Depression treatment is one of the most robust areas of psychedelic research. A growing number of studies on psychedelics for depression have found that psychedelic-assisted therapy can help treat depression with a high degree of success.

The US Food and Drug Administration (FDA) has approved ketamine for depression treatment. The FDA has also given breakthrough therapy status to psilocybin (the psychedelic compound in magic mushrooms) for treating both major depressive disorder and treatment-resistant depression.

Psychedelics are one of the most promising new treatments for depression. Here’s a closer look at how psychedelic therapy for depression works, what the research says, and how you can take advantage of psychedelics for depression.

Psychedelic therapy for depression

Psychedelic therapy involves working with a licensed therapist while under the influence of a psychedelic drug.

A therapist typically guides you through a standard psychotherapy session. Being under the influence of a psychedelic seems to enhance your ability to make lasting mental and behavioral changes. Psychedelics also seem to make it easier to explore deeply held beliefs and patterns, which can be particularly useful in treating depression. 1

Most research on psychedelics for depression has focused on psilocybin and ketamine/esketamine.

Psilocybin

Psilocybin is the active ingredient in psychedelic mushrooms. It causes a variety of effects, including:

  • Visual hallucinations
  • Euphoria
  • Peacefulness
  • Introspective thinking
  • Time distortion (feeling like time is standing still or moving slowly)
  • Ego death (a sense of being one with the universe; losing your sense of individuality)
  • Derealization (feeling like your surroundings aren’t real)
  • Paranoia
  • Anxiety

In 2018, the FDA granted psilocybin breakthrough therapy status to treat treatment-resistant depression—decreasing regulations so that researchers could conduct research on psilocybin and depression more easily.

In 2019, the FDA extended psilocybin’s breakthrough therapy status to include treatment for major depressive disorder.

Numerous human studies have found that psilocybin-assisted therapy is an effective treatment for depression.2,3 A 2021 study found that psilocybin-assisted therapy was as effective as escitalopram (Lexapro), a common prescription antidepressant, at reducing depression.4 Psilocybin caused no significant side effects, which gives it an advantage over selective serotonin reuptake inhibitor (SSRI) antidepressants like Lexapro, Prozac, and Zoloft.

In addition, psilocybin-assisted therapy seems to cause lasting improvements in depression after only one or two sessions. In 2022, researchers conducted a 12-month follow-up with patients who had moderate to severe depression. The patients had done two sessions of psilocybin therapy a year earlier. Twelve months after their second psilocybin session, 75% of patients had maintained at least a 50% reduction in depression symptoms, and 58% of patients had maintained full remission—they no longer had any symptoms of depression.5

Ketamine and esketamine

Ketamine and its related compound, esketamine, are not technically psychedelics. They’re dissociative anaesthetics. However, ketamine often gets included in conversation about psychedelics because it produces many similar effects, including:

  • Depersonalization (feeling like you’re outside your body)
  • Positive mood>
  • Euphoria
  • Calm
  • Visual hallucinations
  • Auditory hallucinations
  • Introspective thought
  • Detachment from reality

In 2000, researchers began researching ketamine as a way to treat depression; they found that it has strong and fast-acting antidepressant effects.6

Research on ketamine and related compounds continued throughout the years, and in 2019, after nearly two decades of strong research, the FDA approved esketamine, a variant of ketamine, as a way to treat treatment-resistant depression.7

It’s still not entirely clear how ketamine works in the brain. Animal studies suggest that it alters NMDA and glutamate receptors in several different brain regions, which promotes feelings of calm and may contribute to its antidepressant effect. Glutamate in particular may play a role in depression that ketamine helps manage.8, 9

Animal research doesn’t always translate to human research, and the mechanism of ketamine in humans is still unclear. That said, research on ketamine’s antidepressant effects is strong, and in the United States, ketamine is a legal therapy for treatment-resistant depression.

How psychedelics change the brain (and why it helps with depression)

Classical psychedelics (psilocybin, LSD, DMT, and mescaline) all work via your brain’s serotonin system. They bind to a special type of serotonin receptor in your brain called the 5HT2A receptor.

5HT2A receptors influence your sensory perception—vision, hearing, touch, and so on—as well as your mood and sense of self. Research suggests that activating 5HT2A receptors has a direct and immediate antidepressant effect.10

In addition to their direct antidepressant effect, psychedelics also seem to trigger deeper mental shifts that can help treat depression and cause lasting positive change.

A 2020 study suggested that psychedelics decrease your sense of self-identity, which makes it easier to confront negative or frightening thoughts, feelings, and behaviors. You become more willing to explore difficult or harmful parts of yourself, and are more willing to accept corrective information about how to deal with those parts.1 As a result, psychedelics can help you make major positive mental and behavioral changes in a short amount of time, especially under the guidance of a therapist.

Psilocybin also increases global integration across your brain—pulling down boundaries and allowing parts of the brain that usually don’t talk to one another to communicate freely. A 2022 study gave depressed participants psilocybin and found that antidepressant effects closely matched increased global brain integration.3 The researchers concluded that psilocybin makes your brain more flexible and open to change, which is a powerful tool for treating depression.

Does psychedelic microdosing work for depression?

Microdosing involves taking a small amount of a psychedelic—usually between 10-20% of a full dose. Proponents of microdosing claim that it provides a variety of benefits, including improved mood.11

In a 2019 survey study, people self-reported that microdosing psychedelics reduced symptoms of depression.12

However, a 2022 double-blind, placebo-controlled trial found that microdosing was no better than placebo at relieving depression.13

Research on microdosing is still early. It’s not yet clear whether microdosing has benefits for depression, or whether it’s placebo effect.

Can psychedelics replace antidepressants?

While psychedelic-assisted therapy shows promise for treating depression, it’s still in its early stages. At the time of this article’s publication, psychedelic-assisted therapy is federally illegal in the United States, unless you receive it as part of a registered clinical study.

If you currently take antidepressant drugs, do not alter or stop your prescription without the guidance of a doctor. Antidepressants physically alter receptors in your brain, and changing or stopping your antidepressant prescription can cause severe mood swings, anxiety, panic attacks, depression, suicidal thoughts, and insomnia.14, 15

Tapering off antidepressants is a careful science. Tapering usually takes at least four to six weeks and can have disastrous effects if done incorrectly.

If you want to stop taking antidepressants or reduce your antidepressant dose, make sure you work with your doctor to develop a plan.

Do psychedelics interact with antidepressants?

Psychedelics do interact with many antidepressants.

Monoamine oxidase inhibitors (MAOIs) can intensify and prolong the effects of psychedelics, often in unpredictable ways.16 Do not combine psychedelics and MAOI medications.

Common MAOI antidepressants include:

  • Isocarboxazid (Marplan)
  • Phenelzine (Nardil)
  • Selegiline (Emsam)
  • Tranylcypromine (Parnate)

Selective serotonin reuptake inhibitors (SSRIs)do the opposite: they decrease or eliminate your response to psychedelic drugs.17 Avoid combining psychedelics and SSRIs, and do not take higher doses of psychedelics to try to compensate for their decreased effectiveness in the presence of SSRIs.

Common SSRI antidepressants include:

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

Consult your doctor if you have questions about interactions between antidepressants and psychedelics.

Frequently asked questions about psychedelics for depression

What psychedelics are used to treat depression?

The FDA has given psilocybin (the active ingredient in psychedelic mushrooms) breakthrough therapy status for treating major depressive disorder and treatment-resistant depression. It’s undergoing promising clinical trials, but is currently still illegal in the U.S. In 2019, the FDA approved ketamine as a legal therapy for treatment-resistant depression.

Is psychedelic therapy for depression legal?

Esketamine is currently legal as an FDA-approved therapy for treatment-resistant depression. Some doctors also prescribe ketamine off-label as a legal treatment for depression. Psilocybin (the compound in mushrooms) shows promise as a way to treat depression, but it’s still under FDA review and is currently illegal in the United States.

Final thoughts

Psychedelics show a great deal of promise as a way to treat depression. Ketamine and esketamine are both established, legal antidepressant therapies, while psilocybin-assisted therapy is still undergoing clinical trials, with positive results. However, psilocybin is currently federally illegal in the United States.

If you’re interested in taking psychedelics for depression, be aware of the legality surrounding the psychedelic drug you choose, as well as potential risks. Do not take psychedelics for a medical reason without first consulting your doctor.

If you take prescription antidepressants like SSRIs or MAOIs, do not combine them with psychedelics, and do not change your dose or try to use psychedelics to replace your antidepressants. The results can be harmful or even fatal. Talk to your doctor and come up with a plan together.

Ketamine therapy is a powerful new approach to treating depression, and psilocybin-assisted therapy shows promise as an effective way to treat depression long-term with few to no side effects. Psilocybin therapy is currently under review by the FDA; in the coming years, it may become legal as a new way to help those with depression.

References

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  2. Davis AK, Barrett FS, May DG, et al. Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder: A Randomized Clinical Trial. JAMA Psychiatry. 2021;78(5):481-489. doi:10.1001/jamapsychiatry.2020.3285
  3. Daws RE, Timmermann C, Giribaldi B, et al. Increased global integration in the brain after psilocybin therapy for depression. Nat Med. 2022;28(4):844-851. doi:10.1038/s41591-022-01744-z
  4. 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. doi:10.1056/NEJMoa2032994
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