Psilocybin is the psychoactive compound in hallucinogenic mushrooms. Humans have used this “magic” mushroom compound in rituals for thousands of years. Psilocybin from mushrooms alters sensory perceptions and even the sense of self. A randomized, placebo-controlled, 6-week trial published in JAMA (Aug. 31, 2023) produced surprisingly long-lasting benefit against major depression. How will clinicians and FDA regulators respond to such positive news about psilocybin.
Available Antidepressants Are Less Effective Than You Think:
Health care professionals prescribe a huge number of antidepressants. According to our calculations, more than 36 million people filled 278.5 million prescriptions for drugs like sertraline, escitalopram, bupropion, trazodone, fluoxetine, citalopram and venlafaxine.
How effective are such drugs? Some people get a great deal of benefit. But an article in the Journal of Clinical Psychiatry (Aug. 14, 2023) notes that:
“Over the last 40 years, the response rate to antidepressants in randomized controlled trials has stagnated between 52% and 54%…Extrapolating from clinical trial data, one can surmise that the specific effects of antidepressants convey only about a 10%–20% advantage over the so called nonspecific factors of treatment, including the placebo effect.”
Put plainly, only about half the people in clinical trials get benefit from antidepressant medications. Because many people in such studies respond favorably to placebo pills, the actual difference between antidepressants and sugar pills is often about 10 to 20%. And yet such drugs have received FDA approval despite some serious side effects including suicidal ideation. They can also be hard to stop.
The Latest Research on Psilocybin for Major Depressive Disorder:
Most health professionals and FDA officials react negatively to psychedelic drugs. That, despite positive results from some surprisingly well-conducted studies. It will be interesting to see how the medical community and federal regulators react to the latest research in JAMA (Aug. 31, 2023).
The investigators who participated in this study were from many prestigious institutions ranging from Yale and John Hopkins University School of Medicine to the University of California San Francisco and Emory University School of Medicine.
There were 104 participants ranging in age from 21 to 65 years of age. They were all suffering from major depression.
There were 51 patients who received a single 25 mg dose of psilocybin under careful psychological support. The placebo group received a single 100 mg dose of niacin (vitamin B3), also with psychological support. Neither the clinicians administering the compounds nor the subjects receiving the pills knew who was getting what.
Over the course of the next six weeks the volunteers were tested using the Montgomery-Asberg Depression Rating Scale (MADRS). This is a standardized way to track the severity of psychological depression. Remember, this was a one-dose clinical trial. The individuals did not take a pill every day over the course of the study.
And the envelope please! In their own words the researchers state:
“In this phase 2 study, treatment with a 25-mg dose of psilocybin administered with psychological support was associated with a statistically and clinically significant reduction in depressive symptoms compared with a niacin placebo, assessed as change in total MADRS score and as rates of sustained response.”
In other words, one single pill of psilocybin (25 mg) administered with careful psychological support produced long-lasting positive results:
“Improvements in depression were apparent within 8 days of psilocybin dosing, consistent with a rapid onset of action, and were maintained across the 6-week follow-up period, without attenuation of the effect, and with higher point prevalence rates of MADRS-defined response and remission than has been observed in recent psilocybin studies of TRD [treatment-resistant depression].”
The authors conclude:
“These findings add to evidence that psilocybin—when administered with psychological support—may hold promise as a novel intervention for MDD [major depressive disorder].”
Putting the JAMA Study Into Perspective:
An editorial published in the same issue of JAMA (Aug. 31, 2023) offered these insights:
First, the authors describe antidepressant medications prescribed to tens of millions of patients:
“…psychotropic medications require chronic use, can be difficult to discontinue, and cause a variety of adverse effects, including weight gain, sexual dysfunction, and feelings of sedation or emotional numbing. Symptoms can reappear, even in stabilized patients, when the medications are discontinued, creating a heartbreaking dilemma for patients.”
The editorialists then go on to discuss the psychedelic experience:
“In contrast, psychedelic therapies address the cause of symptoms rather than merely suppressing them. Here, a medication is administered acutely for only a few sessions—sometimes even a single medication session—in the context of a therapeutic framework that provides the opportunity to integrate and synthesize the revelations that occur during the medication session. The acute pharmacological effects of the medicine, including potential adverse effects, resolve quickly and the safety profile is good. Clinically significant response rates are robust and can be maintained for weeks or months.”
Caution About Psilocybin from Mushrooms:
The researchers used synthetic psilocybin. That way they could be sure of the dose. It was administered under very careful psychological support by trained professionals. That is critically important.
Four of the participants who received psilocybin experienced adverse reactions ranging from a headache to a migraine attack. One person experienced a panic attack. The health professionals who wrote the editorial in JAMA state quite clearly that psychedelics are not a panacea for all depressed patients. They are adamant that there are “no silver bullets in psychiatry.” I could not agree more!
That said, psychedelic therapy does represent a completely new way to treat severely depressed patients. For the right individuals under the right conditions, this approach may open a new door to treating major depression. We shall see how the FDA and the profession of psychiatry responds to this clinical trial.
Psilocybin from Mushrooms Can Change Self-Perception:
How does psilocybin from mushrooms actually work? Psychedelics may help people revise their perceptions of themselves to make important changes in their lives.
That’s the conclusion from an analysis of journals by the participants in a 2014 study (Kennedy Institute of Ethics Journal, Dec., 2022). That research showed that incorporating psilocybin with cognitive behavioral therapy sessions helped people quit smoking for many years.
Reviewing the patients’ post-treatment journals revealed that they started to view themselves as nonsmokers. The lead author suggests that developing a new and different sense of self might help people break old unwanted habits. One participant wrote, for example, “I feel that I am somehow fundamentally different to yesterday.”
Previous Research on the Potential Benefits of Psilocybin:
Until relatively recently, scientists had not conducted much research on hallucinogenic compounds. A significant stigma remained from the 1960s. However, a study from Johns Hopkins (JAMA Psychiatry, Nov. 4, 2020) confirmed that psilocybin can be helpful in treating major depression.
A British study found that it is as effective as escitalopram (Lexapro) in treating depression (New England Journal of Medicine, April 15, 2021). Moreover, a study published in Nature Medicine (April 11, 2022) explained how psilocybin from mushrooms 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. Investigators 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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