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Psilocybin for Depression: What You Should Know

Through the power of a mystical experience and new insights, psilocybin for depression may be a more efficient treatment than traditional pharmaceutical methods.

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Updated April 1, 2022

DoubleBlind // Psychedelic Guides

There are hundreds of different types of magic mushrooms out there, but many are united by one common component—psilocybin—the primary psychoactive compound (although not the only one) in some 200 species of ‘shrooms that gives them that “magic” quality. From offering a sense of connectedness with the world to a newfound appreciation for nature, psilocybin can be life changing. In recent scientific history, researchers have also been probing psilocybin’s power to soothe a troubled mind. 

The pace of psychedelic research has ebbed and flowed in the past: A golden era in the Sixties was followed by a drought of new work that lasted decades. However, scientists have now picked up on a thread first identified during those early decades: the idea that psilocybin, in particular, may have lasting effects on depression. 

“I think they were leaning pretty heavily on that history of evidence to re-explore [psychedelics for depression],” says Alan Davis, a professor at Ohio State University’s school of social work and the author of numerous studies on psilocybin and depression. “However, more recently, there’s been a lot of advances.”

In the past few years, scientists have conducted various clinical trials, and used new techniques to map the drug’s effects on the brain. Here’s what they’ve discovered so far: 

Effects of Shrooms

Two psilocybin mushrooms

Psilocybin use has been linked to euphoria, heightened mood, visual hallucinations, or a change in the perception of time. Often, users also report a renewed sense of connection to the world around them. 

In one small clinical trial of twenty patients, 94 percent reported two major changes in their emotions upon taking psilocybin. They moved from feeling disconnected from themselves or others to feeling a heightened sense of connectedness. They also reported less avoidance of emotions, and more acceptance of their own feelings. 

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“People have these deeply meaningful, sometimes spiritual, sometimes insightful effects that seem to have meaning in their lives,” Davis explains. “They can help them move forward in a different way, then they experienced before.”

These experiences are often extremely powerful. One 2006 survey of 30 people who experienced psilocybin for the first time found that two thirds of respondents rated their trips as one of the top-five most meaningful experiences of their lives. 

Read: How to Take Shrooms

Reviews of studies on psilocybin suggest that there’s low risk of addiction, and no evidence of physiologically toxic overdoses; the most common side effect, says Davis, is a headache. That’s not to say there are no reports of harm. Occasionally, people on psilocybin experience panic attacks, difficult emotions, or the so-called “bad trip,” which in the worst of cases may result in psychosis or “spiritual emergency.” Those with underlying mental health conditions, especially schizophrenia, may want to avoid psychedelics altogether or proceed with the utmost caution.   

Those bad trips can be truly anxiety-inducing: 39 percent of 1,993 psilocybin users who had experienced bad trips rated them as one of the top five most challenging experiences of their lives. 

That’s why researchers who study psilocybin’s approach to conditions like depression don’t just give people the drug and walk away. They get to know their patients well, ensure physical comfort, and provide social support if needed during the therapy. 

Taken together with therapy, psychedelic experiences tend to be powerful and meaningful. They’re not always positive or pleasant, but they do tend to stick with users. 

“[Psilocybin experiences] are usually up there with other big life events, like the birth of a child, or the death of a loved one,” says Davis. 

Psilocybin for Depression Treatment 

Depression is a blanket term for a very complex disease. It can be the result of trauma, other diagnoses, life events, even weather (about one to two percent of people have a form of depression called seasonal affective disorder). 

Because of this, the array of treatment options will depend a lot on the individual’s needs and experiences, which is why consulting with a therapist or doctor is a good way to move forward. 

That said, the existing treatments for depression usually consist of targeted therapy or medications. Therapists can help identify patterns of thinking that can lead to sustained negative self-talk or self-blame, for instance. Medications, on the other hand, can address neurotransmitters—chemical messengers in the brain—that can change the way you feel. 

One working theory, called the monoamine hypothesis of depression, developed in the 1950s is that depression is, in part, caused by imbalances in neurotransmitters serotonin, norepinephrine and dopamine. Although new research has revealed that depression may be more complicated and involve genetic and environmental factors too, major classes of antidepressants still target those hormones; particularly serotonin, a hormone thought to be involved in active and passive coping with stress and anxiety. 

One common class of antidepressants called serotonin reuptake inhibitors (think: Lexapro) stop neurons in the brain from removing serotonin from the spaces between cells, called synapses. This allows serotonin to persist for longer in between those brain cells, and in doing so helps to strengthen circuits in the brain that regulate mood.

These treatments often require regular use to work, and may take months or weeks to truly show effects. The appeal of psilocybin-based treatments, at least at this early stage, is that psilocybin tends to take effect quickly and have longer-lasting effects on mood and reactions to negative emotions, Davis explains. In other words, a patient could reach a better, stronger, or longer-lasting outcome with psilocybin in a much shorter period of time, without repeated use of the substance. 

Davis’ most recent clinical trial on the effects of major depression and psilocybin published in November 2020 measured the effects of two psilocybin dosing sessions on 24 participants. After the treatment, 54 percent of people in the sample were in complete remission from depression, Davis notes. 

“We’re still working on getting our long-term followup published,” he says. “But we actually followed people for twelve months after the treatment. What we’re starting to see is that for a large proportion of those people, they stayed in remission.” 

In the context of people who experience depression due to end-of-life distress, like a cancer diagnosis, psilocybin-based treatment represents a complete “paradigm shift” says Anthony Bossis, a clinical assistant professor at New York University’s department of psychiatry who has run several trials on psilocybin and palliative care. 

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Rather than managing symptoms through the regular use of antidepressants, psilocybin-based therapy is based around a powerful spiritual experience that patients then learn from and integrate over the course of followup sessions. 

“[In psilocybin-based therapy] that the person takes the medicine once, or maybe twice, but it’s the memories, and the insights from the experience that of course is producing these long term changes,” he explains. “It’s not the biological change that happens over a day or two, or four or five hours, but it’s the memories of the experience itself.”

Psilocybin and Depression: What You Need to Know 

Basket filled with psilocybin mushrooms

At a very basic level, when psilocybin is broken down inside the body, it becomes a molecule called psilocin. Psilocin can also bind to serotonin receptors in the brain, but the effects, as research has shown, go far beyond this simple action. In fact, scientists propose that psilocybin creates a “cascade” of changes in the brain that lead to sustained changes or beliefs—including those that may accompany depression. 

For instance, in 2020 one team of scientists led by Morten Kringelbach at the University of Oxford scanned the brains of nine people who received either a dose of psilocybin or a placebo and created a model of the brain that showed the release of neurotransmitters like serotonin and the activation of brain networks. 

That study revealed that psilocybin appears to “destabilize” some of the individual networks in the brain that function on autopilot during regular life, and replace those patterns with more “global” patterns of activation that affect the whole brain. You might think of it like skiing on a mountain after a fresh snow: Instead of falling into the same ridges time after time, you’re able to carve new pathways through the powder, even if you’re still using the same skis on the same mountain. 

That was just one piece of the puzzle. When Kringlebach and his team changed their model to separate the firing of these newfound networks in the brain from the release of neurotransmitters, they found that they didn’t get that destabilizing effect. 

That, Kringelbach explained, suggests that psilocybin’s effects may arise from changing how the brain communicates and altering the flow of neurotransmitters within the brain itself, but this is still a working theory. 

“Using this model will be crucial for understanding how psilocybin can rebalance neuropsychiatric disorders such as treatment resistant depression and addiction,” Kringlebach explained

More detailed neuroimaging studies will help explain the extent of the “cascade” of effects caused by psychedelics. But Davis has seen some of these changes take place in his patients on a macro-scale. It’s almost like hitting a reset button. 

As part of his clinical trial on depression and psilocybin published in November 2020, Davis and his team also collected images of the participants’ brains before and after psilocybin therapy. They noticed that those who suffered from depression also had heightened levels of activity in the amygdala, an area of the brain that helps process emotions like fear, or anxiety. 

“For people who are depressed, this part of the brain overreacts to negative emotional information,” Davis explains. “What we found in this study is that that part of the brain after psilocybin therapy did not respond as strongly to negative emotional information. And so that was related to the antidepressant effects of the drug.” 

Psilocybin Therapy: How to Do Psilocybin for Depression 

There are currently no psilocybin-based drugs approved for depression. That means, for now, psilocybin-based therapy is administered as part of clinical trials. Those clinical trials are done in very specific ways to ensure that patients get the most out of the experience. 

Therapists will often take a “supportive therapy” approach. Before ever receiving a dose of psilocybin in a trial, patients will spend eight to ten hours speaking with researchers or clinicians. They might discuss life history, why they enrolled in the study, and, as Davis explains, the team will work to truly “understand their depression.”

From there, patients might do a dry-run of the dosing session sans-psilocybin. They’ll lie down on a couch, put on a blindfold and listen to calming music. The dosing session will then happen in that exact setting, and the acute effects can last about four to six hours. 

The idea is to have an extremely “inward” experience as Bossis points out.

From offering a sense of connectedness with the world to a newfound appreciation for nature, psilocybin for depression may be a life changing treatment. In recent scientific history, researchers have been probing psilocybin’s potential to soothe a troubled mind. 

That’s not to say that there is no interaction at all during a psilocybin-based experience. Sometimes, people will want to move or talk as they experience physical and emotional effects of the trip, says Davis. But even in that case, the therapist will only provide support if the patient says they want it. 

“We’re not going to force an interaction,” says Davis. “The guide’s purpose during a psilocybin session is to be there, to be supportive, and if it’s needed, attend to any physical or emotional needs.” 

The critical part of psilocybin based therapy actually occurs after the acute effects of the drug (like the trip) are over. This stage is called integration therapy, and can last weeks or months. But it’s an opportunity for the patient to talk about what they experienced during their trip, and discuss how to use the lessons learned in their lives going forward. 

The integration of guided therapy alongside psilocybin-based therapy is one major way the field has moved forward since the 1960s, Bossis explains. After the experience, a therapist that has taken the time to get to know the patient can show them how to integrate lessons learned from that experience. 

“Let’s say they involve forgiving others,” Bossis says. “If that person is still living, the person can go out and actually practice that forgiveness and address those relationships.” 

Psilocybin Depression Studies 

Major clinical trials on psilocybin and depression have covered patients who develop depression after receiving a cancer diagnosis, people who suffer from treatment resistant depression, and most recently, a study of people who suffer from major depression—one of the most common mood disorders in the US. 

“Those are the three different types of depression that might have been examined, and all showed pretty similar results in terms of psilocybin therapy, effectively reducing depression in a lot of people in the studies,” he says. 

That’s not to say that psilocybin research doesn’t face challenges. 

Psychedelic trials have historically been limited to very few types of people. For instance, a review of 18 studies on psychedelic-assisted therapy between 1993 and 2017 found that 82.3 percent of participants were white. This suggests that minorities have historically been underrepresented in psychedelic medicine research. The November 2020 randomized clinical trial on major depression was also mostly composed of white participants, the study authors note. 

Read: Why Taking Psychedelics While on Antidepressants Could Make Treatment Ineffective

Psilocybin studies can also be tricky to design. The gold standard in medicine is a double blind randomized controlled clinical trial where scientists can compare the effect of a treatment on one group to people who got a convincing enough sham treatment to rule out a placebo effect. And, no one knows who gets what until the trial is over. 

The issue with psilocybin studies is that it’s fairly easy to tell who gets the control and who gets the placebo based on the powerful experiences psilocybin creates. 

That’s why scientists have searched for an “active” placebo (one that has some effect) to use in psilocybin studies. As of now, that active placebo is often niacin—a B vitamin. For instance, one major multi-site trial of psilocybin on 80 depression patients (large for a psychedelics trial) is using niacin as their active placebo. In large doses, it can cause an intense “flushing” sensation in the face. 

The other option is to use a slightly different trial design. For instance, Davis’ most recent trial didn’t include a placebo group. Instead scientists used a “wait-list control,” which means that they compared the effects of the therapy to the untreated people who were on a wait-list to participate in the study. 

“We need to test this in a placebo controlled multi site trial with hundreds of participants in order for the FDA to have the data they need to make this available,” Davis says. 

Just because these trials don’t check all of the gold standard boxes, it doesn’t mean the research isn’t valid or even quite powerful. These trials can provide critical safety data, Bossis points out, and may be one more factor that leads to the potential descheduling of psilocybin. 

At the moment, the psilocybin is still classified as a schedule I drug, which means, in the eyes of the United States Drug Enforcement Agency it has “no currently accepted medical use” and high potential for abuse. That said, the FDA has granted breakthrough therapy status to both Usona Institute and Compass Pathways, as both are now on the FDA “fast track” to develop psilocybin therapy for the treatment of depression. 

Psilocybin Dosage

The psilocybin dosages used in clinical trials are usually on the high side, Davis explains. That’s because the effects of psilocybin on depression seem to be related to its acute effects, including the meaningful spiritual experiences people report after during psilocybin treatments.

One recent study may also speak to both the importance of psilocybin dosage and the importance of conducting placebo-controlled trials. In a study released in the journal eLife, 191 people were allowed to randomize themselves—which means that each time they microdosed, they took a pill from an envelope that either contained a placebo or a microdose of a psychedelic (23 percent of people in the study received psilocybin microdoses). 

Some groups received all placebos or all microdoses, but about one third of participants received half placebos and half microdoses, which were scattered randomly in envelopes the participants opened before each session.

When the team looked at how people within groups felt after four weeks of this regimen, they found that people, in general, reported better well-being, mindfulness, and life satisfaction compared to before they started taking pills. 

However, there were no differences between those who had been taking placebos, and those who had been taking microdoses. (Many people couldn’t believe they had actually gotten placebos. As one participant put it, “I’m quite astonished…It seems I was able to generate a powerful ‘altered consciousness’ experience based only the expectation around the possibility of a microdose.”)

In short, the authors argued that if people do feel significant changes as a result of microdosing psychedelics, it’s possible a placebo effect is at work as well. 

Importantly, the sample in this study were generally healthy: Most had no history of mental health problems. Because of this, the authors cautioned not to take their study as clinical evidence, but it does suggest that, when it comes to psilocybin dosing, especially in the microdose area, there’s still a lot of science left to do. 

End-of-Life Distress: Psilocybin for Depression and Anxiety 

End-of-life distress has been one particularly powerful arena for psilocybin research. As Bossis explains, psilocybin therapy represents a shift in how depression or anxiety about dying is actually managed. 

Typically, you might use antidepressants or therapy to manage symptoms or distress about 

death. Psilocybin-based therapy is about “leaning in” to these difficult emotions in a very experiential way, and learning from them. “By doing so, it actually transforms their relationship to the end of life, to death itself, to dying,” he says. 

Studies have documented the power these experiences can have. In 2011, scientists at UCLA ran a pilot study on twelve cancer patients who had advanced stage cancer, and confirmed cases of anxiety over the nature of their disease. They were told they would receive one dose of psilocybin and one of niacin (but weren’t told when they were getting each one). The patients reported long-term reductions in their anxiety, depression and existential dread. 

This study only scratched the surface. In one of Bossis’ particularly noteworthy studies done at New York University in 2016, 29 cancer patients were also given one dose of psilocybin or niacin. Just one day after their psychedelic experiences, 80 percent of these patients no longer met the criteria for depression related to their cancers, and anti-depressant effects were still observed about 6.5 months later. 

In the intervening years, Bossis says there haven’t been many new studies on end-of-life distress and psilocybin, though some patients in Canada have been granted the “right to try” magic mushrooms to help cope with terminal illness. But as far as organized research goes, he’s hoping that will change in the near future. 

“I hope very much within the decade that psilocybin is rescheduled and end-of-life distress is a clinical application for it,” he says. 

The Future of Psilocybin and Depression 

Psilocybin mushroom

Interest in psilocybin-based treatments for depression is soaring, both in the lab and in the greater world. For instance, Compass Pathways 2018 clinical trial on treatment resistant depression was one major reason the FDA granted psilocybin “breakthrough status” meaning that applications to develop drugs based on it might get expedited approval. 

During the 2020 election, Orgeon voted to legalize psilocybin in a therapeutic context. Those over 21, in theory, would be able to consume psilocybin with a state-licensed therapist (though this policy may not go into effect until 2023). 

It’s a sign of a greater acceptance of psilocybin as medicine. However, Davis cautions that it might act as a double-edged sword. Though research into psilocybin is progressing, those large clinical trials have yet to be done. Setting up a trial site in Oregon, at this point, he says might be “a little bit risky.”

“It’s a little bit concerning, from a research perspective, because, you know, we’re currently in the process of doing multi site trials to get FDA approval for this treatment,” he says. 

That’s not to say that psilocybin doesn’t have a good safety profile, and hasn’t already helped people within the trial setting. Within the decade, Bossis hopes that we might see it descheduled, allowing research to truly flourish.

“I think these drugs are really meaning-making- medicine, and they’re going to change how we view depression,” he says.

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