Psilocybin, a key ingredient in “magic mushrooms,” may help control the symptoms of depression. Photo by Mycellenz/Wikimedia Commons
With as many as half of those who use prescription medications to manage depression reporting they still experience severe, often debilitating symptoms, researchers are exploring new options for treating the disease.
Finding safe, effective antidepressants is a big priority in the pharmaceutical industry because they are among the most commonly prescribed drugs in the United States — as many as 1 in 10 people take them regularly, according to the Centers for Disease Control and Prevention.
Recently, the focus has been on psychedelic drugs previously considered “recreational,” such as psilocybin, the intoxicating compound found in “magic mushrooms.”
“There are now many ongoing clinical trials to test psychedelics for various disorders, including depression, obsessive-compulsive disorder, substance use disorder and cluster headache,” researcher and psychiatrist Alex Kwan told UPI in an email.
“The formal approval of these compounds as a treatment option will depend on the results of these clinical trials, which are still at least a couple of years away,” said Kwan, an associate professor of psychiatry at Yale University School of Medicine.
Here is a look at why researchers are looking at these drugs and what the data from the early studies is saying.
Scope of the problem
About 5% of people in the United States have been diagnosed with depression, a mood disorder that causes a persistent feeling of sadness and loss of interest in daily activities, according to the National Institute of Mental Health.
And that is only about half of those nationally who take prescription antidepressants, which are also used to treat anxiety, a closely related condition, and attention-deficit hyperactivity disorder, based on CDC and other estimates.
Also called major depressive disorder or clinical depression, the disease affects sufferers’ emotions and their ability to perform day-to-day tasks, and it can cause physical complications, as well, experts say.
A landmark study published in 2007 by The Lancet found that depression causes more severe declines in quality of life and overall health than heart disease, arthritis, asthma and diabetes.
The findings have led researchers to describe depression as more “disabling” than many of these diseases.
The Food and Drug Administration has approved more than 30 prescription medications and other treatments for depression, with dozens more in clinical trials.
This makes depression treatments one of the fastest-growing markets in the pharmaceutical industry, with nearly $19 billion in annual sales, according to industry researcher Biospace.
Although these drugs work well for many people, up to 15% of those who take them see no improvement in their depression symptoms, while up to 40% experience only a partial response, based on the findings of a 2015 study.
A separate study published by PLOS One in April found that antidepressant therapy did not improve overall well-being in people using them.
“There is a worsening mental health crisis fueled by people with depression not responding to existing treatments,” Matthew Johnson, a professor of psychiatry and behavioral sciences at Johns Hopkins University School of Medicine, told UPI in an email.
And it is this “crisis” that has led researchers to explore the use of compounds that have not traditionally been included in the antidepressant class in managing what some have called treatment-resistant depression.
Esketamine, a derivative of ketamine, or “special K,” as it was once known to recreational users, was cleared for use in patients with severe and/or treatment-resistant depression in 2019.
The sedative, which can foster a trance-like state at certain doses, once was a popular drug in the “rave” culture, but it also has been used as an anesthetic.
For depression, the drug marketed as Spravato is believed to act on the prefrontal cortex — the region of the brain that governs the response to stress.
Chronic stress is a common cause of severe depression, according to the National Institute of Mental Health.
In clinical trials, esketamine, which is only available as a nasal spray and must be administered in a doctor’s office, reduced depression symptoms for up to seven days after each dose.
“With the approval of esketamine for depression treatment, great care was taken to minimize the focus on its psychedelic effects,” Johnson said.
“Patients are essentially told to ignore the fact that they might feel different — it’s just a side effect — so, it really wasn’t framed as a psychedelic,” he said.
Another compound found in a well-known psychedelic drug, psilocybin is a naturally occurring hallucinogenic discovered in the late 1950s in mushrooms harvested from Central America, according to the Johns Hopkins Center for Psychedelic and Consciousness Research, where Johnson works.
It has been used for centuries in Indigenous cultures as a means of spiritual exploration, but in depression it may work like conventional antidepressant medications by acting on serotonin, a brain chemical involved in mood.
“I am particularly optimistic about psilocybin because the beneficial effect seems large and, more importantly, seems to last up to several weeks,” Yale’s Kwan said.
“However, getting the correct dosage is important [and] this is difficult to assess in real world [because] the amount of psilocybin can vary greatly in naturally occurring mushrooms,” he said.
A study published by Nature Medicine in April found that psilocybin reduced the symptoms of depression in adults with the disorder.
Meanwhile, ibogaine is another naturally occurring psychedelic found in plants in Africa and elsewhere, according to the Hopkins Center.
The hallucinogen, known colloquially as “toad” or “venom,” has been used in religious rituals for centuries, but it may also be an effective treatment for mental health conditions ranging from depression to substance use disorder, research indicates.
It is believed to help manage depression symptoms by acting on specific transmitters in the brain that govern mood, although this has not been confirmed in clinical studies.
Ibogaine also has been linked with serious side effects, such as irregular heartbeat, which may limit its use in people with mental health disorders, experts say.
Another psychedelic that may help people with severe depression is dimethyltryptamine, which is a key ingredient in ayahuasca, a hallucinogenic brew used in Indigenous cultures South America for centuries.
In a small study with six participants published in 2015, the compound was found to reduce depression symptoms.
Dimethyltryptamine, ibogaine and psilocybin are naturally occurring substances, according to the Hopkins Center, while studies of synthetic psychedelics such as LSD have not had the same results.
For this reason, experts like Kwan strongly caution against using their recreational forms to “self-medicate” if you have depression, particularly since they have yet to be approved for treating the condition because at higher doses they “can exacerbate symptoms in people prone to psychosis” and there may be other safety issues.
“Psychedelics have rapid and powerful effects on perception and mood, within the several hours of administration,” and anyone using them “should be in a controlled setting monitored by medical professionals,” he said.
“There is a risk of someone doing something to get into an accident while on a ‘bad trip’,” Hopkins’ Johnson added.
“In the grand scheme, the frequency of this happening if pretty low, but it absolutely exists and is a reason why this treatment is best done in the context of screening, support monitoring and follow-up care,” he said.
In addition, most research exploring the use of these drugs as treatments for depression have done so in conjunction with psychotherapy, Johnson said.
Studies also need to confirm optimal dosing and safety, Kwan said. Their use in people with depression and other mental health disorders is so new that professional societies have yet to develop treatment guidelines, though the Mental Health Association, for one, is in the process of doing so.
Still, despite their history as “recreational” substances, researchers believe these drugs hold the potential to treat depression in people who fail to respond to prescription medications, assuming their use is approved by the FDA.
“The presence of risks and concerns about encouraging illicit use should not discourage scientific exploration,” Johnson said. “The recreational use is going to continue whether or not we approve appropriate medical uses with safeguards.”
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