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Medicine Depression

mr peabody

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Welcome! Following is a DIGEST of articles and reports that is constantly updated. Jump in!




Can psilocybin treat severe depression?

Neuroimaging findings predicted response with this hallucinogen at post-treatment week 5 and correlated with decreased depressive symptoms and heightened mystic feelings.

In 1970, the FDA categorized psilocybin as a Schedule 1 drug, largely because of its recreational uses, which include inducing spirituality and synesthesias (e.g., seeing music, hearing art). Recently, several trials of this serotonin 2A agonist have supported further research into its use for treatment-resistant major depressive disorder. The researchers administered psilocybin to 19 medication-free participants with MDD.

Significant decreases in depression occurred post-treatment; 47% of participants met response criteria at 5-week follow-up. On fMRI, blood flow decreased from baseline in temporal (including amygdala) and parietal areas, similar to previous reports. Decreased amygdala activity significantly correlated with improved depression scores and increased feelings of a mystic experience. On resting-state fMRI, connectivity between several cortical areas increased post-treatment, contrary to findings elsewhere. Treatment response at 5 weeks was predicted by increased connectivity post-treatment between the ventromedial prefrontal cortex and inferior parietal cortex and by decreased parahippocampal-prefrontal connectivity.

Both the increased connectivity on post-treatment resting-state fMRI and its predictive value were similar to findings for electroconvulsive therapy, supporting the current study's validity. Experimental options for treatment-resistant MDD include invasive procedures like deep brain stimulation, which requires implanting brain devices with possible long-term adverse effects. Thus, clinicians can tell patients with access to federally funded psilocybin trials that this is a reasonable, noninvasive approach. Further, patients need to know that psilocybin must be taken only in closely supervised research settings because of its capacity to induce unusual psychic experiences.

https://www.jwatch.org/na45292/2017/...ere-depression
 
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mr peabody

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Seasonal Affective Disorder impacts 10 million americans. Are you one of them?

Neuroscience News | Nov 2 2019

This Sunday, November 3, most of America will be traveling back in time—by an hour. That’s when daylight saving time ends and we set back our clocks, signaling the transition into late fall and winter.

With this changing of the clocks, daylight ends earlier. When this happens, some people may experience emerging feelings of sadness and sluggishness, and fluctuations in weight. If you suffer from these symptoms, you may have seasonal affective disorder (SAD), a type of depression related to changes in the seasons. SAD affects an estimated 10 million Americans, with women four times more likely to be diagnosed with it than men. Fortunately, there are treatments available that have proven effective in treating the disorder.

How does one distinguish between SAD and ordinary sadness? What are the possible treatments? And what do scientists know about the underlying causes of the disorder? For answers to some of those questions, BU Today talked to Sanford Auerbach, a School of Medicine associate professor of neurology and psychiatry and director of the Sleep Disorders Center at Boston Medical Center.

What is seasonal affective disorder (SAD)?

SAD refers to changes in mood that occur when symptoms fluctuate according to the season of the year. Most commonly, it refers to depression associated with the winter months, typically fall and winter. It’s thought to be related to the fact that during the winter months we have shorter days.

What are the symptoms?

Typically they are associated with mood changes—depression, for instance. People who suffer from SAD may find that they have difficulty waking up in the morning, that they have less energy, that they have an increased appetite. It may be more difficult for them to concentrate. Maybe they have less motivation to do things.

The flip side of it is that the opposite happens in the shorter months, like spring and early summer, where people will perhaps sleep a little less, are maybe more energetic, maybe more active, maybe even in some cases a little more “hypomanic,” a little on the manic side.

From a technical perspective, it’s not just a matter of being depressed in the winter months. It’s also being manic, if you will, in the longer days. So basically, it’s a disorder of mood that seems to be linked to the seasons.

How do you recognize that you are suffering from SAD and not something else?

That’s tricky, because although people have latched onto the fact that in a lot of cases it’s related to the light cycle, there are also a lot of other things that go on—work changes, holidays, colder weather—that may be more stressful for some people than others. So there are many factors. The way you recognize it is that over the course of several years, you see that there’s a recurrent theme: every four months, you start to have these changes in mood. So after this happens maybe three years or more, then you could consider that it’s SAD.

How many people suffer from SAD? Are certain individuals more at risk than others?

When you look at temperate climates, I think it’s estimated that 5 percent of the population may have this. Certainly for people who live in areas where you don’t see such great variation in seasons, it’s not as likely to occur. The extreme would be people who live in equatorial areas. There, the times don’t shift much. They have close to 12-hour days all year round. Whereas people farther north or farther south can have very long days in the summer but very short, or nonexistent, days in the winter.

What are the treatment options for people with SAD?

There are a couple of options here. One is to use some sort of light therapy. You can get easily available light boxes. Usually the prescription is to be exposed to 10,000 lux. One lux is one candle-foot power—the amount of light that you get if you’re one foot away from one candle. Usually they’re full-spectrum lights, and usually the intensity varies according to how far it is from you. You want to sit in front of it in the morning for about 30 minutes each day. Morning exposure tends to be much more powerful than exposure in the evening or the middle of the day.

The other option is to treat it like depression. A lot of things that have been shown to be effective for depression are effective for SAD, like the usual sort of antidepressants.

Are there ways to prevent SAD or mitigate its symptoms?

Start treating it before it happens. Or, in the winter, move down to South America.

What do doctors and scientists still not know about SAD?

I think that figuring out what it is about the light that these cells in the back of the eye particularly implicated in this, needs to be studied a bit more. And some of those pathways are being studied more.

People who suffer from SAD may find that they have difficulty waking up in the morning, that they have less energy, that they have an increased appetite. It may be more difficult for them to concentrate. Maybe they have less motivation to do things.

People are also trying to figure out, is it the light intensity? A few people have adjusted light gradually, like a sunrise—is that more effective or less effective?

What about the genetics of it? How can you predict who’s at a greater risk than others for this? One of the troubles of the light therapy is it varies a little bit from person to person, from researcher to researcher. The idea is to sit in front of the light for 30 to 60 minutes, but that requires some lifestyle changes and a time commitment.

What do you hope for in the near future regarding SAD research?

I think it’s important to appreciate the impact of light on mood, but also cognition. They are very closely related because cognition does fluctuate with mood. What is the effect of these seasonal affective disorders on things like memory and cognition in general? Is it better to take your harder courses in the fall semester or the spring semester?

 
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mr peabody

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Albert Hofmann


Treating depression with psychedelics

Depression is a challenging and often long-term condition that can be very difficult to treat. In clinical studies, psychedelics have shown significant long-term positive impact on mood, even when used in just a single session.

Many people who have suffered from depression and later recovered find that they need a combination of approaches to stay healthy. Good nutrition, exercise, more time with friends, lower stress, and personal introspection (through therapy, psychedelics, or meditation) can be a powerful combination.

For decades, psychedelics such as psilocybin mushrooms and LSD have been used in clinical studies, private therapy, and at home to alleviate depression. Recently, the prescription medication ketamine has shown incredible results for depression.

Here’s one man’s story from a recent clinical study, as reported in the New York Times:

As a retired psychologist, Clark Martin was well acquainted with traditional treatments for depression, but his own case seemed untreatable as he struggled through chemotherapy and other grueling regimens for kidney cancer. Counseling seemed futile to him. So did the antidepressant pills he tried.

Nothing had any lasting effect until, at the age of 65, he had his first psychedelic experience. He left his home in Vancouver, Wash., to take part in an experiment at Johns Hopkins medical school involving psilocybin, the psychoactive ingredient found in certain mushrooms.

Today, more than a year later, Dr. Martin credits that six-hour experience with helping him overcome his depression and profoundly transforming his relationships with his daughter and friends. He ranks it among the most meaningful events of his life, which makes him a fairly typical member of a growing club of experimental subjects.

Clinical studies that use psilocybin and LSD to study depression have a very simple protocol. Participants are invited to come to a research room that has been setup to feel comfortable and they take a dose of the substance. A researcher sits with them for the duration of the experience (4-6 hours) and may talk them through any anxiety that arises. But generally, the participants simply remain quiet and feel the experience, following where their thoughts and feelings take them.

This setup can be replicated at home or in another comfortable setting. The most essential elements are a comfortable space, plenty of time to stay in the experience, and someone you trust who can support you during the experience.

-howtousepsychedelics.org
 
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mr peabody

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Ketamine relieves depression by restoring damaged neural connections

CBC Radio | Apr 13, 2019

The anaesthetic drug ketamine might have a reputation as a psychedelic party drug, but in lower doses it's been shown to bring remarkable — almost immediate — relief to severe and otherwise untreatable cases of depression. And now scientists think they know why: it helps restore synapses in the brain that are destroyed by stress.

"Ketamine is this really exciting drug that is fundamentally different from many of the other antidepressants that we use, in that it has these rapid effects," said Dr. Conor Liston, a neuroscientist and psychiatrist in the Feil Family Brain & Mind Research Institute at Weill Cornell Medicine in New York City, in conversation with Quirks & Quarks host Bob McDonald.

In the last few years, psychedelics have been going through a bit of a renaissance as scientists explore the therapeutic potential these drugs can provide.

Dr. Pierre Blier, the director of the mood disorders research unit at the Royal Ottawa Mental Health Centre and a professor at the University of Ottawa, has studied the use of ketamine in reducing suicidal thoughts in patients with severe and treatment-resistant depression.

"What is striking is that we also saw, like other researchers, a very important effect — almost everybody experiences a decrease in suicidal ideation," said Blier. "And that's the major impact."

Compared to traditional antidepressants, ketamine works very quickly. Most patients who take it for depression experience relief within hours. That relief can last for days, weeks or even months before patients relapse.

Dr. Conor Liston became interested in ketamine because these transitions are similar to what people with episodic depression experience when they get sick, then better, only to relapse again.

"This investigation into ketamine is actually part of a larger project underway in my lab where we're trying to understand the mechanisms that mediate transitions between depressive episodes," said Liston, senior author of a study looking at these mechanisms, published recently in the journal Science.

Ketamine restores connections in the brain

Depression is not just bad for the mind, it's bad for the brain. Our bodies release the hormone cortisol when we're stressed, but also during periods of depression. When we're particularly stressed or if there's a chemical imbalance in the brain, cortisol can damage neural connections in key areas of our brain.

"What we showed in our work," said Liston, "is that ketamine and chronic stress are actually doing opposite things — so there's a loss of connections after chronic stress in this brain region. And ketamine is actually acting to restore some of the exact same connections that have been lost during stress."

New brain connections maintain 'well state'

"One surprising part of their study was that changes in behaviour in the mice that indicated a lifting of the effects of depression actually came before restoration of any faulty connections occurred — only hours after the mice had been given the drug," said Liston.

"That right there told us that they couldn't be required for inducing ketamine's effects initially," said Liston.

Ketamine works on the brain's glutamate neurotransmitter, which is involved in communicating between nerve cells. The researchers think this is what provides the immediate effects of relief, which then becomes reinforced with the formation of new synapses.

"What we found is that those new connections are really important for stabilizing the brain in a 'well state,'" added Liston.

Augmenting ketamine's antidepressant effects

These findings may shed light on the variability in how long ketamine works to keep depression at bay, and also provide a glimpse how episodic depression can start and stop.

"These new connections might explain why it is that some individuals have long lasting benefits from ketamine whereas others do not," said Liston. "What we think our study is showing us is that the formation of these new connections is really important in determining whether — when you get better, you stay better, or do you become depressed again."

If scientists can find a way to stabilize these connections, maybe they can make the effects of ketamine last longer. This is a concern because it's not yet known if ketamine is safe to take repeatedly on a long-term basis.

According to Liston, there are a number of routes to explore to stabilize the neural connections ketamine helps rebuild. Potentially another drug could work to further stabilize those connections. "Or," he suggests, "transcranial magnetic stimulation to the brain. or perhaps even a behavioural intervention as simple as exercise, could help maintain those connections."

Liston plans on testing some of these potential interventions to augment the effects of ketamine.

Ketamine hasn't been approved for psychiatric treatment in Canada. A ketamine nasal spray designed to treat intractable depression has been submitted to Health Canada for approval in January. It is currently being reviewed under the Priority Review Policy.

Anna Beyeler, a neuroscientist from the Université de Bordeaux in France, cautions that "although ketamine's effect on depression is apparent within hours, the drug can have side effects including sedation, detachment from reality, and even addiction."

https://www.cbc.ca/radio/quirks/apr...abilizing-the-brain-in-a-well-state-1.5093729
 
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mr peabody

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Ayahuasca tea helps patients rapidly overcome severe depression*

An article published this week in Psychological Medicine shows ayahuasca providing rapid and sustained anti-depressant effects for people with severe Treatment-Resistant Depression.

The paper was published by researcher and Kahpi.net teacher Dr Julio de Araujo, whose team at the Brain Institute in Natal, Brazil have been investigating the effects of ayahuasca on depression since 2014. The study included 29 patients with Treatment-Resistant Depression given a single dose of ayahuasca or a placebo. Those who received the ayahuasca scored significantly lower on both depression scales used for rating their states, and these effects were sustained for one week.

The results of the study appear promising and timely. Depression is, without a doubt, one of the most severe global epidemics of the modern age. The World Health Organizations Depression and Other Common Disorders (2017) report provides an estimate that over 300 million people worldwide suffer from it, and according to a paper published by the Columbia University Mailman School of Public Health, this number is on the rise.

Today, pretty much wherever in the world you live, you are likely to have at least one family member or friend who is depressed.

With varying degrees of success, clinical depression can be treated with regular psychotherapy, antidepressants, and lifestyle changes. But not everyone has the time or the energy to dedicate to a full-on treatment regime. And few depressed patients are in any shape to achieve that.

And then, there are cases of depression so severe that pharmaceutical and psychological therapy are powerless to help. In this stage, the disorder is referred to as Treatment-Resistant Depression, and it is alarmingly frequent. It is estimated that around 30% of patients with Major Depressive Disorder fall in this category.

There have been positive findings with a compound called ketamine, that is more in the grey zone between psychedelics and medication. This substance is often used for starting and maintaining anesthesia, but also holds a special place in many an underground ravers party drawer due to its trance-like sedative effects.

Ketamine trials have so far shown excellent results, especially in eliminating suicidal ideation. A few peer-reviewed, double-blind, randomized, placebo-controlled studies have found rapid antidepressant effects in ketamine therapy. One trial reported 35% of patients maintained the effect after one week. Another study found this percentage to be lower, at 13%.

Ayahuasca, however, is illegal in some forms and places, and is a highly intense undertaking in terms of its effects. This traditional shamanic brew has been gaining attention in the past decades as a spiritually transformational tool. Could it be used to help with an affliction such as depression? Some have compared a single ayahuasca experience to ten years of therapy.

Psychedelics such as ayahuasca are becoming increasingly recognized as tools for combating many different mental health disorders. Psychedelic therapists suggest ayahuasca can help the individual access and change deep, unconscious patterns of thought and behavior.

"Depression, obsession, eating disorders--all are exacerbated by the tyranny of the ego and the fixed narratives it constructs about our relationship to the world," writes Michael Pollan. "By temporarily overturning that tyranny and throwing our minds into an unusually plastic state, psychedelics, with the help of a good therapist, give us an opportunity to propose a new, more constructive story about the self and its relationship with the world--one that just might stick."

The anecdotal reports and psychological studies on the benefits of ayahuasca and psychedelics are accompanied by fascinating neuroscientific studies.

A recent model of brain functioning proposed by Dr. Robin Carhart-Harris and Professor David Nutt, who are among the biggest names in psychedelic research, suggests there is an important biochemical basis to ayahuasca therapy.

Selective serotonin reuptake inhibitors (SSRIs), the most common medication used for treating depression, block the reuptake of serotonin, the neurotransmitter associated with feelings of well-being and happiness. This means that more of it stays in the space between neural synapses, and is available to bind to the receiving cell synapses, rather than be reabsorbed by the neuron endings. This process is thought, according to traditional models, to work by blocking two brain receptors in particular: the 5-HT1A and the 5-HT2A receptors.

Carhart-Harris and Nutt argue that the inhibition of 5-HT2A receptors, which are the brain areas precisely targeted by psychedelics such as psilocybin and ayahuasca, could be more important than previously thought. They suggest blocking 5-HT2A receptors enables a process they refer to as active coping to help the brain actively addresses the source of stress. The brain does this by enhancing its plasticity or adaptive capacity.

If these scientists are correct in their suggestion, psychedelics might have a very important role to play in overcoming depression and other common mental health disorders.

This is a discovery we are on the brink of confirming. After a few promising studies published by Osorio and Sanches, we now finally have, with last weeks Psychological Medicine article, a fully fleshed out, double-blind, randomized, placebo-controlled ayahuasca trial. And the results are more than encouraging.

Interestingly, compared to the previous studies conducted with the psychedelic compound ketamine, the authors of the recent ayahuasca study noticed a difference in immediate and later effects. Ketamine produced responses from between 37% and 70% of patients on day one, decreasing to between 7% and 35% on day 7. In this ayahuasca trial, 50% of patients responded positively on day 1, and this number increased to 64% by day 7.

As usual in conducting medical trials, these effects need to be replicated on a larger number of participants throughout different societies in order to be validated. However, this study can be considered to be the strongest scientific demonstration to date of ayahuascas potential to heal.

*From the article here: https://kahpi.net/ayahuasca-tea-rapi...re-depression/


 
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mr peabody

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Can LSD treat depression?

By Rachel Nania

When routine therapies and medications failed to help Ayelet Waldman overcome intense mood swings and a deep depression, she turned to something that is generally associated with harm, not health: LSD. Waldman is the last person in the world who, under normal circumstances, would be associated with drugs. Prior to her experiment, living in Berkeley, California was her closest tie to a tab of acid.

“I’m like the lady in yoga pants with the skinny vanilla latte standing in front of you at Starbucks,” said Waldman, a Harvard Law School graduate and former corporate lawyer.But the mom of four was desperate. Her mood disorder was destroying her life and threatening her relationship with her family. At her lowest point, she was suicidal. “That’s when I realized I needed to try something drastic,” she said.

Waldman heard about microdosing, or taking tiny doses of drugs, thanks to its growing presence in the media. Researchers at Johns Hopkins and New York universities have studied the impact of psychedelic drugs on cancer patients for anxiety, and the FDA recently approved large-scale trials to test the effect of ecstasy on post-traumatic stress disorder in combat veterans.

After reading up on microdosing, Waldman didn’t need much convincing. Procuring the illegal substance, however, wasn’t so easy. Waldman, who is married to Pulitzer Prize-winning novelist Michael Chabon, started asking friends, neighbors, anyone she knew, if they had any idea where she could get LSD. “And everybody looked at me like I was completely crazy,” she said. Finally, someone told her about an old professor who had been microdosing for years. Soon after, she found a small envelope in her mailbox with the name “Lewis Carroll” on the return address. Inside the envelope was a small blue bottle of LSD diluted in distilled water. (Waldman said she ordered an LSD drug kit on Amazon to be sure.)

Not knowing what to expect, Waldman told a friend she was taking a new medication for the first time and asked her to come over in case there were any side effects. There were no voices, no flashing colors and no groovy trips. Just a return to her normal. “About 90 minutes later, I looked out my window and my dogwood tree was in bloom. And I thought, ‘Oh, the tree looks so beautiful today.’ And that was the first time anything had looked beautiful in a really, really long time,” Waldman said about her experience with microdosing.

“I just felt like the fog — the ugly, miserable fog of depression — was gone. And at the end of the day, I thought to myself, ‘Wow. That was a really good day.’” Waldman details her experience with microdosing in her new book, A Really Good Day: How Microdosing Made a Mega Difference in My Mood, My Marriage, and My Life.

Her blue bottle of LSD is now empty, but her hope for a future open to alternative drug therapies is not. “We should be studying these drugs because we have an epidemic of depression … people are suffering, people are in pain,” she said.

Right now, Waldman has to work really hard to maintain equilibrium. She receives therapy, is on a hormone patch and “does a lot of different things.” She wishes she could still microdose LSD and knows it’s always a possibility if her really good days turn really bad.

“I also know that if I become suicidal again, and I feel like I’m facing a choice between breaking the law or killing myself, I will once again choose to break the law,” she said.


 
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mr peabody

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Ketamine hailed as 'a miracle for treating severe depression'

By Sara Solovitch

It was November 2012 when Dennis Hartman, a Seattle business executive, managed to pull himself out of bed, force himself to shower for the first time in days and board a plane that would carry him across the country to a clinical trial at the National Institute of Mental Health (NIMH) in Bethesda.

After a lifetime of profound depression, 25 years of therapy and cycling through 18 antidepressants and mood stabilizers, Hartman, then 46, had settled on a date and a plan to end it all. The clinical trial would be his last attempt at salvation.

For 40 minutes, he sat in a hospital room as an IV drip delivered ketamine through his system. Several more hours passed before it occurred to him that all his thoughts of suicide had evaporated.

"My life will always be divided into the time before that first infusion and the time after," Hartman says today. "That sense of suffering and pain draining away. I was bewildered by the absence of pain."

Ketamine has been around since the early 1960s. It is a staple anesthetic in emergency rooms, regularly used for children when they come in with broken bones and dislocated shoulders. Its an important tool in burn centers and veterinary medicine, as well as a notorious date-rape drug, known for its power to quickly numb and render someone immobile.

Since 2006, dozens of studies have reported that it can also reverse the kind of severe depression that traditional antidepressants often don't touch. The momentum behind the drug has now reached the American Psychiatric Association, which, according to members of a ketamine task force, seems headed toward a tacit endorsement of the drug for treatment-resistant depression.

Experts are calling it the most significant advance in mental health in more than half a century. They point to studies showing ketamine not only produces a rapid and robust antidepressant effect; it also puts a quick end to suicidal thinking.

Traditional antidepressants and mood stabilizers, by comparison, can take weeks or months to work. In 2010, a major study published in JAMA, the journal of the American Medical Association, reported that drugs in a leading class of antidepressants were no better than placebos for most depression.

A growing number of academic medical centers, including Yale University, the University of California at San Diego, the Mayo Clinic and the Cleveland Clinic, have begun offering ketamine treatments off-label for severe depression, as has Kaiser Permanente in Northern California.

The next big thing?

"This is the next big thing in psychiatry," says L. Alison McInnes, a San Francisco psychiatrist who has enrolled 58 severely depressed patients at Kaiser's San Francisco clinic. She says her long-term success rate of 60 percent for people with treatment-resistant depression who try the drug has persuaded Kaiser to expand treatment to two other clinics in the Bay Area. The excitement stems from the fact that its working for patients who have spent years cycling through antidepressants, mood stabilizers and various therapies.

"Psychiatry has run out of gas," she says. "There are a significant number of depressed people who don't respond to antidepressants, and we've had nothing to offer them other than cognitive behavior therapy, electroshock therapy and transcranial stimulation."

McInnes is a member of the APAs ketamine task force, assigned to codify the protocol for how and when the drug will be given. She says she expects the APA to support the use of ketamine treatment early this year.

The guidelines, which follow the protocol used in the NIMH clinical trial involving Hartman, call for six IV drips over a two-week period. The dosage is very low, about 1/10 of the amount used in anesthesia. And when it works, it does so within minutes or hours.

"It's not subtle," says Enrique Abreu, a Portland, Ore., anesthesiologist who began treating depressed patients with it in 2012. "It's really obvious if it's going to be effective. And the response rate is unbelievable. This drug is 75 percent effective, which means that three-quarters of my patients do well. Nothing in medicine has those kind of numbers."

So far, there is no evidence of addiction at the low dose in which infusions are delivered. Ketamine does have one major limitation: Its relief is temporary. Clinical trials have found that relapse usually occurs about a week after a single infusion.

Ketamine works differently from traditional antidepressants, which target the brains serotonin and noradrenalin systems. It blocks N-methyl-D-aspartate (NMDA), a receptor in the brain that is activated by glutamate, a neurotransmitter.

In excessive quantities, glutamate becomes an excitotoxin, meaning that it overstimulates brain cells.

"Ketamine almost certainly modifies the function of synapses and circuits, turning certain circuits on and off," explains Carlos Zarate, NIMH chief of neurobiology and treatment of mood disorders, who has led the research on ketamine. "The result is a rapid antidepressant effect."

Rapid effect

A study published in the journal Science in 2010 suggested that ketamine restores brain function through a process called synaptogenesis. Scientists at Yale University found that ketamine not only improved depression-like behavior in rats but also promoted the growth of new synaptic connections between neurons in the brain.

Even a low-dose infusion can cause intense hallucinations. Patients often describe a kind of lucid dreaming or dissociative state in which they lose track of time and feel separated from their bodies. Many enjoy it; some dont. But studies at NIMH and elsewhere suggest that the psychedelic experience may play a small but significant role in the drugs efficacy.

"It's one of the things that's really striking," says Steven Levine, a Princeton, N.J., psychiatrist who estimates that he has treated 500 patients with ketamine since 2011. "With depression, people often feel very isolated and disconnected. Ketamine seems to leave something indelible behind. People use remarkably similar language to describe their experience: a sense of connection to other people, a greater sense of connection to the universe."

Although bladder problems and cognitive deficits have been reported among long-term ketamine abusers, none of these effects have been observed in low-dose clinical trials. In addition to depression, the drug is being studied for its effectiveness in treating obsessive-compulsive disorder, post-traumatic stress disorder, extreme anxiety and Rett syndrome, a rare developmental disorder on the autism spectrum.

Booster treatments

The drugs fleeting remission effect has led many patients to seek booster infusions. Hartman, for one, began his search before he even left his hospital room in Bethesda.

4 years ago, he couldn't find a doctor in the Pacific Northwest willing to administer ketamine. "At the time, psychiatrists hovered between willful ignorance and outright opposition to it," says Hartman, whose depression began creeping back a few weeks after his return to Seattle.

It took nine months before he found an anesthesiologist in New York who was treating patients with ketamine. Soon, he was flying back and forth across the country for bimonthly infusions.

Upon his request, he received the same dosage and routine he received in Bethesda: six infusions over two weeks. And with each return to New York, his relief seemed to last a little longer. These days, he says that his periods of remission between infusions often stretch to six months. He says he no longer takes any medication for depression besides ketamine.

"I don't consider myself permanently cured, but now its something I can manage," Hartman says, "like diabetes or arthritis. Before, it was unmanageable, it dominated my life
and prevented me from functioning."


In 2012 he helped found the Ketamine Advocacy Network, a group that vets ketamine clinics, advocates for insurance coverage and spreads the word about the drug.

And word has indeed spread. Ketamine clinics, typically operated by psychiatrists or anesthesiologists, are popping up in major cities around the country.

Levine, for one, is about to expand from New Jersey to Denver and Baltimore. Portland's Abreu recently opened a second clinic in Seattle.

Depression is big business. An estimated 15.7 million adults in the United States experienced at least one major depressive episode in 2014, according to the NIMH.

"There's a great unmet need in depression," says Gerard Sanacora, director of the Yale Depression Research Program. "We think this is an extremely important treatment. The concern comes if people start using ketamine before CBT [cognitive behavioral therapy] or Prozac. Maybe someday it will be a first-line treatment. But we are not there yet."
 
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I kind of don't want to interrupt the flow of all your great posting mr peabody, cos these are some really nicely collated and organised pieces of insight and research that you've been bringing together in this forum. Really impressive work, thanks for taking the time to share it all! :D
 

mr peabody

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We visited a clinic that offers 45-minute ketamine infusions for depression

Ketamine is emerging as a potential new treatment for some types of depression. Researchers call it "the most important discovery in half a century." We visited a ketamine clinic that offers 45-minute infusions of the therapy in San Francisco.

After a 45-minute infusion of ketamine, clients at a clinic in San Francisco are not partying. Instead, they're in a state of quiet contemplation reclining on cushioned chairs, listening to music, or occasionally striking a tranquil yoga pose.

These clients are patients at one of ten ketamine clinics operated by XYZ Neurotherapies, a network that offers the treatments to people diagnosed with severe forms of anxiety and depression. Ketamine is best known for its illegal recreational uses, it is a powerful dissociative that can induce feelings of being separated from one's own body. But it is also one of the safest and most widely used legal anesthetics. And ketamine's utility as an antidepressant has recently started to gain attention.

A spate of studies over the past several years suggests ketamine may provide swift and powerful relief to people suffering from some of the hardest-to-treat forms of depression an illness that is the leading disability worldwide. Those findings have been so promising, in fact, that some researchers are calling it "the most important discovery in half a century." However, the US Food and Drug Administration has not yet approved ketamine for the treatment of anxiety or depression.

XYZ Neurotherapies San Francisco is offering treatments to thousands of patients anyway, and is one of an estimated 50 to 100 such clinics operating across the US. Here's what it's like.

Inside a ketamine clinic

XYZ Neurotherapies is a cross between clinical and therapeutic. In each treatment room, a reclining clinical chair sits facing a large window. In the corner is a chair decorated with a colorful crocheted blanket.

"We're striking a balance between a clinical setting and a home setting," Steve Levine, a psychiatrist and the CEO of XYZ Neurotherapies, told Business Insider.

Each two-hour visit includes 45 minutes of ketamine infusion, 45 minutes of a saline drip, and a consultation with Alison McInnes, a physician who founded a regional ketamine therapy program with Kaiser Permanente.

"Therapy and ketamine go together like peanut butter and chocolate," Levine said. "And with our approach, you have someone with an extensive background in mental health and therapy always present, and talk therapy happens before and after the infusion."

At XYZ, most patients receive 10 infusions over the course of 10 weeks, three in the first week, two in the second, and one infusion in the third, fourth, and fifth weeks. The last two infusions are spread between weeks seven and 10. Doctors who track patient progress, and people to fill out a standard depression and anxiety questionnaire before each treatment and the following day.

A single infusion costs $650, and insurance doesn't officially cover any of that, but Levine said his team can typically get providers to reimburse "a lot of it."

As with any treatment approach, there are drawbacks. Most studies on ketamine use in people with depression have been limited to about two weeks, so it remains unclear how long the benefits last. And not all clinics offering ketamine infusions are like Levine's network, which always has a psychiatrist or mental health professional on staff. Furthermore, such treatments often range from $400 to $1,000 per infusion around the US, a price tag that can leave vulnerable patients paying out of pocket and not getting reimbursed at all. Plus there's the fact that the FDA has only approved ketamine for use as an anesthetic.

Existing treatments for depression are very limited, however.

'Why the heck aren't we using this?'

Levine said that when he first saw a study about ketamine's impact on people with severe depression, it "spun his head around."

Treatments for depression, like talk therapy and antidepressants, mostly haven't improved since they were introduced in the 1950s. Decades of research suggest that those existing treatments don't work that well for everyone, and may not work at all for some. Yet physicians and psychiatrists have been doling out the same medications to clients for 70 years.

Some scientists seeking a new approach have looked to psychedelics like ayahuasca and psilocybin, which reduce depressive symptoms by increasing the connectivity between certain parts of the brain. "So it's not a complete surprise that they're also exploring the depression-reducing qualities of ketamine," Levine said.

But research has suggested that ketamine might stand out as conferring seemingly fast, widespread benefits to people with the condition. A 2012 review of four preliminary studies in patients with severe depression concluded that approximately 65-70% of patients responded well to ketamine. The other 30% either did not have a significant response, or their relief from depression was only short-lived.

"The findings were unanticipated, especially the robustness and rapidity of benefit," the authors wrote. "Ketamine appeared to directly target core depressive symptoms such as sad mood, suicidality, helplessness and worthlessness, rather than inducing a nonspecific mood-elevating effect."

Levine read everything he could on the treatment while maintaining his private psychiatry practice.

"Here's an incredibly safe medicine that works within hours," he said. "So my immediate question was, 'Why the heck aren't we using this?'"

He eventually decided to start his own clinics. The first treatment center opened in 2011 in Princeton, New Jersey, and the other nine followed between 2015 and 2017.

New findings on ketamine

A study published in the journal Scientific Reports in May was the first large, non-preliminary study to show that ketamine appears to provide significant relief to people suffering from some of the hardest-to-treat forms of depression. The finding did not go unnoticed. Johnson and Johnson is developing a form of ketamine that could be better tolerated and would be marketed as an antidepressant; Allergan is in the last phase of clinical trials with a drug that acts on the same receptor as ketamine.

For the most recent study, researchers at UC San Diego turned to an FDA database with records from more than 8 million patients. Using this data, the researchers homed in on patients who'd been given ketamine as a treatment for their chronic pain. Then they looked at how their depression symptoms compared to the depression symptoms in people who received other pain medications.

The findings were striking. The patients who took ketamine reported symptoms of depression 50% less frequently than patients who were given other combination of drugs for pain.

"This reduction in depression is specific to ketamine and is known to be much more rapid than current antidepressants," the researchers wrote in their paper, adding that their observations were "very promising for people with serious depression or thoughts of suicide."

"These patients cannot afford to wait up to six weeks for reductions in their depressive symptoms,"
they wrote.

Beyond a reduction in their symptoms of depression, the patients on ketamine also reported significantly less pain than those given the other drugs. They were also less likely to experience the unpleasant side-effects that frequently come with other pain medications like constipation, vomiting, and nausea.

Still, the ketamine had its own negative side effects, including kidney failure and low blood pressure.

For Levine, however, those negatives pale in comparison to the host of downsides that can accompany most treatments for depression.

"When you're treating very very ill people, you will have side effects. That's a reality," Levine said, adding, "these are people who've been sick for decades and heard from multiple doctors that there's nothing else they can do. We're enabling them to get back to their normal lives."

http://www.businessinsider.com/ketam...fusion-2017-10
 
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mr peabody

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Treating depression with ketamine


Just how exactly ketamine works is still unclear, but research suggests the antidepressant effects of ketamine arise from its relationship with glutamate, a neurotransmitter in the brain that sends messages related to motor function, emotion, and memory. Because ketamine targets a completely different system than conventional antidepressants (the glutamate system) it seems that the transmission of glutamate plays a key role in depression.

Human clinical studies on using ketamine to treat depression are promising. In 2006, a team at the National Institute of Mental Health (NIMH) assessed the effects of ketamine on a group of 18 study participants diagnosed with major, treatment-resistant depression. The participants who received ketamine showed significant improvement in depression symptoms compared to the placebo group within 110 minutes of administration, and 35% of those treated with ketamine still showed benefits a week later.

A follow-up study in 2013 looked at the effects of a related compound called Laniceme, which is similar in chemical makeup to ketamine but lacks its psychoactive properties. Patients treated with laniceme also showed improvements in symptoms of depression, but the change was not quite as pronounced as with ketamine. These findings suggest that the psychedelic qualities of ketamine actually enhance its antidepressant effects rather than hamper it.

Currently, clinical trials by the same NIMH research group are underway. We should be hearing the official results in the next few months, but anecdotal evidence from study participants so far is very promising. As one woman interviewed by NPR reported of her experience, It was almost immediate, the sense of calmness and relaxation.

Another participant said: "Monday afternoon I felt like a completely different person. I woke up Tuesday morning and I said, Wow, there's stuff I want to do today. And I woke up Wednesday morning and Thursday morning and I actually wanted to do things. I wanted to live life."

-PsychedelicTimes
 
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DMT as a catalyst for moving beyond depression


I wanted to do a short talk for you today, on the extremely beneficial results my experiences with DMT have had regarding my journey to overcome depression.

A few years back, I would never have chosen to stand up here in front of you all, it would have petrified me. I am still nervous, but through my experiences with DMT, I realise how so many of my actions are either driven from fear, or driven from love, and in this moment, I choose love. I also think it is really important to communicate honestly and openly about our experiences.

Aged sixteen, at a trance party in north London, a friend and I brought a handful of Fat Freddy paper blotters. Soon after, on a hillside in Wiltshire, I had my first acid trip. It was incredible - awe-inspiring, life changing, mind-opening- all of the above.

By the time I was 18, I had my share of psychedelic experiences. I valued them all, but underneath the outward psychedelic playfulness, I was struggling. I was suffering from depression and anxiety, and tripping was something I needed to shelve for a while. In my heart I knew I had found a tool that could open my eyes to a new way of seeing, but I was damaged from the experience of growing up in a society full of prejudice, with an education system preaching out a misguided interpretation of the route towards a successful life.

In trying to protect myself, I shut out that part of me that entheogens had opened up, and began to self-destruct. During the following eight years, I was diagnosed with anxiety and depression and started the toxic journey into psychiatric medications. I also started self-medicating, found heroin and fostered a heinous dependency on opiates.

Fast forward fourteen years, to a year and a half ago, I was engaged to my wonderful partner Phil, I had a home in north London and I had been clean from opiates for five and a half years. However, despite much of my life having turned around, I was depressed, full of fear and lacking direction. I had tried medication, therapy, mindfulness, meditation, yet I nonetheless continued to experience periods of deep depression.

I have always been interested in the entheogenic experience and altered states of consciousness. DMT was to my small amount of knowledge at that time, one of the strongest psychedelics known to mankind. The thought of re-engaging with the psychedelic experience in my depressed frame of mind might now seem a little unhinged. I knew of the importance of set and setting, and I knew that a depressed state of mind was not an ideal set, for my initial experience with DMT. Apart from the one very influential experience with the plant medicine Ibogaine, during the height of my addiction, I had not touched any psychedelic substances for well over a decade. After all that time without ingesting an entheogen, I felt intuitively called to experience DMT, I was looking for answers and that is where my search took me.

DMT has been the catalyst for more personal positive change than anything else I have come across in my life. Since that initial experience, my partner, my brother and I have had many wonderful ceremonies together, and the realisations and lessons I have taken from those sessions continued to astound and assist me to move forwards towards a place in which I can honestly say I have never felt happier.

I am not standing here holding DMT on a pedestal as the bringer of all solutions, and it is certainly not for everyone. But for me, it was exactly what the doctor ordered, or rather didn't. DMT has been a catalyst, it has been a gift and a tool, enabling me to look far beyond my personal circumstances, to let go of the fear I was carrying, to recognise home truths and to embrace a life of lightness and love, rather than the dark and somewhat heavy path I had been manifesting.

One of the primary things I have become aware of is just how fear driven my life was previously. I have always considered myself a creative person, however during one trip, I realised what an overwhelming role fear had played in my creative process. The fear of whatever artwork or piece of writing I was working on not being good enough, and the need to try and control the outcome of the creative process. So much of my anxiety and depression was driven by this sense of fear. And my awareness of how pointless that was, has allowed me to begin the journey of letting it go.

My experiences with this medicine have also been very helpful for my relationships.My brother is an open-hearted loving person and we had always been very close, but like so many families, we had created certain dynamics that were not benefitting our relationship. During one particular DMT ceremony, I found myself connecting to what some may term the the Godhead, or source - my brother could tell I was having a somewhat intense experience and came and sat on the floor in-front of me, meditating and holding the space. When I opened my eyes, I saw him and in that moment, I was convinced that he was me, that I was him and my awareness was of a connection to his core spirit.

It felt as though our consciousness had somehow merged together, and the love that I felt both for him and therefore for myself, was so overwhelming, I began to cry. I was then suddenly acutely aware of this deep sense of sadness I had been carrying around with me for a very long time. It wasn't that I didn't previously intellectually understand that, but rather that I could now feel it whole-heartedly, and in truly connecting to that, I was able to let it go. Ever since that moment, the connection I feel to my brother and to myself, has extended beyond what I could have ever hoped for.

Feeling, experiencing, knowing the connectivity that exists between all life on this planet, is truly an incredible catalyst for moving past a persons everyday concerns. When it comes to joyful means of moving past depression, experiencing that white light of pure connectivity with source, definitely beats psychiatric medication and therapy.

It can feel so easy to feel insignificant, lost and alone in this consumer driven society, so lacking in equality and an ethical mind-set. Having the opportunity to experience whole-heartedly, that what we see is not all there is - that surrounding us, every moment of every day, the life-force energy that connects every human, animal and plant, is so rich, so beautiful complex and sacred. It is beyond enough to remind you who you really are. And remembering that kernel of truth, has for me, been a gateway to a sense of inner peace and love, that put simply, annihilated the delusion of mental health problems I was so caught up in.

The concept of a universal consciousness and the infinite power of love and connectivity that we are all a part of, were ideas that I thought I understood, but understanding something intellectually, and truly feeling it, knowing it beyond a shadow of a doubt, are so entirely different.

The word Entheogen literally means generating God, or the divine, within, used to describe a plant or substance that generates the mystical experience. To me, this perfectly describes my experiences with dmt. I am a person who really needs to experience things himself, and this has had mixed results, leading to both the most wonderful of life experiences, and some pretty harsh ones. I have always had a real interest in various eastern philosophies. However, I have also been extremely put off by religious doctrine and in many ways I had allowed that to affect my own spiritual journey. DMT has been a catalyst for spiritual shifts. Author James Oroc describes in what I believe to be a perfect manner, the 5-MeO-DMT experience, and though I only have minimal experience with 5-MeO, as I find it a lot harder to source, I relate much of what he says in Tryptamine Palace to my experiences with DMT...

"As I let go, I experience dissolution into an omniscient state of oneness, a place where there is no difference between God, the physical universe, or me. We have ceased to exist as separate entities and now resonate as One. I resonate with the possession of a knowledge that radiates with the surest sense of Love, that is in everything and is everything.. and so much more. It is a conscious love more intelligent than anything we have ever known, a Love so great that it defies the need for a physical form and yet paradoxically realizes itself in us and in all creation. I become that love and I know everything is One."


If you are someone who just shut down on hearing the use of the word God in association with the exploration of altered states through plant medicines, I totally get that. I am the last person on earth to stand here and get all evangelical, and referencing God in this instance, has in my mind very little to do with any organised religion that I am aware of, and more to do with a sense of Oneness and infinite Love that we all possess and are part of. Now, I really do sound like a hippy! But, it just the way I feel. And, it is working out for me.

Since re-entering the world of entheogenic exploration, with the help of my partner I have methodically cut back on all psychiatric medications I accumulated over the past ten years. Alongside my daily meditation, yoga and mindfulness practice, throwing myself back into creativity, and using DMT as a reset button when necessary, my life is blossoming in a beautiful direction, my relationships are better than ever, and my depression is almost non-existent. And I know that DMT has played a considerable role in that process - I am hugely grateful for that! I love the psychedelic and proud campaign thats going on at the moment within the psychedelic society, in this mixed up western society weve lost so much of what is sacred. The consumption of entheogens has been at the core of humanities search for the sacred since the earliest days of our societies. It is only in the confused values of our contemporary western mindset, that such explorations are not upheld with the importance that they should be, but hopefully we can be part of changing that!

https://psychedelicsociety.org.uk/blog/dmt-depression
 
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mr peabody

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Albert Hofmann


Two things psychedelics do for people with depression

In 2016, researchers approached the European Medicines Agency seeking approval to use psilocybin in the treatment of anxiety and depression in patients with life-changing diagnoses. “Existential distress” is not an official DSM diagnosis, the regulators pointed out, so the national health services won’t cover it. But there’s a signal here that psilocybin could be useful in treating depression, so why don’t you do a big, multi-site trial for that?

The EMA was responding not only to the Hopkins and NYU data but also to the small “feasibility study” of the potential of using psilocybin to treat depression that Robin Carhart-Harris had directed in David Nutt’s lab at Imperial College. In the study, the initial results of which appeared in Lancet Psychiatry in 2016, researchers gave psilocybin to six men and six women suffering from “treatment-resistant depression”—meaning they had already tried at least two treatments without success. There was no control group, so everyone knew he or she was getting psilocybin.

After a week, all of the volunteers showed improvement in their symptoms, and two-thirds of them were depression-free, in some cases for the first time in years. Seven of the twelve volunteers still showed substantial benefit after three months. The study was expanded to include a total of twenty volunteers; after six months, six remained in remission, while the others had relapsed to one degree or another, suggesting the treatment might need to be repeated. The study was modest in scale and not randomized, but it demonstrated that psilocybin was well tolerated in this population, with no adverse events, and most of the subjects had seen benefits that were marked and rapid.*

The EMA was sufficiently impressed with the data to suggest a much larger trial for treatment-resistant depression, which afflicts more than 800,000 people in Europe.

Rosalind Watts was a young clinical psychologist working for the National Health Service when she read an article about psychedelic therapy in the New Yorker. The idea that you might actually be able to cure mental illness rather than just manage its symptoms inspired her to write to Robin Carhart-Harris, who hired her to help out with the depression study, the lab’s first foray into clinical research. Watts guided several sessions and then conducted qualitative interviews with all of the volunteers six months after their treatments, hoping to understand exactly how the psychedelic session had affected them.

Watts’s interviews have uncovered two “master” themes. The first was that the volunteers depicted their depression foremost as a state of “disconnection,” whether from other people, their earlier selves, their senses and feelings, their core beliefs and spiritual values, or nature. Several referred to living in “a mental prison,” others to being “stuck” in endless circles of rumination they likened to mental “grid-lock.” I thought of Carhart-Harris’ hypothesis that depression might be the result of an overactive Default Mode Network, the part of the brain where rumination appears to take place. The Imperial depressives also felt disconnected from their senses. “I would look at orchids,” one told Watts, “and intellectually understand that there was beauty, but not experience it.”

For most of the volunteers, the psilocybin experience had sprung them from their mental jails, if only temporarily. One woman in the study told me that the month following her session was the first time she had been free from depression since 1991. Others described similar experiences:

“It was like a holiday away from the prison of my brain. I felt free, carefree, re-energized.”

“It was like the light switch being turned on in a dark house.”

“You’re not immersed in thought patterns; the concrete coat has come off.”

“It was like when you defrag the hard drive on your computer . . . I thought, ‘My brain is being defragged, how brilliant is that!’”

For many of the volunteers, these changes in the experience of their own minds persisted:

“My mind works differently. I ruminate much less, and my thoughts feel ordered, contextualized.”


Several reported reconnecting to their senses:

“A veil dropped from my eyes, things were suddenly clear, glowing, bright. I looked at plants and felt their beauty. I can still look at my orchids and feel that: that is one thing that has really lasted.”

Some reconnected to themselves: “I had an experience of tenderness toward myself. At its most basic, I feel like I used to before the depression.” Others reconnected to other people:

“I was talking to strangers. I had these full long conversations with everybody I came into contact with.”

“I would look at people on the street and think, ‘How interesting we are’—I felt connected to them all.”


And to nature:

“Before, I enjoyed nature; now I feel part of it. Before I was looking at it as a thing, like TV or painting. You’re part of it, there’s no separation or distinction, you are it.”

“I was everybody, unity, one life with 6 billion faces. I was the one asking for love and giving love, I was swimming in the sea, and the sea was me.”


The second master theme was a new access to difficult emotions, emotions that depression often blunts or closes down completely. Watts hypothesizes that the depressed patient’s incessant rumination constricts his or her emotional repertoire. In other cases, the depressive keeps emotions at bay because it is too painful to experience them.

This is especially true in cases of childhood trauma. Watts put me in touch with a thirty-nine-year-old man in the study, a music journalist named Ian Rouiller, who, along with his older sister, had been abused by his father as a child. As adults, the siblings brought charges against their father that put him in jail for several years, but this hadn’t relieved the depression that has trailed Ian for most of his life.

“I recall the moment when this horrible cloud first came over me. It was in the family room of a pub called the Fighting Cocks in St. Albans. I was ten.” Antidepressants helped for a while, but “putting the plaster over the wound doesn’t heal anything.” On psilocybin, he was able for the first time to confront his lifelong pain — and his father.

“Normally, when Dad comes up in my head, I just push the thought away. But this time I went the other way.” His guide had told him he should “go in and through” any frightening material that arose during his journey.

“So this time I looked him in the eye. That was a really big thing for me, to literally face the demon. And there he was. But he was a horse! A military horse standing on its hind legs, dressed in a military outfit with a helmet, and holding a gun. It was terrifying, and I wanted to push the image aside, but I didn’t. In and through: Instead, I looked the horse in the eyes—and promptly started to laugh, it was so ridiculous."

“That’s when what had been a difficult trip really turned. Now I had every sort of emotion, positive, negative, it didn’t matter. I thought about the refugees in Calais and started crying for them, and I saw that every emotion is as valid as any other. You don’t cherry-pick happiness and enjoyment, the so-called good emotions; it was okay to have negative thoughts. That’s life. For me, trying to resist emotions just amplified them. Once I was in this state, it was beautiful—a feeling of deep contentment. I had this overwhelming feeling—it wasn’t even a thought—that everything and everyone needs to be approached with love, including myself.”


Ian enjoyed several months of relief from his depression as well as a new perspective on his life—something no antidepressant had ever given him. “Like Google Earth, I had zoomed out,” he told Watts in his six-month interview. For several weeks after his session, “I was absolutely connected to myself, to every living thing, to the universe.” Eventually, Ian’s overview effect faded, however, and he ended up back on Zoloft.

“The sheen and shine that life and existence had regained immediately after the trial and for several weeks after gradually faded,” he wrote one year later. “The insights I gained during the trial have never left and will never leave me. But they now feel more like ideas,” he says.

He says he’s doing better than before and has been able to hold down a job, but his depression has returned. He told me he wishes he could have another psilocybin session at Imperial. Because that’s currently not an option, he’ll sometimes meditate and listen to the playlist from his session. “That really does help put me back in that place."

More than half of the Imperial volunteers saw the clouds of their depression eventually return, so it seems likely that psychedelic therapy for depression, should it prove useful and be approved, will not be a onetime intervention. But even the temporary respite the voluneers regarded as precious, because it reminded them there was another way to be that was worth working to recapture. Like electroconvulsive therapy for depression, which it in some ways resembles, psychedelic therapy is a shock to the system—a “reboot” or “defragging”—that may need to be repeated every so often. (Assuming the treatment works as well when repeated.) But the potential of the therapy has regulators and researchers and much of the mental health community feeling hopeful.

“I believe this could revolutionize mental health care,” Watts told me. Her conviction is shared by every other psychedelic researcher I interviewed.

https://tonic.vice.com/en_us/article...ith-depression
 
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Psilocybin helps depressed patients re-connect to the world

New research sheds light on how psilocybin helps people overcome depressive symptoms. It appears to promote change from disconnection to connection, and from avoidance to acceptance. The drug can profoundly alter the way a person experiences the world by producing changes in mood, sensory perception, time perception, and sense of self.

Scientists have recently starting re-examining at whether psilocybin can be used in the treatment of mental illnesses, and the initial results are promising.

"Although many of us think of psychedelics as dangerous drugs, its time for a rethink," explains the study's corresponding author, Rosalind Watts of Imperial College London. When used carefully in clinical research settings, psychedelics have been reported to have a profoundly beneficial effect on many peoples lives. They are non-toxic, non-addictive, have very few side effects, and could potentially offer relief for people suffering from a range of psychological difficulties."

In the current qualitative study, which was published in the Journal of Humanistic Psychology, researchers interviewed patients from a clinical trial of psilocybin for treatment-resistant depression. (The initial results of the clinical trial were published in The Lancet.)

"Working in a community mental health team, I realised that conventional mental health treatments (antidepressants, CBT) were not working for many people. I also watched my best friend struggle with depression for many years," Watts told PsyPost.

"When she told me she was going to do an ayahuasca ceremony in Peru, I knew nothing about psychedelic therapy and thought it was a terrible idea. But she came back home with a sparkle in her eye that I hadn't seen for years, and told me that the depression had finally lifted. So I thought to myself this looks promising, lets find out more."

A number of themes emerged after the researchers questioned 6 women and 13 men who had undergone psychedelic therapy 6 months prior.

First, the participants described depression as a state of disconnection, which was reversed with psilocybin. Secondly, the psychedelic treatment helped them confront, process, and accept painful memories and thoughts. Thirdly, they described previous depression treatments as reinforcing the disconnection and avoidance they felt, while psilocybin worked in the opposite way.

"The reset switch had been pressed so everything could run properly, thoughts could run more freely, all these networks could work again. It unlocked certain parts which were restricted before," one participant explained.

"I got a wider perspective, I stepped back. It helped me appreciate that the world is a big place that there is a lot more going on than just the minor things that were going on in my head," another participant told the researchers.

A third remarked: "My previous treatments, talking therapy and meds, were next to useless, utterly useless. My experience of psilocybin has been very positive. I believe there is an unknown physiological and neurochemical change in me, I am absolutely convinced of that."

Or as another participant summed it up: Now there is a greater sense of were all in the same boat; less unease.

There were no serious adverse events reported during the psilocybin sessions. But a few participants had troubling psychological experiences which resolved themselves before the session was over. A few participants also wished they had received more psychotherapy following the drug session.

"The psychedelic experience is not to be taken lightly," Watts explained. "Participants in our study found psilocybin therapy to be preferable to other treatments they had tried, but that does not mean it was easy. Many of them had experiences of deep grief, sadness and fear, and relied upon the support of their guides to enable them to fully accept and process these emotions."

"It's very early days: the sample sizes are small, and we need to determine the role of placebo effects. Randomized control trials in the United States (John Hopkins, NYU) have started to address the question about placebo effects with similar promising findings. Upcoming randomized control trials in Europe will continue to investigate."


http://www.psypost.org/2017/08/study...ct-world-49407
 
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Are magic mushrooms the answer to depression?

A new study has found that ingesting small doses of psilocybin can actually reset the mind of a depressed person. Researchers gave 19 patients diagnosed with depression that did not respond well to conventional treatment, two doses of the psychoactive drug. And the findings offer hope for those with persistent depression: All 19 patients experienced decreased depressive symptoms one week after the second dose of the mushrooms. 47% percent reported decreased depression and a more relaxed mood five weeks after the treatment.

Dr. Robin Carhart-Harris, the head of psychedelic research at the Imperial College London who led the study, said it is the first time psilocybin has been shown to produce clear changes in brain activity in depressed people. He likened the effect of the mushrooms on patients to rebooting a computer, saying it was a kick start out of depression.

"Several of our patients described feeling reset after the treatment and often used computer analogies," he said. "One said he felt like his brain had been defragged, like a computer hard drive, and another said he felt rebooted."

The scientists also used MRI scans on the patients to track how ingesting the mushrooms changed the activity in their brains. According to the Independent, the drug stabilized activity in a part of the brain linked to depression.

Carhart-Harris study is just the latest that has suggested the key to fighting depression could lie in drugs that are currently illegal. In 2015, Professor David Nutt of the Imperial college teamed up with Amanda Feilding from the Beckley Foundation for a study, which found very promising results that LSD could help curb depression as well, according to The Guardian.

Author Ayelet Waldman even wrote a book called A Really Good Day that details her experience with taking microdoses of LSD to stabilize her mood. She talked to The Atlantic about her book, saying that taking small doses of the psychedelic drug every three days gave her really good days and helped her manage mental health issues. "It is not so much an acid trip as an acid errand," she said.

But as The New York Times reported, there is reason to be cautious regarding LSD; it is hard to know how potent any dose is, meaning someone could think they are taking just a little bit of a psychoactive drug, but ingest much more than they can handle.

And according to NBC News, LSD is viewed as too strong and long-lasting by many in the medical community. Instead, NBC wrote, "psilocybin and MDMA are the star players in psychedelic research at the moment, but still require additional research."

Carhart-Harris agrees that more studies are needed but added that he is excited about what has been found through research so far. "Larger studies are needed to see if this positive effect can be reproduced in more patients," he wrote on the Imperial College London website. But these initial findings are exciting and provide another treatment avenue to explore.

http://www.miamiherald.com/news/nation-world/world/article178668006.html#storylink=cpy\
 
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mr peabody

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Psychedelics as a life-changing treatment for depression

Scientist Robin Carhart-Harris wants to use psychedelic drugs to treat psychiatric disorders, and early results are promising. But can he convince big pharma and the public of their potential? For half a century, researchers interested in psychedelic drugs have inhabited the fringes of neuroscience. In the UK, Carhart-Harris is responsible for making this field of study respectable again. He has spent much of the past decade investigating the ways certain compounds give rise to uncommon conscious states. He thinks that LSD, psilocybin and DMT are powerful tools for accessing the brain. He also believes that psychedelics could potentially be used for treating mental illness. Current treatments for depression, anxiety and addiction can be life-saving, but they also have limits. About a third of people treated for depression never fully recover.

In 2006, a study by Francisco Moreno at the University of Arizona, Tucson, found that psilocybin reduced the symptoms of obsessive-compulsive disorder in nine patients. Then, in 2011, another study found that the same alkaloid significantly eased the anxiety of people dying of cancer. Each year, there are progressively more clinical trials with psychedelics. In 2016, three investigated the therapeutic action of psilocybin; another looked at ayahuasca.

A few years ago, Carhart-Harris undertook a study to see if psilocybin could be used to treat depression. He enlisted 20 people who had tried at least two courses of medication, so called treatment-resistant depressives. On average they had lived with the disorder for 17 years. On dosing day, each patient arrived at Imperial at 9am. After answering a questionnaire, they were led to a room that had been decorated to look more like a bedroom than a clinic, with drapes, flowers, music playing and electric lights that flickered like candles. After swallowing the psilocybin capsule, the patients were invited to stretch out on a bed. Two psychiatrists stayed in the room – Carhart-Harris believes that a soothing environment and psychological support before, during and after dosage is essential. People on psychedelics are psychically vulnerable; anxiety and paranoia are not uncommon.

When the results came in, they showed that the depression had reduced in all of the patients. (The results reflect the experiences of 19 people; one dropped out.) Three weeks after dosage, nine were in remission; after five weeks, all but one felt less depressed. For some of the participants, the treatment was life changing. “Before, I was like a beetle on its back, now I am on my feet again,” reported one. Another went out for dinner with his wife for the first time in six years, feeling “like a couple of teenagers”.

By studying LSD, Carhart-Harris has found that psychedelics do something unusual to the default-mode network. In a 2016 study published in the Proceedings of the National Academy of Sciences journal, he injected 20 healthy volunteers with either 75 micrograms of LSD or saline, a placebo, on two separate occasions. As the drugs kicked in, volunteers reported a “sense of eerie dread” as their anchorage in the world shifted. “Usually, depending on how it goes, there’s a bit of a kick back, there’s some anxiety.”

They then had two fMRI scans followed by a magnetoencephalography (MEG) scan. If the various scans pointed to the same mechanisms, the results would be stronger. Afterwards, volunteers responded to a questionnaire so that scan data could be correlated with experience. Statements included “sounds influenced things I saw” and “edges appeared warped”. In the brains of the volunteers, as the visual network became more connected, the blood flow in the default-mode network receded, indicating that it had lost its force. For the participants, this correlated with a change in the way they processed the world. The monkey mind had gone quiet.

In society we talk approvingly of “well-rounded” individuals and “getting ourselves together.” But a little chaos can be a good thing. In certain psychiatric disorders, the brain becomes entrenched in pattern. Someone with depression might have relentlessly negative thoughts about themselves; people with obessive-compulsive disorder get trapped in repetitive action.

Carhart-Harris believes psychedelics work like a reset button. He likes the analogy of shaking a snow globe. Under LSD, as the default-mode network disbanded, other segregated parts of the volunteers’ brains began communicating in an unpredictable way – a state of increased entropy. Psychedelics seem to break down entrenched ways of thinking by dismantling the patterns of activity on which they rest.

For instance, the most-prescribed class of antidepressants, selective serotonin reuptake inhibitors (SSRIs), raise levels of serotonin by blocking its natural reabsorption. When we are anxious or stressed, parts of the brain become overactive. Serotonin, a neurotransmitter, binds to receptors that are prevalent in those regions, the 5-HT1A receptors. Once bound to the receptor, serotonin initiates a signal that decreases the activity of the neurons. By keeping the 5-HT1A receptors doused in serotonin for longer than normal, SSRIs calm the stress circuitry. But they also blunt emotion more generally.

Psychedelics work on the brain rather differently. Though they also temper serotonin, they target the 5-HT2A receptors, concentrated in the cortex. Humans have vastly more cortex than other species, and the 2A receptors are dense in regions with human-specific traits such as introspection, reflection, mental time travel and the self itself.

Carhart-Harris thinks that when psychedelics disrupt the level of connectedness in the cortex they create space for insight and catharsis, and for patients, the process can be difficult. “You need to be able to say to people: this could be tough, it could at times be the worst experience of your life and you may see your worst fears staring at you in the face.” But he believes that the process can be freeing. “I think it’s possible to know your defences and know your insecurities and through knowing them not be at the mercy of their force.”

In 2017, Carhart-Harris gave a talk at a conference called Breaking Convention. Held at the University of Greenwich, the program listed 150 speakers from across the psychedelics spectrum. In the question-and-answer session, Carhart-Harris’s hand shot up. “Have you plotted the correlation between the affinity of psychedelics for the 5-HT7 receptor and the drug’s potency?” Ray said that he had not. “I think that you should, it’s important.” People fidgeted: this was not a hostile crowd.

Afterwards, Carhart-Harris left the conference and stopped in a local cafe for lunch. He was quiet. “How can you present such poor science? I think that people should be allowed to speculate. But the people who contribute to the mainstream perception that this research is pseudo-scientific undermine the field.”

The episode had tapped into something deeper. Research with drugs that are strictly controlled by the law is not straightforward. In the UK, LSD is a class A, schedule 1 drug. Heroin, which causes more harm to individuals and society than LSD, and is addictive, is in the slightly less prohibitive schedule 2 because it is a diamorphine, which can be used for medication. For a lab to stock LSD it must acquire a licence from the Home Office and meet certain criteria, such as having a fridge that is bolted to the wall. All this is demoralising. It took Carhart-Harris three years to execute the psilocybin-depression pilot.

Funding is also an issue. Big pharma companies are generally not inclined to back research into drugs that are illegal and un-patentable. Carhart-Harris’ studies have been largely financed by grants, donations and crowdfunding. In 2016, he applied to the Wellcome Trust, the largest charitable supporter of science in the UK. When he was shortlisted, he thought he stood a chance. He had meticulously designed the two trials he was hoping to carry out if he got the 1 million-plus grant. But one of the judges on the panel took issue with his suggestion that “well-being” should be a primary outcome. Carhart-Harris had the impression that the judge considered it flowery. He didn’t get the grant.

Of all the psychedelic drugs, Carhart-Harris believes that psilocybin is probably the closest to becoming legal. It has fewer stigmas attached to it, and in the brain, LSD is active for far longer, making it less practical in the clinic, while DMT is probably too powerful. The fact that psilocybin occurs naturally in mushrooms also helps. It could be marketed as a natural alternative to antidepressants. He believes that, one day, psychedelic therapy will be available on the NHS, just like SSRIs and cognitive behavioural therapy are today.

This spring, he plans to do another psilocybin study, this time directly pitching psychedelics against SSRIs. 50 people living with depression will receive either daily doses of escitalopram, an antidepressant, or a single shot of psilocybin, plus therapy. The contest is unequal, in one sense, because those taking escitalopram will have a regular reminder that they are taking medication. “Maybe psilocybin will work at least as well, that’s my prediction,” Carhart-Harris says.

"But imagine that psilocybin is more effective? That’s really quite…” he tails off. “That would be something.”

http://www.wired.co.uk/article/psychedelics-lsd-depression-anxiety-addiction
 
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mr peabody

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Microdosing LSD safer than taking antidepressants

When Ayelet Waldman embarked on an experiment to relieve her dark moods with tiny doses of LSD, she was understandably hesitant. But Waldman got some surprisingly reassuring advice from David Presti, a professor of neurobiology and expert on the effects of drugs on the brain at the University of California, Berkeley.

"I really think there's something going on with microdosing," Presti told her. "I think when people do get around to researching it, its going to be relatively easy to demonstrate positive effects that are better than conventional antidepressants, which are awful."

Is microdosing LSD really as safe as, or perhaps even safer than, taking anti-depressants? "Oh absolutely," Presti said.

Waldman recounts in her book, A Really Good Day: How Microdosing Made a Mega Difference in My Mood, My Marriage, and My Life, published January 2017 by Penguin Random House.

"The problem with prescription antidepressants is they have all kinds of side effects, and we have no idea, really, what they are doing," Presti said. "They cost a lot of money, and they are marketed with all kinds of flimflam."

What these drugs have on their side that LSD doesn't are controlled, clinical trials that demonstrate safety and efficacy of the drugs. And yet, the evidence is still quite mixed. Selective serotonin re-uptake inhibitors, or SSRIs, simply don't work for a lot of people with depression, and most users experience negative side effects, some of which can be quite nasty.

Meanwhile, psychedelic drugs are quite safe. We actually dont know how much LSD it would take to kill a person since no ones ever taken enough to find out. Bad trips happen, but they end when the drugs effects wear off, and the drug itself appears to cause no lasting harm to the mind or body. And the tiny amounts used in microdosing, which are too small to cause hallucinations or even make you feel high, the risk of negative outcomes might be almost inconsequential.

But do they work? No government-approved study has looked at the effects of microdosing on depression, procrastination, low energy, or any of the other ills it is purported to relieve. And yet, the volume of anecdotal evidence is substantial. James Fadiman and Sophia Korb, researchers with Sofia University, have collected thousands of reports from people who microdose, and they are overwhelmingly positive. A few people have reported to him that they tried it, and it didn't work or they didn't like it, and they stopped. But the vast majority report benefits, including surprising and unexpected things, like relief from chronic pain or the physical and emotional symptoms associated with the menstrual cycle.

The largest barrier to research is money. Pharmaceutical companies wont pay to research drugs they cant patent, and governments are wary of investing in science on illegal and controversial drugs. Philanthropy and crowdfunding are beginning to step up to fill the gap. A group called Fundamental is currently raising money for several research projects relating to psychedelic medicine, including one led by Amanda Feilding and the Beckley/Imperial Research Programme that might become the first to demonstrate in a controlled way the effects of LSD microdosing on mood and cognition.

Clinical research is expensive and time consuming, but if the early results are even close to as encouraging as the anecdotal reports, momentum will surely build. In the meantime, those curious or desperate enough will continue to find a way to experiment on themselves, Schedule 1 contraband or not.

https://www.inverse.com/article/3516...waldman-presti
 
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mr peabody

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Magic mushrooms may reset the brains of depressed patients

A new study adds to growing evidence supporting the benefits of psychedelics to treat mental illnesses. Researchers report psilocybin is effective in reducing symptoms for people with treatment resistant depression. The study reveals the compound resets the activity of a brain network associated with depression, helping to improve symptoms in patients for up to 5 weeks following treatment.

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 to treat a small number of patients with depression for 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 a 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.

Edmond Safra Professor of Neuropsychopharmacology and author of the paper, added: "Larger studies are needed, but these initial findings are exciting and provide another treatment avenue to explore."

http://neurosciencenews.com/magic-mu...ssed-patients/
 
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mr peabody

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Ketamine being used to manage Treatment Resistant Depression

Studies continue to pour in about the efficacy of Ketamine for Depression as well as chronic pain syndromes such as Reflex Sympathetic Dystrophy. That is why Ketamine is now being used to treat chronic nerve pain and symptoms related to Reflex Sympathetic Dystrophy (RSD) and Treatment Resistant Depression (TRD).

Reflex Sympathetic Dystrophy (RSD), also referred to as Complex Regional Pain Syndrome (CRPS), is a chronic condition involving a malfunction of the nervous system, including the peripheral nerves and brain. Though its mechanism is not clearly known, RSD results in a persistent arm and leg pain, and is usually triggered by a prior injury, surgery, stroke or other events. IV ketamine treatments are incredibly effective in alleviating chronic nerve pain associated with RSD by blocking NMDA receptors that signal the pain. In turn, when delivered in high dosages, IV ketamine infusions produce significant results in Treatment-Resistant Depression (TSD) when conventional methods have failed.

http://www.prweb.com/releases/2018/02/prweb15246708.htm
 
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mr peabody

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Can psychedelics ‘reconnect’ depressed patients with their emotions?

Imperial College London researchers report psilocybin can help to relieve symptoms of depression without the "dulling" of emotions associated with SSRIs. Psychedelics could help to maintain long term mental health for those with treatment resistant depression.

Working out if someone is happy, angry or afraid, from the look on their face, is a skill we may take for granted. For some people, however, such as those with chronic depression, this innate ability to pick up on and respond to emotional prompts like a facial expression can be disrupted, with the brain becoming oversensitive to negative stimuli.

While antidepressants drugs can help to combat the symptoms of depression for patients, they can dampen how the brain processes strong emotions, effectively turning down the dial on the hypersensitivity to negative emotions but also ‘blunting’ intense positive mood.

Now, findings from a small trial carried out at Imperial College London suggest that psychedelics, like magic mushrooms, may hold the key to sidestepping some of these effects in treating depression, by reviving the brain’s activity and effectively reconnecting patients with their emotions.

Previous research has shown that psilocybin – the active compound in magic mushrooms – may help to alleviate symptoms in patients with persistent depression by ‘resetting’ brain activity.

Treating depression

In a recent study, published in the journal Neuropharmacology, the Psychedelic Research Group at Imperial focused on the potential of the drug to change brain activity in key areas involved in emotional processing.

They found that after treatment with psilocybin, patients with depression who did not respond to conventional treatments, reported improvements in their mood and symptoms. However, the researchers also observed a stronger response to emotional faces with increased brain activity in an area called the amygdala – the almond-shaped region of the brain involved in processing emotions and which is known to play a role in depression.

The findings suggest an alternative pathway to tackling the changes seen in the depressed brain, which could potentially avoid some of the side effects seen with SSRIs, the most commonly prescribed antidepressants.

“Our findings are important as they reveal biological changes after psilocybin therapy and, more specifically, they suggest that increased emotional processing is crucial for the treatment to work,” explained Leor Roseman, first author of the study and a member of the Psychedelic Research Group.

Changing brain activity

In the small, open label trial – which means the patients knew what they were taking – a total of 20 volunteers with depression were recruited and asked not to take any antidepressant medication in the 2 weeks leading up to the trial. They were then given two oral doses of psilocybin alongside psychiatric support, receiving an initial low dose of the drug before taking a second, much stronger therapeutic dose a week later.

In order to capture changes in brain activity, 19 of the volunteers completed fMRI scans before and after the treatment. They were shown images of human faces that were either happy, scared or neutral, with the fMRI capturing their responses as changes in blood flow throughout different regions of the brain.

Following treatment, patients reported feeling emotionally re-connected and accepting, with one patient describing the experience as an ‘emotional purging’. Results from the scans reveal that patients had a stronger response to emotional faces (happy and fearful) following psilocybin treatment, particularly in the amygdala.

The authors highlight that follow up studies are needed to confirm the effects are directly related to the drug, rather than other factors, such as the psychological support provided during the trial or stopping their SSRIs.

Larger trials are now planned by the group, in which patients with depression don’t know whether they are receiving psilocybin, an SSRI or placebo, alongside parallel studies done in healthy non-depressed people. These studies will also aim to find out if psychedelic therapy has any lasting impact on activity in the amygdala and emotional processing.

“Having a healthy control group in future studies should be helpful in answering some of these questions,” said Roseman.

‘Mystical’ experience

In a second paper, published in the journal Frontiers in Pharmacology, Roseman and team used questionnaires to capture patients’ feelings about the quality of their experience under the psilocybin and how this related to their depressed changes.

One of the dimensions of experience the researchers looked at has been called the ‘mystical experience’, which includes feelings of unity, the loss of boundaries of the self, and transcending time and space during the treatment.

They found that the stronger a patient rated this experience, the greater their decreases in depressive symptoms weeks after treatment, suggesting the mystical element of their psychedelic experience may help them maintain long-term mental health.

The group is planning further studies which will compare psilocybin with a leading antidepressant for patients with treatment-resistant depression. The trials are set to begin early this year.

http://neurosciencenews.com/depressi...hedelics-8315/
 
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Ketamine-like psychedelics may offer new hope for Treatment-Resistant Depression

An interview with psychiatrist Carlos Zarate, MD

What do we know about the effectiveness of ketamine for depression?

Dr Zarate: There have now been many published clinical trials, and most of them have found that it is effective in treatment-resistant depression. The response and remission rates within a very short period of time are pretty prominent. It is efficacious even in treatment-resistant depression, meaning patients that have failed multiple antidepressants, and in many cases electroconvulsive therapy, which is one of the most effective treatments. And ketamine is efficacious in treatment-resistant bipolar depression, for which, unfortunately, we have very few treatment options. Further clinical research suggests that ketamine does have—although this is preliminary—very rapid antisuicidal efficacy and seems to have effects on anhedonia.

You’re among the researchers who are studying other glutamatergic modulators for depression. Why pursue these likely more expensive therapies when we could just use ketamine?

Dr Zarate: Ketamine, unfortunately, has certain limitations. When ketamine is administered intravenously, we see dose-related side effects, such as psychotomimetic and dissociative side effects. For example, one might experience a distortion of time, one might see trails of light or hear muffled sounds. There are also effects that result in transient elevations in blood pressure and heart rate, temporary impairments of cognition. There is the risk, with continued indiscriminate use, of hepatotoxicity and also reports that it might lead to a cystitis. In terms of oral administration, it’s poorly absorbed. So although it will likely have an important clinical use in people with treatment-resistant depression, it would be very important to come up with drugs that are better tolerated [that] one can even give in people who do not have treatment-resistant depression. Newer treatments would also not have the risk of abuse potential that occurs with ketamine.

Are other agents that are in the pipeline with the same mechanism of action as ketamine?

Dr Zarate: The original preclinical evidence linking the NMDA receptor blocking or antagonism has led to a decade of preclinical and clinical studies with NMDA receptor antagonists, with the hopes of achieving the rapid antidepressant effects of ketamine, but without the side effects or risk of abuse. But the efforts to develop better or alternate versions of ketamine have been fraught with many difficulties from the start. Several broad and subunit selective receptor antagonists either failed or did not demonstrate the efficacy in treatment-resistant depression, or showed minimal efficacy. This has led to questions about whether preclinical studies [that] demonstrated the promise of NMDA receptor antagonism will actually lead to better treatments. So with that in mind, additional targets have been looked at in terms of its mechanism of action and some postulate that enhanced AMPA receptor throughput might be implicated in rapid antidepressant-acting agents.

For instance, there is a drug called rapastinel, an NMDA receptor modulator, that seems to have rapid antidepressant effects with a better side effect profile [than ketamine] that is currently being developed in treatment-resistant depression. Preclinical studies suggest that it also activates AMPA receptors.

There is another NMDA receptor modulator called AV-101. It seems to block the glycine site that is outside of the NMDA receptor channel. AV-101 is currently in the clinic and is being tested for treatment-resistant depression. Animal studies suggest it would have acute, rapid antidepressant effects, and without the side effects of ketamine.

Building on this work, our group in collaboration with other laboratories began to explore the cellular and molecular effects of ketamine, and we have found that the effects appear to be largely NMDA-receptor independent. Blocking an NMDA receptor appears to be linked to the side effects of dissociation and to the increases of blood pressure, and potentially to the abuse potential.

What about esketamine?

Dr Zarate: The current form of ketamine is what we call racemic ketamine. That means it’s formed by 2 isomers; enantiomers R [arketamine] and S [esketamine]. We have known for many years now that esketamine is much more potent as an anesthetic analgesic agent than arketamine. [Esketamine] is now being developed for intranasal use. You could have fewer side effects. It’s currently in phase 3 studies. The phase 2 studies have been encouraging, showing that intranasal esketamine produces rapid antidepressant [effects], and suggestsantisuicidal ideation effects, as well.

Do you think these agents will potentially change the landscape of depression and treatment?

Dr Zarate: The mere fact of having rapid-acting agents would minimize the cumulative time ill—that is time that our patients spend in depression—thus minimizing the consequences of unremitting depression. And, in theory, [they] would minimize the impact of depression on brain and body health because depression not only has effects on brain, but it does have significant effects on body that are deleterious either by altering immune or inflammatory functions. So a rapid-acting agent that is robust will get our patients back to their lives with minimal disruption and hopefully restore hope.

Could these agents even potentially replace SSRIs?

Dr Zarate: That’s a very good question. Because of its side effect profile and its risk for abuse, it would be very hard to bring ketamine earlier into the decision tree—that is, when somebody’s experiencing their first or second episode of depression. But imagine if you were to have a ketamine without the abuse potential or the side effects. Very early, within the first episode of depression, or even [the] second, one could probably intervene. Some people have dozens of major depressive episodes that wipe away years of optimal function and ability to work, to contribute to society, have a family. Then imagine you’re intervening very early in depression. You will eliminate all that time ill.

Are there any other hallucinogens that you’re interested in?

Dr Zarate: We are carefully following the wonderful work by our colleagues around the world. Ayahuasca, for example, is being reported to have rapid antidepressant effects and to be useful for treatment-resistant depression. Psilocybin [is] out there as well. LSD for either PTSD or anxiety. MDMA or ecstasy is another one. In a controlled research setting, we may be able to study patients or individuals who are exposed to these [agents] using brain imaging or other techniques to see what precisely they do in the brain. So I’m in favor of trying to learn as much as we can, but as long as it’s ethically and safely done.

Is there a way to sum up why hallucinogens may help for psychiatric conditions?

Dr Zarate: Some have suggested that [they] turn on or off certain circuits at the precise and important time. Some have used the lay term of rebooting the brain. And you can imagine that maybe certain circuits have been stuck and functioning in the wrong manner, but treatments such as hallucinogens, electroconvulsive therapy, scopolamine—which is another treatment [that] seems to have effects in depression—ketamine, might temporarily reboot certain aspects of the brain function at specific circuits. It seems that plasticity and connectivity might be very important aspects of how these drugs might work. Whether they do it in a similar way or dissimilar way, we don’t know yet.

https://medworksmedia.com/ketamine-l...nt-depression/
 
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