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mr peabody

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How MDMA and Psilocybin are shaking up Psychiatry*

by Paul Tullis | NATURE | 27 Jan 2021

Regulators will soon grapple with how to safely administer powerful psychedelics for treating depression and post-traumatic stress disorder.

On a sunny day in London in 2015, Kirk Rutter rode the Tube to Hammersmith Hospital in hopes of finally putting an end to his depression.

Rutter had lived with the condition off and on for years, but the burden had grown since the death of his mother in 2011, followed by a relationship break-up and a car accident the year after. It felt as if his brain was stuck on what he describes as “an automatic circuit,” repeating the same negative thoughts like a mantra: “‘Everything I do turns to crap.’ I actually believed that,” he recalls.

The visit to Hammersmith was a preview. He would be returning the next day to participate in a study, taking a powerful hallucinogen under the guidance of Robin Carhart-Harris, a psychologist and neuroscientist at Imperial College London. Years of talking therapy and a variety of anti-anxiety medications had failed to improve Rutter’s condition, qualifying him for the trial.

“Everyone was super nice, like really lovely, and especially Robin,” Rutter recalls. Carhart-Harris led him to a room with a magnetic resonance imaging (MRI) machine, so researchers could acquire a baseline of his brain activity. Then he showed Rutter where he would spend his time while on the drug. Carhart-Harris asked him to lie down and played him some of the music that would accompany the session. He explained that he would have on hand a drug that could neutralize the hallucinogen, if necessary. Then the two practised a grounding technique, to help calm Rutter in the event that he became overwhelmed. Without warning, Rutter burst into tears.

“I think I knew this was going to be unpacking a lot — I was carrying a bit of a load at the time,” Rutter says.

When Rutter returned the next day, one of the researchers handed him two pills containing a synthetic form of psilocybin, the psychoactive ingredient found in magic mushrooms. Rutter lay down on the bed and put on headphones and an eye mask. Soon, images of Sanskrit text appeared to him. Later, he saw golden bejewelled structures. Then his mind went to work on his grief.

The Imperial study was one of a spate of clinical trials launched over the past few years using illicit psychedelic drugs such as psilocybin, lysergic acid diethylamide (LSD) and MDMA (3,4-methylenedioxymethamphetamine, also known as molly or ecstasy) to treat mental-health disorders, generally with the close guidance of a psychiatrist or psychotherapist. The idea has been around for decades — or centuries in some cultures — but the momentum has picked up drastically over the past few years as investors and scientists have begun to champion the approach again (see ‘Psychedelics take flight’).

Once dismissed as the dangerous dalliances of the counterculture, these drugs are gaining mainstream acceptance. Several states and cities in the United States are in the process of legalizing or decriminalizing psilocybin for therapeutic or recreational purposes. And respected institutions such as Imperial; Johns Hopkins University in Baltimore, Maryland; the University of California, Berkeley; and the Icahn School of Medicine at Mount Sinai in New York City have opened centres devoted to studying psychedelics. Several small studies suggest the drugs can be safely administered and might have benefits for people with intractable depression and other psychological problems, such as post-traumatic stress disorder (PTSD). One clinical trial involving MDMA has recently ended, with results expected to be published soon. Regulators will then be considering whether to make the treatment available with a prescription.

Psychedelic-assisted psychotherapy could provide needed options for debilitating mental-health disorders including PTSD, major depressive disorder, alcohol-use disorder, anorexia nervosa and more that kill thousands every year in the United States, and cost billions worldwide in lost productivity.

But the strategies represent a new frontier for regulators. “This is unexplored ground as far as a formally evaluated intervention for a psychiatric disorder,” says Walter Dunn, a psychiatrist at the University of California, Los Angeles, who sometimes advises the US Food and Drug Administration (FDA) on psychiatric drugs. Most drugs that treat depression and anxiety can be picked up at a neighbourhood pharmacy. These new approaches, by contrast, use a powerful substance in a therapeutic setting under the close watch of a trained psychotherapist, and regulators and treatment providers will need to grapple with how to implement that safely.

“The clinical trials that have been reported on depression have been done under highly circumscribed and controlled conditions,” says Bertha Madras, a psychobiologist at Harvard Medical School who is based at McLean Hospital in Belmont, Massachusetts. That will make interpreting results difficult. A treatment might show benefits in a trial because the experience is carefully coordinated, and everyone is well trained. Placebo controls pose another challenge because the drugs have such powerful effects.

And there are risks. In extremely rare instances, psychedelics such as psilocybin and LSD can evoke a lasting psychotic reaction, more often in people with a family history of psychosis. Those with schizophrenia, for example, are excluded from trials involving psychedelics as a result. MDMA, moreover, is an amphetamine derivative, so could come with risks for abuse.

But many researchers are excited. Several trials show dramatic results: in a study published in November 2020, for example, 71% of people who took psilocybin for major depressive disorder showed a greater than 50% reduction in symptoms after four weeks, and half of the participants entered remission. Some follow-up studies after therapy, although small, have shown lasting benefits.

“Sometimes with a therapeutic, you look at the data and think, ‘It slightly moved the needle,’” says Jennifer Mitchell, a neurologist at the Weill Institute for Neurosciences at the University of California, San Francisco, who worked on the recently finished MDMA trial. “Then you see MDMA and you’re like, ‘Never mind that.’ It’s a very different effect size.” Rutter was so moved by his experience with psilocybin that he has consulted for one of the companies sponsoring trials of the compound.
Rave new world

The current wave of interest in the therapeutic potential of psychedelics is something of a renaissance. In the 1950s and 1960s, scientists published more than 1,000 articles on using psychedelics as a psychiatric treatment; the drugs were tested on around 40,000 people in total4. Then, as recreational use of the drugs spread, they were banned and the FDA constricted supplies for research. Only recently have neuroscientists and psychopharmacologists such as Carhart-Harris had the technology to start unpicking how they work in the brain. That has given them some insights as to how these compounds might help in psychiatric disease.

Researchers started exploring the biological effects of psychedelics in the late 1990s, using neuroimaging techniques such as positron emission tomography before and after volunteers used the drugs, or in conjunction with antagonists that dampen some of their effects. The studies show similarities in how brains respond to psychedelics such as psilocybin and LSD, as well as DMT, the active ingredient in ayahuasca, and to mescaline, a psychedelic compound derived from the peyote cactus. They all act on receptors for serotonin, a neurotransmitter that affects mood.

Serotonin is also the target of the predominant class of psychiatric drugs known as selective serotonin reuptake inhibitors, or SSRIs. It is now thought that these antidepressants work not by flooding the brain with the neurotransmitter, as was initially assumed, but by stimulating neuroplasticity — the brain’s ability to forge new neuronal connections. There is some evidence that psychedelic drugs, such as psilocybin, enhance neuroplasticity in animals, and limited evidence suggests that the same might happen in human brains7,8. Clinical studies also suggest that the biological effects work best in concert with human guidance.

"Psychedelics activate a therapeutic, dreamlike state, intensifying sensory perception, and memories pop up like little films,” says Franz Vollenweider, a psychiatrist and neurochemist at the University Hospital of Psychiatry in Zurich, Switzerland, and one of the pioneers of the modern era of psychedelic research. He thinks that this receptive state of mind provides an opportunity to help people escape from rigid patterns of thought, not unlike Rutter’s automatic circuit.

“People get locked into disorders like depression because they develop this system of thinking which is efficient, but wrong,” says David Nutt, a psychopharmacologist at Imperial College London and an outspoken supporter of evidence-based reforms to government policies concerning illegal drugs. Psychiatry has a term for such thinking: rumination. The idea behind psychedelic therapy is that the receptive state that the drug confers opens the door to fresh ideas about how to think about the past and future, which the therapist can reinforce. “There is a growing evidence base to the principle that this is very much about a synergy between drug-induced hyper-plasticity and therapeutic support,” says Carhart-Harris, who trained with Nutt.

Rutter says his journey with Carhart-Harris was focused, but flexible. When Rutter first removed a pair of eye shades after the drug took effect, the therapist appeared “fractured” and seemed to have another eye in the centre of his forehead. “I should imagine I look quite strange to you now,” Carhart-Harris said. Rutter burst out laughing and Carhart-Harris joined him. When the laughter stopped, the two men started talking. Rutter wanted to discuss his resentments, which led to pondering about the word ‘relent’ and its etymology. Carhart-Harris looked it up for him on his laptop. “That was a lovely moment, actually,” Rutter says. He returned for a second session with a stronger dose of the drug, followed by a second MRI and an ‘integration’ session, to discuss the experiences.

"The treatment made me look at grief differently”, Rutter says. “It was a realization that actually it wasn’t helping, and letting go wasn’t a betrayal.”

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Clinical hurdles

Testing these drugs effectively and translating the clinical research into actual treatments will prove challenging, however. Two of the most closely watched studies have grappled with this. One is the recently completed MDMA trial, which was testing the approach in people with severe PTSD. It was a phase III study, usually the final stage before drug regulators decide whether to approve a treatment, and it involved 90 participants at 15 sites around the world. MAPS sponsored the study, but has not so far released the results.

Meanwhile, the mental-health-care company COMPASS Pathways in London is running a phase IIb trial — testing different dosages of psilocybin for treatment-resistant depression.

Evaluating the results won’t be simple. One concern revolves around controls. Most individuals given a placebo will know that they are not receiving a powerful hallucinogen. Some studies evaluating psychedelics have attempted to address this by giving people in the control group a pill containing niacin, which elicits a physical sensation — usually a flushing response in the skin. Mitchell says that some participants in her MDMA study who’ve been given the drug thought they received the placebo, while some taking the placebo believed that they had been given the drug.

The studies’ designers must also tackle how important the non-drug aspects of the trial are to the results. These include the mindset of the individual going into the experience, and the environment in which it takes place.

The vibe is definitely hotel spa at the treatment rooms for the COMPASS study at Utrecht University Medical Centre in the Netherlands. There’s a Mexican-style blanket folded at the foot of a twin-size bed. Beanbag chairs hug a potted palm in the corner. And a poster of Van Gogh’s Almond Blossom adorns one wall. All 24 sites in the study are similarly decorated.

Then there’s the training and experience of the therapists guiding both the dosing sessions and the drug-free integration sessions. COMPASS, which became a public company in September and earned a stock-market valuation exceeding US$1 billion, developed a five-tier training programme for therapists in its trial. Company co-founder and chief innovation officer Ekaterina Malievskaia says site investigators must adhere to the training if the company expects to win regulators’ approval.

Madras goes further to say that the conditions of the trial will have to be replicated for any wider roll-out of the drugs. They “have to be approved under the stringent conditions in which they were investigated”, she says. But the path forward for mandating such conditions is unclear. For the US FDA, there is a mechanism to ensure that drugs are administered in a specific way: Risk Evaluation and Mitigation Strategies, or REMS. Through REMS, the agency can require prescribing physicians and pharmacists to be certified for a treatment strategy designed to mitigate the risks associated with a drug — such as addiction and dependency for opiate prescription. REMS could be used with psychedelics, Dunn says. The effect would be to bundle the delivery of the drug with the therapy component, and potentially certify practitioners. A source working on one of the trials says that discussions are under way with the FDA over whether therapists who administer the drugs ought to be trained, what that training might involve and whether therapist certification should be required.

Certification could mean legitimizing therapists who have been ‘treating’ individuals with the drugs illegally for as long as 30 years. But some of these therapists might resist the advice, or the involvement, of a government that has driven them underground.

Approvals still have a long way to go. Towards the end of 2020, MAPS reported in a news release that there are statistically significant differences in the response between the control and placebo groups in its MDMA trial (see go.nature.com/362xsvp). But the company won’t say more about the results until it releases the full data some time this year. It is also recruiting for a second phase III study using MDMA therapy for people with moderate-to-severe PTSD, which it aims to complete before the end of the year. COMPASS expects to have results from its phase IIb study on psilocybin by that time, and the company says it is planning a phase III study.

Robert Malenka, a psychiatrist and neuroscientist at Stanford University in California who has studied MDMA’s effects on rodents, says he thinks that some psychedelic drugs will eventually earn approval as treatments for certain conditions. “They have potential to be — I want to use the right analogy — a part of our toolset for treating patients,” he says. But he warns against overzealousness, particularly a brand of evangelism he’s seen among some of the underground purveyors of psychedelic-assisted psychotherapy. “I don’t think they’re going to be miracle cures,” he says.

He argues that the hypotheses for how the drugs might be working in the brain still need further research, and that investigating compounds that provide the same benefits without the hallucinatory effects could prove worthwhile in the long run. Others point out that SSRIs work for many individuals without clinicians fully understanding their mechanism.

Regarding the clinical work, however, Madras says she’s concerned by the studies’ size and design. She noted that many of them recruit people who have had previous experience taking psychedelics. Those who are attracted to this type of experience, she argues, might be more likely to say positive things about it. Nutt has said that working with experienced users of the drugs minimizes the chance of adverse events. But there are other potential confounders, according to Madras. “The consent forms tell you what the expectations are,” she says. “So there’s bias on the part of the subjects.”

Rutter says that despite all that, he is convinced that the treatment he received in 2015 changed his life for the better. In the weeks after his sessions, he found himself wondering whether the automatic circuit would return. “I was terrified,” he says, “and I realized I’ve got a little bit of control over this, right?” The thought had never occurred to him before.

A week or so later, he was out with friends at a shopping centre and sensed the return of optimism and openness. “It felt like somebody had opened a window in a stuffy room.” Five years later, his depression has not returned.

*From the article here :
 
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Will the Magic of Psychedelics Transform Psychiatry?

Psychedelics have come a long way since their hippy heyday. Research shows that they could alleviate PTSD, depression and addiction. So will we all soon be treated with magic mushrooms and MDMA?

by Mattha Busby The Guardian | 7 Nov 2021

Imagine a medicine that could help people process disturbing memories, sparking behavioural changes rather than merely burying and suppressing symptoms and trauma. For the millions suffering with post-traumatic stress disorder (PTSD) and depression, such remedies for their daily struggles could be on the horizon. Psychiatry is rapidly heading towards a new frontier – and it’s all thanks to psychedelics.

In an advanced phase trial published in Nature in May, patients in the US, Israel and Canada who received doses of the psychedelic stimulant MDMA, alongside care from a therapist, were more than twice as likely than the placebo group to no longer have PTSD, for which there is currently no effective treatment, months later. The researchers concluded that the findings, which reflected those of six earlier-stage trials, cemented the treatment as a startlingly successful potential breakthrough therapy. There are now hopes that MDMA therapy could receive approval for certain treatments from US regulators by 2023, or perhaps even earlier – with psilocybin, the active ingredient of magic mushrooms, not far behind in the process. (A small study at Johns Hopkins University, published last year, suggested it could be four times more effective than traditional antidepressants.)

You could say interest in psychedelics is mushrooming. Last month, in a first for psychedelics since the war on drugs was launched in the 1970s, US federal funding was granted for a psilocybin study, to treat tobacco addiction, following pressure by lawmakers, including Alexandria Ocasio-Cortez. This marks a jaw-dropping turnaround for hallucinogenic drugs. Even 10 years ago, they were effectively taboo in many academic fields and halls of power. But as the intellectual rationale behind the war on drugs has become increasingly untenable, hundreds of millions of dollars have been pumped into psychedelic pharmaceutical research. “Psychedelics are the most extraordinary tools for studying the mind and brain,” says Dr David Luke, co-founding director of the psychedelic consciousness conference, Breaking Convention. “It’s a hot-button topic with around a dozen dedicated research centres at top-level universities around the world.”

Academic and scientific enthusiasm around psychedelics has been increasing amid exasperation over the lack of advancement in psychiatry. “It has not progressed as a field of medicine relative to others for decades, and many psychiatrists have been deeply frustrated,” Luke claims. Yet there appears to be a set of long-ignored tools to treat causes rather than simply addressing symptoms, and psychedelics could do for psychiatry what the microscope did for biology, he says. “They work to treat the underlying commonalities of a range of mental illnesses and potentially prevent their occurrence, too.”

Unfounded claims that psychedelic drugs have no medical uses, as the US Congress once declared, and are fundamentally dangerous, kept research endeavours in a straitjacket. Possibly more accurately, there were concerns that the drugs prod people into becoming more rebellious. “It’s not that psychedelics are dangerous, it’s that they give you dangerous ideas,” says Dennis McKenna, ethnopharmacologist and author. “That was the basic reason why there was such an overreaction and clampdown, because it was such a turbulent time with the Vietnam war.” Politicians rather than scientists or clinicians were in the driving seat behind systematically suppressing research, and usage.

This was all part of psychedelics’ mind-bending ride. Their use has increased under the radar, spurred on by cultural shifts in the west. Over the past decade, the recreational and spiritual use of hallucinogens has shed its taboos, following thousands of years of continued use in the Amazon, Mexico, Siberia and elsewhere.

“I realise for the first time this is the only genuine, religious experience I’ve ever had,” pop icon Sting recently said. “For me, the meaning of the universe cracked open.” He was followed more recently by Miley Cyrus and Lindsay Lohan, who have both told of their experiences attending plant medicine ceremonies. Not long ago, UK fitness icon Joe Wicks outlined his plans to visit the Amazon to drink the hallucinogenic healing medicine ayahuasca, after his lockdown workout sessions went viral. Coldplay frontman Chris Martin has told of his “really wonderful” experience with magic mushrooms, which provided “the confirmation I needed about how I feel about the universe”. It increasingly seems that public declarations of psychedelic use are in vogue.

Former Texas governor Rick Perry, a self-described “historically very anti-drug person”, is convinced psychedelics can transform the lives of war veterans suffering from severe PTSD, who are always on guard for danger, unable to sleep and behave self-destructively. “All of that properly done in the right type of clinical setting will save a multitude of lives,” he told local media earlier this year, referring to people he knows who have been abroad from the US for psychedelic treatment. With his public support, a state bill to expedite the study of psychedelics was passed in May.

“Psychedelic medicine has the potential to completely change society’s approach to mental health treatment, and research is the first step to realising that transformation,” said representative Alex Dominguez, a Democrat who sponsored the bill, in a statement at the time. “It’s said that ‘As goes Texas, so goes the nation.’ While states across the country consider how best to address the mental health crisis facing our nation, I hope they once again look to Texas for leadership.”

How did the mood music change so quickly for hallucinogens? Researchers were steadily unshackled – after groundbreaking research into the so-called “God molecule” DMT forced the door open – and promising data emerged as paradigm shifts solidified.

Ceremonies with ayahuasca are known to increasingly take place from London to Sydney. In the US, the União de Vegetal church and some Santo Daime congregations have in the past 15 years gained the legal right to use the DMT-containing brew for religious purposes because it is central to their beliefs. The Native American Church, which has some 250,000 members, gained the right to use mescaline-containing cactus peyote as a sacrament in the US – where it grows naturally in the southwestern desert – back in 1994. Meanwhile, Decriminalize Nature, which argues humans have an unalienable right to develop their own relationship with natural plants, persuaded US authorities in half a dozen municipalities, including Washington DC, to decriminalise all plant medicines, also in May. Earlier this year, the Californian senate passed a bill to legalise the possession and social sharing of psychedelics. Oregon has already voted to decriminalise the possession of personal amounts of all drugs, while psilocybin therapy has been licensed and the state’s health department has been tasked with licensing magic-mushroom growers and training people to administer them.Denver is even training emergency first responders in psychedelic harm reduction, a US first.

Increasing numbers of trials have reported steady doses of dazzlingly promising results for people with a risk of psychological issues. A study in the Lancet last year found that a high dose of psilocybin significantly reduces depressive syndromes and markedly improves anxiety for sustained periods. This appears to be due to the fostering of stronger communication between usually disconnected parts of the brain, engendering a higher state of consciousness as people are less constrained and more able to process emotions.

Former Texas governor Rick Perry.

Former Texas governor Rick Perry

“The fact that a drug given once can have such an effect for so long is an unprecedented finding,” New York University psychiatrist Stephen Ross told the New Yorker of a 2016 study that laid the groundwork for further research. “We have never had anything like it in the psychiatric field.” One of the key mooted advantages of psychedelics over existing drugs is that they work holistically to make the neuroplastic brain more malleable, therefore freeing people from long-held beliefs and memories – opening them evermore to new concepts and states of mind. Thus, they allow the brain to reset and rewire itself, rather than simply dampening down symptoms and even causing serious side-effects. This positions psychedelic therapies as revolutionary for addiction and OCD treatment, and a host of other treatment-resistant conditions, too. A large trial by scientists at the University of São Paulo also shows ayahuasca – a mixture of Amazonian shrubs – significantly reduces the severity of patients’ depression.

Extinction Rebellion co-founder Gail Bradbrook credited her use of ayahuasca and iboga, the psychedelic African shrub used in coming-of-age ceremonies and to combat addiction, with inspiring her campaign strategy, which has helped force environmental issues to the forefront of the debate in the UK.

“There’s a growing body of research indicating that psychedelics tend to greatly increase our connection to nature, even if you take them in a sterile research environment,” says Luke. Attitudes and ecological behaviours also change positively. In one survey, he found that the majority of people who used psychedelics stated that taking them had made them more concerned for the natural environment, had changed their diet and increased the amount of gardening they did. Users were also found to become more involved in environmental activism as feelings of compassion deepened. “Given that we are in the grip of an extremely fast, manmade, mass extinction event, the largest in millions of years, then we need every tool at our disposal, including psychedelics, or we might not even make it as a species ourselves,” he says.

Fitness guru Joe Wicks

Joe Wicks

As with renewable energies, markets are responding to the gargantuan potential profits to be made amid the new consciousness and the wheels of capitalism are now in full motion. The multi-billion-pound alcohol, pharmaceutical and wellness markets are facing serious disruption thanks to the ascendance of psychedelics. Magic mushrooms are even being legally imported into the US for the first time, for research, after a maiden delivery earlier this year. On the recreational side, high-street psychedelic dispensaries have been popping up in Canada despite their sale remaining illegal. Brazen vendors say there is already enough research to prove the drugs are safe.Naturally, there is a clamour among the disrupters to consolidate their companies’ positions at the forefront of the pharmaceutical psychedelics market.

Mental health company Compass was the first to be granted a patent for synthetic psilocybin in early 2020. It was subsequently granted another two in March for an oral psilocybin depression treatment, but faces criticism for an alleged intellectual property land grab that may hinder scientific research by limiting competition. Another 37 patents are being considered by US authorities, with 66 already granted, according to a patent tracker. One company even patented LSD for eating disorders before they had begun investigating whether it was effective.

Françoise Bourzat, a trainer of psychedelic guides in the Mazatec tradition and co-author of Consciousness Medicine, takes a dim view of how big capital is attempting to monopolise treatments rooted in thousands of years of wisdom traditions and discovered by indigenous people. “Money talks. We can’t stop this tsunami. But we need to emphasise the importance of reciprocity, social justice, accessibility and the sacredness of the work,” she implores. Companies should support education and healthcare provision in indigenous communities, given the profit they stand to make, she argues, since the medicines more belong to them – “they just didn’t patent.”

Lindsay Lohan seen out and about in Manhattan in 2019 in New York City.

Lindsay Lohan has spoken about her experience.

She also has concerns over the manner in which treatment with psilocybin, and other psychedelics, could be delivered. “This work is rooted not in medical treatment but in the sacred practice of connecting with traditions that are both indigenous in nature and spiritual in practice,” says Bourzat, who is advising in Oregon on the state’s development of facilitator training. “The Mazatec community in Mexico use the mushroom for connection with the divine and curing tensions and physical ailments that for them are connected to a spiritual blockage or absence of energy circulating in the body and the heart. They connect sickness with unprocessed emotion, which is probably a sound conclusion.”

Many of the medicines (though not magic mushrooms, which are simple to grow and relatively ubiquitous) are finite resources, and already face serious pressure.

The manner of patenting and overharvesting carries a dark paradox given that psychedelics are supposed to engender more enlightened and selfless states. “The purpose of medicine is to create a bigger, deeper, more thorough experience of our inner functioning, our physical functioning, our emotional functioning, our energetic functioning, our spiritual functioning, our relational functioning, how we are with the land,” Bourzat told podcast Berkeley Talks. “Mushrooms bring it to your face, like, ‘This is your illness.’ By knowing your illness, you resolve your illness, you deal with it, you treat it from within yourself. The mushroom helps you see the truth.”

The fear among psychedelic advocates is that a potential deprioritisation of the human aspect of care – whether through sterile environments or through prescriptions where patients chart their development through apps without human contact – could be detrimental to the benefits of the treatment. “The mainstream medicalised approach that is emerging is minimising the value of human support. This work is supposed to be done within relationships,” Bourzat says.

McKenna agrees that it would be foolish for the pharmaceutical industry to ignore the culture and historical context of psychedelic usage, particularly if only those who are ill are allowed access. He believes everyone should have access to them, and not just in private clinical settings as appears the case with recently approved ketamine. The icon among psychonauts declares: “Any future regulatory frameworks should not set up situations where you have to be sick in order to take a psychedelic legally.”

 
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Revisiting the Potential of Psychedelic Drugs in Psychiatry*

by Cell Press | Medical Xpress | 2 April 2020

Before they were banned about a half century ago, psychedelic drugs like LSD and psilocybin showed promise for treating conditions including alcoholism and some psychiatric disorders. In a commentary publishing April 2 in the journal Cell, part of a special issue on medicine, researchers say it's time for regulators, scientists, and the public to "revisit drugs that were once used but fell out of use because of political machinations, especially the war on drugs."

Brain imaging over the past 20 years has taught scientists a lot about how these drugs act on different areas of the brain, says first author David Nutt, a professor and neuropharmacologist at Imperial College London. "There's mechanistic evidence in humans of how these drugs affect the brain," he says. "By back-translating from humans to rodent models, we can see how these drugs produce the powerful neuroplastic changes that explain the long-term alterations we see in humans."

Nutt is a prominent proponent of conducting controlled trials to examine the potential benefits of psychedelics. He is also chair of the scientific advisory board for COMPASS Pathways, a for-profit company that is leading clinical research to test the safety and efficacy of psilocybin-assisted therapy for treatment-resistant depression. The treatment has been granted breakthrough therapy designation from the US Food and Drug Administration. The group also plans to launch a similar study for obsessive-compulsive disorder.

In the Cell commentary, Nutt and his colleagues write about the "psychedelic revolution in psychiatry." They explore specific questions in research, including what is known about the receptors in the brain affected by these drugs and how stimulating them might alter mental health. They also address what's been learned so far about so-called microdosing, the value of the psychedelic "trip," and what researchers know about why the effects of these trips are so long-lasting.

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David Nutt

Brain imaging has shown that the activity of psychedelic drugs is mediated through a receptor in brain cells called 5-HT2A. "There is a high density of these receptors in the thinking parts of the brain," Nutt explains.

The key part of the brain that appears to be disrupted by the use of psychedelics is the default mode network. This area is active during thought processes like daydreaming, recalling memories, and thinking about the future—when the mind is wandering, essentially. It's also an area that is overactive in people with disorders like depression and anxiety. Psychedelics appear to have long-term effects on the brain by activating 5-HT2A receptors in this part of the brain. More research is needed to understand why these effects last so long, both from a psychological perspective and in terms of altered brain functioning and anatomy.

The authors note the challenges in obtaining materials and funding for this type of research. "Before LSD was banned, the US NIH funded over 130 studies exploring its clinical utility," they write. "Since the ban, it has funded none."

Nutt highlights the early potential of psychedelic drugs for treating alcoholism, which the World Health Organization estimates to be the cause of about one in 20 deaths worldwide every year. "If we changed the regulations, we would have an explosion in this kind of research," Nutt says.

"An enormous opportunity has been lost, and we want to resurrect it. It's an outrageous insult to humanity that these drugs were abandoned for research just to stop people from having fun with them. The sooner we get these drugs into proper clinical evaluation, the sooner we will know how best to use them and be able to save lives."

*From the article here :
 
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Psychedelics: A Paradigm Shift for Psychiatry

by Amanda Feilding | Beckley Foundation | 22 May 2020

In the UK, 1 in 4 people are affected by mental illness. 1 in 3 teenage girls suffer from an anxiety or depressive disorder, and suicide is the leading cause of death in the young. Nearly 50% of the population will develop a mental health disorder at some point during their lifetime, and the World Health Organization has declared that depression is the leading cause of disability. Mental illness costs the UK economy an estimated 100 billion pounds every year.

The number of antidepressants prescribed in England has more than doubled in the last decade, with the most common treatment being SSRIs. Of the 30% of patients who receive no benefit from current pharmacological treatment, up to 15% will go on to kill themselves.

Against this backdrop, it is surprising that no major breakthrough in drug development for depression and other psychological disorders has happened in the past three decades, since the discovery of SSRIs.

In the last 20 years, research from the Beckley Foundation and others has found that psychedelics such as psilocybin can produce dramatically higher rates of efficacy than any other available treatments. As tools to aid psychotherapy, they work immediately, after a single or a few doses, with benefits lasting weeks, months or years, with no negative or long-term side-effects.

As part of the Beckley/Imperial Psychedelic Research Program, in 2016 we investigated the effects of psilocybin-assisted psychotherapy in treatment-resistant depression. The patients we recruited had suffered from moderate-to-severe depression for an average of eighteen years, and had received no relief from conventional medicines or psychotherapy. A first session with a small dose of psilocybin confirmed that the compound was well-tolerated by each patient. In another session shortly after, a larger dose – with more intensely felt psychoactive effects – was given. Two clinicians stayed with the patients in a softly lit, comfortable room, allowing the patients to experience a mostly uninterrupted journey, with occasional ‘check-ins’ to make sure they were doing well.

A week after the second session, all patients showed a reduction in depression severity, with 67% of them meeting criteria for complete remission. These impressive results were robust over time: at three-months 42% of all patients remained depression-free, and more than half displayed significant improvements in depression severity relative to their pre-psilocybin scores.

Since the 1960’s I have been greatly interested in the mechanisms underlying the changing states of consciousness brought about by psychedelics. Our fMRI studies with psilocybin and LSD investigated the changes in blood supply within the brain as well as neuronal connectivity. In doing so we have begun to reveal the mechanisms underlying the significant promise of these compounds as tools to aid psychotherapy.

One of the most striking effects we observed was a decrease in blood supply and thus activity within the Default-Mode Network (the DMN), a collection of widespread brain regions that work together to coordinate the activity of diverse areas of the brain, in doing so controlling our conscious experience and maintaining our sense of self. When the DMN disintegrates under LSD or psilocybin, the inhibitory control it normally exerts over the other areas of the brain weakens, allowing for a dramatic increase in global connectivity, allowing regions to communicate with distant partners with which they typically do not talk. As well as producing the subjective experience of ‘ego dissolution’, this process leads to the emergence of a more complex, less predictable, and more flexible state of consciousness. In this state, long-lasting changes can take place, repressed memories can be accessed, and the maladaptive thought processes of depression and other psychological disorders can be reset, like a computer being rebooted.

The potential for psychedelic-assisted psychotherapy does not stop at treating depression. Dysfunction of the DMN is implicated in a whole host of other mental health conditions, including addiction, obsessive-compulsive disorder, anxiety, and PTSD, among others. What characterizes them all is an excessive pattern of thought or behavior becoming rigid and entrenched, almost impossible to break out of despite an awareness of their destructiveness. An experience of a ‘peak state’, brought about by a psychedelic, provides a chance for an individual to see the inner self and the outer world afresh, affording an opportunity to begin anew.

Although a deeper understanding of brain mechanisms underlying this treatment has only been made possible by modern neuroimaging techniques, the potential for psychedelics to heal in this way is not a recent discovery. LSD was considered a wonder-drug when it first appeared in the 1950’s. Hundreds of published papers and thousands of patient reports testified to its promise for new treatments for a wide range of illnesses. A recent meta-analysis of the best-controlled studies conducted in the 1960’s using LSD for alcohol use disorder – a condition which, to this day, has notoriously poor treatment outcomes– found a single session to be more successful in treating alcohol dependence than daily doses of acamprosate or naltrexone, our current go-to pharmacological interventions. Bill Wilson, the founder of Alcoholics Anonymous, wanted to include LSD-therapy in the treatment program for alcohol dependence, understanding that the subjective effects of LSD – which we now know to be caused by the disintegration of the DNM and an increased plasticity of the brain state– can help to achieve a change in perspective that allow recovery to begin.

Psychedelic-assisted psychotherapy can create a truly revolutionary paradigm-shift in psychiatry. This is not some far-off medical advance visible on the horizon, awaiting some technological breakthrough before becoming feasible. Psychedelic-assisted therapy could be made available in clinics right away, were it not for repressive regulation. But the psychedelics remain among the most heavily restricted compounds in the world: in the UK, they are Schedule 1 drugs under the Misuse of Drugs Act and Misuse of Drugs Regulations. Both classifications categorize the psychedelics as having no medical use, as well as being extremely dangerous.

It is now clear that both of these accusations are demonstrably untrue. The foregoing examples provide a brief introduction to their therapeutic potential. Our studies have found that, when administered by skillful clinicians in controlled environments, psychedelics present no significant risk and are not addictive. Meanwhile, recent population studies –analyzing information from more than 120,000 people – have found no link between psychedelic use and mental health problems.

Modern psychiatry is failing huge numbers of people. The research undertaken in the last decade has suggested many areas where psychedelics could be invaluable for alleviating the suffering of mental health issues. And yet, further research is constantly obstructed by legislation that makes it prohibitively expensive, extremely time-consuming, or impossible for researchers to access the materials we need at affordable prices.

The hesitance of some towards reforming these regulations is easily enough understood. An entire generation has been told that psychedelics are harmful to health, that they are toxic and dangerous. But a more informed attitude is possible – indeed it is already endorsed by many, if not most. The potentially deadly opiate family contains morphine, a useful painkiller.

Amphetamines can be prescribed as a treatment for ADHD, or become a drug of potential abuse when taken recreationally as a stimulant. With the appropriate clinical oversight, a compound’s therapeutic benefits can vastly outweigh its risks. By moving psychedelics from Schedule 1 to Schedule 2, where morphine and amphetamines currently sit, doctors can prescribe them to those in need, and further research can be carried out much more easily.

Our approach to these drugs has so far been characterized by patterns of thought and behavior that have become rigid and entrenched, hard to break out of despite an awareness of their destructiveness. Let us put health, and the reduction of suffering ahead of political expediency and rigid-thinking: the time to act is now.

http://beckleyfoundation.org/2018/0...psychedelics-a-paradigm-shift-for-psychiatry/
 

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Back to the future: Psychedelic drugs in psychiatry

by Peter Grinspoon, MD | Harvard Medical School | 11 Jun 2021

Recently, psychedelic drugs have once again taken popular culture by storm. From the psychedelic startup companies newly forming on Wall Street to a recent New York Times article that claims "psychedelic drugs are closer to medicinal use," it seems that there is a renewed media and medical interest in acid (LSD), mushrooms (psilocybin), ecstasy (MDMA), ayahuasca, DMT (dimethyltryptamine), and ketamine.

As an author’s disclaimer, my own life has long intersected with psychedelic drugs. In 1979 (at age 14), I remember reading my father Lester Grinspoon’s book Psychedelic Drugs Reconsidered, which urged, with his usual prescience, an open-minded reappraisal about the therapeutic potential of this class of drugs.

According to Michael Pollan, "for most of the 1950s and early 1960s, many in the psychiatric establishment regarded LSD and psilocybin as wonder drugs" for treating depression, anxiety, trauma, and addiction, among other ailments. As these drugs came to be associated with the 1960s counterculture, and as stories began to surface about bad trips and psychotic breaks, "the exuberance surrounding these new drugs gave way to moral panic." Now the pendulum is swinging back, and the interest in their usefulness as a tool to help treat a variety of psychiatric conditions is rapidly growing.

What are psychedelics?

Psychedelic drugs are a loosely grouped class of drugs that are able to induce altered thoughts and sensory perceptions. At high doses some of them, such as LSD, can cause visual hallucinations. Many people have heard of "magic mushrooms" which contain the active ingredient psilocybin. Psilocybin can also alter perceptions and cause hallucinations at high doses. Other drugs, such as ecstasy, primarily affect one’s mood and sensation of closeness with others. Still others, such as ketamine, have traditionally been used as anesthetics, but also act as hallucinogens and can cause dreamlike states. Ayahuasca, which is found in the jungles of South America, has been used by traditional cultures for centuries. While these drugs and medicines are loosely described under a general rubric, there are big differences between them.

How do psychedelics work?

According to Dr. Jerrold Rosenbaum, the director of the newly created Center for the Neuroscience of Psychedelics at Massachusetts General Hospital and former psychiatrist-in-chief at MGH, the short answer is, "Psychedelics induce the brain to change transiently in ways that appear to allow a reset to take place and permit alterations in previously 'stuck' ways of feeling and thinking about things." There are likely several ways in which psychedelics can accomplish this: new connections are briefly made in neural networks while the resting state of the brain (or the "default mode network") loses connectivity — then it restores itself. "It’s like rebooting your computer." This is how stuck patterns of thinking are thought to shift. Also, new connections between neurons are formed, a process that is called neuroplasticity. Finally, the psychedelic drugs themselves can put patients into a transientstate where they can better process memories, feelings, and past trauma, and can "reemerge with a new perspective on them that is freeing and healing"— also called psychedelic-assisted therapy.

Is there evidence for using psychedelics medicinally?

To the extent that research has been allowed on drugs and medicines that aren’t yet legal, the answer is an increasing and resounding yes. A 2021 study in JAMA Psychiatry concluded that "This randomized clinical trial found that psilocybin-assisted therapy was efficacious in producing large, rapid, and sustained antidepressant effects in patients with major depressive disorder." Another 2021 study in the New England Journal of Medicine showed that patients with moderate to severe major depressive disorder who received two doses of psilocybin did just as well — if not better — at six weeks than patients who received daily dosages of escitalopram (an antidepressant medication). A 2021 study from Nature, which was a randomized, double-blind, placebo-controlled study (the gold standard for research), showed that "MDMA-assisted therapy is highly efficacious in individuals with severe PTSD, and treatment is safe and well-tolerated."

There have been many studies of ketamine as a treatment for depression that does not respond to other treatments. And it has been approved as an option for selected patients with treatment-resistant depression.

There is also great interest in the use of psychedelic medicines in hospice/end of life care. These medications can help people overcome their fear of death, and can help make the process of dying a more meaningful and spiritual experience.

What are the pros and the cons?

Some of these drugs, such as MDMA, are considered to be potential drugs of misuse, given the euphoria they can cause. Possible adverse effects of some psychedelics could include dizziness, drowsiness, extreme dissociation from reality, panic attacks, and nausea. Their illegality makes them more dangerous, and people using street drugs can suffer medical complications from taking contaminated drugs.

Despite their burgeoning promise in the field of psychiatry, psychedelic drugs are not yet considered to be mainstream medicine, and their use is still largely condoned only in experimental or monitored settings. These substances can cause severe impairment and should not be used without a guide who is not under the influence, who can provide calming support and/or call for help if someone is having a bad trip or an adverse reaction.

On the plus side, for the conditions described above, they present a novel and incredibly promising treatment avenue for some of the most difficult-to-treat psychiatric conditions, such as PTSD or treatment-resistant depression. With proper supervision, they are relatively safe. Some patients say the experience of psychedelics can truly be life-altering. This is thought to be in part because the use of psychedelics frequently helps people to experience what is best described as mystical experiences, and that these experiences have been associated with improved outcomes.

Future exploration of psychedelic drugs

As my father said in a 1986 paper, referring to psychedelic drugs, "The problem is not so much how to get these drugs off the streets, but how to get them back in the laboratories, hospitals, and other supervised settings." Just because a drug can be enjoyed or misused, or has been associated with a counterculture or a particular set of political values, that shouldn’t mean that it ought to be locked away forever — especially when there is promising evidence of potential benefit for some of the cruelest conditions that affect humanity.

It is incredibly exciting to see what the future of psychedelic therapy holds.

 
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