Active Agent in 'Magic Mushrooms' May Be Therapeutic

Deborah Brauser

January 24, 2012

January 24, 2012 — A new imaging study supports a growing body of evidence that the hallucinogen psilocybin, the active ingredient in 'magic mushrooms', may have potential in the treatment of depression, anxiety, and possibly cluster headaches.

A study of 30 healthy volunteers showed decreased brain blood flow and venous oxygenation in the cingulate cortex and the medial prefrontal cortex after the participants received intravenous injections of psilocybin.

"We were surprised because we thought that psilocybin was going to increase brain activity in regions like the visual cortex, which would explain the visual changes. But it actually switched off certain areas," coinvestigator David J. Nutt, FMedSci, psychiatrist and professor of neuropsychopharmacology at the Imperial College London, told Medscape Medical News.

"Remarkably, the decreases were localized to important connector hubs in the brain that serve as key junctions for information transfers. Knocking out these key hubs with psilocybin appears to allow information to travel more freely, probably explaining why people's imaginations become more vivid and animated and the world is experienced as unusual," added lead author Robin Carhart-Harris, PhD, also from the Neuropsychopharmacology Unit at Imperial College London.

Dr. Robin Carhart-Harris

He noted that these areas of the brain are known to be overactive in patients with depression and that antidepressants, psychotherapy, and even meditation are used to bring the activity in these regions "back to normal."

Dr. Carhart-Harris said that although the study's results are preliminary and that more research is needed before definitive claims can be made about the therapeutic value of psychedelics, "the initial signs are promising."

The study was published online January 23 in Proceedings of the National Academy of Science.

Growing Body of Evidence

According to the investigators, previous "anecdotal reports" have suggested that psychedelics may be beneficial in reducing symptoms of cluster headaches.

In a recent pilot study published in September 2010 in Archives of General Psychiatry and reported by Medscape Medical News at that time, Charles S. Grob, MD, and colleagues from the University of California, Los Angeles also found that in patients with advanced-stage cancer, psilocybin significantly decreased anxiety compared with placebo. It also decreased the participants' depressive symptoms.

Dr. Charles Grob

"We were able to establish good safety parameters, and no one sustained any psychological or physiological adverse effects. And we also saw some indication of diminished anxiety and improved mood over various points in time," Dr. Grob told Medscape Medical News.

Other studies examining the effects of psilocybin in the treatment of anxiety for patients with cancer are currently underway at Johns Hopkins University and at New York University.

Researchers from Johns Hopkins also recently found that healthy people given psilocybin often describe their experiences as among the most meaningful of their whole lives, comparable to such things as the birth of their first child or getting married, reported Dr. Carhart-Harris.

We wanted to know what is going on in people's brains to produce such profound effects.

"So we wanted to know what is going on in people's brains to produce such profound effects," he said.

Psychedelic State

The current study included 30 healthy adult volunteers who had used "magic mushrooms" in the past but not in the previous 6 weeks. All volunteers participated in 2 site visits at least 14 days apart. In 1 visit, intravenous injections of psilocybin were given; in the other visit, injections of placebo were infused.

Dr. Carhart-Harris explained that intravenous administration of psilocybin was chosen because the onset with that method is "much more rapid" and the duration of effects briefer than when it is administered orally.

Two complementary functional magnetic resonance imaging (fMRI) techniques were used to image brain changes from waking consciousness to a psychedelic state. These were used to measure differences before and after infusions in cerebral blood flow and venous oxygenation.

In the first procedure, 15 of the participants (67% men; mean age, 34.1 years) were scanned using arterial spin labeling perfusion. The other group of 15 volunteers (87% men; mean age, 32 years) underwent blood-oxygen level-dependent (BOLD) fMRIs.

Results showed that in comparison with the participants who received placebo, the participants who underwent arterial spin labeling after receiving psilocybin had significantly decreased blood flow in the subcortical and cortical regions of the brain, especially in the thalamus, anterior cingulate cortex (ACC), medial prefrontal cortex (mPFC), and posterior cingulate cortex (PCC).

Participants who underwent BOLD fMRI scans showed significantly decreased signals in the mPFC, ventral PCC, putamen, and subthalamic nuclei after receiving psilocybin compared with placebo.

Decreased activity in the [ACC/mPFC] was a consistent finding and the magnitude of this decrease predicted the intensity of the subjective effects.

"Decreased activity in the [ACC/mPFC] was a consistent finding and the magnitude of this decrease predicted the intensity of the subjective effects," report the investigators.

No increases in cerebral blood flow or BOLD signal were found in any brain region.

Research Denied

In further "seed-based pharmaco-physiological interaction/functional connectivity analysis," psilocybin use was associated with a significant decrease "in the positive coupling" between the mPFC and PCC regions.

Dr. Carhart-Harris pointed out that these results were found in individuals who had tried psilocybin before.

"This is likely to have biased our results in favor of the positive outcomes. It's also important to emphasize that psychedelic drugs can be harmful if taken in an irresponsible manner, without psychological support."

Nevertheless, he noted that this study, along with others, suggest that people often experience a lifting of mood after taking psilocybin.

"That begs the question: could psilocybin be effective for people with depression? On the back of our biological findings, we have submitted a grant application to support a study that will address this question," said Dr. Carhart-Harris.

"We think that in depression, people are continually overlinking thoughts and ruminations and we think this may help break that link," added Dr. Nutt. "We've also heard case reports that it's been useful in treating obsessive-compulsive disorder, so it would be great if research were to also look at that area too."

Making these drugs illegal…has denied research and possibly patients' benefits for 40 years, and we need to turn that around.

"Making these drugs illegal…has denied research and possibly patients' benefits for 40 years, and we need to turn that around," said Dr. Nutt.

Short-term Drop

Dr. Carhart-Harris said that it is not clear whether all psychedelics have the same neural mechanism, but he speculated that those psychedelics that have been shown to work through the serotonin system, such as lysergic acid diethylamide (LSD) and dimethyltryptamine (DMT), probably do produce similar effects in the brain.

"These investigators were trying to establish what the neurobiological basis might be for the subjective effects and potentially therapeutic value of psilocybin," said Dr. Grob, professor of psychiatry at Harbor-UCLA Medical Center.

"It's a very interesting study using state-of-the-art brain imaging technologies that were not available until recently and finding diminished blood flow in certain areas of the brain, particularly in the [mPFC] and the cingulate cortex," he said.

"They're suggesting that a short-term drop in blood flow in these areas may be a correlate to the subjective effects observed."

Dr. Grob, who was not involved with this research, noted that these findings are different from those reported in a study conducted in the late 1990s by Swiss investigators in which positron emission tomography (PET) was used to evaluate the effects of psilocybin use.

"Using PET, they found some indication in these areas of increased blood flow. So the current investigators are saying their fMRI study may be showing the very initial effect, the short-term effect. But over time it equilibrates, and you then see the increased blood flow."

He added that the finding of a decrease in the hypothalamus was also noteworthy.

"Given that psilocybin and other psychedelics may reduce symptoms of cluster headaches, this is interesting because cluster headaches have been associated with increased hypothalamic cortical blood flow," explained Dr. Grob.

Perhaps we have new evidence here for the underlying neurobiologic substrate of 2 subjective effects of psilocybin: the improvement of mood, and the alleviation of cluster headaches.

"So perhaps we have new evidence here for the underlying neurobiologic substrate of 2 subjective effects of psilocybin: the improvement of mood, and the alleviation of cluster headaches."

Ongoing Stigma

Although Dr. Grob noted that more research is needed, he said that the ongoing stigmatization of psychedelics continues to provide obstacles.

"By the 1960s, psilocybin, LSD, and other drugs had gotten out of the laboratory setting and became particularly appealing to young, adventuresome people who often had no idea how to take these compounds safely. As the situation became seen as a public risk, clinical research with these drugs went dark for several decades," he said.

"Now, I think it's possible for investigators to safely take a fresh look at these compounds to help us understand consciousness and psychopathology, and perhaps to help us develop new and more effective treatment models."

However, he noted that as they are, these compounds could not be used in the clinical setting because they would require specialized training and certification.

"I think over time, and I think it will take a long time to get to that point, if we continue to have some success demonstrating safety and efficacy, then conditions will have to be created where this type of drug could possibly be used by specially trained facilitators," said Dr. Grob.

Decades have elapsed since these drugs were associated with a culture of upheaval. I think it's important to now explore the potential value they may hold in novel treatment paradigms.

"Decades have elapsed since these drugs were associated with a culture of upheaval. I think it's important to now explore the potential value they may hold in novel treatment paradigms."

The study authors and Dr. Grob have disclosed no relevant financial relationships.

PNAS. Published online January 23, 2012. Abstract

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