Psilocybin is the psychoactive compound in hallucinogenic mushrooms. Humans have used this magic mushroom compound in rituals for thousands of years. The compound alters sensory perceptions and even the sense of self. Medical science has overlooked it until relatively recently, however. A study from Johns Hopkins (JAMA Psychiatry, Nov. 4, 2020) confirms that psilocybin can be helpful in treating major depression. A British study has found that it is as effective as escitalopram (Lexapro) in treating depression (New England Journal of Medicine, April 15, 2021). A study published in Nature Medicine this week helps explain how psilocybin might overcome depression.
A Very Short History of Antidepressants:
Anyone who has ever suffered from a bout of depression knows how devastating it is. You lose your zest for life. You feel empty. When depression lasts for several weeks and is accompanied by feelings of hopelessness and helplessness, it is called MDD (major depressive disorder). Other symptoms include insomnia or sleeping too much, loss of appetite, difficulty concentrating, indecisiveness and/or challenges with remembering simple things. Such a mood disorder requires professional intervention!
Depression destroys the quality of life for tens of millions of Americans. Families are disrupted and sometimes lives are cut short.
A TB Drug vs. Depression:
Antidepressants have been available since the early 1950s. The very first one was discovered by accident. A drug developed to treat tuberculosis, iproniazid, had the unexpected side effect of improving patients’ moods.
This led to a class of medications called MAO inhibitors such as phenelzine (Nardil) and tranylcypromine (Parnate). While these drugs helped ease major depression in some patients, they also had drawbacks. Side effects and food and drug interactions made it hard to use these drugs safely. That said, there is a growing recognition that MAO inhibitors may work when other antidepressants fail.
Since then, the pharmaceutical industry has developed dozens of other antidepressants such as amitriptyline (Elavil), fluoxetine (Prozac) and sertraline (Zoloft). Overall, these drugs work a bit better than placebos for alleviating major depression. However, they are slow to take effect and they also come with their own sets of side effects. You can read about balancing the benefits and risks of antidepressants at this link.
Psilocybin, the Magic Mushroom Ingredient, Against Depression:
Now, an entirely new kind of treatment is being explored by researchers at Johns Hopkins Medicine. Researchers there reported in 2016 that the psychedelic agent psilocybin could ease the existential despair of people who had been diagnosed with a life-threatening cancer (Journal of Psychopharmacology, Nov. 30, 2016). More than 80 percent of the volunteers for this study reported greater life satisfaction and lower death anxiety.
The research team has tested the magic mushroom compound psilocybin against major depression (JAMA Psychiatry, Nov. 4, 2020). The volunteers for this study, who were not on other antidepressants, got two doses of psilocybin. They had significant reductions in the assessments of their depression five weeks and eight weeks after these sessions.
The scientists concluded:
“Findings suggest that psilocybin with therapy is efficacious in treating MDD [major depressive disorder], thus extending the results of previous studies of this intervention in patients with cancer and depression and of a nonrandomized study in patients with treatment-resistant depression.”
This study demonstrated the value of this psychedelic compound when administered in a therapeutic setting with skilled psychological support. A renowned psychiatrist wrote in the accompanying editorial that this research should be followed up with “real-world validation” (JAMA Psychiatry, Nov. 4, 2020).
Psilocybin Compared to Escitalopram for Depression:
As we noted above, antidepressants can take several weeks to kick in against depression. That’s why psychiatrists are interested in psychedelic compounds such as psilocybin derived from mushrooms. Several studies, including four randomized, controlled clinical trials, have reported that two treatments with psilocybin led to improvements in symptoms of depression.
A study conducted by researchers in the Department of Brain Sciences at the Imperial College of London compares psilocybin to a standard antidepressant called escitalopram. It is sold under the brand name Lexapro. After six weeks, both groups reported less depression (New England Journal of Medicine, April 15, 2021). The two treatment groups reported the same amount of benefit. Adverse event rates were similar in both groups, but the psilocybin caused less anxiety, dry mouth or sexual dysfunction.
A Possible Explanation for How Psilocybin from Mushrooms Might Work:
Researchers at the University of California, San Francisco and at Imperial College, London, explain why they undertook this investigation:
“Psilocybin therapy shows antidepressant potential, but its therapeutic actions are not well understood. We assessed the subacute impact of psilocybin on brain function in two clinical trials of depression.”
They recruited patients whose major depression had not responded to standard therapies (Nature Medicine, April 11, 2022). The double-blind trial recruited 59 patients and randomly assigned them to either psilocybin or the antidepressant escitalopram (Lexapro).
The investigators conclude:
“In light of growing evidence for the antidepressant efficacy of psilocybin therapy, the present findings advance our understanding of its possible underlying brain mechanisms.”
Brain imaging revealed changes in connectivity between brain areas amongst the individuals getting psilocybin. No such changes were seen with Lexapro. Rapid symptom relief corresponded to the altered brain circuitry.
One of the researchers summarized:
“For the first time we find that psilocybin works differently from conventional antidepressants – making the brain more flexible and fluid, and less entrenched in the negative thinking patterns associated with depression.”
Some scientists describe this as brain “rewiring.” In other words, people seem to be able to get out of ruminating thought patterns and undue self-focus. And the benefits come on surprisingly fast. Of course no one should try this on their own. Skilled therapists are essential for positive outcomes.
The authors conclude this about Psilocybin from Mushrooms:
“In summary, depression is a major public health problem associated with huge burden and cost. Here, we identify a robust, reliable and potentially specific biomarker of response to psilocybin therapy for depression. Our results may help to explain why psilocybin therapy holds promise as a new treatment option in psychiatry.”
Not the First Time the Magic Mushroom Ingredient Worked for MDD:
A few years ago, two research groups published their findings that psilocybin decreases depression and anxiety in people with life-threatening cancer. (We wrote about those studies here. We also did an interview with Dr. Jeffrey Guss, one of the researchers.) Then a group of British researchers reported that psilocybin may be helpful for some people with hard-to-treat depression ( Neuropharmacology, Nov. 2018).
They used functional MRI imaging to scan the brains of 20 volunteers with resistant depression. During the scans, the subjects were shown pictures of faces with happy, fearful or neutral expressions. Then they had two sessions in which they took psilocybin under controlled conditions, with people present to provide psychological support.
Following the second session the volunteers went through another functional MRI scan. The imaging concentrated on the right amygdala, the brain structure thought to be responsible for emotional processing. Many antidepressants seem to have the effect of dampening emotions. However, psilocybin seemed to increase emotional reactions.
Individuals whose brains responded more strongly to fearful faces were more likely to report improvement in their depression in the following weeks. Thirteen of the subjects were measurably less depressed one day after the experiment finished. Nine of them were still feeling less depressed five weeks later.
The investigators concluded:
“Based on the present results, we propose that psilocybin with psychological support is a treatment approach that potentially revives emotional responsiveness in depression, enabling patients to reconnect with their emotions.”
The overall results suggest that there is still work to do. After all, fewer than half of the volunteers were able to maintain a normal mood for more than a month after the treatment. The researchers acknowledge that the next step is to conduct a randomized controlled trial. They would also like to do comparative research with SSRI-type antidepressants such as fluoxetine.
The Johns Hopkins researchers have now conducted a randomized clinical trial. That’s great, but we want to see comparative data. How does the magic mushroom ingredient psilocybin compare to both traditional antidepressants as well as the newer esketamine (Spravato) nasal spray? You can learn more about this treatment at this link.
Will people suffering from MDD be willing to consider a psychedelic substance in a controlled therapeutic setting? Will psychiatrists and other therapists be willing to contemplate such an unorthodox treatment process?
You can learn more about psilocybin by listening to Show 1084: Psilocybin, Cancer & Spiritual Awakening. You may also find this show of interest:
Show 1188: The Healing Potential of Psychedelic Drugs
For decades, there was no research on the potential uses of psychedelic drugs. Scientists are now starting to explore how these drugs may help.
For more information about depression, you may want to read our eGuide to Dealing with Depression.
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