an understanding and knowledgeable physician for further advice.

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