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DEPRESSION | +80 articles

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Can psilocybin treat severe depression?

by Barbara Geller, MD | NEJM Journal | 3 Nov 2017

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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Ketamine relieves depression by restoring damaged neural connections

CBC Radio | 13 Apr 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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Psychedelics as antidepressants

by Austin Lim | Scientific American | 30 Jan 2021

The treatments of the future may arise from a long-stigmatized class of drugs.

The first modern antidepressants were originally tuberculosis medications, created from leftover World War II rocket fuel. In 2019, the Federal Drug Administration approved Spravato for depression, a chemical that was originally a veterinary anesthetic and later used recreationally as a club drug.

Why shouldn’t tomorrow’s antidepressants also come from unexpected sources?

Rising COVID infection rates and death tolls lead millions to worry about their own health and safety as well as that of loved ones. These concerns compound daily stressors that can include grief, economic insecurity, job loss, food and housing insecurities—all factors that are contributing to rising suicide rates.

The reliable joyful distractions such as weddings, family gatherings and spontaneous get-togethers are on hold. Unsurprisingly, anxieties combined with decreased human interaction have led otherwise healthy people to depression and a sudden increase in prescriptions of antidepressant medications.

And for some people, these drugs are effective at keeping a person out of their persistent cycle of negative thoughts, a symptom that defines clinical depression. As of 2018, nearly one in eight Americans use antidepressants. Unfortunately, more than a third of patients are resistant to the mood-improving benefits of medicine’s best antidepressant drugs.

These people are not completely out of options, and science is steadily working to find ways to help them. There are chemicals already out there that can restore their mood balance, and in some cases, even save their lives. Unfortunately, these drugs have a name that wrongfully conjures up controversy and alarmist news headlines: hallucinogens.

Chemicals such as lysergic acid diethylamide (LSD), psilocybin (magic mushrooms) and dimethyltryptamine (DMT) are more accurately called “serotonergic psychedelics” among the neuroscience community. Outside of this group however, many people don’t think of these compounds as antidepressants to be distributed by white-coat-wearing psychiatrists. Instead, they imagine whimsical blotter papers passed around by washed-up hippies at Grateful Dead concerts.

And yet, researchers in the U.K. have already been given the green light to begin clinical trials for using DMT for treating depression.

To a neuroscientist whose focus is the striatum, a brain area involved in complex conditions ranging from depression to addiction, it’s evident that these drugs have tremendous promise for a safe, happier future.

Many states are looking to reevaluate the legal status of psychedelics. This is a start at improving the public perception of psychedelic use, which can ultimately encourage more to seek psychedelic therapy in psychiatric practice.

Denver, Oakland and Santa Cruz, Calif., are among the first American cities to legalize psilocybin. The recently approved Measure 110 in Oregon decriminalizes LSD. Legislation has been moving forward in New Jersey, Washington, D.C., and Vermont to downgrade the severity of punishments for possession of psychedelics.

All of these measures represent a reframing that looks at the science of the drug rather than a set of beliefs about the drug.

The stigma against psychedelics could be a result of its status as a controlled substance. Since its criminalization in the 1960s and subsequent vilification by the media, LSD was seen as a public nuisance and enemy. But prior to this, the National Institutes of Health funded more than 130 studies to explore the benefits of psychedelic therapy.

Today, psychedelics still fall into the federal classification of Schedule I drugs, which carry the highest penalties associated with their possession and use. Because of government regulations, controlled substances are difficult to study, even in a clinical setting.

But this hasn’t completely stopped researchers from examining their benefits. Recent studies have arrived at several noteworthy conclusions.

First and foremost is the safety of these drugs. At the correct doses, psychedelics are well tolerated, producing only minor side effects such as transient fear, perception of illusions, nausea/vomiting or headaches. These fleeting side effects pale in comparison to the severity of commonly prescribed antidepressants, which include dangerous changes in heart rate and blood pressure, paradoxical increases in suicidality, and withdrawal symptoms.

As far as outcomes go, psychedelics in combination with psychotherapy are remarkably efficient at treating depression. Compared to selective serotonin reuptake inhibitors, or SSRIs, the current gold standard in antidepressant medication, psychedelics have a faster effect on patients, sometimes effective with only a single therapy session. On the other hand, anti-depressants often take weeks before a reversal of depression is observed.

Psychedelics also have a longer-lasting effect than an SSRI regimen. A 2015 study of more than 190,000 Americans demonstrated that past history of psychedelic use decreases the odds of suicidal thoughts or actions over the course of a lifetime, whereas a history of other drug use (such as sedatives or inhalants) increases these risks.

Psychedelic therapy may reverse the symptoms of other complex psychiatric conditions. Evidence suggests that anxiety, obsessive-compulsive disorder and tobacco or alcohol misuse disorder may also be treated with psychedelics.

It is still unclear how much these treatments will cost, but one study predicts that psychedelic therapy for post-traumatic stress disorder could save each patient $100,000 over a 30-year window.

Putting aside preconceptions about these drugs, if objectively comparing their properties to the other drugs that someone can easily buy at a convenience store, their safety becomes apparent.

Psychedelics have extremely low addictive potential. Tobacco is regarded as one of the most addictive substances, ranked just behind heroin and cocaine—not to mention the significant shortages in life span that make tobacco use the number one leading cause of preventable death.

Alcohol use contributes significantly to risk of harm to oneself and others. However, using alcohol and using tobacco products are both widely perceived as socially acceptable. “Why aren’t you drinking?” is a common (yet intrusive and unfair) question in social circles.

They are also very safe compounds with low toxicity profiles. A woman who took a dose of LSD 550 times higher than a typical dose lived without any medical attention; imagine the life-threatening consequences of drinking just five times as much alcohol as normal. (Not only did she survive, but she also noticed a significant reduction in her chronic pain condition, and was able to decrease her usage of morphine as part of her pain management treatment.)

Certainly, people have been injured while taking psychedelics. Most famously, Diane Linkletter, daughter of radio and TV personality Art Linkletter, tragically died by suicide in 1969, presumably while taking LSD. Following her death, Linkletter became a prominent voice in the anti-LSD movement. It is unclear whether LSD led her to suicide, but no drugs were detected in her autopsy report.

Other documented cases include instances of people using psychedelics of questionable purity or in unknown doses, and almost always in conjunction with other drugs.

Psychedelics given in a therapeutic context are pure substances, created by trained chemists and pharmacologists. Dosages are therefore carefully calculated to produce the minimum necessary therapeutic effect.

Equally importantly, these drugs are delivered under close supervision by behavioral psychiatrists who carefully monitor the mindset and the surroundings of the patient. This limits the outside influences that could cause the patient to behave unpredictably, hurting themselves or others.​


Austin Lim​

Austin Lim, Ph.D., is a professor of neuroscience at DePaul University and a Public Voices Fellow through The OpEd Project. His degree is from the University of Chicago.

 
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Can LSD treat depression?

by Rachel Nania | WTOP News } 7 Feb 2017

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.

*From the article here :
 
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Ketamine hailed as 'a miracle for treating severe depression'

by Sara Solovitch | Washington Post } 1 Feb 2016

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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The scientific evidence for using ketamine to treat acute and chronic depression

by Psychedelic Times Staff | 7 Apr 2017

One of the biggest downfalls in the conventional treatment of depression is the amount of time it takes for the drugs to take effect. Conventional antidepressants like SSRIs largely target the serotonin system—which has long been thought to be the hormone responsible for depression—but the medical community acknowledges that these medicines are far from ideal. In addition to unwanted side effects, serotonin-based therapies don’t work for everyone, and most importantly, they can take up to 2-3 weeks for their effects to be felt.

The lag in effect has caused researchers to reevaluate the way depression works. The treatment gap inherent in many antidepressants suggests that therapies like serotonin target systems further removed from the central functions of depression in the brain. Over time, the effects of serotonin eventually reach their proper target, but the delayed effect implies that a serotonin imbalance is not the primary cause of depression.

Even for people struggling with treatment-resistant depression, ketamine has been known to bring a depressive episode to a halt almost immediately—usually within a day or even a few hours of treatment. Recent research into this ability backs up the evidence that we may be targeting the wrong parts of the brain. But beyond brain chemistry, ketamine’s transpersonal qualities trigger a breakthrough experience that helps people get to the root of their depression.

The evidence for treating depression with ketamine

Just how exactly ketamine works is still unclear, but research suggest that 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, while few, 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—evaluated under the Hamilton Depression Inventory—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.”

What you can expect from ketamine-assisted psychotherapy

By now, you might be curious about treating your depression with ketamine, but what exactly can you expect from a ketamine session? Depending on the dose, the feelings that arise during the experience can range from empathogenic to ego-dissolving, and the psychoactive properties of ketamine mean there is the possibility of seeing visions similar to what you’d experience with other psychedelics. But while the actual experience can be intense, it’s the feelings that linger in the aftermath of ketamine that make it so promising as an antidepressant.

Like the participants in the NIMH study, most people experience an immediate break from depressive symptoms and are left with feelings of love, compassion, and peace in the days following. A study published in the International Journal of Transpersonal Studies termed this phenomena as ketamine’s “psychedelic afterglow,” a state characterized by people’s reports of “increased psychological clarity, feelings of being cleansed, increased confidence, feelings of happiness and well-being, state of inner peace, feelings of detachment, motivation to improve oneself, and strong feelings of empathy for everyone.” These effects are usually most pronounced in the days afterward but can last weeks or even months after treatment.

However, not all treatments are created equal, and leading experts on ketamine are quick to point out that, ideally, ketamine should always be used in conjunction with psychotherapy for a lasting benefit. The same study that described ketamine’s psychedelic afterglow also outlines the three basic stages of ketamine-assisted psychotherapy (which will look very familiar to anyone versed in the principles of psychedelic therapy): preparation, administration, and integration.

In the preparatory phase, a counselor or therapist works with the individual to determine the appropriate dose and set expectations for the experience, explaining that ketamine may induce personal insights that can sometimes be intense. In the next step, the medicine is actually administered in a clinical setting, with medical staff on hand in case of an emergency. In the final integration stage, which begins as soon as the session is over, a therapist works with the person to integrate the insights they’ve gained from the experience as it relates to their depression. Having a therapist on hand before, during, and after the experience creates a network of support that helps individuals uncover and process any deeply-rooted psycho-emotional issues the treatment brings up.

Using ketamine responsibly

While ketamine is not known to be biologically addictive or to cause death or injury from acute administration, there are some risks you should be aware of before undertaking a ketamine experience. The periodic use of ketamine hasn’t shown to have permanent effects, but continuous use can lead to psychological dependence, and preliminary research suggests that the continued use of ketamine at high doses may damage the urinary tract and kidneys. Working with a certified clinician or therapist can help you avoid these risks and get the most benefit from your ketamine experience.

As a dissociative anesthetic, ketamine has powerful analgesic, anxiolytic, and anesthetic properties, which make it ideal for people dealing with depression that arises from chronic pain. Beyond these physiological effects, the unique psychoactive properties of ketamine can—with the support of psychotherapy—help individuals identify and address any long-held trauma that may be contributing to their depression. Rather than simply diminishing the symptoms of depression, ketamine’s transpersonal qualities offer the chance at a breakthrough experience that can jump-start your recovery.

 
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Albert Hofmann

The two things psychedelics do for people with depression

by Michael Pollan | VICE | 22 May 2018

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

by Eric Dolan | PsyPost | 2 Aug 2017

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?

by Josh Magness | Miami Herald | 14 Oct 2017

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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Psychedelics as a life-changing treatment for depression

by Nicola Davison | WIRED | 12 May 2018

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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Microdosing LSD safer than taking antidepressants

by Jacqueline Ronson | INVERSE | 7 Aug 2017

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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Magic mushrooms may reset the brains of depressed patients

Imperial College London | Neuroscience News | 13 Oct 2017

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.

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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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Psychedelics are transforming the way we understand depression and its treatment

by Robin Carhart-Harris | The Guardian | 20 Apr 2021

Mental illness is the 21st century’s leading cause of disability, affecting an estimated billion people across the world. Depression is the number one contributor: more than 250 million people have this condition globally. The number of people prescribed antidepressant medications, the first-line treatment for depression, increases each year, and the market for them is valued at approximately $15bn (£11bn). Yet depression prevalence rates have not decreased since accurate record-keeping began. One reason for this paradox is the failure of science to adequately explain how and why depression occurs.

Psychiatry has long sought and failed to find a compelling biomedical explanation for depression. One popular idea, the “serotonin hypothesis”, was inspired by the observation that drugs that increase the activity of this naturally occurring brain chemical have antidepressant effects. First produced in the mid-1980s, Prozac (chemical name fluoxetine) is the most famous selective serotonin reuptake inhibitor (SSRI) antidepressant. Of these, Cipralex (escitalopram) is one of the newest and best performing.

While the serotonin hypothesis has some scientific foundation, it has been massively oversold by the pharmaceutical industry. This has stoked scepticism about one-sided, neurochemical explanations for depression, which suggest, for instance, that people are depressed because their serotonin levels are too low. The latest evidence indicates that SSRIs such as escitalopram are only marginally more effective at treating depression than a placebo, with response rates tending to average around 50-60%. Other limitations of SSRIs include poor compliance, symptoms when people stop taking them, unpleasant side-effects and a sluggish onset of antidepressant effects.

I began investigating an alternative to antidepressant medicines about 15 years ago as part of my PhD. Psilocybin, a constituent of “magic mushrooms”, is a classic psychedelic. When taken in high doses, it profoundly alters the quality of one’s conscious awareness, producing complex visions and releasing suppressed memories and feelings. After completing a series of studies involving psilocybin, including an earlier trial of its effects among people with treatment-resistant depression, I set out to design a more rigorous test that might help to contextualise the drug’s therapeutic promise. The resulting trial was completed last year, and its findings have now been published in the New England Journal of Medicine.

It was a double-blind, randomised, controlled trial involving 59 people with moderate to severe depression. They were randomly allocated to one of two treatment groups: one in which the main treatment was a six-week course of the conventional SSRI antidepressant, escitalopram, and another in which the main treatment was two high-dose psilocybin therapy sessions.

Those in the escitalopram group did about as well as one would expect, based on previous SSRI trial data and the relatively short, six-week course. Across four different measures of depressive symptoms, the average response rate to escitalopram at the end of the trial was 33%. In comparison, psilocybin worked more rapidly, decreasing depression scores as early as one day after the first dosing session. At the end of the trial, the average response rate to psilocybin therapy was more than 70%.

While we suspected that psilocybin might perform well compared to the SSRI, we had not expected it to perform as well as it did. In fact, the initial main hypothesis for this trial was that the psilocybin therapy would have superior effects on psychological wellbeing, but not on depression severity scores. This prediction was generally supported, but people in the psilocybin group also showed evidence of greater improvements across most depression measures, as well as anxiety symptoms, work and social functioning, suicidal feelings and the ability to feel emotion and pleasure.

Both groups experienced similar levels of side-effects, but the escitalopram group experienced worse drowsiness, dry mouth, sexual dysfunction and anxiety. In the psilocybin group, the most prevalent side-effect was a mild to moderate headache one day after dosing. Six-month follow-up work is now under way to test our prediction that the positive effects seen in the psilocybin group will be longer lasting.

So why does psilocybin appear to be a more successful treatment for depression than a typical antidepressant? Brain imaging data from the trial, alongside the psychological data we collected, appears to show that while SSRIs dampen emotional depth by reducing the responsiveness of the brain’s stress circuitry, helping to take the edge off depressive symptoms, psilocybin seems to liberate thought and feeling. It does this by “dysregulating” the most evolutionarily developed aspect of our brain, the neocortex. When this liberation occurs alongside professional psychological support, the most common outcome is a renewed breadth of perspective. Psychedelic therapy seems to catalyse a type of psychological growth that is conducive to mental health, overlapping in many respects with spiritual growth.

The most exciting aspect of this trial is a sense that we are on the verge of a paradigm shift in mental healthcare linked to an improved understanding of the origins of depression, and how we can most effectively treat it. In my view, this shift will take us away from an outdated and myopic “drug-alone” perspective that has dominated psychiatry for several decades, and towards a multi-level “biopsychosocial” model. This model sees the symptoms of depression as an adaptive response to adversity, with decipherable – albeit complex – psychosocial causes. Psychedelics can treat depression by activating powerful brain states that have evolved in humans to catalyse deep psychological change. When these “hyper-plastic” states are combined with a nurturing environmental context, defensive habits of mind and behaviour can undergo a healthy, potentially enduring revision.

These ideas aren’t confined to the academy. Since I wrote about developments in psychedelic medicine for the Guardian last year, the US state of Oregon has voted in favour of legalising psilocybin therapy, a senate bill has been introduced to decriminalise psychedelic drugs in California, and policies are also being reviewed in New York, Washington DC, New Jersey, Florida, Canada, Australia and the UK. The Australian government has pledged A$15m (£8.5m) to psychedelic research, while two new research centres dedicated to studying psychedelic medicine have been announced at major US universities. Of course, our study certainly isn’t a licence for people to self-medicate. But these are exciting developments – and show that governments are recognising the benefits of psychedelic therapies.

Many obstacles have already slowed the progress of psychedelic medicine, and there will doubtless be more, from litigation issues to moral objections. If we’re to achieve a population-level improvement in psychological wellbeing, this road won’t be easy. Despite the recent landmark trial, I do sometimes wonder if we will make it at all. One thing I am more certain of, however, is that we must try.

 
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Can psychedelics ‘reconnect’ depressed patients with their emotions?

Imperial College London | Neuroscience News | 15 Jan 2018

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 saved my life’

by Ryan Castillo | Dancing Astronaut | 21 Feb 2018

Ketamine has undergone promising clinical trials in Australia and America to treat depression using IV drips with micro-doses of Ketamine.

An anesthetic drug, Ketamine is now increasingly being used as a revolutionary — and sometimes life-saving — medication for those struggling with treatment-resistant depression, who are chronically suicidal or experience frequent psychotic episodes. After turning to every other treatment on the market, including over 40 sessions of electroshock therapy, one member of New Zealand’s trials, Jemima Lomax-Sawyers, associates Ketamine with saving her life:

“I am so much more stable than I was a year ago. Stable to the point that I am able to make decisions about my wellness that I would not have been able to make in the past…Things feel lighter inside my head. I have more energy, I can concentrate better.”

That is why Sawyers and others like her are extremely concerned that New Zealand’s only Ketamine Clinic would no longer be accepting new patients, and that current patients may be taken off its lists once new treatment plans are agreed upon with the country’s Ministry of Health.

“For many of us, ketamine was our last chance, our only chance for living a life out of hospital, or even for living full stop,” says Sawyers. “Ketamine gave me some hope back: the glimmer that I might actually be able to live life without the constant worry of relapse, hospitalisation, then having to pick myself up and put all the pieces back together again and again and again.”

http://dancingastronaut.com/2018/02/...ne-saved-life/
 
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Magic mushrooms: Treating depression without dulling emotions

by Ana Sandoiu | Medical News Today | 16 Jan 2018

Two new studies confirm the hypothesis that the psychoactive compound found in "magic mushrooms" may be a useful treatment for depression, avoiding some of the side effects of conventional antidepressants.

At Medical News Today, we have reported on a range of studies that pointed to psilocybin — the psychoactive substance in "magic mushrooms" — as a potential remedy for depression.

Two such studies showed that the psychoactive compound can reduce feelings of anxiety and depression in people with advanced cancer, while another small trial suggested that the compound could succeed where previous depression treatment has failed.

Treating depression can be challenging not only because some depression types are treatment-resistant, but also because existing therapies have a range of unwanted side effects.

One such adverse effect frequently reported by people living with depression is the "emotional blunting," indifference, or apathy that comes with taking antidepressants.

A new study — which was carried out by researchers at Imperial College London (ICL) in the United Kingdom — suggests that magic mushrooms could treat depression while avoiding these side effects.

The new research consists of two studies, both of which were led by Leor Roseman, a member of the Psychedelic Research Group at ICL.

Participants felt 'emotionally reconnected'

In the first study, published in the journal Neuropharmacology, 20 people diagnosed with moderate to severe depression participated in two dosing sessions with psilocybin.

Using functional MRI (fMRI), the team scanned the brains of the participants while they looked at pictures of emotive expressions. The scans were taken before and after each drug intervention.

In order to assess the impact of the treatment on depression, the subjects were all provided with psychological support before, during, and after the intervention.

After the treatment, the participants reported feeling better, "emotionally re-connected, and accepting."

The fMRI scans revealed a stronger brain response to emotive faces. Specifically, the scientists saw more activity in the brain's amygdala, an emotion-processing area associated with depression. The study authors explain:

"Based on the present results, we propose that psilocybin with psychological support is a treatment approach that potentially revives emotional responsiveness in depression, enabling patients to reconnect with their emotions."

Roseman comments on the new findings, saying they "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."

But the authors also caution that more research is needed to establish firmly whether the positive effects were due to the psychoactive compound itself, the psychological counseling, or the interruption of the antidepressant treatment the subjects had been on before the study.

"Having a healthy control group in future studies should be helpful in answering some of these questions," Roseman admits.

'Mystical experience' improves efficacy

The second paper, published in the journal Frontiers in Pharmacology, examined whether or not the quality of the psychedelic experience was linked with the success of the treatment.

Roseman and colleagues gave questionnaires to another group of 20 volunteers who underwent two treatment sessions with psilocybin.

The researchers looked at the so-called feeling of oceanic boundlessness, which is a "mystical-type experience" involving feelings of unity and a lack of boundaries between the self and the universe.

The study revealed that the more strongly the participants felt this experience, the better was their mental health in the long-term.

Depressive symptoms subsided, and the mental benefits lasted for weeks after the treatment in participants who reported a strong mystical experience.

"Future therapeutic work with psychedelics may consider investigating ways which enhance mystical-type experience and reduce anxiety, given the growing evidence that this serves the efficacy of the treatment model," conclude the authors.

The researchers say they plan on carrying out larger trials with a healthy control group in which the effects of psilocybin could be compared with an existing antidepressant.

"We also want to investigate how the amygdala responds a longer time after treatment," Roseman adds, "which will inform us about longer-term effects — compared to the first study, which was only looked at 1 day after the therapy."

Additionally, in light of the findings of their second study, the group recommends that future trials with psychedelics should aim to enhance the "mystical" aspect of the experience.

https://www.medicalnewstoday.com/articles/amp/320636
 
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New clues in the psychedelic treatment of depression*

by Patrick Smith | The Third Wave | May 10 2018

Depression, despite affecting millions worldwide, is still a condition that we don’t fully understand.

In fact, we understand it so poorly that typical pharmaceutical treatments indiscriminately target whole neurochemical systems, resulting in unstable effectiveness and a host of side-effects.

Up to 44% of people suffering from depression have not found relief from typical antidepressant therapies. Even patients who find some form of relief from the usual prescribed antidepressants need frequent doses, sometimes causing unpleasant side-effects, and these drugs often lose their effectiveness after several years of treatment.

But where pharmaceuticals are failing, psychedelics could be a new hope.

Psilocybin mushrooms and depression

Recent large studies, using psychedelics such as psilocybin mushrooms, have shown that a single moderate dose of these substances can significantly reduce depression scores in patients with treatment-resistant depression. The antidepressant effect of psychedelics also last much longer than typical treatments, with reduced depression scores maintained for several months after treatment.

A big part of the reason psychedelics seem to be so effective at treating depression is due to their ability to induce a ‘mystical’ experience. Participants who describe a highly spiritual or personally meaningful experience with psilocybin were more likely to have reductions in depression scores, according to one study – and the strength of the mystical experience has also been directly linked to psychedelics’ anti-addiction effects.

It appears there is something special about having a transcendental encounter during treatment. Linking this powerful effect of psychedelics to their mechanisms of action in the brain is helping scientists start to piece together the way that depression works, and potentially the best ways of treating it.

A recent review, from psychedelic icons Dr Robin Carhart-Harris and Professor David Nutt, presents a new, all-encompassing model of depression, that explains how both typical antidepressants and psychedelic therapies could help treat depression in different way.

So what does this mean for our use of psychedelics?

Although this ‘bipartite’ theory of depression highlights how typical antidepressants may work, it also shows that the most important treatment of depression lies through the 5-HT2A receptor system. And psychedelics activate this receptor system with inscrutable precision.

The review also highlights the immense importance of environment and context during a psychedelic experience. Because psychedelics increase cognitive flexibility, and make us more sensitive to external stimuli, their therapeutic benefit relies heavily on the way in which they’re administered.

So before people dive in and take a big dose of psilocybin to self-treat their depression, they should consider why they’re doing so, and whether they’re doing it in an optimal environment. People should never take psychedelics in vulnerable situations, unfamiliar locations, or without sober people they trust to guide and look after them.

Ideally, psychedelic therapy will always be administered by professionals. However, until an accessible and affordable framework for psychedelic therapy is created, people should educate themselves about responsible use. There are plenty of resources available to help people learn about safe and effective psychedelic journeying; including an extensive microdosing course for those not ready to jump in at the deep end of psychedelic healing.

*From the article here :
https://thethirdwave.co/new-clues-ps...nt-depression/
 
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The depression drug researchers are calling "the most important discovery in half a century'


- Ketamine is emerging as a potential new drug for depression — the first of its kind in 35 years.
- Johnson & Johnson plans to file for FDA approval of a nasal spray formula called esketamine this year.
- On Saturday, they presented new research suggesting the drug worked well alongside a traditional antidepressant for a month.
- Like any drug, however, it also had some unpleasant side effects.
- Other companies are also going after ketamine-inspired antidepressants.

Ketamine, which has been called "the most important discovery in half a century," just got a step closer to becoming the first new depression drug in 35 years.

Johnson & Johnson, one of the pharmaceutical companies pursuing the drug's fast-acting antidepressant qualities, presented some promising new research on Saturday that could raise the drug's profile as a potential treatment for the condition.

It's a dramatic departure for a compound that most people know either as a surgical anesthetic or a party drug. And it's a seemingly welcome one, according to physicians and psychiatrists who say they've grown tired of giving patients the same mediocre drugs for the past four decades.

Johnson & Johnson isn't the only drugmaker that's hot on the ketamine trail. Allergan is in the last phase of clinical trials with a drug that acts on the same receptor as ketamine, and San Francisco drugmaker VistaGen is studying a similar ketamine-inspired drug.

J&J's version of ketamine is a nasal spray made with a compound called esketamine, the chemical mirror image of ketamine. In its latest clinical trial, the company's neuroscience partner, Janssen Research, wanted to show that the spray was safe, well tolerated, and superior to both a placebo and a traditional antidepressant.

To do it, the researchers had 236 adults with treatment resistant depression — known as one of the hardest forms to treat — take a traditional antidepressant for four weeks alongside a nasal spray. Only half of them got a spray with J&J's drug in it; the other half got a placebo.

Their results were promising: The people who got the real spray saw significantly better improvements in their depressive symptoms than those who got the placebo, over the course of 28 days. More importantly, it is also the first time a novel treatment has come out on top even when compared to a traditional antidepressant drug.

The findings come roughly a month after J&J published the results of a small, preliminary version of this study which suggested that over the course of a single day, the spray and traditional antidepressant combo was better than a placebo and traditional antidepressant combo. That study, however, suggested the results diminished over the course of four weeks, while the longer and larger study suggests they might not.

The emerging science on ketamine

Depression is one of the world's leading causes of death. Current treatments for depression, which take roughly five weeks to begin to take effect, may not work well in up to 80% of the people who get them.

Most existing antidepressants, from Abilify to Zoloft, work by plugging up the places where our brain takes up serotonin, a chemical messenger that plays a key role in mood. The result is more free-floating serotonin and, in some people, relief from a dark curtain of depressive symptoms.

Like serotonin receptors, those for NMDA play an important role in our mood and help keep our emotions in check. But NMDA receptors also keep our brain's synapses — the delicate branches that serve as the ecosystem for our thoughts — flexible and resilient.

Potentially because of depression's damaging effects on these brain switches, it appears to cause our synaptic branches to shrivel up and in some cases even to die. Scientists think existing antidepressants send help to those branches indirectly over time by way of serotonin. Ketamine, by contrast, delivers its aid directly to the source, plugging up NMDA receptors like a cork in a bottle, and nipping depressive symptoms within hours.

A 2012 study published in the journal Science analyzed ketamine's rapid ability to reduce depressive symptoms in people who'd failed to respond to other drugs. The authors called ketamine "the most important discovery in half a century." Five years later, researchers concluded in a study in the American Journal of Psychiatry that the drug's antidepressant effects appeared to last at least a month.

Still, like any drug, ketamine has a range of unpleasant side effects, the most troublesome of which appears to be its tendency to produce what are known as dissociative, or "out of body," experiences.

Experts worry those effects could lead patients to either react negatively to the experience and not want to repeat it, or react positively and want to repeatedly use, potentially leading to a drug-use disorder.

In J&J's most recent study, patients reported other side effects as well, including dizziness, headache, blurred vision, and nausea.
The biggest unanswered question: long-term effects

Besides its immediate side-effects, some researchers approach ketamine with hopeful caution for another reason.

Without a good number of long term studies on ketamine for depression, it's tough to know what the drug's effects might look like over the course of several months or years. Its beneficial effects, for example, could wear off; other negative side effects could emerge as well.

Allergan and VistaGen are currently doing long term studies of their new drug candidates, which act on the same pathway as ketamine but appear to have substantially fewer side effects; results from those trials are expected in the next two years.

J&J is also pursuing more research on its nasal spray ketamine formula, some of which will include longer trials. Company representatives told Business Insider that in addition to the research they've presented so far, they also have plans to study the nasal spray formula in teens with major depression who are at imminent risk for suicide.

The company is expecting to file for approval of their drug with the US Food and Drug Administration later this year.

http://www.businessinsider.com/depre...r=US&IR=T&IR=T
 
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My experience with ketamine therapy for depression

@Foreigner's great report from 2013 (chapters 1-5)

I’ll be using this thread to talk about my use of low-dose ketamine as a mental health aid, specifically for chronic depression that has never been really cured with conventional treatment.

My inspiration comes partly from Jamshyd’s Ketamine Regimen, but I did not attach my report to his thread because there are going to be some divergences in opinion, plus I just have a lot to say and I’d like to be thorough.

I originally was not going to write a report on this but in reflecting upon my own struggle with trying to get more precise information about how to carry out this regimen, I believe my input would help someone out there who might have already been considering this approach but is going through a similar challenge. Also, I feel there is just not enough first-person reporting on this regimen to coincide with the research findings, and it's a gap I would like to contribute to filling.

Most importantly, this regimen appears to have worked for me, and I believe that seed of truth deserves to shine somewhere.

Disclaimer

Although I am trained in the scientific method, this work was not carried out in a professional setting. Please keep in mind that this regimen remains controversial. Although NMDA antagonists offer a wealth of promise for the future treatment of depression and other mental health issues, most sources admit that ketamine is a rather raw and unrefined approach for this purpose, and is being employed until better alternatives can be developed. You should therefore not be considering this regimen unless the conventional approaches have all failed.

Another warning I must give – probably more important than the above – is that this regimen is for those who embody the utmost self-discipline. Ketamine’s euphoric and transcendent properties make it a substance easily abused. Even in a low-dose regimen, the temptation to do “just a little more this dose” can be ever present. Each brief period of euphoria makes you feel as though you are close to a supreme truth, if only you could do just a little more to figure it out. Do not chase this feeling, it is a transient, false lure. If you can avoid the pitfalls by always sticking to the allotted dose, this regimen could very well work for you. For those who lack the discipline, I believe a clinical setting where someone else controls the allotment would be more ideal.

Side effects

Ketamine is not without its side effects, and this is not a perfect therapy, even for someone like me who is in a state of finely tuned health. (For more details, see the section on "negative effects" below.)

Because I am an eastern medicine practitioner, I am able to pick up on subtle signs of physiological changes more readily than the more obvious western diagnostic signs. From day one there were impacts to the kidneys and urinary system. Urine was darker no matter how much I hydrated, and there was usually floating matter in the urine. There was minor kidney colic as well as spasm of the kidney meridian down the inside of the legs. My kidneys were in a constant state of trying to purge, including at night time when I was awoken repeatedly to urinate. I had minor lower back pain (also a kidney sign).

Liver and gallbladder both took a hit too. The constant bitter taste in my mouth, red and dry eyes, and systemic sluggishness due to processing metabolites, were not major, but still noteworthy.

I’m prone to insomnia and ketamine made it much worse. My sleeping schedule was basically in chaos for most of the time and I slept at all random hours on the 24 hour clock. But then, this happens to me when I take most drugs, even cannabis. If you are prone to insomnia I strongly urge you to approach this regimen with caution, but with that said, this might actually help your sleep for all I know.

Though the evidence remains inconclusive, there is the uncharted risk of Olney’s lesions in the brain. This is admittedly due to higher doses of ketamine and regular abuse. I personally believe that the risk is unfounded but it’s one that prospective users of this regimen should know about. Interestingly, Jamshyd mentioned that using gabapentin in combination with this therapy helped him a great deal. This link states that, "In medical settings, NMDA receptor antagonists are used as anaesthetics, so GABA-A receptor positive allosteric modulators are used to effectively prevent any neurotoxicity caused by them." This could suggest that any potential toxicity of ketamine could be at least partially mitigated by gabapentin, though I did not use it so I cannot comment.

The science

The empirical evidence behind ketamine being an effective diffuser of depressive and suicidal states has already been explored relatively thoroughly in Jamshyd’s thread. I will however add these summary links for further reading:

http://www.sciencedaily.com/releases...0819141913.htm
http://www.sciencedaily.com/releases...1004141747.htm

In most of the clinical research they administered single larger doses, which usually resulted in temporary depression relief for up to 7-10 days. The regimen I am using, modelled after Jamshyd’s, is based on the hypothesis that ultra low, frequent dosing could have a more cumulative nootropic effect on the NMDA system and therefore could result in longer lasting relief, as well as actual regeneration of synaptic tissue.

A slow release transdermal patch would work great for ketamine. I came across reports of some hospitals using these for post-operative pain in gynecological procedures, but it was formulated to work locally and not pass the blood brain barrier. Since the pharmaceutical industry is hard at work making non-psychedelic NMDA medications, don’t expect a ketamine patch for depression to happen anytime soon.

Why I chose to do this

A combination of reasons really. One reason is that I anecdotally noticed being in a better mood after a brief stint of recreational ketamine use almost 10 years ago, and that already got me thinking about it. The main reason though is that my unusual metabolism means I process most oral pharmaceuticals irregularly from the established norms. I either suffer rarer side effects or I have no effects at all. SSRIs have proven to be of limited value to me. Ketamine’s rapid action means I would have to endure side effects for less time if the medicine ends up working, and its injectable form means I can bypass the limitations of the digestive route.

Additionally, I’ve long since had the perception that trauma after trauma in my life has caused unfavourable neurological and personality changes, combined with past heavy drug abuse with MDMA, and these are all aspects which talk therapy and conventional pharmaceuticals have never seemed to help me recover from. Eventually there comes a time when you've talked until the cows came home and you still feel unfulfilled; and sometimes, it really is just a neurochemical imbalance and there is nothing outwardly the matter anymore. I would describe myself this way.

For a very long time there has been that missing link - something in my mind that feels blocked, unable to be overcome or bypassed. It's not necessarily about logic, but it has felt like a deficit. Now the science about PTSD is more clear on this, but effective reparative alternatives are either still under development or simply not being offered. If there is any remote chance that low-dose ketamine could act as a regenerative nootropic to years of traumatic down-regulation, it’s a chance I’m willing to take.

Last but not least, I needed a medicine that has a psychoactive component in order to connect psychospiritually to the process, which is the opposite of the emotionally deadening effects that conventional anti-depressants sometimes induce. Without this necessary quality, no therapy can work for me. I’m of the opinion that modern medicine should not be trying so hard to demonize “euphoria” as an unwanted side effect of medication, as bliss can be a useful healing tool in the right context.

Preparation advice

I only acquired 1g of pure ketamine, more than enough to last for one cycle of this regimen. Though I am not prone to addiction, the choice to not purchase more was a precautionary measure to prevent abuse. I advise anyone doing this procedure to do the same. Even if you decide to do a second cycle of treatment, just acquire the additional amount at that time, and not in advance.

I recommend titrating your solution so that you are only administering 0.5cc per dose because I found regular injections of bacteriostatic solution (plus the ketamine itself) to be dehydrating and imbalancing to the electrolytes of my body.

I timed this regimen during a period when I would be off work and free of the usual daily obligations. I let my closest and most supportive friends know what I was about to do, both because I planned to still spend time with them while there was ketamine in my system, and because I wanted them to observe me for positive or negative personality changes. (Hey, sometimes it’s possible to go off the deep end and not realize it!) I also made sure the fridge was stocked so that going outside was optional, and had a good playlist of tunes at the ready in case silence became a burden.

Basically, try to make life as materially easy on yourself as you can. During this period of neuroplasticity, you don’t want to be bogged down with run of the mill minutiae. Treat this as therapy and build your healing container accordingly.

In my case I decided that a healthy balance between social time and alone time were necessary. Exposure to the outside world allowed me to alter my approaches and reactions to many different situations, at will, thanks to the enhanced novelty effect. (More on this later.) Being with friends helped me to expand the pallet of venues and events that I could practice new ways of being in. Then, being alone allowed time for deep reflection, inner processing, and connecting with whatever was surfacing. Even at low doses, I would not recommend isolating oneself as dissociatives can be illusory.

I do believe that ketamine in of itself relieves the symptoms of depression, but perhaps more crucially than that, it offers the opportunity for you to explore the root of it. You can just sit there and do nothing while the biochemistry does some of the work for you, or you can go a bit further and delve into your own psyche. The choice is yours.

Continued here:

http://www.bluelight.org/vb/threads/669468-Experience-with-ketamine-therapy-for-depression
 
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Psychedelics and depression*

by Emily Deans | Psychology Today | 30 Jun 2018

Psychedelics are substances that induce a "non-ordinary" state of consciousness. In use for thousands of years (at least), the medical potential for potent mind-altering substances has come in and out of vogue.

Mescaline was isolated in 1897 and used in experiments as a truth serum and for treatments of psychiatric disorders just after the second world war. LSD was made freely available to scientists by the pharmaceutical company, Sandoz, and widely used in medical research in the 1950s and 60s, with tens of thousands of patients (and researchers) giving it a try for conditions such as schizophrenia and alcohol dependence. LSD was also used in psychotherapy to "assist" patients in recovering from their neuroses, for severe pain patients. Albert Hofmann published the synthesis of psilocybin in 1959 and it too was studied for a variety of conditions. Surprisingly, little concern was raised about the safety of psychedelics in these early papers.

In today's psychiatry, psychedelics are considered possibly dangerous kindlers of ongoing psychotic disorders, particularly for people with personal or family histories of schizophrenia and bipolar disorder, and should be avoided. It would be malpractice (not to mention illegal) for a doctor to administer LSD to a schizophrenic patient today. However, the lack of success of almost any therapy, medicine or otherwise, for treatment resistant depression and some addiction disorders has led researchers to consider studying psychedelics again, starting with ketamine.

All of these agents seem to act on a particular serotonin receptor, 5HT-2A, and ketamine additionally is an antagonist at the NMDA receptor. Activation of this serotonin receptor seems to influence "existential concepts of self, including moral values, self-identity, and purpose." It brightens the mood and makes people feel motivated to change. Interestingly, modern studies of ketamine for depression focus on low dose (typically 0.5mg/kg over 40 minutes in an IV, whereas 1-4.5mg/kg are typically used for anesthesia), and that the psychedelic properties of ketamine are minimized at this dose. However, some studies showed that the amount of dissociation symptoms measured during the infusion correlated with a longer antidepressant effect. All ketamine studies tend to be rather small, and some show no correlation between psychedelic and antidepressant effects.

The other psychedelic with some promising modern research is psilocybin, derived from mushrooms. It too has a number of small studies for alcohol and tobacco addiction, end of life anxiety and depression, obsessive compulsive disorder, and treatment resistant depression. Scientists in London used fMRI to look for brain mechanisms in their study of psilocybin and depression. 19 patients were given psilocybin, and all 19 had their depression scores drop significantly (in fact, on average, depression scores were cut in half) a week after the dose. 47% still met the criteria for treatment response 5 weeks after the dose.

The fMRIs were interesting too, showing decreased blood flow in the amygdala (the "fear" center of the brain) in correlation with antidepressant effects. fMRI can measure overall "connectivity" of the brain, or how much communication is going on between the different parts. Increased connectivity of some parts of the prefrontal cortex and parietal lobe predicted treatment response at 5 weeks, as did decreased connectivity between the parahippocampal and prefrontal cortices.

In all these modern studies, carefully done in controlled conditions with medical and psychological support, psychedelics seem to immediately reduce depressive symptoms and promote positive change. The side effects of ketamine include vital sign changes, and some folks who take ketamine and psilocybin experience distressing hallucinations and dislike feelings of dissociation (others seem to like this feeling). Given that the only other end-of-line treatment that works very quickly for depression and, especially, acute suicidality, is electroshock therapy, the risks and benefits of psychedelics in this context is a different (currently experimental) conversation than for standard outpatient treatment. It seems likely, unless larger studies take a surprising turn, that ketamine, especially, is going to be used more in general practice, particularly in closely monitored settings such as locked inpatient psychiatric units and emergency rooms. This is not the optimism of a 1950s researcher who likes to dabble in LSD with his patients...this is science.

*From the article here :
https://www.psychologytoday.com/us/blog/evolutionary-psychiatry/201806/hallucinogens-and-depression
 
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