Mindfulness meditation enhances positive effects of psilocybin

October 24, 2019

Science Daily/University of Zurich

Recent years have seen a renewed interest in the clinical application of classic psychedelics in the treatment of depression and anxiety disorders. Researchers of the University of Zurich have now shown that mindfulness meditation can enhance the positive long-term effects of a single dose of psilocybin, which is found in certain mushrooms.

Hallucinogens such as LSD or psilocybin, the active ingredient in "magic mushrooms," alter the perception of those who take them: The boundaries between the self and the world begin to dissolve and feelings of bliss and unity are triggered. Such experiences of self-transcendence and reduced self-focus are similar to those brought about by mindfulness meditation. They can reduce stress, prompt feelings of enduring happiness and increase empathy and altruism. In contrast to this, exaggerated self-focus, recurring negative thoughts and emotions about one's self, and impaired social interactions are characteristic features of psychiatric disorders such as depression.

Enhanced experience of self-transcendence

Researchers at the University Hospital of Psychiatry Zurich have now for the first time examined the potential synergistic effects of combining mindfulness meditation and psilocybin. The scientists recruited 40 meditation experts who were taking part in a five-day mindfulness retreat. In the double-blind study, the participants were administered either a single dose of psilocybin or a placebo on the fourth day of the group retreat. Using various psychometric and neurocognitive measurements, the team of researchers were able to show that mindfulness meditation increased the positive effects of psilocybin, while counteracting possible dysphoric responses to the psychedelic experience. "Psilocybin markedly increased the incidence and intensity of self-transcendence virtually without inducing any anxiety compared to participants who received the placebo," says first author Lukasz Smigielski, who conducted the study directed by UZH professor of psychiatry Franz Vollenweider.

Sustained beneficial effects

At the four-month follow-up, the meditation experts who had been given psilocybin demonstrated more beneficial changes in psychosocial functioning, better self-acceptance and more empathy than the placebo control group. According to Vollenweider, the intensity of self-transcendence experienced during the retreat played a key role for these enduring changes. In a previously published study, he and his team used magnetic resonance imaging to show that experiences of self-transcendence result in lasting changes to neural connections in the brain, and more specifically in the regions that are active when we think about ourselves.

The research group found that besides meditation depth, the participants' openness and optimism were conducive to a positive response to psilocybin. "These factors can help us predict a positive response," says Vollenweider. At the same time, skills that are trained during mindfulness meditation -- such as regulating one's attention and reappraising emotions -- seem to buffer potential negative reactions to psilocybin.

Potential for treating affective disorders

"Our findings shed light on the interplay between pharmacological and extra-pharmacological factors in psychedelic states of mind," says Vollenweider. "They indicate that mindfulness training enhances the positive effects of a single dose of psilocybin, and can increase empathy and permanently reduce ego-centricity. This opens up new therapeutic avenues, for example for the treatment of depression, which is often accompanied by increased self-focus and social deficits."

https://www.sciencedaily.com/releases/2019/10/191024075003.htm

A scientific first: How psychedelics bind to key brain cell receptor

September 17, 2020

Science Daily/University of North Carolina Health Care

For the first time, scientists solved the high-resolution structure of these compounds when they are actively bound to the 5-HT2A serotonin receptor on the surface of brain cells. This discovery is already leading to the exploration of more precise compounds that could eliminate hallucinations but still have strong therapeutic effects. Psilocybin - the psychedelic compound in mushrooms - has already been granted breakthrough status by the FDA to treat depression.

Psychedelic drugs such as LSD, psilocybin, and mescaline cause severe and often long-lasting hallucinations, but they show great potential in treating serious psychiatric conditions, such as major depressive disorder. To fully investigate this potential, scientists need to know how these drugs interact with brain cells at the molecular level to cause their dramatic biological effects. Scientists at UNC-Chapel Hill and Stanford have just taken a big step in that direction.

For the first time, scientists in the UNC lab of Bryan L. Roth, MD, PhD, and the Stanford lab of Georgios Skiniotis, PhD, solved the high-resolution structure of these compounds when they are actively bound to the 5-HT2A serotonin receptor (HTR2A) on the surface of brain cells.

This discovery, published in Cell, is already leading to the exploration of more precise compounds that could eliminate hallucinations but still have strong therapeutic effects. Also, scientists could effectively alter the chemical composition of drugs such as LSD and psilocybin -- the psychedelic compound in mushrooms that has been granted breakthrough status by the FDA to treat depression.

"Millions of people have taken these drugs recreationally, and now they are emerging as therapeutic agents," said co-senior author Bryan L. Roth, MD, PhD, the Michael Hooker Distinguished Professor of Pharmacology at the University of North Carolina School of Medicine. "Gaining this first glimpse of how they act at the molecular level is really important, a key to understanding how they work. Given the remarkable efficacy of psilocybin for depression (in Phase II trials), we are confident our findings will accelerate the discovery of fast-acting antidepressants and potentially new drugs to treat other conditions, such as severe anxiety and substance use disorder."

Scientists believe that activation of HTR2A, which is expressed at very high levels in the human cerebral cortex, is key to the effects of hallucinogenic drugs. "When activated, the receptors cause neurons to fire in an asynchronous and disorganized fashion, putting noise into the brain's system," said Roth, who holds a joint faculty appointment at the UNC Eshelman School of Pharmacy. "We think this is the reason these drugs cause a psychedelic experience. But it isn't at all clear how these drugs exert their therapeutic actions."

In the current study, Roth's lab collaborated with Skiniotis, a structural biologist at the Stanford University School of Medicine. "A combination of several different advances allowed us to do this research," Skiniotis said. "One of these is better, more homogeneous preparations of the receptor proteins. Another is the evolution of cryo-electron microscopy technology, which allows us to view very large complexes without having to crystalize them."

Roth credits co-first author Kuglae Kim, PhD, a postdoctoral fellow in his lab, for steadfastly exploring various experimental methods to purify and stabilize the very delicate serotonin receptors.

"Kuglae was amazing," Roth said. "I'm not exaggerating when I say what he accomplished is among the most difficult things to do. Over three years in a deliberate, iterative, creative process, he was able to modify the serotonin protein slightly so that we could get sufficient quantities of a stable protein to study."

The research team used Kim's work to reveal the first X-ray crystallography structure of LSD bound to HTR2A. Importantly, Stanford investigators then used cryo-EM to uncover images of a prototypical hallucinogen, called 25-CN-NBOH, bound together with the entire receptor complex, including the effector protein Gαq. In the brain, this complex controls the release of neurotransmitters and influences many biological and neurological processes.

The cryo-EM image is like a map of the complex, which Kim used to illustrate the exact structure of HTR2A at the level of amino acids -- the basic building blocks of proteins such as serotonin receptors.

Roth, a psychiatrist and biochemist, leads the Psychoactive Drug Screening Program, funded by the National Institute of Mental Health. This gives his lab access to hallucinogenic drugs for research purposes. Normally, these compounds are difficult to study in the lab because they are regulated by the Drug Enforcement Agency as Schedule 1 drugs.

Roth and colleagues are now applying their findings to structure-based drug discovery for new therapeutics. One of the goals is to discover potential candidates that may be able offer therapeutic benefit without the psychedelic effects.

"The more we understand about how these drugs bind to the receptors, the better we'll understand their signaling properties," Skiniotis says. "This work doesn't give us the whole picture yet, but it's a fairly large piece of the puzzle."

https://www.sciencedaily.com/releases/2020/09/200917181259.htm

Antianxiety and antidepressant effects from a single dose of psychedelic drug persist years later in cancer patients

January 28, 2020

Science Daily/New York University

Following up on their landmark 2016 study, researchers at NYU Grossman School of Medicine found that a one-time, single-dose treatment of psilocybin, a compound found in psychedelic mushrooms, combined with psychotherapy appears to be associated with significant improvements in emotional and existential distress in cancer patients. These effects persisted nearly five years after the drug was administered.

In the original study, published in the Journal of Psychopharmacology, psilocybin produced immediate, substantial, and sustained improvements in anxiety and depression and led to decreases in cancer-related demoralization and hopelessness, improved spiritual well-being, and increased quality of life. At the final 6.5-month follow-up assessment, psilocybin was associated with enduring antianxiety and antidepressant effects. Approximately 60 percent to 80 percent of participants continued with clinically significant reductions in depression or anxiety, sustained benefits in existential distress and quality of life, as well as improved attitudes toward death.

The present study, publishing online Jan. 28 in the same journal, is a long-term follow-up (with assessments at about 3 years and 4.5 years following single-dose psilocybin administration) of a subset of participants from the original trial. The study reports on sustained reductions in anxiety, depression, hopelessness, demoralization, and death anxiety at both follow-up points.

Approximately 60 percent to 80 percent of participants met criteria for clinically significant antidepressant or anxiolytic responses at the 4.5 year follow-up. Participants overwhelmingly (71 to 100 percent) attributed positive life changes to the psilocybin-assisted therapy experience and rated it among the most personally meaningful and spiritually significant experiences of their lives.

"Adding to evidence dating back as early as the 1950s, our findings strongly suggest that psilocybin therapy is a promising means of improving the emotional, psychological, and spiritual well-being of patients with life-threatening cancer," says the 2016 parent study's lead investigator, Stephen Ross, MD, an associate professor of psychiatry in the Department of Psychiatry at NYU Langone Health. "This approach has the potential to produce a paradigm shift in the psychological and existential care of patients with cancer, especially those with terminal illness."

An alternative means of treating cancer-related anxiety and depression is urgently needed, says Ross. According to statistics from several sources, close to 40 percent of the global population will be diagnosed with cancer in their lifetime, with a third of those individuals developing anxiety, depression, and other forms of distress as a result. These conditions, experts say, are associated with poorer quality of life, increased rates of suicide, and lowered survival rate. Unfortunately, conventional pharmacologic treatment methods like antidepressants work for less than half of cancer patients and tend to not work any better than placebos. In addition, they have no effect whatsoever on existential distress and death anxiety, which commonly accompany a cancer diagnosis and are linked to a hastened desire for death and increased suicidality, says Ross.

The researchers say psilocybin may provide a useful tool for enhancing the effectiveness of psychotherapy and ultimately relieving these symptoms. Although the precise mechanisms are not fully understood, experts believe that the drug can make the brain more flexible and receptive to new ideas and thought patterns. In addition, previous research indicates that the drug targets a network of the brain, the default mode network, which becomes activated when we engage in self-reflection and mind wandering, and which helps to create our sense of self and sense of coherent narrative identity. In patients with anxiety and depression, this network becomes hyperactive and is associated with rumination, worry, and rigid thinking. Psilocybin appears to acutely shift activity in this network and helps people to take a more broadened perspective on their behaviors and lives.

How the Original Research and Follow-up Were Conducted

For the original study, the NYU Langone team provided 29 cancer patients with nine psychotherapy sessions, as well a single dose of either psilocybin or an active placebo, niacin, which can produce a physical flush sensation that mimics a psychedelic drug experience. After seven weeks, all participants swapped treatments and were monitored with clinical outcome measures for anxiety, depression, and existential distress, among other factors.

Although researchers found that the treatment's antianxiety and antidepressant qualities persisted 6.5 months after the intervention, little was known of the drug's effectiveness in the long term. The new follow-up study is the longest-spanning exploration of psilocybin's effects on cancer-related psychiatric distress to date, the study authors say.

"These results may shed light on how the positive effects of a single dose of psilocybin persist for so long," says Gabby Agin-Liebes, PhD candidate, lead investigator and lead author of the long-term follow-up study, and co-author of the 2016 parent study. "The drug seems to facilitate a deep, meaningful experience that stays with a person and can fundamentally change his or her mindset and outlook," she says.

Agin-Liebes, who is pursuing her PhD in clinical psychology at Palo Alto University in California, cautions that psilocybin does not inherently lead to positive therapeutic effects when used in isolation, and in uncontrolled, recreational settings, and "should be taken in a controlled and psychologically safe setting, preferably in conjunction with counseling from trained mental health practitioners or facilitators," she adds.

Next, the researchers plan to expand this research with larger trials in patients from diverse socioeconomic and ethnic groups who have advanced cancer-related psychiatric and existential distress.

"This could profoundly transform the psycho-oncologic care of patients with cancer, and importantly could be used in hospice settings to help terminally ill cancer patients approach death with improved emotional and spiritual well-being," says Ross.

https://www.sciencedaily.com/releases/2020/01/200128115423.htm

Reclassification recommendations for drug in 'magic mushrooms'

Reclassification recommendations for drug in 'magic mushrooms'

If phase III clinical trials are successful, researchers suggest categorizing the drug as schedule IV

September 26, 2018

Science Daily/Johns Hopkins Medicine

In an evaluation of the safety and abuse research on the drug in hallucinogenic mushrooms, Johns Hopkins researchers suggest that if it clears phase III clinical trials, psilocybin should be re-categorized from a schedule I drug -- one with no known medical potential -- to a schedule IV drug such as prescription sleep aids, but with tighter control.

 The researchers summarize their analysis in the October print issue of Neuropharmacology.

 "We want to initiate the conversation now as to how to classify psilocybin to facilitate its path to the clinic and minimize logistical hurdles in the future," says Matthew W. Johnson, Ph.D., associate professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine. "We expect these final clearance trials to take place in the next five years or so."

Following the Controlled Substances Act of 1970, any drug with the potential for abuse is categorized based on criteria that take into account whether the drug has accepted medical use, and its safety and the potential for abuse. Although preliminary research studies suggest that psilocybin may be effective for smoking cessation and for disorders such as cancer-specific depression and anxiety, it must clear phase III clinical trials before the Food and Drug Administration can be petitioned to reclassify it.

Studies in animals and humans both show low potential for abuse, the researchers say. When rats push a lever to receive psilocybin, they don't keep pushing the lever like they do for drugs such as cocaine, alcohol or heroin. When it comes to human studies, people who have used psilocybin typically report using it a few times across their lifetime.

As for safety, studies show it frequently falls at the end of the scales with the least harm to users and society, say the researchers. Psilocybin also is lowest in the potential for lethal overdose as there is no known overdose level.

"We should be clear that psilocybin is not without risks of harm, which are greater in recreational than medical settings, but relatively speaking, looking at other drugs both legal and illegal, it comes off as being the least harmful in different surveys and across different countries," says Johnson.

That being said, although psilocybin is relatively less harmful than other drugs and not prone to compulsive abuse, the researchers don't recommend releasing psilocybin into patients' hands even with a prescription. "We believe that the conditions should be tightly controlled and that when taken for a clinical reason, it should be administered in a health care setting monitored by a person trained for that situation," says Johnson. The researchers foresee that the process for psilocybin use in the clinic would be similar to how an anesthesiologist prescribes and administers a drug, minimizing the potential for abuse or harm.

https://www.sciencedaily.com/releases/2018/09/180926082159.htm

'Magic mushrooms' may 'reset' the brains of depressed patients

October 13, 2017

Science Daily/Imperial College London

Patients taking psilocybin to treat depression show reduced symptoms weeks after treatment following a 'reset' of their brain activity.

The findings come from a study in which researchers from Imperial College London used psilocybin -- the psychoactive compound that occurs naturally in magic mushrooms -- to treat a small number of patients with depression in whom conventional treatment had failed.

In a paper, published today in the journal Scientific Reports, the researchers describe patient-reported benefits lasting up to five weeks after treatment, and believe the psychedelic compound may effectively reset the activity of key brain circuits known to play a role in depression.

Comparison of images of patients' brains before and one day after they received the drug treatment revealed changes in brain activity that were associated with marked and lasting reductions in depressive symptoms.

The authors note that while the initial results of the experimental therapy are exciting, they are limited by the small sample size as well as the absence of a control group -- such as a placebo group -- to directly contrast with the patients.

Dr Robin Carhart-Harris, Head of Psychedelic Research at Imperial, who led the study, said: "We have shown for the first time clear changes in brain activity in depressed people treated with psilocybin after failing to respond to conventional treatments.

"Several of our patients described feeling 'reset' after the treatment and often used computer analogies. For example, one said he felt like his brain had been 'defragged' like a computer hard drive, and another said he felt 'rebooted'. Psilocybin may be giving these individuals the temporary 'kick start' they need to break out of their depressive states and these imaging results do tentatively support a 'reset' analogy. Similar brain effects to these have been seen with electroconvulsive therapy."

Over the last decade or so, a number of clinical trials have been conducted into the safety and effectiveness of psychedelics in patients with conditions such as depression and addictions, yielding promising results.

In the recent Imperial trial, the first with psilocybin in depression, 20 patients with treatment-resistant form of the disorder were given two doses of psilocybin (10 mg and 25 mg), with the second dose a week after the first.

Nineteen of these underwent initial brain imaging and then a second scan one day after the high dose treatment. Carhart-Harris and team used two main brain imaging methods to measure changes in blood flow and the crosstalk between brain regions, with patients reporting their depressive symptoms through completing clinical questionnaires.

Immediately following treatment with psilocybin, patients reported a decrease in depressive symptoms -- corresponding with anecdotal reports of an 'after-glow' effect characterised by improvements in mood and stress relief.

Functional MRI imaging revealed reduced blood flow in areas of the brain, including the amygdala, a small, almond-shaped region of the brain known to be involved in processing emotional responses, stress and fear. They also found increased stability in another brain network, previously linked to psilocybin's immediate effects as well as to depression itself.

These findings provide a new window into what happens in the brains of people after they have 'come down' from a psychedelic, where an initial disintegration of brain networks during the drug 'trip', is followed by a re-integration afterwards.

Dr Carhart-Harris explained: "Through collecting these imaging data we have been able to provide a window into the after effects of psilocybin treatment in the brains of patients with chronic depression. Based on what we know from various brain imaging studies with psychedelics, as well as taking heed of what people say about their experiences, it may be that psychedelics do indeed 'reset' the brain networks associated with depression, effectively enabling them to be lifted from the depressed state.

The authors warn that while the initial findings are encouraging, the research is at an early stage and that patients with depression should not attempt to self-medicate, as the team provided a special therapeutic context for the drug experience and things may go awry if the extensive psychological component of the treatment is neglected. They add that future studies will include more robust designs and currently plan to test psilocybin against a leading antidepressant in a trial set to start early next year.

Professor David Nutt, Edmond J. Safra Professor of Neuropsychopharmacology and director of the Neuropsychopharmacology Unit in the Division of Brain Sciences, and senior author of the paper, added: "Larger studies are needed to see if this positive effect can be reproduced in more patients. But these initial findings are exciting and provide another treatment avenue to explore."

https://www.sciencedaily.com/releases/2017/10/171013091018.htm

Hallucinogenic drug psilocybin eases existential anxiety in people with life-threatening cancer

December 1, 2016

Science Daily/Johns Hopkins Medicine

In a small double-blind study, Johns Hopkins researchers report that a substantial majority of people suffering cancer-related anxiety or depression found considerable relief for up to six months from a single large dose of psilocybin -- the active compound in hallucinogenic "magic mushrooms."

The researchers cautioned that the drug was given in tightly controlled conditions in the presence of two clinically trained monitors and said they do not recommend use of the compound outside of such a research or patient care setting.

The Johns Hopkins team released its study results, involving 51 adult patients, concurrently with researchers from New York University Langone Medical Center, who conducted a similarly designed study on 29 participants. Both studies are published in the Journal of Psychopharmacology on Dec. 1.

The Johns Hopkins group reported that psilocybin decreased clinician- and patient-rated depressed mood, anxiety and death anxiety, and increased quality of life, life meaning and optimism. Six months after the final session of treatment, about 80 percent of participants continued to show clinically significant decreases in depressed mood and anxiety, with about 60 percent showing symptom remission into the normal range. Eighty-three percent reported increases in well-being or life satisfaction. Some 67 percent of participants reported the experience as one of the top five meaningful experiences in their lives, and about 70 percent reported the experience as one of the top five spiritually significant lifetime events.

"The most interesting and remarkable finding is that a single dose of psilocybin, which lasts four to six hours, produced enduring decreases in depression and anxiety symptoms, and this may represent a fascinating new model for treating some psychiatric conditions," says Roland Griffiths, Ph.D., professor of behavioral biology in the Departments of Psychiatry and Behavioral Sciences and of Neuroscience at the Johns Hopkins University School of Medicine. He notes that traditional psychotherapy offered to people with cancer, including behavioral therapy and antidepressants, can take weeks or even months, isn't always effective, and in the case of some drugs, such as benzodiazepines, may have addictive and other troubling side effects.

Griffiths says his team's new study grew out of a decade of research at Johns Hopkins on the effects of psilocybin in healthy volunteers, which found that psilocybin can consistently produce positive changes in mood, behavior and spirituality when administered to carefully screened and prepared participants. The study was designed to see if psilocybin could produce similar results in psychologically distressed cancer patients.

"A life-threatening cancer diagnosis can be psychologically challenging, with anxiety and depression as very common symptoms," says Griffiths. "People with this kind of existential anxiety often feel hopeless and are worried about the meaning of life and what happens upon death."

For the study, the investigators recruited 51 participants diagnosed with life-threatening cancers, most of which were recurrent or metastatic. They were chosen from a total of 566 individuals reached through flyers, web advertisements and physician referrals. Most participants had breast, upper digestive, GI, genitourinary or blood cancer, and each had been given a formal psychiatric diagnosis, including an anxiety or depressive disorder.

Half of the participants were female with an average age of 56. Ninety-two percent were white, 4 percent were African-American and 2 percent were Asian.

Each participant had two treatment sessions scheduled five weeks apart, one with a very low psilocybin dose (1 or3 milligrams per 70 kilograms) taken in a capsule and meant to act as a "control" placebo because the dose was too low to produce effects. In the other session, participants received a capsule with what is considered a moderate or high dose (22 or 30 milligrams per 70 kilograms).

To minimize expectancy effects, the participants and the staff members supervising the sessions were told that the participants would receive psilocybin on both sessions, but they did not know that all participants would receive one high and one low dose. Blood pressure and mood were monitored throughout the sessions. Two monitors aided participants during each session, encouraging them to lie down, wear an eye mask, listen to music through headphones and direct their attention on their inner experience. If anxiety or confusion arose, the monitors provided reassurance to the participants.

In addition to experiencing changes in visual perception, emotions and thinking, most participants reported experiences of psychological insight and often profound, deeply meaningful experiences of the interconnectedness of all people.

The researchers assessed each participant's mood, attitude about life, behaviors and spirituality with questionnaires and structured interviews before the first session, seven hours after taking the psilocybin, five weeks after each session and six months after the second session. Immediately after the sessions, participants completed questionnaires assessing changes in visual, auditory and body perceptions; feelings of transcendence; changes in mood; and more.

Structured clinical interviews, such as the Hamilton Depression Rating Scale and the Hamilton Anxiety Rating Scale, and patient questionnaires, like the Beck Depression Inventory and the State-Trait Anxiety Inventory, assessed depression and anxiety. Other questionnaires assessed quality of life, death acceptance, meaningful existence, optimism and spirituality -- generally defined as a search for the meaning of life and a connection to something bigger than one's self. To measure the changes in attitudes, moods and behavior over time, the researchers administered a questionnaire that assessed negative or positive changes in attitudes about life, mood and behavior.

With regard to adverse effects, Griffiths says 15 percent of participants were nauseated or vomited, and one-third of participants experienced some psychological discomfort, such as anxiety or paranoia, after taking the higher dose. One-third of the participants had transient increases in blood pressure. A few participants reported headaches following the session.

"Before beginning the study, it wasn't clear to me that this treatment would be helpful, since cancer patients may experience profound hopelessness in response to their diagnosis, which is often followed by multiple surgeries and prolonged chemotherapy," says Griffiths. "I could imagine that cancer patients would receive psilocybin, look into the existential void and come out even more fearful. However, the positive changes in attitudes, moods and behavior that we documented in healthy volunteers were replicated in cancer patients."

Up to 40 percent of people with cancer suffer from a mood disorder, according to the National Comprehensive Cancer Network.

Anticipating wide interest in the psilocybin research from scientists, clinicians and the public, the journal solicited 11 commentaries to be co-published with the study results written by luminaries in psychiatry, palliative care and drug regulation, including two past presidents of the American Psychiatric Association, a past president of the European College of Neuropsychopharmacology, the former deputy director of the U.S. Office of National Drug Control Policy, and the former head of the U.K. Medicines and Healthcare Products Regulatory Authority. In general, the commentaries were supportive of the research and of using these drugs in a clinical setting as tools for psychiatry.

https://www.sciencedaily.com/releases/2016/12/161201094448.htm

Magic mushroom compound psilocybin could provide new avenue for antidepressant research

May 17, 2016

Science Daily/The Lancet

Psilocybin -- a hallucinogenic compound derived from magic mushrooms -- may offer a possible new avenue for antidepressant research, according to a new study published in The Lancet Psychiatry today.

The small feasibility trial, which involved 12 people with treatment-resistant depression, found that psilocybin was safe and well-tolerated and that, when given alongside supportive therapy, helped reduce symptoms of depression in about half of the participants at 3 months post-treatment. The authors warn that strong conclusions cannot be made about the therapeutic benefits of psilocybin but the findings show that more research in this field is now needed.

"This is the first time that psilocybin has been investigated as a potential treatment for major depression," says lead author Dr Robin Carhart-Harris, Imperial College London, London, UK. "Treatment-resistant depression is common, disabling and extremely difficult to treat. New treatments are urgently needed, and our study shows that psilocybin is a promising area of future research. The results are encouraging and we now need larger trials to understand whether the effects we saw in this study translate into long-term benefits, and to study how psilocybin compares to other current treatments."

Depression is a major public health burden, affecting millions of people worldwide and costing the US alone over $200 billion per year. The most common treatments for depression are cognitive behaviour therapy (CBT) and antidepressants. However, 1 in 5 patients with depression do not respond to any intervention, and many relapse.

"Previous animal and human brain imaging studies have suggested that psilocybin may have effects similar to other antidepressant treatments," says Professor David Nutt, senior author from Imperial College London "Psilocybin targets the serotonin receptors in the brain, just as most antidepressants do, but it has a very different chemical structure to currently available antidepressants and acts faster than traditional antidepressants."

The trial involved 12 patients (6 women, 6 men) with moderate to severe depression (average length of illness was 17.8 years). The patients were classified as having treatment-resistant depression, having previously had two unsuccessful courses of antidepressants (lasting at least 6 weeks). Most (11) had also received some form of psychotherapy. Patients were not included if they had a current or previous psychotic disorder, an immediate family member with a psychotic disorder, history of suicide or mania or current drug or alcohol dependence.

Patients attended two treatment days -- a low (test) dose of psilocybin 10mg oral capsules, and a higher (therapeutic) dose of 25mg a week later. Patients took the capsules while lying down on a ward bed, in a special room with low lighting and music, and two psychiatrists sat either side of the bed. The psychiatrists were present to provide support and check in on patients throughout the process by asking how they were feeling. Patients had an MRI scan the day after the therapeutic dose. They were followed up one day after the first dose, and then at 1, 2, 3, and 5 weeks and 3 months after the second dose.

The psychedelic effects of psilocybin were detectable 30 to 60 minutes after taking the capsules. The psychedelic effect peaked at 2-3 hours, and patients were discharged 6 hours later. No serious side effects were reported, and expected side effects included transient anxiety before or as the psilocybin effects began (all patients), some experienced confusion (9), transient nausea (4) and transient headache (4). Two patients reported mild and transient paranoia.

At 1 week post-treatment, all patients showed some improvement in their symptoms of depression. 8 of the 12 patients (67%) achieved temporary remission. By 3 months, 7 patients (58%) continued to show an improvement in symptoms and 5 of these were still in remission. Five patients showed some degree of relapse.

The patients knew they were receiving psilocybin (an 'open-label' trial) and the effect of psilocybin was not compared with a placebo. The authors also stress that most of the study participants were self-referred meaning they actively sought treatment, and may have expected some effect (5 had previously tried psilocybin before). All patients had agreement from their GP to take part in the trial. They add that patients were carefully screened and given psychological support before, during and after the intervention, and that the study took place in a positive environment. Further research is now needed to tease out the relative influence of these factors on symptoms of depression, and look at how psilocybin compares to placebo and other current treatments.

Writing in a linked Comment, Professor Philip Cowen, MRC Clinical Scientist, University of Oxford, Oxford, UK, says: "The key observation that might eventually justify the use of a drug like psilocybin in treatment-resistant depression is demonstration of sustained benefit in patients who previously have experienced years of symptoms despite conventional treatments, which makes longer-term outcomes particularly important. The data at 3 month follow-up (a comparatively short time in patients with extensive illness duration) are promising but not completely compelling, with about half the group showing significant depressive symptoms. Further follow-ups using detailed qualitative interviews with patients and family could be very helpful in enriching the assessment."

https://www.sciencedaily.com/releases/2016/05/160517083044.htm