Treating Severe Depression With Hallucinogenic Drugs

Medically Reviewed By William C. Lloyd III, MD, FACS
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Psilocybin mushrooms growing in magic mushroom breads on an isolated plastic environment being collected by expert hands wearing white latex medical gloves; fungi hallucinogen drug production concept

LSD and magic mushrooms are psychedelic, illegal drugs long used by people seeking to get high. But increasingly today, these and other hallucinogens are being studied as treatments for depression, especially in people who haven't had success from at least two different antidepressant drugs. If you are among the 17 million Americans who suffer from depression—or the 5 million who have severe, treatment-resistant depression—are such drugs an answer for you?

How can hallucinogenic drugs alleviate treatment-resistant depression?

Researchers say some psychedelic drugs appear to work much more quickly than traditional antidepressants—in a matter of hours or days rather than weeks or months—and can "reset" a brain mired in severe depression. For example, a mind-altering drug, esketamine, was approved in 2019 by the FDA (U.S. Food and Drug Administration) to treat treatment-resistant depression, after studies showed it could save lives by rapidly quelling suicidal impulses.


Esketamine, which is delivered by a nasal spray in a doctor's office, is a form of a decades-old anesthetic drug called ketamine, which can produce hallucinations and has an illegal, recreational form called Special K. Ketamine is available as a treatment for depression, often in specialized clinics, where it is administered intravenously under medical supervision.

Other psychedelic drugs are still being studied and are available only as part of clinical trials. Of these, one drug in particular shows promise for treating severe, treatment-resistant depression: psilocybin, the psychoactive compound found in ’magic mushrooms.’


The FDA has twice recognized psilocybin as a potential breakthrough therapy for depression treatment and fast-tracked its study. Compass Pathways, based in London, received this breakthrough therapy designation in 2018 for its research into using a synthetic, pill-based form of psilocybin to reverse treatment-resistant depression. Compass is running a clinical trial involving 216 participants at 20 sites in Europe and North America; results are expected by December 2020.

Last year, the FDA also awarded breakthrough therapy designation to Usona Institute, a Wisconsin nonprofit, for its study of psilocybin to treat major depressive disorder (another term for clinical depression), with results anticipated by February 2021.

In another ongoing study, Imperial College in London's Center for Psychedelic Research is examining how psilocybin's effectiveness compares to that of a common antidepressant, escitalopram (Lexapro). In 2017, the college's researchers found that half of 20 patients with severe treatment-resistant depression who were given psilocybin showed improvement after three weeks, and for some, this effect lasted over a year.

Psilocybin appears to work in the brain by causing the fear center—the amygdala—to quiet down, while increasing communication and interaction in brain circuits that had been slowed by depression. However, the drug has side effects; in addition to the expected hallucinations, people may experience paranoia, dizziness, nausea and vomiting. Taking psilocybin is also time-consuming: a medically supervised psilocybin ‘trip’ also may last four to six hours, a significant investment of patient and therapist time.

Psychedelic drugs may relieve symptoms of depression.

Other hallucinogens are being explored for their ability to treat depression in general. These include LSD (lysergic acid diethylamide, also known as ‘acid’); MDMA (known as ecstasy or molly); DMT (N,N-Dimethyltryptamine) and 5-MeO-DMT. Here's an overview:

  • LSD, which comes from a fungus that infects rye, was first studied for how it could help relieve depression in the 1950s and 1960s. However, its mind-bending, psychedelic trips caused it to rise in popularity among young people, and in 1966 it became illegal, which shut down research into its potential benefits. In recent years, studies have resumed. Researchers in a clinical trial of 60 depressed people at University Hospital in Basel, Switzerland, are exploring its effects on depression, with results expected in 2023. Downsides to LSD include the longer time that patients under the influence must be supervised (six to 16 hours), as well as such side effects as perceptual disturbances, anxiety, and even depression.
  • MDMA is a mood-altering, stimulating drug that has shown mixed results in its use for depression treatment. It has also been studied as a potential treatment for PTSD in combat veterans. Some studies indicate it can alleviate depression, especially as part of clinically supervised research that includes extensive interaction with a therapist (talk therapy). Other studies show it can cause depression, with patients feeling happy for the first few days after treatment, but then swinging from an elevated mood to a depressed one about five days later—an effect that can be long-lasting.
  • DMT is found in many plants and animals, and is a common component of a mind-altering drink called ayahuasca (used for centuries in ritual ceremonies in South America). A 2019 study by researchers at University of California, Davis found microdoses of DMT relieved depression and anxiety in rats.
  • 5-MeO-DMT, chemically different from DMT, is found in the venom of Sonoran Desert toads and in certain plants. In a 2019 study by Johns Hopkins University, 80% of the 362 adult participants who took 5-MeO-DMT said it improved their depression and anxiety. ’Trips’ with this drug only take 30 to 90 minutes, which makes it easier to work into a therapy schedule.

Don't try psychedelic drugs on your own.

Psilocybin has been decriminalized in some areas of the country, such as Oakland, California and Denver, Colorado, while you can find ketamine at IV ketamine clinics. But, it's best to consult your doctor or mental health provider (ideally a psychiatrist or nurse practitioner who can prescribe medicine) before trying these, especially if you have a personal or family history of schizophrenia or bipolar disorder, which could put you at risk for psychotic reactions. Talk with your doctor about the benefits and risks of hallucinogenic drugs based on your circumstances.

Hallucinogenic drugs need to be administered in controlled, medically supervised settings, with highly trained personnel to check on you and treat any side effects. These drugs may show promise, but if taken improperly, they also could be perilous.

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Medical Reviewer: William C. Lloyd III, MD, FACS
Last Review Date: 2020 Jun 2
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