How psychedelic drug psilocybin works on brain

June 5, 2020

Science Daily/Johns Hopkins Medicine

To see how psychedelics impact the claustrum, a mysterious region of the brain believed to control the ego, researchers compared the brain scans of people after they took psilocybin with their scans after taking a placebo.

Perhaps no region of the brain is more fittingly named than the claustrum, taken from the Latin word for "hidden or shut away." The claustrum is an extremely thin sheet of neurons deep within the cortex, yet it reaches out to every other region of the brain. Its true purpose remains "hidden away" as well, with researchers speculating about many functions. For example, Francis Crick of DNA-discovery fame believed that the claustrum is the seat of consciousness, responsible for awareness and sense of self.

What is known is that this region contains a large number of receptors targeted by psychedelic drugs such as LSD or psilocybin ¾ the hallucinogenic chemical found in certain mushrooms. To see what happens in the claustrum when people are on psychedelics, Johns Hopkins Medicine researchers compared the brain scans of people after they took psilocybin with their scans after taking a placebo.

Their findings were published online on May 23, 2020, in the journal NeuroImage.

The scans after psilocybin use showed that the claustrum was less active, meaning the area of the brain believed responsible for setting attention and switching tasks is turned down when on the drug. The researchers say that this ties in with what people report as typical effects of psychedelic drugs, including feelings of being connected to everything and reduced senses of self or ego.

"Our findings move us one step closer to understanding mechanisms underlying how psilocybin works in the brain," says Frederick Barrett, Ph.D., assistant professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine and a member of the school's Center for Psychedelic and Consciousness Research. "This will hopefully enable us to better understand why it's an effective therapy for certain psychiatric disorders, which might help us tailor therapies to help people more."

Because of its deep-rooted location in the brain, the claustrum has been difficult to access and study. Last year, Barrett and his colleagues at the University of Maryland, Baltimore, developed a method to detect brain activity in the claustrum using functional magnetic resonance imaging (fMRI).

For this new study, the researchers used fMRI with 15 people and observed the claustrum brain region after the participants took either psilocybin or a placebo. They found that psilocybin reduced neural activity in the claustrum by 15% to 30%. This lowered activity also appeared to be associated with stronger subjective effects of the drug, such as emotional and mystical experiences. The researchers also found that psilocybin changed the way that the claustrum communicated with brain regions involved in hearing, attention, decision-making and remembering.

With the highly detailed imaging of the claustrum provided by fMRI, the researchers next hope to look at the mysterious brain region in people with certain psychiatric disorders such as depression and substance use disorder. The goal of these experiments will be to see what roles, if any, the claustrum plays in these conditions. The researchers also plan to observe the claustrum's activity when under the influence of other psychedelics, such as salvinorin A, a hallucinogen derived from a Mexican plant.

https://www.sciencedaily.com/releases/2020/06/200605121512.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

Why are some mushrooms 'magic?'

Study offers evolutionary explanation, could pave way for neurological treatments

February 27, 2018

Science Daily/Ohio State University

The work helps explain a biological mystery and could open scientific doors to studies of novel treatments for neurological disease, said lead researcher Jason Slot, an assistant professor of fungal evolutionary genomics at The Ohio State University.

Mushrooms that contain the brain-altering compound psilocybin vary widely in terms of their biological lineage and, on the surface, don't appear to have a whole lot in common, he said.

From an evolutionary biology perspective, that is intriguing and points to a phenomenon in which genetic material hops from one species to another -- a process called horizontal gene transfer, Slot said. When it happens in nature, it's typically in response to stressors or opportunities in the environment.

He and his co-authors examined three species of psychedelic mushrooms -- and related fungi that don't cause hallucinations -- and found a cluster of five genes that seem to explain what the psychedelic mushrooms have in common.

"But our main question is, 'How did it evolve?'" Slot said. "What is the role of psilocybin in nature?"

Slot and his co-authors found an evolutionary clue to why the mushrooms gained the ability to send human users into a state of altered consciousness. The genes responsible for making psilocybin appear to have been exchanged in an environment with a lot of fungus-eating insects, namely animal manure.

Psilocybin allows fungi to interfere with a neurotransmitter in humans and also insects, which are probably their bigger foe. In flies, suppression of this neurotransmitter is known to decrease appetite.

"We speculate that mushrooms evolved to be hallucinogenic because it lowered the chances of the fungi getting eaten by insects," Slot said. The study appears online in the journal Evolution Letters.

"The psilocybin probably doesn't just poison predators or taste bad. These mushrooms are altering the insects' 'mind' -- if they have minds -- to meet their own needs."

And the reason that unrelated species have the same genetic protection probably comes down to the fact that they commonly grow in the same insect-rich mediums: animal feces and rotten wood.

This work could guide medical science by pointing researchers in the direction of other molecules that could be used to treat disorders of the brain, Slot said.

Psilocybin has been studied for the treatment of a variety of mental disorders, including treatment-resistant depression, addiction and end-of-life anxiety. A handful of researchers in the U.S. are looking at potential treatment applications, and much of the work is happening abroad. Strict drug laws have delayed those types of studies for decades, Slot said.

https://www.sciencedaily.com/releases/2018/02/180227115548.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

Psilocybin inhibits the processing of negative emotions in the brain

May 7, 2014

Science Daily/University of Zurich

Emotions like fear, anger, sadness, and joy enable people to adjust to their environment and react flexibly to stress and strain and are vital for cognitive processes, physiological reactions, and social behaviour. The processing of emotions is closely linked to structures in the brain, i.e. to what is known as the limbic system. Within this system the amygdala plays a central role -- above all it processes negative emotions like anxiety and fear. If the activity of the amygdala becomes unbalanced, depression and anxiety disorders may develop.

Researchers at the Psychiatric University Hospital of Zurich have now shown that psilocybin, the bioactive component in the Mexican magic mushroom, influences the amygdala, thereby weakening the processing of negative stimuli. These findings could "point the way to novel approaches to treatment" comments the lead author Rainer Krähenmann on the results which have now been published in the medical journal Biological Psychiatry.

Psilocybin inhibits the processing of negative emotions in the amygdala

The processing of emotions can be impaired by various causes and elicit mental disorders. Elevated activity of the amygdala in response to stimuli leads to the neurons strengthening negative signals and weakening the processing of positive ones. This mechanism plays an important role in the development of depression and anxiety disorders. Psilocybin intervenes specifically in this mechanism as shown by Dr. Rainer Krähenmann's research team of the Neuropsychopharmacology and Brain Imaging Unit led by Prof. Dr. Franz Vollenweider.

Psilocybin positively influences mood in healthy individuals. In the brain, this substance stimulates specific docking sites for the messenger serotonin. The scientists therefore assumed that psilocybin exerts its mood-brightening effect via a change in the serotonin system in the limbic brain regions. This could, in fact, be demonstrated using functional magnetic resonance imaging (fMRI). "Even a moderate dose of psilocybin weakens the processing of negative stimuli by modifying amygdala activity in the limbic system as well as in other associated brain regions," continues Krähenmann. The study clearly shows that the modulation of amygdalaactivity is directly linked to the experience of heightened mood.

Next study with depressive patients

According to Krähenmann, this observation is of major clinical importance. Depressive patients in particular react more to negative stimuli and their thoughts often revolve around negative contents. Hence, the neuropharmacologists now wish to elucidate in further studies whether psilocybin normalises the exaggerated processing of negative stimuli as seen in neuroimaging studies of depressed patients -- and may consequently lead to improved mood in these patients. .

Rainer Krähenmann considers research into novel approaches to treatment very important, because current available drugs for the treatment of depression and anxiety disorders are not effective in all patients and are often associated with unwanted side effects.

https://www.sciencedaily.com/releases/2014/05/140507095756.htm

First trial to investigate magic mushrooms as a treatment for depression delayed by UK and EU regulations

April 7, 2013

Science Daily/British Neuroscience Association

The world's first clinical trial to explore the use of the hallucinogenic ingredient in magic mushrooms to treat depression is being delayed due to the UK and EU rules on the use of illegal drugs in research.

Professor David Nutt, president of the British Neuroscience Association and Professor of Neuropsychopharmacology at Imperial College London (UK), will tell the BNA's Festival of Neuroscience today (Sunday) that although the UK's Medical Research Council has awarded a grant for the trial, the Government's regulations controlling the licensing of illegal drugs in research and the EU's guidelines on Good Manufacturing Practice (GMP) have stalled the start of the trial, which was expected to start this year. He is calling for a change to the regulations.

He will tell the meeting at the Barbican in London, that his research has shown that psilocybin, the psychedelic ingredient in magic mushrooms, has the potential to alleviate severe forms of depression in people who have failed to respond fully to other anti-depressant treatments. However, psilocybin is illegal in the UK; the United Nations 1971 Convention on Psychotropic Substances classifies it as a Schedule 1 drug, one that has a high potential for abuse with no recognised medical use, and the UK has classified it as a Class A drug, the classification used for the most dangerous drugs. This means that a special licence has to be obtained to use magic mushrooms in research in the UK, and the manufacture of a synthetic form of psilocybin for use in patients is tightly controlled by EU regulations.

Prof Nutt will say: "The law for the control of drugs like psilocybin as a Schedule 1 Class A drug makes it almost impossible to use them for research and the reason we haven't started the study is because finding companies who could manufacture the drug and who are prepared to go through the regulatory hoops to get the licence, which can take up to a year and triple the price, is proving very difficult. The whole situation is bedevilled by this primitive, old-fashioned attitude that Schedule 1 drugs could never have therapeutic potential, and so they have to be made impossible to access."

"The knock-on effect is this profound impairment of research. We are the first people ever to have done a psilocybin study in the UK, but we are still hunting for a company that can manufacture the drug to GMP standards for the clinical trial, even though we've been trying for a year to find one. We live in a world of insanity in terms of regulating drugs at present. The whole field is so bogged down by these intransient regulations, so that even if you have a good idea, you may never get it into the clinic."

He will say that the regulations need to be changed. "Even if I do this study and I show it's a really useful treatment for some people with depression, there's only four hospitals in this country that have a licence to hold this drug, so you couldn't roll out the treatment if it worked because the regulations would make it difficult to use," he said.

Prof Nutt and his team at Imperial College London (UK) have shown that when healthy volunteers are injected with psilocybin, the drug switched off a front part of the brain called the anterior cingulate cortex, which is known from previous imaging studies to be over-active in depression. "We found that, even in normal people, the more that part of the brain was switched off under the influence of the drug, the better they felt two weeks later. So there was a relationship between that transient switching off of the brain circuit and their subsequent mood," he will explain. "This is the basis on which we want to run the trial, because this is what you want to do in depression: you want to switch off that over-active part of the brain.

"The other thing we discovered is that the major site of action of the magic mushrooms is to turn down a circuit in the brain called the 'default mode network', which the anterior cingulate cortex is part of. The default mode network is a part of the brain between the front and back. It is active when you are thinking about you; it coordinates the thinking and emotional aspects of you."

The researchers discovered that the 'default mode network' had the highest density of 5HT2A receptors in the brain. These are known to be involved in depression and are the targets for a number of existing anti-depressive drugs that aim to improve levels of serotonin -- the neurotransmitter [1] that gives people a sense of well-being and happiness. Psilocybin also acts on these receptors.

"We have found that people with depression have over-active default mode networks, and they are continually locked into a mode of thinking about themselves. So they ruminate on themselves, on their incompetencies, on their badness, that they're worthless, that they've failed; these things are not true, and sometimes they reach delusional levels. This negative rumination may be due to a lack of serotonin and what psilocybin is doing is going in and rapidly replacing the missing serotonin, switching them back into a mind state where they are less ruminating and less depressed," Prof Nutt will say.

The proposed trial will be for patients with depression who have failed two previous treatments for the condition. Thirty patients will be given a synthetic form of psilocybin and 30 patients will be given a placebo. The drug (or placebo) will be given during two, possibly three, carefully controlled and prepared 30-60 minute sessions. The first session will be a low dose to check there are no adverse responses, the second session will give a higher, therapeutic dose, and then patients can have a third, booster dose in a later session if it's considered necessary. While they are under the influence of the drug, the patients will have guided talking therapy to enable them to explore their negative thinking and issues that are troubling them. The doctors will follow up the patients for at least a year.

"What we are trying to do is to tap into the reservoir of under-researched 'illegal' drugs to see if we can find new and beneficial uses for them in people whose lives are often severely affected by illnesses such as depression. The current legislation is stopping the benefits of these drugs being explored and for the last 40 years we have missed really interesting opportunities to help patients."

Ethical approval for the trial was granted in March and Prof Nutt says he hopes to be able to start the trial within the next six months -- so long as he can find a manufacturer for the drug.

[1] Neurotransmitters are chemicals that transmit signals from neurons (nerve cells) to target cells.

[2] Funding: The Beckley Foundation has funded part of Prof Nutt's research, and the Medical Research Council has agreed a grant for the proposed clinical trial.

Abstract title: "Can we use psychedelic drugs to treat depressions?" Symposium: "Treating depression with antidepressants: where are we now and where are we going?"

https://www.sciencedaily.com/releases/2013/04/130407090832.htm

Magic mushrooms' effects illuminated in brain imaging studies

January 24, 2012

Science Daily/Imperial College London

Brain scans of people under the influence of the psilocybin, the active ingredient in magic mushrooms, have given scientists the most detailed picture to date of how psychedelic drugs work. The findings of two studies being published in scientific journals this week identify areas of the brain where activity is suppressed by psilocybin and suggest that it helps people to experience memories more vividly.

In the first study, published January 23 in Proceedings of the National Academy of Sciences (PNAS), 30 healthy volunteers had psilocybin infused into their blood while inside magnetic resonance imaging (MRI) scanners, which measure changes in brain activity. The scans showed that activity decreased in "hub" regions of the brain -- areas that are especially well-connected with other areas.

The second study, due to be published online by the British Journal of Psychiatry on January 24, found that psilocybin enhanced volunteers' recollections of personal memories, which the researchers suggest could make it useful as an adjunct to psychotherapy.

Professor David Nutt, from the Department of Medicine at Imperial College London, the senior author of both studies, said: "Psychedelics are thought of as 'mind-expanding' drugs so it has commonly been assumed that they work by increasing brain activity, but surprisingly, we found that psilocybin actually caused activity to decrease in areas that have the densest connections with other areas. These hubs constrain our experience of the world and keep it orderly. We now know that deactivating these regions leads to a state in which the world is experienced as strange."

The intensity of the effects reported by the participants, including visions of geometric patterns, unusual bodily sensations and altered sense of space and time, correlated with a decrease in oxygenation and blood flow in certain parts of the brain.

The function of these areas, the medial prefrontal cortex (mPFC) and the posterior cingulate cortex (PCC), is the subject of debate among neuroscientists, but the PCC is proposed to have a role in consciousness and self-identity. The mPFC is known to be hyperactive in depression, so psilocybin's action on this area could be responsible for some antidepressant effects that have been reported. Similarly, psilocybin reduced blood flow in the hypothalamus, where blood flow is increased during cluster headaches, perhaps explaining why some sufferers have said symptoms improved under psilocybin.

In the British Journal of Psychiatry study 10 volunteers viewed written cues that prompted them to think about memories associated with strong positive emotions while inside the brain scanner. The participants rated their recollections as being more vivid after taking psilocybin compared with a placebo, and with psilocybin there was increased activity in areas of the brain that process vision and other sensory information.

Participants were also asked to rate changes in their emotional wellbeing two weeks after taking the psilocybin and placebo. Their ratings of memory vividness under the drug showed a significant positive correlation with their wellbeing two weeks afterwards. In a previous study of 12 people in 2011, researchers found that people with anxiety who were given a single psilocybin treatment had decreased depression scores six months later.

Dr Robin Carhart-Harris, from the Department of Medicine at Imperial College London, the first author of both papers, said: "Psilocybin was used extensively in psychotherapy in the 1950s, but the biological rationale for its use has not been properly investigated until now. Our findings support the idea that psilocybin facilitates access to personal memories and emotions.

"Previous studies have suggested that psilocybin can improve people's sense of emotional wellbeing and even reduce depression in people with anxiety. This is consistent with our finding that psilocybin decreases mPFC activity, as many effective depression treatments do. The effects need to be investigated further, and ours was only a small study, but we are interested in exploring psilocybin's potential as a therapeutic tool."

The researchers acknowledged that because the participants in this study had volunteered after having previous experience of psychedelics, they may have held prior assumptions about the drugs which could have contributed to the positive memory rating and the reports of improved wellbeing in the follow-up.

Functional MRI measures brain activity indirectly by mapping blood flow or the oxygen levels in the blood. When an area becomes more active, it uses more glucose, but generates energy in rapid chemical reactions that do not use oxygen. Consequently, blood flow increases but oxygen consumption does not, resulting in a higher concentration of oxygen in blood in the local veins.

In the PNAS study, the volunteers were split into two groups, each studied using a different type of fMRI: 15 were scanned using arterial spin labelling (ASL) perfusion fMRI, which measures blood flow, and 15 using blood-oxygen level-dependent (BOLD) fMRI. The two modalities produced similar results, strongly suggesting that the observed effects were genuine.

The studies were carried out with a Home Office licence for storing and handling a schedule 1 drug and were approved by NHS research ethics committees. All the volunteers were mentally and physically healthy and had taken hallucinogenic drugs previously without any adverse response. The research involved scientists from Imperial, the University of Bristol and Cardiff University and was funded by the Beckley Foundation, the Neuropsychoanalysis Foundation, Multidisciplinary Association for Psychedelic Studies, and the Heffter Research Institute.

https://www.sciencedaily.com/releases/2012/01/120123152043.htm

Single dose of 'magic mushrooms' hallucinogen may create lasting personality change

September 29, 2011

Science Daily/Johns Hopkins Medical Institutions

A single high dose of the hallucinogen psilocybin, the active ingredient in so-called "magic mushrooms," was enough to bring about a measurable personality change lasting at least a year in nearly 60 percent of the 51 participants in a new study, according to the Johns Hopkins researchers who conducted it.

Lasting change was found in the part of the personality known as openness, which includes traits related to imagination, aesthetics, feelings, abstract ideas and general broad-mindedness. Changes in these traits, measured on a widely used and scientifically validated personality inventory, were larger in magnitude than changes typically observed in healthy adults over decades of life experiences, the scientists say. Researchers in the field say that after the age of 30, personality doesn't usually change significantly.

"Normally, if anything, openness tends to decrease as people get older," says study leader Roland R. Griffiths, a professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine.

The research, approved by Johns Hopkins' Institutional Review Board, was funded in part by the National Institute on Drug Abuse and published in the Journal of Psychopharmacology.

The study participants completed two to five eight-hour drug sessions, with consecutive sessions separated by at least three weeks. Participants were informed they would receive a "moderate or high dose" of psilocybin during one of their drug sessions, but neither they nor the session monitors knew when.

During each session, participants were encouraged to lie down on a couch, use an eye mask to block external visual distraction, wear headphones through which music was played and focus their attention on their inner experiences.

Personality was assessed at screening, one to two months after each drug session and approximately 14 months after the last drug session. Griffiths says he believes the personality changes found in this study are likely permanent since they were sustained for over a year by many.

Nearly all of the participants in the new study considered themselves spiritually active (participating regularly in religious services, prayer or meditation). More than half had postgraduate degrees. The sessions with the otherwise illegal hallucinogen were closely monitored and volunteers were considered to be psychologically healthy

"We don't know whether the findings can be generalized to the larger population," Griffiths says.

As a word of caution, Griffiths also notes that some of the study participants reported strong fear or anxiety for a portion of their daylong psilocybin sessions, although none reported any lingering harmful effects. He cautions, however, that if hallucinogens are used in less well supervised settings, the possible fear or anxiety responses could lead to harmful behaviors.

Griffiths says lasting personality change is rarely looked at as a function of a single discrete experience in the laboratory. In the study, the change occurred specifically in those volunteers who had undergone a "mystical experience," as validated on a questionnaire developed by early hallucinogen researchers and refined by Griffiths for use at Hopkins. He defines "mystical experience" as among other things, "a sense of interconnectedness with all people and things accompanied by a sense of sacredness and reverence."

Personality was measured on a widely used and scientifically validated personality inventory, which covers openness and the other four broad domains that psychologists consider the makeup of personality: neuroticism, extroversion, agreeableness and conscientiousness. Only openness changed during the course of the study.

Griffiths says he believes psilocybin may have therapeutic uses. He is currently studying whether the hallucinogen has a use in helping cancer patients handle the depression and anxiety that comes along with a diagnosis, and whether it can help longtime cigarette smokers overcome their addiction.

"There may be applications for this we can't even imagine at this point," he says. "It certainly deserves to be systematically studied."

Along with the National Institute on Drug Abuse, this study was funded by the Council on Spiritual Practices, Heffter Research Institute and the Betsy Gordon Foundation.

Other Hopkins authors of the research include Matthew W. Johnson, Ph.D, and Katherine A. MacLean, Ph.D.

https://www.sciencedaily.com/releases/2011/09/110929074205.htm

Mechanism of Hallucinogens' Effects Discovered

February 2, 2007

Science Daily/Cell Press

The brain mechanism underlying the mind-bending effects of hallucinogens such as LSD, mescaline, and psilocybin has been discovered by neuroscientists. They said their discoveries not only shed light on the longtime mystery of how hallucinogens work, but that the findings also offer a pathway to understanding the function of drugs used to treat neuropsychiatric disorders, which are now being used largely without an understanding of their fundamental mechanism.

Stuart Sealfon, Jay Gingrich, and colleagues published their findings in the February 1, 2007 issue of the journal Neuron, published by Cell Press.

Researchers have long known that hallucinogens activate specific receptors in the brain, called 5-HT2A receptors (2ARs), that are normally triggered by the neurotransmitter serotonin. Neurotransmitters are chemicals that one brain cell launches at receptors on another to trigger a nerve impulse in the receiving cell. However, a fundamental mystery has been why other compounds that activate the same receptors are not hallucinogenic.

In their studies, the researchers compared the differences between the effects of LSD and a nonhallucinogenic chemical that also activates 2AR receptors on the mouse neural machinery. Since the animals could not report the kinds of perception-altering effects that humans experience on hallucinogens, the researchers determined hallucinogenic properties by measuring a head twitch response the mice characteristically showed when under hallucinogens but not when under nonhallucinogens.

The scientists concentrated their studies on the cortex of the brain, which earlier studies had shown to be the center for action of the hallucinogens. Their analysis revealed that LSD produced genetic, electrophysiological, and internal cellular signaling responses that were distinctively different from those induced by a nonhallucinogenic compound.

They also explored whether 2ARs were central to the hallucinogenic effect of LSD by producing mice lacking the receptors, but in which receptor activity could be selectively restored in the cortex. The researchers found that mice without functioning receptors showed no hallucinogenic response to LSD, but restoring the receptors rendered LSD hallucinogenic in the animals.

The researchers wrote that "These studies identify the long-elusive neural and signaling mechanisms responsible for the unique effects of hallucinogens."

They also concluded that "The strategy we developed to elucidate [hallucinogen] action should be applicable to [central nervous system]-active compounds, with therapeutic potential in other disorders. Thus, our findings may advance the understanding of neuropsychiatric disorders that have specific pharmacological treatments whose mechanisms of action are not fully understood."

https://www.sciencedaily.com/releases/2007/01/070131135536.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