• Psychedelic Medicine

PSYCHIATRY | +40 articles

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The psychedelic revolution is coming. Psychiatry may never be the same.

Psilocybin and MDMA are poised to be the hottest new therapeutics since Prozac. Universities want in, and so does Wall Street. Some worry a push to loosen access could bring unintended consequences.

by Andrew Jacobs | New York Times | 11 Nov 2021

It’s been a long, strange trip in the four decades since Rick Doblin, a pioneering psychedelics researcher, dropped his first hit of acid in college and decided to dedicate his life to the healing powers of mind-altering compounds. Even as antidrug campaigns led to the criminalization of Ecstasy, LSD and magic mushrooms, and drove most researchers from the field, Dr. Doblin continued his quixotic crusade with financial help from his parents.

Dr. Doblin’s quest to win mainstream acceptance of psychedelics took a significant leap forward on Monday when the journal Nature Medicine published the results of his lab’s study on MDMA, the club drug popularly known as Ecstasy and Molly. The study, the first Phase 3 clinical trial conducted with psychedelic-assisted therapy, found that MDMA paired with counseling brought marked relief to patients with severe post-traumatic stress disorder.

The results, coming weeks after a New England Journal of Medicine study that highlighted the benefits of treating depression with psilocybin, the psychoactive ingredient in magic mushrooms, have excited scientists, psychotherapists and entrepreneurs in the rapidly expanding field of psychedelic medicine. They say it is only a matter of time before the Food and Drug Administration grants approval for psychoactive compounds to be used therapeutically — for MDMA as soon as 2023, followed by psilocybin a year or two later.

After decades of demonization and criminalization, psychedelic drugs are on the cusp of entering mainstream psychiatry, with profound implications for a field that in recent decades has seen few pharmacological advancements for the treatment of mental disorders and addiction. The need for new therapeutics has gained greater urgency amid a national epidemic of opioid abuse and suicides.

“Some days I wake up and can’t believe how far we’ve come,” said Dr. Doblin, 67, who now oversees MAPS, a multimillion dollar research and advocacy empire that employs 130 neuroscientists, pharmacologists and regulatory specialists working to lay the groundwork for the coming psychedelics revolution.

The nation’s top universities are racing to set up psychedelic research centers, and investors are pouring millions of dollars into a pack of start-ups. States and cities across the country are beginning to loosen restrictions on the drugs, the first steps in what some hope will lead to the federal decriminalization of psychedelics for therapeutic and even recreational use.

“There’s been a sea change in attitudes about what not long ago was considered fringe science,” said Michael Pollan, whose best-selling book on psychedelics, “How to Change Your Mind,” has helped destigmatize the drugs in the three years since it was published. “Given the mental health crisis in this country, there’s great curiosity and hope about psychedelics and a recognition that we need new therapeutic tools.”

The question for many is how far — and how fast — the pendulum should swing. Even researchers who champion psychedelic-assisted therapy say the drive to commercialize the drugs, combined with a growing movement to liberalize existing prohibitions, could prove risky, especially for those with severe psychiatric disorders, and derail the field’s slow, methodical return to mainstream acceptance.

Dr. Doblin’s organization, MAPS, is largely focused on winning approval for drug-assisted therapies and promoting them around the globe, but it is also pushing for the legalization of psychedelics at the federal level, though with strict licensing requirements for adult recreational use.

Numerous studies have shown that classic psychedelics like LSD and psilocybin are not addictive and cause no organ damage in even high doses. And contrary to popular lore, Ecstasy does not leave holes in users’ brains, studies say, nor will a bad acid trip lead to chromosome damage.

But most scientists agree that more research is needed on other possible side effects — like how the drugs might affect those with cardiac problems. And while the steady accumulation of encouraging data has softened the skepticism of prominent scientists, some researchers warn against the headlong embrace of psychedelics without stringent oversight. Although “bad trips” are rare, a handful of anecdotal reports suggest that psychedelics can induce psychosis in those with underlying mental disorders.

Dr. Michael P. Bogenschutz, a professor of psychiatry who runs the four-month-old Center for Psychedelic Medicine at NYU Langone Health, said most of the clinical studies to date had been conducted with relatively small numbers of people who were carefully vetted to screen out those with schizophrenia and other serious mental problems.

That makes it hard to know whether there will be potential adverse reactions if the drugs are taken by millions of people without any guidance or supervision. “I know it sounds silly but, Kids, don’t take these at home,” Dr. Bogenschutz said. “I would just encourage everyone to not get ahead of the data.”


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The rush to invest

Psychedelics are suddenly awash in money.

Dr. Doblin can remember when research funding was nearly impossible to come by. But MAPS is flush now, having raised $44 million over the past two years.

“I spend a lot of my time saying no to investors,” said Dr. Doblin, whose work has been funded by an unlikely collection of philanthropists, among them Rebekah Mercer, the Republican political donor, and David Bronner, a liberal heir to the liquid soap company Dr. Bronners.

Johns Hopkins, Yale, the University of California, Berkeley, and Mount Sinai Hospital in New York are among the institutions that have recently established psychedelic research divisions or are planning to do so, with financing from private donors.

And scientists are conducting studies on whether psychedelics can be effective in treating everything from depression, autism and opioid addiction to anorexia and the anxieties experienced by the terminally ill.

More than a dozen start-ups have jumped into the fray, and the handful of companies that have gone public are collectively valued at more than $2 billion. Field Trip Health, a two-year-old Canadian company that trades on the Canadian Stock Exchange and the OTC Markets Group, has raised $150 million to finance dozens of high-end ketamine clinics in Los Angeles, Chicago, Houston and other cities across North America. Compass Pathways, a Nasdaq-listed health care company that has raised $240 million, is conducting 22 clinical trials across 10 countries of psilocybin therapy for treatment-resistant depression.

Investors have been encouraged by the changing politics, a shift inspired in part by the nation’s accelerating embrace of recreational marijuana and by public weariness over America’s endless war on drugs. Last year, Oregon became the first state to legalize the therapeutic use of psilocybin. Denver, Oakland, Calif., and Washington, D.C., have decriminalized the drug, and several states, including California, are mulling similar legislation. Though the drugs remain illegal under federal law, the Justice Department has so far taken a hands-off approach to enforcement, similar to how it has handled recreational marijuana.

Even some Republicans, a group that has traditionally opposed the liberalization of drug laws, are starting to come around. Last month, the former Texas governor Rick Perry, citing the high rates of suicide among war veterans, called on his state’s legislators to support a Democratic-sponsored bill that would establish a psilocybin study for patients with PTSD.

“We’ve had 50 years of government propaganda around these substances, and thanks to the research and a grass-roots movement, that narrative is changing,” said Kevin Matthews, a psilocybin advocate who led Denver’s successful ballot measure.


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Early pioneers: Dr. William Richards, left, and Dr. Roland R. Griffiths.

Decades in the wilderness

Long before Nancy Reagan warned the nation to just say no to drugs and President Richard Nixon supposedly pronounced Timothy Leary “the most dangerous man in America,” researchers like William A. Richards were using psychedelics to help alcoholics go dry and cancer patients cope with end-of-life anxiety.

The drugs were legal, and Dr. Richards, then a psychologist at the Maryland Psychiatric Research Center, was among scores of scientists studying the therapeutic prowess of entheogens, the class of psychoactive substances that humans have used for millenniums. Even years later, Dr. Richards and other researchers say, many early volunteers called the psychedelic sessions the most important and meaningful experiences of their lives.

But as the drugs left the lab in the 1960s and were embraced by the counterculture movement, the country’s political establishment reacted with alarm. By the time the Drug Enforcement Administration issued its emergency ban on MDMA in 1985, funding for psychedelic research had largely disappeared.

“We were learning so much, and then it all came to an end,” said Dr. Richards, 80, and now a researcher at Johns Hopkins University School of Medicine.

These days, the Center for Psychedelic and Consciousness Research at Johns Hopkins, created two years ago with $17 million in private funding, is studying, among other things, psilocybin for smoking cessation and the treatment of depression associated with Alzheimer’s as well as more spiritual explorations involving religious clergy.

“We have to be careful not to overpromise, but these are fantastically interesting compounds with numerous possible uses,” said Roland R. Griffiths, the center’s founding director and a psychopharmacologist whose 2006 study, on which he is a co-author with Dr. Richards, administered psilocybin to healthy volunteers — one of the first psychedelic studies to win F.D.A. approval in a generation.

Though researchers are still trying to understand the cognitive and therapeutic mechanics of psychedelics, they have concluded that psilocybin, DMT and other psychoactive chemicals can help people feel more tolerance, understanding and empathy. They also induce neuroplasticity, the brain’s ability to change and reorganize thought patterns, enabling people with psychological disorders to find new ways to process anxiety, depression or deeply embedded trauma.

“They can help people who have lost the plotline of their lives,” Dr. Doblin said.


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The trip business

The future of psychedelic medicine can already be glimpsed at a suite of plush, soothingly decorated “journey rooms” that occupy the top floor of an office building in Midtown Manhattan. The clinic, run by Field Trip Health, is a year-old venture where patients wear eyeshades and listen to electronic music and Tibetan chanting, as they are administered six ketamine injections over the course of several weeks.

The 90-minute trips are interspersed with therapist-guided “integration sessions” to help participants process their experiences and work on achieving their mental health goals. A typical course of four sessions starts at $4,100, though some insurance companies reimburse patients for a portion of the cost.

Ketamine is not a classic psychedelic; it is an anesthetic perhaps best known as both a club drug and a horse tranquilizer. But at higher doses, it can produce hallucinations, and it has shown promise treating major depression and severe PTSD, though the effects tend to be less enduring than therapies with psilocybin or MDMA. Ketamine, however, has a distinct advantage over those other drugs: It is the only one in the United States that is legally available to patients outside a clinical study.

Emily Hackenburg, Field Trip’s clinical director, said the drug was only one component of a demanding therapeutic process. “The drug is not a magic bullet,” she said.

Joe, a marketing executive in his mid-40s who has battled depression and anxiety for decades, said he decided to visit the company’s Atlanta location after seeing one of its ads on Facebook. Antidepressants, he said, left him emotionally brittle, and his years of psychotherapy were of little use. (He asked that his full name be withheld,
citing the stigmas surrounding both mental illness and mind-altering drugs.)

In an interview one week after his final session, he described a newfound awareness of the factors that could drive him to despair: his “alpha male” obsession with success, the frustrations stoked by his 9-year-old daughter’s misbehavior and the poor eating and drinking habits that often leave him feeling unwell.

In a follow-up conversation two weeks later, Joe said the therapy’s effects were beginning to fade. He said that he was eager to try psilocybin-assisted therapy. “I’m really looking forward to the day when that becomes legal.”

So, too, is Field Trip. The company, which got its start opening cannabis clinics across Canada, is planning to test psilocybin therapy next month in Amsterdam, where magic mushroom truffles are legal. And its scientists are currently developing a new psychedelic that carries the therapeutic punch of psilocybin but works in about half the time — about two to three hours. Creating a proprietary short-lived psychedelic would reduce the staffing costs of supervised sessions, but more important, it would give the company lucrative exclusivity over its new drug. Other biotech companies are also developing new psychedelic compounds.

Ronan Levy, Field Trip's executive chairman, said the company was hoping to grab a slice of the $240 billion that Americans spend each year on mental health services.

“We are riding the forefront of what I think is going to be a significant cultural and business wave,” he said.

To veteran scientists who lived through the nation’s earlier star-crossed love affair with psychedelics, such corporate boosterism is both thrilling and troubling. They are mindful about potential missteps that could undo the progress of recent years, and they question whether the coming commercialization could limit access to those with limited financial means.

Dr. Charles S. Grob, a professor of psychiatry at U.C.L.A.’s school of medicine who has spent decades researching hallucinogens, worries that commercialization and a rush toward recreational use could prompt a public backlash, especially if increased availability of the drugs leads to a wave of troubling psychotic reactions.

What is needed, he said, are rigorous protocols and a system to train and credential psychedelic medicine professionals. “We have to be very attentive to safety parameters, because if conditions are not properly maintained, there is a risk for some people to go off the rails psychologically,” he said. “And if the primary motivator is extracting profit, I feel the field is more vulnerable to mishaps.”

Dr. Doblin shares some of those concerns, even if his institute stands to profit handsomely. Although MAPS is a nonprofit, it has recently created a corporate entity and hired management consultants to help plot the future of legalized MDMA therapy.

Winning F.D.A. approval would give MAPS at least six years of exclusivity to market its MDMA-guided treatments for PTSD, with a potential windfall of $750 million. Most of that money, he said, would help train a generation of psychedelic practitioners, fund lobbying efforts to require insurance coverage for such treatments and promote new therapies around the world. “Our goal is mass mental health,” he said, explaining the organization’s rejection of private investment. “It’s not to amass a whole bunch of money.”

Despite his optimism, Dr. Doblin is not blind to the possibility that society’s fascination with psychedelics could sour. “We’ve made so much progress so fast but there are so many challenges ahead,” he said. “I realize we could screw things up at the last minute so I’m not planning to celebrate any time soon.”

 
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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.

“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.

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.”

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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Psychedelic Psychiatry: A Revolution set to Transform our Mental Health?

by Adrienne Rivlin | L.E.K. | 21 Apr 2021

Mental health conditions such as depression, anxiety, PTSD, schizophrenia, and addiction are both widespread and notoriously difficult to treat. Their incidence is also growing, a trend that has been exacerbated by the worldwide Covid-19 pandemic. Unfortunately, this tragedy is compounded by the largely unsatisfactory treatment paradigms that are currently available for patients. Many find medicines ineffective or suffer side effects that are intolerable, and there are high relapse rates. Consequently, mental illness remains implicated in the deaths of thousands of individuals each year and is responsible for massive human suffering and economic productivity loss. The global cost of mental health conditions is projected to reach $6 trillion by 2030. Senior academics, clinicians, policymakers and charities regularly refer to a present-day mental health crisis.

However, remarkable recent successes in psychedelic clinical trials may soon offer hope for patients, particularly MDMA for PTSD and psilocybin for depression and anxiety. As a result of these successes — coupled with US Food and Drug Administration (FDA) breakthrough designation, inward capital investment and evolving sentiment towards these treatments — we are at the dawn of a new era in treatment for mental illness.

These developments present new commercial opportunities in a market projected to be worth more than $40 billion by 2025 for a pharmaceutical sector that has largely retreated from psychiatry research. Whilst there are over 200 biotech companies in North America and Europe focused on the psychedelic space, large-cap biopharmaceutical companies like GSK and AstraZeneca have largely scaled back research efforts in psychiatry. In fact, estimates suggest that psychopharmacological drug research amongst large-cap pharmaceutical companies has fallen by 70% in the last 10-15 years, mainly due to the perceived difficulty in completing psychiatric clinical trials.

Nonetheless, these companies may wish to re-enter the space through acquisition, licensing, partnering or developing competing products. Notwithstanding exciting scientific and clinical advancements, there exist several underappreciated future regulatory and commercial challenges; biopharmaceutical companies should address these proactively now to ensure the best chances of success going forward.
A chequered past — the rise, fall and re-emergence of psychedelics

Psychedelics are a class of psychoactive substances that alter mood and senses and can cause hallucinations. The most common are ketamine, ibogaine (found in the plant family Apocynaceae), psilocybin (magic mushrooms), LSD, mescaline (derived from the peyote cactus), 3,4-methylenedioxymethamphetamine (MDMA) and N,N-Dimethyltryptamine (DMT, the active ingredient in ayahuasca). Some of these occur naturally in mushrooms and other plants, whilst others are synthesised in a laboratory. Many have cultural associations that stretch back for millennia and were used for their apparent healing abilities, rituals and ceremonies, recreation, and pleasure; others have a more modern pedigree.

In Western culture, psychedelics appeared in the 1940s and ’50s, used mainly in scientific, academic settings for bona fide research purposes — usually in mental health fields such as psychiatry, neuropharmacology and neuropsychopharmacology. However, their migration out of the lab during the 1960s to become increasingly associated with recreational drug-taking in the hippie counter-cultural movement prompted a backlash that resulted in a prohibition on drug classification schedules worldwide — a situation which persists today (see Figure 1). Academically sound research became almost impossible except for a few diehard researchers like Professor David Nutt at Imperial College, London. His dedication to evidence-based research eventually saw the medical use of psychedelics become fashionable again by the early 2000s.

The resurgence in academic research from well-respected institutions like Johns Hopkins University and New York University is to be welcomed, not least because there is evidence of individuals increasingly using psychedelics to illegally self-treat their mental ill-health. For example, a Global Drug Survey found 6,500 of 110,000 people questioned took ecstasy, mushrooms or LSD as a form of self-medication. Greater academic research would help to guide safer treatment of mental ill-health and reduce the need for self-treatment.

Formal scientific study today focuses on understanding how brains respond to psychedelics — which all act on serotonin receptors — using neuro-imaging techniques like positron emission tomography (PET). There are now over 100 ongoing psychedelic trials for a variety of mental illnesses including depression, anxiety and addiction.

Currently, the only FDA- and European Medicines Agency (EMA) approved psychedelic treatment for a mental illness, in this case treatment-resistant depression, is Janssen’s nasal spray Spravato. Its primary ingredient is esketamine (chemically derived from one half of the ketamine molecule). Ketamine itself appears on the World Health Organizations’s (WHO) essential medicine list but as a general anaesthetic. However, it is used off-label for various conditions, including depression, anxiety and suicidal ideation, usually via ketamine infusion clinics. Whilst ketamine itself acts quickly (usually within hours), concerns exist about ketamine’s potential for abuse and addictiveness, so other companies, like VistaGen Therapeutics, are researching ketamine alternatives with a similar mechanism of action but a safer pharmacological profile. One of its candidates received FDA fast-track designation in 2018 for both depression and pain indications.
A revolution in therapy?

The formal evidence generated so far for psychedelics across a broad range of mental disorders appears strong. In many instances, the effect sizes that have been seen in clinical studies to date have been far superior to those observed in traditional treatments for mental ill-health such as depression. Psychedelics appear to act quickly, have long-lasting effects (especially for depression) and are well-tolerated. Although research into exactly how they work is still ongoing, it is thought that psychedelics improve the neuroplasticity of the brain, allowing it to break old connections and form new ones in a very short space of time. In fact, the evidence has been so strong that in 2017 the FDA designated MDMA a ‘breakthrough’ therapy for PTSD and in 2018 further named two psilocybin-based drugs as having demonstrated ‘breakthrough’ qualities — COMPASS Pathways (treatment-resistant depression) and the Usona Institute (major depressive disorder) — making licensing approval likely as early as 2023.

From a physiological perspective, the current evidence base suggests that when administered under trial conditions and in a therapeutic dose, psychedelics appear safe with a low-risk profile. MDMA can, though, increase heart rate and blood pressure, and psychedelics also have the potential to be misused, risking psychosis in some circumstances. Understandably then, both manufacturers and regulators are keen to ensure that trials — and eventually commercialisation — proceed safely with risks appropriately mitigated.

As well as strengthening the scientific and clinical evidence for psychedelic substances, an important innovation that providers are currently developing, alongside the drugs themselves, is the combination with different forms of psychotherapy. Indeed, an emerging consensus seems to be building that the magnitude of the effects witnessed is likely the result of a combination of both drugs and therapeutic support. As a result, providers have been actively setting up or buying clinics to better control the patient experience. For example, Field Trip has clinics in Toronto, New York Los Angeles, Chicago, Atlanta, Houston and Amsterdam whilst Eleusis bought Kalypso Wellness Centers, a chain of clinics predominantly in Texas.
Future challenges

Whilst the scientific and clinical evidence base continues to strengthen, there remain a number of challenges that companies will need to work through as these therapies progress towards commercial maturity.​

1. Cost to serve​

As currently trialled, psychedelic therapy could prove costly to provide. Many of the trials presently underway involve both a drug (or drug combination) and a therapy component; in effect, this bundles the two into a single regimen. In the US, it is likely that this will be regulated through the FDA’s Risk Evaluation and Mitigation Strategies (REMS) system, which forces specific requirements in drug administration. Although intended to mitigate risk, it will also likely have a significant cost implication if the therapy component is required and strictly regulated.

Further, the therapy requires highly trained and experienced therapists; for example, COMPASS developed a five-tier therapist training programme. The expense of initially training and possibly having to maintain the accreditation of therapists is likely to be material.

Finally, the length of therapy sessions varies between different providers and by type of psychedelic, but a single treatment lasting four to six hours is not unusual. This is vastly longer than typical analogous talking therapies, which usually last one hour for an individual session. It is likely, therefore, that the cost of administering these sessions in specially designed rooms will be high.​

2. Reimbursement​

Whilst reimbursement pathways for drugs alone are typically well laid out and well-funded in most global economies, this is usually not the case for psychological therapies. For drug/therapy combinations, the processes of receiving reimbursement are quite complicated and fragmented in most countries, because funding tends to come from different sources. Reimbursement codes for both the drug and the service as a combination will need to be sought, and if not available, advocated for.​

3. Large-scale production​

One of the most significant challenges to commercial success is likely to be how to produce standardised organic compounds consistently and in industrial quantities. It is difficult and expensive to isolate the active ingredients, and it has never been achieved at a significant scale previously. Even producing uniform doses for trials has proved problematic, with supply constraints pushing prices for pharmaceutical-grade psilocybin to around $7,000-$10,000 per gram. One solution could be to synthesise psychedelics like psilocybin without recourse to their natural ingredient, in this case mushrooms. COMPASS Pathways’ patented production approach, for instance, allows it to access higher yields than would be possible by trying to grow mushrooms.​

4. The non-medical ‘wellness’ market​

Whilst the current focus is on the medical — rather than recreational — use of psychedelics, it is likely that the market may mature in this direction. As with the rapidly evolving cannabis market, there may be more money to be made through a wellness application compared to a purely medical one, for instance, in micro-dosing kits taken at home or in spiritual retreats at so-called health farms. This raises challenges due to the potentially overlapping populations of patients as well as the trust and credibility issues related to companies seeking to play in both the medical and wellness spaces.
Conclusion

As the market senses the repositioning of psychedelics from dangerous to therapeutic, there has been an influx of recent investment and the creation of a raft of specialist companies focused on advancing psychedelics through to commercialisation. With many of the barriers to widespread psychedelic use fading and with larger trials in populations of greater diversity already underway, approval timelines within the next two to three years appear likely. Companies should expedite plans now for how to overcome the significant challenges in bringing these exciting therapies to market.


 
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How will Psychiatrists Administer Psychedelic Treatments?

As a new industry emerges, therapists need to be educated.

by Derek Beres | BIG THINK | 1 Feb 2021
  • Psychedelic therapy is predicted to become a $7 billion industry by 2027.
  • Emerging research on psilocybin, MDMA, ibogaine, and LSD is showing a lot of promise in treating a variety of conditions.
  • Therapists will not be able to write a script and send patients on their way, which will create a new training model.
Psychedelic therapy is imminent. Within six years, the market for this new wave of therapeutics is predicted to reach nearly $7 billion. With advocates and investors like Tim Ferriss leading the way, protocols for implementing psilocybin, MDMA, LSD, and ibogaine into treatments for depression, PTSD, addiction recovery, and existential distress are being crafted right now.

How will psychiatrists adapt to these new substances?

This is no easy question. Unlike antidepressants currently on the market, you cannot visit a psychiatrist or general practitioner and receive a script within 10 minutes—a longstanding issue in modern psychiatry, especially given that antidepressants don’t work better than talk therapy (or as this meta-analysis shows, work better in conjunction with psychotherapy) and carry with them many physical risks. One of the most prominent side effects is weight gain, which has the potential to lead to a whole series of further physical and mental health problems.

Psychedelics are also not without risks. Early results from esketamine—this ketamine variant is not actually a psychedelic but has been generally lumped into the same category and provides a cautionary tale—have not been overly encouraging:

“Through an analysis of adverse events reported to the FDA, the authors found several adverse events related to the use of esketamine nasal spray, such as dissociation, sedation, feeling drunk, completed suicide, and especially suicidal and self-injurious ideation.”

This isn’t to write off the protocol, which has shown efficacy in trials (though not without issues either). Anecdotal reports have been positive for some depression sufferers. More importantly, the emerging ketamine clinics across North America feature robust protocols that run counter to many current antidepressant-driven psychiatric evaluations. We should continue to explore this line of therapeutics, just more carefully.



The Multidisciplinary Association for Psychedelic Studies (MAPS) foresaw the possibility of psychedelic therapy decades ago. The organization’s founder, Rick Doblin, argued against the scheduling of MDMA in the mid-80s. The group’s training protocols for MDMA, ayahuasca, ibogaine, and LSD are holistic and include screening sessions, pre-treatment meetings, day-long sessions, and post-treatment integration.

You cannot ingest psychedelics and go about your day. Unlike SSRIs and SNRIs, they don’t take weeks for you to feel the effects. This is an entirely different model than current psychiatry protocols. If psychedelic therapy is going to be integrated into psychiatry, mental health professionals need training. They’ll have to adapt. Cutting corners will be impossible.

Besides overcoming the hurdle of federal regulations (which is quickly happening), psychedelics should be subject to Risk Evaluation and Mitigation Strategies (REMS), writes Paul Tulls in Nature. This means these novel therapies will be administered according to current FDA guidelines.

“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.”

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This will not be without its challenges. As Tullis writes, some therapists have been skirting federal law by offering psychedelic therapy for 30 years, reminiscent of LSD sessions in the 1950s and MDMA therapy in the 1970s. In fact, LSD was subjected to over 1,000 studies before being criminalized, though it’s admittedly hard to offer a placebo. (Niacin has worked in some trials.) The comprehensive protocols being developed now have early pioneers to thank.

Psychedelics are also entering an industry with standard practices. Some therapists are likely to remain skeptical; others might not train properly before administering the drugs, which could create problems for the entire industry should some patients experience adverse effects. Psychotherapy will always be necessary before and after administration. In an industry where many are accustomed to writing scripts, not providing in-depth existential explorations with their patients—and many patients are accustomed to quick visits that result in refills—a giant learning curve is necessary.

While many are hopeful that psychedelic therapy will have broad appeal, the more likely result is a slow integration with specialized clinics (such as with ketamine today). There will undoubtedly be players with no history of psychedelics involved only for economic gain; we’re already seeing it with tens of millions of dollars pouring into companies. The competing forces of revenue maximization and psychedelic ritual are likely to create friction.

Regardless, this emerging industry requires funding to get off the ground. We just need to temper expectations with the real-world consequences of the psychedelic model—a hard sell in a world accustomed to quick returns. And we’ll need therapists willing to explore uncharted territory on its own terrain, not the ground they’re accustomed to walking on.



Stay in touch with Derek on Twitter and Facebook. His most recent book isHero’s Dose: The Case For Psychedelics in Ritual and Therapy.”

 
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A brief history of psychedelic psychiatry

by Mo Costandi | The Guardian

On 5th May, 1953, the novelist Aldous Huxley dissolved four-tenths of a gram of mescaline in a glass of water, drank it, then sat back and waited for the drug to take effect. Huxley took the drug in his California home under the direct supervision of psychiatrist Humphry Osmond, to whom Huxley had volunteered himself as “a willing and eager guinea pig.”

Osmond was one of a small group of psychiatrists who pioneered the use of LSD as a treatment for alcoholism and various mental disorders in the early 1950s. He coined the term psychedelic, meaning ‘mind manifesting’ and although his research into the therapeutic potential of LSD produced promising initial results, it was halted during the 1960s for social and political reasons.

Born in Surrey in 1917, Osmond studied medicine at Guy’s Hospital, London. He served in the navy as a ship’s psychiatrist during World War II, and afterwards worked in the psychiatric unit at St. George’s Hospital, London, where he became a senior registrar. While at St. George’s, Osmond and his colleague John Smythies learned about Albert Hoffman’s discovery of LSD at the Sandoz Pharmaceutical Company in Bazel, Switzerland.

Osmond and Smythies started their own investigation into the properties of psychedelics and observed that mescaline produced effects similar to the symptoms of schizophrenia, and that its chemical structure was very similar to that of the hormone and neurotransmitter adrenaline. This led them to postulate that schizophrenia was caused by a chemical imbalance in the brain, but these ideas were not favourably received by their colleagues.

In 1951 Osmond took a post as deputy director of psychiatry at the Weyburn Mental Hospital in Saskatchewan, Canada and moved there with his family. Within a year, he began collaborating on experiments using LSD with Abram Hoffer. Osmond tried LSD himself and concluded that the drug could produce profound changes in consciousness. Osmond and Hoffer also recruited volunteers to take LSD and theorised that the drug was capable of inducing a new level of self-awareness which may have enormous therapeutic potential.

In 1953, they began giving LSD to their patients, starting with some of those diagnosed with alcoholism. Their first study involved two alcoholic patients, each of whom was given a single 200-microgram dose of the drug. One of them stopped drinking immediately after the experiment, whereas the other stopped 6 months later.

Several years later, a colleague named Colin Smith treated another 24 patients with LSD, and subsequently reported that 12 of them had either “improved” or “well improved” as a result of the treatment. “The impression was gained that the drugs are a useful adjunct to psychotherapy,” Smith wrote in a 1958 paper describing the study. “The results appear sufficiently encouraging to merit more extensive, and preferably controlled, trials.”

Osmond and Hoffer were encouraged, and continued to administer the drug to alcoholics. By the end of the 1960s, they had treated approximately 2,000 patients. They claimed that the Saskatchewan trials consistently produced the same results – their studies seemed to show that a single, large dose of LSD could be an effective treatment for alcoholism, and reported that between 40 and 45% of their patients given the drug had not experienced a relapse after a year.

At around the same time, another psychiatrist was carrying out similar experiments in the U.K. Ronald Sandison was born in Shetland and won a scholarship to study medicine at King’s College Hospital. In 1951, he accepted a consultant’s post at Powick Hospital near Worcester, but upon taking the position found the establishment to be overcrowded and decrepit, with patients being subjected to electroshock treatment and lobotomies.

Sandison introduced the use of psychotherapy, and other forms of therapy involving art and music. In 1952, he visited Switzerland where he also met Albert Hoffman, and was introduced to the idea of using LSD in the clinic. He returned to the U.K. with 100 vials of the drug – which Sandoz had by then named ‘Delysid’ – and, after discussing the matter with his colleagues, began treating patients with it (in addition to psychotherapy) towards the end of 1952.

Sandison and his colleagues obtained results similar to those of the Saskatchewan trials. In 1954 they reported that “as a result of LSD therapy, 14 patients recovered (av. Of 10.4 treatments)... 1 was greatly improved (3 treatments), 6 were moderately improved (av. of 2 treatments) and 2 not improved (av. of 5 treatments).”

These results drew great interest from the international mass media, and as a result, Sandison opened the world’s first purpose-built LSD therapy clinic the following year. The unit, located on the grounds of Powick Hospital, accommodated up to 5 patients who could receive LSD therapy simultaneously. Each was given their own room, equipped with a chair, sofa, and record player. Patients also came together to discuss their experiences in daily group sessions. (This backfired later, however: In 2002, the National Health Service agreed to pay a total of £195,000 in an out-of-court settlement to 43 of Sandison’s former patients.)

Meanwhile in Canada Osmond’s form of LSD therapy was endorsed by the co-founder of Alcoholics Anonymous and the director of Saskatchewan’s Bureau on Alcoholism. LSD therapy peaked in the late 1950s and early 1960s, and was widely considered to be “the next big thing” in psychiatry, which could supersede electroconvulsive therapy and psychosurgery. At one point, it was popular among Hollywood superstars such as Cary Grant.

Two forms of LSD therapy became popular. One, called psychedelic therapy, was based on Osmond and Hoffer’s work, and involved a single large dose of LSD alongside psychotherapy. Osmond and Hoffer believed that psychedelics are beneficial therapeutically because of their ability to make patients view their condition from a fresh perspective.

The other, called psycholytic therapy, was based on Sandison’s regime of several smaller doses, increasing in size, as a adjunct to psychoanalysis. Sandison’s clinical observations led him to believe that LSD can aid psychotherapy by inducing dream-like hallucinations that reflected the patient’s unconscious mind and enabling them to relive long-lost memories.

Between the years of 1950 and 1965, some 40,000 patients had been prescribed one form of LSD therapy or another as treatment for neurosis, schizophrenia, and psychopathy. It was even prescribed to children with autism. Research into the potential therapeutic effects of LSD and other psychedelics had produced over 1,000 scientific papers and six international conferences. But many of these early studies weren’t particularly robust, lacking control groups, for example, and likely suffered from what researchers call publication bias, whereby negative data are excluded from the final analyses.

Even so, the preliminary findings seemed to warrant further research into the therapeutic benefits of psychedelic drugs. The research soon came to an abrupt halt, however, mostly for political reasons. In 1962, the U.S. Congress passed new drug safety regulations, and the Food and Drug Administration designated LSD as an experimental drug and began to clamp down on research into its effects. The following year, LSD hit the streets in the form of liquid soaked onto sugar cubes; its popularity grew quickly and the hippy counterculture was in full swing by the summer of 1967.

During this period, LSD increasingly came to be viewed as a drug of abuse. It also became closely associated with student riots anti-war demonstrations, and thus was outlawed by the U.S. federal government in 1968. Osmond and Hoffer responded to this new legislation by commenting that “it seems apt that there is now an outburst of resentment against some chemicals which can rapidly throw a man either into heaven or hell.” They also criticised the legislation, comparing it to the Victorian reaction to anaesthetics.

The 1990s saw a renewed interest in the neurobiological effects and therapeutic potential of psychedelic drugs. We now understand how many of them work at the molecular level, and several research groups have been performing brain-scanning experiments to try to learn more about how they exert their effects. A number of clinical trials are also being performed to test the potential benefits of psilocybin, ketamine and MDMA to patients with depression and various other mood disorders. Their use is still severely restricted, however, leading some to criticise drug laws, which they argue are preventing vital research.

Huxley believed that psychedelic drugs produce their characteristic effects by opening a “reducing valve” in the brain that normally limits our perception, and some of the new research seems to confirm this. In 1963, when he was dying of cancer, he famously asked his wife to inject him with LSD on his deathbed. In this, too, it seems that he was prescient: Several small trials suggest that ketamine alleviates depression and anxiety in terminally ill cancer patients and, more recently, the first American study to use LSD in more than 40 years concluded that it, too, reduces anxiety in patients with life-threatening diseases.

*From the article (including references) here :
 
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The Readiness of Psychiatrists to Implement Psychedelic-Assisted Psychotherapy

Lisa A. Page(1,2), Ahmad Rehman(1), Habib Syed(3), Kathryn Forcer(3), Graham Campbell(4)

1Brighton and Sussex Medical School, Brighton, United Kingdom
2Sussex Partnership National Health Service (NHS) Foundation Trust, Worthing, United Kingdom
3Brighton and Sussex University Hospitals National Health Service (NHS) Trust, Brighton, United Kingdom
4Small Pharma Ltd., London, United Kingdom

Introduction: Psychedelic-assisted psychotherapy is a promising approach in psychiatry; evidence is growing and it may not be long before mainstream services are expected to offer it to selected patients. This pilot study examined the attitudes and knowledge of NHS psychiatrists of all levels towards psychedelic-assisted psychotherapy and explored potential barriers and facilitators to its implementation.
Methods: A mixed-methods approach was adopted, using a cross-sectional survey and focus groups. All psychiatrists in one NHS mental health trust were approached by email to participate. The survey was analysed using a simple descriptive approach and thematic analysis was used for the focus groups.
Results: Eighty-three (26 percent) psychiatrists participated in the survey. All psychiatrists were familiar with one or more psychedelic substances. Although 77.2% felt that there should be a role for controlled or therapeutic use of psychedelics, trainees appeared better informed than non-training grade psychiatrists. Psychiatrists of all grades did not feel prepared to participate in the delivery of psychedelic-assisted psychotherapy. Thematic analysis of the focus groups identified three main themes in relation to psychedelic-assisted psychotherapy: “need for knowledge,” “openness to change,” and “uncertainty.”
Discussion: NHS psychiatrists are positive about the potential for psychedelic-assisted therapy to advance psychiatric practise. However, psychiatrists are lacking in confidence or preparedness to implement this treatment should it become a mainstream option and significant training needs were identified. Thematic analysis highlighted the need for societal shifts as well as professional ones.

Introduction

Psychedelic-Assisted Psychotherapy (PAP) offers a potentially promising and novel therapeutic approach in psychiatry (13). The evidence base for the use of PAP in mental disorders is growing (46) against a backdrop of considerable public interest https://www.bbc.co.uk/mediacentre/proginfo/2021/19/the-psychedelic-drug-trial. There is particular interest in the use of PAP in depressive disorders (7, 8), cancer-related anxiety (9) and alcohol dependence (10). Trials are ongoing in these and other mental disorders and psilocybin was designated a “breakthrough therapy” by the US Food and Drug Administration (FDA) in 2019.

Psychedelics are potent serotonergic hallucinogens that induce perceptual changes and elicit altered states of consciousness; they are understood to act via the full or partial agonism of cortical 5-hydroxy tryptamine 2A receptors (3, 1113). Increasingly psychedelics are seen as safe medicines, with limited abuse potential, and a rapid yet novel action (3).

What Is Psychedelic-Assisted Psychotherapy?

PAP typically entails a series of psychotherapeutic sessions with three distinct phases: induction, psychedelic and integrative phases (14, 15). The induction sessions focus on the therapeutic relationship and the patient is prepared for the psychedelic session to come. The psychedelic session, of which there is usually one but sometimes more, involves the patient ingesting a psychedelic substance in the presence of therapist guides. The therapist guides are typically mental health professionals—psychologists, psychotherapists or psychiatrists—who monitor and if necessary, guide the patient through the experience. The number of psychedelic sessions and the psychedelic dose varies depending on the research design and the type of psychedelic used. During the subsequent integrative sessions, the therapists help facilitate patient understanding and interpretation of the psychedelic experience with aim of achieving long-term change (14). To date, psychiatrists have played several important roles in the (research) deployment of PAP, including: research leadership, patient selection, risk management, prescriber and therapist guide.

Why Might PAP Be Offered Within Mainstream Services?

PAP offers an alternative and novel approach compared to existing pharmacological or psychological approaches (3). As the evidence builds for the effectiveness of PAP in differing mental disorders, health services may soon be routinely expected to offer it—especially for patients who have not responded to existing treatments and remain functionally impaired. Despite this possibility, it is not known whether the workforce who would provide PAP, including psychiatrists, is prepared to do so.

Are Psychiatrists Ready for PAP?

To our knowledge, there has been only one previous study looking at the psychiatrists' attitudes towards the use of psychedelics (16). In 2018, Barnett et al. surveyed members of the American Psychiatric Association about their views on the use of hallucinogens; they found that 80.5% of respondents felt there should be more research in relation to hallucinogens and psychiatric disorder, but less than a third felt that hallucinogens were likely to improve outcomes when used with psychotherapy. A substantial minority (25 percent) felt that hallucinogens were unsafe even under medical supervision. This study also showed that trainee psychiatrists and male psychiatrists tended to be less concerned about the risk of hallucinogens and more optimistic about their potential.

Since 2018, the evidence for PAP has strengthened and we were keen to build on the work of Barnett et al. to find out whether British psychiatrists held similar attitudes to US psychiatrists. Most British psychiatrists work in a nationalised healthcare system (the NHS), unlike their US counterparts. Furthermore, we sought to understand what psychiatrists saw as the potential difficulties of implementing PAP, which represents a considerable paradigm shift compared to current practise.

The primary objective of this pilotstudy was to investigate the awareness, knowledge and attitudes of NHS Psychiatrists towards the possible introduction of PAP within a nationalised healthcare system. Secondary objectives included identifying potential barriers and facilitators to the adoption of PAP within psychiatric practise.​

Methods

A mixed methods approach was adopted by using both a (quantitative) cross-sectional survey and (qualitative) focus groups. We restricted our study to questions about classic hallucinogens, such as LSD, psilocybin, mescaline, and deliberately did not include questions about related drugs such as MDMA or ketamine.

Cross-Sectional Survey

First, an invitation to participate in an e-survey was sent by email to all Psychiatrists within one NHS mental health trust in England in January 2021. The mental health trust provides mental health and learning disability services across all ages to a population of nearly 1.7 million people from a large and geographically diverse area. A reminder email was sent ~2 weeks after the first invite to maximise response. The survey was developed, refined and piloted by the research team with the aim of eliciting psychiatrists' views on key aspects of PAP. Specifically, the survey examined awareness, knowledge and attitudes towards PAP and elicited psychiatrists' views as to how confident they would feel to refer patients for PAP or provide PAP within their practise. In addition, the survey elicited psychiatrists' opinions on current effectiveness of psychotherapeutic and pharmacological approaches in the treatment of depression, anxiety and substance use disorders.

In order to include a representative sample of psychiatrists from different sub-specialties and with varying levels of experience and seniority, all psychiatrists from one NHS mental health trust were invited to participate. Therefore, psychiatrists in training, as well as those working permanently in specialty doctor and consultant posts were included in the sampling frame. The survey was hosted on Qualtrics and all responses were anonymous.

Basic descriptive statistics were used to analyse the survey data. An a-priori decision was taken to investigate whether age was a contributing factor in psychiatrists' decision to be more or less prepared to get involved with PAP, we therefore divided psychiatrists into three age groups (i.e., ≤ 34, 35–54, and ≥55 years) and used the chi-squared test to compare their responses.

Focus Groups

Second, we convened two focus groups for psychiatrists from the same NHS trust. The invitation to participate in the focus groups was embedded in the survey invite and again at the end of the survey—the sample was therefore purposive. The focus groups were facilitated by two members of the research team (KF and HS) and were hosted on a virtual platform due to Covid-19 restrictions. No previous knowledge of PAP was required and the facilitators spent a short period at the beginning of each focus group describing PAP and how PAP was being used in research settings. The research team developed a schedule for use with the focus groups, which ensured that psychiatrists' attitudes about PAP were explored in depth as were potential barriers and facilitators to the adoption of PAP in psychiatric practise.

The focus groups were audio-recorded and then transcribed before the audio files were destroyed. All contributions were anonymised and no personally identifiable information was stored. The transcripts were analysed using Thematic Analysis by two members of the research team (KF & LP). The analytic approach was based on the work of Braun and Clarke (17).

Ethical Approval and Sponsorship

NHS ethical approval was not required for the study, but good ethical procedures were followed throughout. The study was sponsored by Sussex Partnership NHS Foundation Trust.​

Results

Cross-Sectional Survey

The questionnaire was sent out to a total of 323 psychiatrists, of whom 48 were trainees (i.e., they were rotating through core training or higher specialist trainee posts in psychiatry) and 275 were consultants or specialty doctors (i.e., they were working in permanent, non-training grade posts). In total, 83 (26 percent) responses were received, of which 63 (76 percent) were either consultants or specialty doctors and 20 (24 percent) were trainees. A greater proportion of trainees responded to the survey than non-training grade doctors (42 vs. 23 percent). Just over half of survey participants were aged between 35 and 54 years (n = 48; 58 pecent), whilst 17 (21 percent were aged over 54 years and 14 (17 percent) were aged 34 or younger.

Most sub-specialties were represented. Participants' most common specialty area was Community General Adult Psychiatry (43 percent) followed by Old Age Psychiatry (22 percent) and Inpatient General Adult Psychiatry (14 percent). The majority of participants identified as being from White British/White other ethnic backgrounds (82 percent), with 7.2% identifying as being from Asian backgrounds and 3.6% from Black African/Caribbean or Black British backgrounds. There were slightly more male participants than female (55.4 vs. 43 percent).

Views on Existing Treatments for Non-psychotic Mental Illness

Participants overwhelmingly indicated that they felt existing psychotherapeutic and pharmacological treatments for anxiety and depression were either extremely or moderately effective. There was less certainty that existing treatments were effective for substance use disorders, with 49.4% of participants viewing psychotherapeutic treatments for these disorders as only slightly effective or ineffective; and 77.1% viewing pharmacological treatments as slightly effective or ineffective.

Familiarity With Psychedelics and PAP

All Psychiatrists had heard of at least one psychedelic substance. The most recognised psychedelics were LSD, magic mushrooms, psilocybin (the active component of magic mushrooms) and mescaline. See Table 1 for details.

TABLE 1
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Table 1. Psychiatrists' familiarity with psychedelics substances.


Around a third of participants (34 percent) believed that psychedelic substances should be decriminalised in the UK, with a fifth (21 percent) believing that the benefits outweighed the harms. Most participants (77 percent) believed that there was a role for controlled or therapeutic use of psychedelics in society.

Regarding the therapeutic use of psychedelics, 60.2% were not familiar or only slightly familiar with the use of psychedelics for this purpose, and only 9.6% felt very familiar with this type of use. Only two respondents, who were both trainees, had direct experience of participating in PAP. Overall, trainees demonstrated better knowledge of PAP than non-training grade doctors, with a greater proportion having read journal articles or attended academic lectures. The popular press was also endorsed as a medium by which trainees, in particular, had gained information about PAP. See Figure 1 for how participants gained knowledge about PAP and how this differed between trainees and non-training psychiatrists.

FIGURE 1
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Figure 1. Exposure of psychiatrists to Psychedelic-Assisted Psychotherapy. This figure shows the proportion (percent of psychiatrists who have been exposed to PAP and through which mediums. Total number of responses = 83; Training grade psychiatrists = 20; Non-training grade psychiatrists = 63.


Involvement With PAP

Overall, psychiatrists felt unprepared to participate in the practise of PAP; specifically, most did not feel prepared to prescribe psychedelics, act as a PAP guide or support psychologists in the delivery of PAP. Participants indicated a little more confidence to discuss PAP with patients or refer them for PAP treatment. There was little difference between trainees and non-training grade psychiatrists in terms of preparedness. See Figure 2 for how confident and prepared psychiatrists felt to get involved with PAP.

FIGURE 2
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Figure 2. Psychiatrists' confidence and preparedness to be involved with Psychedelic- Assisted Psychotherapy. This figure outlines how confident and prepared Psychiatrists felt to participate in various aspects of PAP. Total number of responses = 83; Training grade psychiatrists = 20; Non-training grade psychiatrists = 63.


Psychiatrists' Age Did Not Predict Preparedness or Confidence to Deliver PAP

We had an a-priori hypothesis that younger Psychiatrists would express more confidence in getting involved in the practise of PAP. However, this was not borne out as there was no difference (p = 0.7 percent in the proportion of older (i.e., ≥ 55 years) vs. middle-aged (i.e., 35–54 years) vs. younger (i.e., ≤ 34 years) psychiatrists who felt confident to discuss or refer patients for PAP; to prescribe psychedelics or to support psychology colleagues in the delivery of PAP.

Focus Groups

The focus groups consisted of 3 or 4 participants in each group—more were expected but there were drop outs on the day. There was a mixture of male and female participants. Participants were from a range of sub-specialties and had differing levels of experience.

Thematic analysis of the focus group transcripts led to the development of codes and sub-codes. These were iteratively organised and re-organised, from which three overarching themes eventually emerged and were felt to adequately represent the issues that had arisen during the focus groups. Each theme was reviewed and revised until an agreed theme definition was arrived at. The first theme addressed the “Need for knowledge” that psychiatrists identified when thinking about the use of PAP; the second theme recognised “Openness to change” both within the profession and wider society; and the third theme was one of “Uncertainty” for themselves as practitioners, their patients and the frameworks in which they practised. The themes are described in more detail below. A thematic map was developed, which illustrated how each theme was related to its underlying codes—see Figure 3. A table detailing the themes, codes, sub-codes and exemplar extracts is provided in the Supplementary Material accompanying this paper.

FIGURE 3
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Figure 3. Thematic map detailing the main themes and codes from the thematic analysis of focus groups held with Psychiatrists.


Theme 1: Need for Knowledge

Psychiatrists were seeking a firmer evidence base for PAP and identified a need for well-conducted, funded research on the topic. Much of their own knowledge about PAP had come from their informal networks, rather than from formal sources. Psychiatrists also felt there was a need for better knowledge amongst the general public about psychedelic substances specifically, and psychoactive drugs more generally.

Theme 2: Openness to Change

Considerable hope and openness towards PAP was expressed. Psychiatrists felt optimistic that PAP had the potential to offer therapeutic benefit to patients for whom little else had worked. They identified PAP as a novel treatment, which could work quickly in the right circumstances. Psychiatrists also wondered about the openness of society to accept or tolerate the therapeutic use of psychedelics.

Theme 3: Uncertainty

Much uncertainty was expressed. Psychiatrists were unsure how their specific skills might be used in the provision of PAP and there was a range of opinion about how involved psychiatrists should be. There was concern about the potential risks of PAP for some patients, whilst simultaneously recognising the benefits for others. There was scepticism that the structures that support psychiatric practise (i.e., legislative, NHS, professional governance) were ready to support psychiatrists in the delivery of PAP.​

Discussion

Psychedelic-assisted Psychotherapy (PAP) is not yet a treatment that is available beyond the confines of research trials, but interest in its use is growing amongst psychiatric researchers (2, 3) and the public. Assuming the evidence for PAP continues to grow, there will be increasing pressure for PAP to be offered within NHS services. This mixed-methods study was a first attempt to explore knowledge and preparedness amongst practising NHS Psychiatrists about the potential for them to deliver PAP. By using both quantitative and qualitative approaches we were able gain a richness of understanding that would not have been possible had we used only one of these approaches.

The large cross-sectional survey of NHS Psychiatrists of all grades from one large provider mental health trust demonstrated that most psychiatrists are familiar with psychedelic substances and, to some extent, PAP. However, psychiatrists in training appeared better informed about PAP than non-training grade colleagues. Trainees had used a wide range of media to gain knowledge on the topic; this, perhaps, reflects their need to inform themselves generally about advances in psychiatry in preparation for exams—albeit that PAP does not yet feature in their post-graduate curriculum in the UK. The finding that trainees were more familiar with the emerging research was consistent with findings from a previous US study (16), although we did not find an effect of age as they did. Our findings suggested that stigma towards psychedelics was perhaps lower amongst UK psychiatrists, as 77.2% of our study participants felt there was a role for controlled or therapeutic use of psychedelics, whereas around half of the US participants felt that psychedelics were unsafe even in this context.

The survey showed that a substantial minority of NHS psychiatrists felt confident to discuss PAP with their patients or refer them to others for treatment. However, there was a lack of confidence and preparedness amongst psychiatrists to actually deliver or participate in PAP themselves. This is perhaps not surprising given the relatively few modern era clinical trials that have emerged and the legal restrictions that work with psychedelics involves. Our study has highlighted significant training needs for psychiatrists if PAP were to be implemented in NHS practise. Our prediction that younger psychiatrists would feel more confident in the use of PAP was not borne out and training needs are likely to be common across psychiatrists of all seniority and experience.

The thematic analysis of the focus groups enabled a more nuanced exploration of the factors that might be important in providing PAP within NHS settings. The uncertainty surrounding PAP was an important theme and showed that Psychiatrists are not just uncertain about their own role in PAP, but also the uncertain risks and benefits for patients. Recent research from Ireland suggested that just over a half of mental health service users would accept treatment with PAP if a doctor recommended it (18). It seems likely that psychiatrists will be increasingly asked about PAP by patients and be expected to have a working knowledge or who it benefits and how to access it. There was additional uncertainty about how supporting structures around psychiatrists would respond to the introduction of PAP.

The need for more knowledge at multiple levels was emphasised and the need for the public to be educated about the topic prior to its widespread adoption. However, beyond these concerns about how PAP would be conducted and for whom it would be suitable, there was a strong theme of openness to change and excitement at PAP's potential to benefit patients for whom existing treatments have failed. The energy and optimism that (some) psychiatrists identified in relation to PAP would be helpful for services to harness should PAP become a treatment option in NHS clinical practise. PAP is not a straight-forward intervention and to deploy it within existing services will require a focus on implementation and the involvement of enthusiastic psychiatrists.

Study Strengths and Weaknesses

Strengths of the study included the surveying of all psychiatrists across an entire NHS mental health trust and the involvement of all sub-specialties and levels of experience. The response rate (26 percent) was lower than ideal, although not unusual for a survey of this type. It therefore remains possible that there was response bias, such that psychiatrists who were already more knowledgeable about PAP differentially responded to the survey and were more likely to participate in the focus groups. Certainly, proportionally more trainees participated in the survey than non-training grade doctors, which may have been due to a greater enthusiasm amongst trainees for this topic or may have reflected the greater time pressures on non-training grade doctors. Furthermore, although the sample was likely to be relatively representative of UK psychiatrists—particularly those practising in England—it is not clear that this would hold true for psychiatrists practising in other countries. The mixed-methods approach was an advantage, which is likely to have facilitated richer insights by utilising quantitative and qualitative methods. Nevertheless, more focus groups with more attendees may have elicited additional or different themes, as we could not be certain that saturation of themes was achieved.

The findings of this pilot study suggest that for psychiatrists to develop the necessary expertise and confidence in PAP, they will need support to train and accredit in this new approach. In addition, our findings suggest that getting the support and training structures right for psychiatrists will likely be insufficient unless there is public education about PAP and some degree of societal shift. Formal guidelines, curricula and training—devised in conjunction with regulators and organisations that educate and support psychiatrists—will be needed before psychiatrists will feel ready to participate in the delivery of this promising new treatment paradigm. For example, a multi-disciplinary group from Canada recently recommended that a National Advisory Council be created to make recommendations and around training and accreditation for clinicians involved in the provision of PAP there (19). In summary, however strong the research evidence for the efficacy of PAP in psychiatric disorders, our findings suggest this will be insufficient for PAP to be implemented within NHS mental health services without considerable attention on the workforce needed to deliver it.

 
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Therapeutic Use of LSD in Psychiatry*

Juan José Fuentes(1), Francina Fonseca(1,2,3), Matilde Elices(1,4), Magí Farré(5,6), Marta Torrens(1,2,3)

1Institut de Neuropsiquiatria i Addiccions, Hospital del Mar, Barcelona, Spain
2Addiction Research Group (GRAd), Neuroscience Research Program, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain
3Psychiatry Department, Universitat Autònoma de Barcelona (UAB), Cerdanyola del Vallès, Spain
4Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM, Madrid, Spain
5Clinical Pharmacology Department, Hospital Universitari Germans Trias i Pujol (IGTP), Badalona, Spain
6Pharmacology Department, Universitat Autònoma de Barcelona (UAB), Cerdanyola del Vallès, Spain


Lysergic acid diethylamide (LSD) was studied from the 1950s to the 1970s to evaluate behavioral and personality changes, as well as remission of psychiatric symptoms in various disorders. LSD was used in the treatment of anxiety, depression, psychosomatic diseases and addiction. However, most of the studies were not performed under contemporary standards, and it has taken several decades for a resurgence of interest in LSD research and its therapeutic potential for psychiatry. The aim of this review is to identify controlled and randomized clinical trials that assess the potential use of LSD in psychiatry. PRISMA guidelines for systematic review were followed. A literature search of PubMed and Psychedelic bibliography from MAPS' databases was performed as well as a manual search of references from evaluated studies. Only randomized-controlled clinical trials were included. Study quality was systematically calculated by using the Cochrane Collaboration Tool for assessing risk of bias. A final selection of 11 articles was made after considering inclusion and exclusion criteria. LSD was administered to 567 patients in a dose ranging from 20 to 800 mcg. Despite the design heterogeneity of clinical trials, positive results were observed, thus revealing the therapeutic potential of LSD to reduce psychiatric symptomatology, mainly in alcoholism. The vast majority of authors describe significant and positive short-term changes in patients, despite the fact that in some studies an important homogenization was observed between the LSD treatment group and control group at long-term follow-up. Multiple variables regarding LSD treatment therapeutic approach and quality of experience were revealed and related to therapeutic outcomes. LSD is revealed as a potential therapeutic agent in psychiatry; the evidence to date is strongest for the use of LSD in the treatment of alcoholism. Despite the difficulty of designing proper double blind clinical trials with this substance, new studies that conform to modern standards are necessary in order to strengthen our knowledge on its use and open new doors in the future.

Introduction​

Since its discovery in 1938 by Swiss chemist Albert Hofmann, LSD has maintained an unstable relationship with psychiatry. Hofmann synthesized LSD in an effort to develop ergot derivatives with the goal of reducing postpartum hemorrhage. Some years later, after accidentally getting into contact with a small dose, he was the first subject in history to experience its effects. At the end of the 1940s, there was great interest among psychiatrist in the potential use of LSD as a therapeutic agent, which was actually marketed by Sandoz laboratories under the brand name “Delysid” in the 1950s and used in several psychiatric departments in Europe and America. Even the US Army and CIA experimented with this substance as a truth serum, and LSD was further investigated by the US Army as a potential incapacitating agent, however without success. After its prohibition in USA in 1967, due to an increase in popularity and its association with counter-cultural movements, it has taken several decades for a resurgence of interest in its therapeutic potential for psychiatry.

LSD is part of the pharmacological group known as “classical hallucinogens” or “psychedelics” (term coined by Osmond in 1957), sharing its chemical structure with psilocybin and dimethyltryptamine (DMT) as a variant of indolamine (chemical structure similar to the neurotransmitter serotonin).

The term “classical hallucinogen” is a widely accepted synonym in the literature, with a greater emphasis on the alteration of the perception that these substances cause, although its use has been controversial as it does not specify the effect of these agents in consciousness and the self, as indicated by recent psychological and biological studies. LSD could also be defined, from an anthropological perspective, as an “entheogen”, which implies that users experience (mainly in a religious, shamanic or spiritual context) an altered state of consciousness: “as if the eyes had been cleansed and the person could see the world as new in all respects."

Classical hallucinogens are psychoactive substances that are believed to mediate their effects mainly through an agonist activity in the serotonin 2A receptor (5-HT2A). Experimental studies have previously shown that the use of 5-HT2A antagonists attenuate the main effects of these substances, both in rats and human subjects.

Other receptors which may contribute to the effects of these agents are the serotonin 2C and 1A receptors, as well as other effects in the dopaminergic and noradrenergic system. Likewise, these are potent regulators of transcription factors, which could mediate a potential mechanism of action in the synaptic structure with greater persistence of their effects over time.

LSD is one of the most potent classical hallucinogens available, with active doses between 0.5 and 2 cg/kg (100–150 mcg per dose). Its half-life is approximately 3 h, varying between 2 and 5 h, and its psychoactive effects are prolonged over time (up to 12 h depending on the dose, tolerance, weight and age of the subject). Recently LSD has been used in microdoses as low as 10 mcg to enhance performance.

The usual mental effects of LSD are distortion of sense of time and identity, alteration in depth and time perception, visual hallucinations, sense of euphoria or certainty, distorted perception of the size and shape of objects, movements, color, sounds, touch and body image and delusions.

Concerning safety, the administration of classical hallucinogens carries some risks. One of them is the so-called “bad trip” or “challenging experience”, described as an acute state of anxiety, dysphoria and confusion, which can lead to unpredictable behavior in uncontrolled or unsupervised environments. Another possible risk is the exacerbation of psychotic disorders or the generation of prolonged psychotic reactions, which could be related to the subject's previous predisposition. Although no contemporary study has reported psychosis after the administration of classical hallucinogens, an adequate screening of previous psychotic episodes and the patient's vulnerability is necessary for the use of these substances. Another possible adverse effect is a modest increase in blood pressure and heart rate; therefore, patients with severe cardiovascular disease should be excluded from the administration of this agent. Other usual absolute contraindications are pregnancy, epilepsy or paranoid personality traits. The remaining adverse effects should not limit its therapeutic use.

As a recreational drug, LSD does not entail physical dependence as withdrawal syndrome, as do most of these substances (opioids, cocaine, cannabis and methamphetamine). Its frequent or long-term use can lead to tolerance, and after a single dose, emotional, physical and mental stability is quickly recovered. Likewise, classical hallucinogens in general, and LSD in particular, exhibit very low physiological toxicity, even at very high doses, without any evidence of organic damage or neuropsychological deficits associated with their use. Their safety has recently led to considering LSD as one of the safest psychoactive recreational substances.

However, LSD remains one of the most stigmatized and legally restricted agents among psychoactive substances. It is still included in Schedule I of the United Nations classification of drugs, restricting its use in research and making it difficult to potentially use it as a therapeutic tool in medicine. This classification has recently been questioned by various authors. A few decades ago, anecdotal reports of suicidal acts in recreational users were published, and intensely emphasized by the media. These attempts are in contrast with some recent population studies, which show significant associations between the use of a single dose of classical hallucinogens and a decrease in the likelihood of psychological distress and suicide. Other recent studies also established a clear link between life-time use of classical hallucinogens and a lower probability of developing mental problems, as well as a positive association, although non-significant, regarding several variables related to mental health. Nevertheless, the unpredictability of subject behavior makes it necessary to adequately control the environment and monitor the reaction of each individual.

Regarding its therapeutic potential, LSD was used from the 1950s to the 1970s to achieve behavioral and personality changes, as well as remission of psychiatric symptoms in various disorders. LSD was used in the treatment of anxiety, depression, psychosomatic diseases and addiction. During that time, it was also observed that LSD together with suitable accompaniment during its administration, could reduce pain, anxiety and depression in patients with advanced cancer Other studies involving larger patient samples also established its safety and promising results in patients with terminal cancer. Studies in schizophrenic patients, however, reached less response to the same dose and worse clinical outcomes compared with non-schizophrenics patients, and negative effects on these patients have been described, both in LSD experience itself and later benefits. The data indicate that the responsivity of schizophrenic patients to the administration of LSD is less than that of normal subjects.

Prediction of individual responses to LSD depends on several variables, some of which were already discussed at the international LSD therapy conference in 1965. LSD reaction involves a series of complex interactions between doses, “set” (thoughts, mood and expectations of the subject prior to treatment) and “setting” (the physical and interpersonal environment in which the subject undergoes treatment). Three different major approaches to LSD use as a treatment were then applied to clinical research: “psycholytic therapy”, “psychedelic-chemotherapy” and “psychedelic-peak therapy.” In psycholytic therapy, mainly practiced in Europe, low-moderate doses (25-200 mcg) of this drug were used in more than one therapeutic session of psychodynamic orientation. In psychedelic-chemotherapy, drug use itself was emphasized at relatively high doses (200 mcg or more), with a very limited or absent psychotherapeutic approach. As for psychedelic-peak therapy (or “psychedelic therapy”), it involves administering a single and relatively high dose with the aim of triggering a mystical-type experience (“peak experience” or “ego dissolution” as synonyms). This approach should include the proper prior preparation of the patient (set) and a comfortable environment during the session (setting), as well as a discussion on it during subsequent follow-up sessions with the subject (after-care related to LSD session) (63). Mystical experiences are referred to as those in which a sense of unity with the environment is experienced achieving a vivid transcendental experience at an emotional, cognitive and ego-structural level, after a previous and personal therapeutic preparation. The aim is to catalyze rapid and fundamental changes in the value system and self-image of the subject.

Despite the foregoing, most clinical studies involving the use of LSD were published between the 1960s and 1970s, up to the strict prohibition of its use in research. Obviously, most of these studies were not performed under contemporary standards. The purpose of this systematic review is to identify controlled and randomized clinical trials that assess the potential use of LSD in psychiatry and identify variables controlled by the researcher as potentially related to therapeutic outcomes. This is with the aim of informing a discussion on the benefits and challenges of integrating contemporary classic hallucinogens research into modern clinical trial designs and providing a guide for further research involving LSD as a therapeutic agent.​

Methods​

Data Acquisition and Search Strategy

This study was conducted according to the requirements established in the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) protocols (66).

Pubmed database was searched for the following terms: [“lysergic acid diethylamide” OR “LSD” OR “lysergic acid diethylamide” (MeSH Terms)] OR “lysergic acid”) AND [“therapeutics”(MeSH Terms) OR “mental disorder” (MeSH Terms) OR “therapy” OR “psychotherapy” OR “treatment”]. In addition, MAPS' Psychedelic Bibliography (www.maps.org) was also consulted. To ensure literature saturation, the electronic search was supplemented by a manual review of the reference lists from eligible publications. Two authors independently screened the titles and abstracts yielded by the search against the inclusion criteria. Full reports for all titles that appear to meet the inclusion criteria were obtained. Reviewers resolved disagreements by discussion. The search was limited to the time period compressed between 01-01-1950 and 05-05-2019, based on the results obtained in the reference search.

Search results were examined by two authors reading the titles and abstracts. Each potentially relevant publication found during the search was retrieved and assessed for its use in this review after inclusion and exclusion criteria were specified.​

Data Items

Dosage, frequency and duration of the treatment, for both experimental and control interventions were extracted. Patient's characteristics (including age, gender and diagnosis) and inclusion/exclusion criteria were extracted together with country, trial design, trial size, and length of follow up. For non-pharmacological comparators, type, frequency and duration of the intervention were extracted, if appropriate.

As studies with different diagnostic groups were included, outcomes varied depending on the psychiatric condition under study. In any case, change scores from baseline or endpoint were extracted. Side effects and overall tolerability were also studied.​

Eligibility Criteria

Randomized controlled trials of LSD as a therapeutic tool for psychiatry were included. This review included only randomized controlled clinical trials involving patients with a diagnosis of mental illness. Experimental studies in healthy volunteers were excluded. Trials with no control group or not randomized, animal studies, observational studies, review papers, qualitative studies, case reports, opinion pieces or comments, letters or editorials, conference abstract, posters and books chapters were excluded. Of interest were interventions using LSD, as a stand-alone treatment or as an adjunctive treatment. Only studies comparing LSD with other interventions were included. Active and non-active comparators were included.​

Quality Assessment

The Cochrane Collaboration risk of bias assessment tool was used to determine the quality of the studies (67). This tool involves an assessment of six specific domains: 1) sequence generation, 2) allocation concealment, 3) blinding of participants, 4) personnel and outcome assessors, 5) incomplete outcome data, and 6) selective outcome reporting and other sources of bias. The tool was applied to each RCT independently by two authors. Discrepancies were resolved through discussion with a third author.​

Results

A total of 3,668 papers were identified through the search in Pubmed, and 12 additional records were found through other sources (manual search based on review papers and meta-analysis). After the removal of duplicates and exclusion based on titles or abstracts, 43 papers were screened in more detail for eligibility. Subsequently, another 32 were excluded, which resulted in the 11 papers used in this systematic review. This process is described in the PRISMA flowchart (Figure 1). The quality of the great majority of the clinical trials found did not conform to modern standards, with a non-randomized control group or without control group itself. The highest quality of trials was observed in studies on the therapeutic use of LSD in alcoholism.

FIGURE 1​
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Figure 1 PRISMA flowchart of selected abstracts and articles.

The detailed description of all studies included and their main results can be found in Tables 1 and 2.

TABLE 1​
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Table 1 Details of studies: design, diagnosis and measurement.

TABLE 2​
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Table 2 Details of studies: set, setting and main findings.

Place and Publication Date of the Study

Among the selected clinical trials, 3 were carried out in Canada, 7 in the USA and 1 in Switzerland. Tables 1 and 2 show these clinical trials ordered by date of publication. Note the important 41-year interval between the study by (63); and the modern study by Gasser et al.​

Quality Assessment of Studies

A summary of risk of bias is presented in Table 3. Based on the definitions provided by the Cochrane risk of bias assessment tool (67), no trials were assessed to show a high risk of bias related to sequence generation, and all trials used random assignment. Moreover, all trials attempted to conceal allocation, but most of them were judged to have unclear risk of allocation concealment because did not describe methods in detail.

TABLE 3​
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Table 3 Quality assessment of all included studies based on the risk of bias.

Five trials were judged to have a high risk of bias due to blinding of patients or staff. In two of them, treatment allocation was concealed only until the time of the possible LSD session, and in the other three trials no attempt of blindness or to single blind was made or designed. The rest of them used double-blind designs with active placebo, but in “Smart et al.” blinding of one of the two control groups (control group without active placebo) was not explicitly described.

All trials were judged to have low or an unclear risk of bias due to independent and blind assessment. In one trial the outcome assessor was not explicitly described as allocation-blind and in another one the assessment was collected by self-report questionnaire, confirmed by telephone interview with a close relative or friend. The rest of them had independent and allocation-blind assessors.

Two trials were judged to have a high risk of bias due to incomplete outcome data, because participants were excluded if they did not complete the intended treatment program or if received additional doses of LSD.

Four studies had substantial rates of missing participants at follow-up. However, retention rates were generally high, and data missed in one of the trials (63) was only representative at 12 and 18 months, not at 6 months. In the other three trials, authors considered missing participants as unimproved.

Three trials were judged to have a high risk of bias because of possible selective outcome reporting, presenting lack of clarity at short-term follow-up clinical outcome and giving more detailed data at medium or late-term follow-up. Another trial was judged to have an unclear risk because some measures were not strictly reported.

Finally, four trials were judged to have a high risk of other sources of bias. In one of them, due to baseline imbalance (full-dose LSD participants were less likely to be divorced and more likely to have prior admissions for alcohol treatment), other trial due to treatment time (full-dose LSD participants were more likely to have more psychotherapy hours) and the rest of them due to a shorter time of hospitalization [from one day (71) to a few days (74)] for the LSD treatment group and not the control group. Two last trials presented unclear risk of bias due to uneven concurrent use of other pharmacological treatments during study between participants.​

LSD Dosage and Method​

LSD was administered to 567 patients in a dose range from 20 to 800 mcg. The oral route was significantly the most used one, while one study used the intravenous route and another one did not describe the route used. A single dose of LSD was the procedure of choice for most selected clinical trials. Other studies opted for a dosage-escalation approach, and some offered the possibility of repeating LSD doses at 2–3 week intervals.

The concomitant use in some of the studies of other pharmacological principles, such as dextroamphetamine prior to the dose of LSD, or chlorpromazine or promazine after LSD treatment is worth mentioning. Since the therapeutic potential of LSD may be underestimated or masked by such treatments.​

Safety and Adverse Effects

Most studies describe exclusion criteria for patients to be treated with LSD. Severe organic disease (mainly at neurological and cardiovascular levels) was a common exclusion criteria.

“Gasser et al.” do not rule out those patients with cardiovascular disease, due to the idiosyncrasy of subjects under study (life-threatening diseases). Two of the studies also excluded those patients with a history of severe affective disorder. Most clinical trials discarded those patients with active psychosis for the study, but some of them did not rule out patients with a history of psychosis in the past. It is noteworthy that in the study of Tomsovic and Edwards, LSD was administered to a subgroup of 12 patients diagnosed with schizophrenia (withdrawn from Table 1, due to modern exclusion criteria), to which they applied a separate statistical analysis that showed better results for the subgroup of non- schizophrenics who had received a single LSD dose.

Two cases of serious adverse effects were reported. In one of the studies, authors described a tonic–clonic seizure, without subsequent complications, in a patient with a previous history of seizures in a context of abstinent clinical symptoms. In another one, a case of prolonged psychosis was reported in a 21-year-old patient with a previous history of recurrent psychotic episodes in the context of hospitalization during adolescence. This patient received psychotherapy and antipsychotic medication, recovering without later complications. No other serious adverse effects were described in the remaining 565 subjects.​

Control Group and Active Placebo

Five studies within our review designed a control group for which no drug was administered, and three others had a control group in which the usual treatment was applied to patients during hospitalization. In “Savage et al.” the control group had the added benefit of participating in one hour and a half group therapy sessions three times a week, which were defined as eclectic (focused on the solution of specific problems through group interaction). Most studies (see Table 1) had a control group in which active placebo was used, and four of them used LSD itself at a lower dose. The difficulty in maintaining patient and therapist uncertainty, even with active placebo, is underlined by authors. With ephedrine sulfate, in 19 of 20 cases the therapist correctly guessed which type of drug was administered to the patient, and 20 mcg of LSD was considered too low a dose to avoid unmasking the control group, both for patient and therapist.​

Treatment Program and “Set”

There was great heterogeneity among the clinical trials chosen for this review in terms of patient preparation and the general therapeutic program to which LSD treatment was added. Table 2 shows the type of treatment program used in each study, ranging from 24 h to 90 days from the start of treatment to patient discharge. The treatment program between different studies also differed in structure, varying between highly structured intensive programs (with five weekly meetings, seminars, group and individual therapy, occupational therapy and rehabilitation program) and the absence of a specific program.

Preparation of the subject for LSD treatment ranged from very brief orientation to extensive preparation with the aim of promoting the therapeutic experience. Preparation time (pre-LSD session, Table 2), ranged from a few hours to 5 weeks. The only information provided to subjects in some cases was the great variation in the individual response of the drug, or very brief data on the nature of response , with no intention to perform previous therapy. One of these authors points out that the previous preparation of patients to LSD administration was possibly insufficient for achieving therapeutic objectives.

Despite heterogeneity, there was a trend among most modern trials within our review to emphasize the importance of the “set” of the subjects to be studied, devoting more time and providing them with a structure. In the earliest study meeting these characteristics , patients were previously informed of the nature of the drug, stating whether they would receive a small or a large dose. Within the LSD group of treatment (full-dose or active placebo), approximately half of the patients performed the session during the first 3 weeks, with the remaining subjects receiving LSD treatment during the last 3 weeks. There was a non-significant trend towards better results among those who received treatment during the last 3 weeks, which was highlighted by the authors as a positive association between “set” and therapeutic outcomes.​

Therapeutic Approach and “Setting”

Therapeutic Approach

Again, great heterogeneity was observed among studies regarding the therapeutic approach during the treatment with LSD. Two studies applied an approach based on active and directed interviews focused on problems derived from alcohol dependence. In one of these trials, these interviews were described as an attempt to discover alternatives to alcohol use, and to define patient attitudes regarding the transfer with the therapist, the act of moving towards drinking, parental relationships, suicidal ideation or sexual behavior.

In three of the studies , no psychotherapy attempts were made during the treatment session. In one of them, an effort was made to maintain a supportive environment, which included non-verbal communication. In another study, three different approaches were used during the LSD session, defined as “psychedelic therapy,” “hypnodelic therapy” and “silent observation”, to study possible differences in their therapeutic potential. The author described “an active, dynamically oriented psychotherapy, with the primary focus on major problem areas”, which contrast with the description of “psychedelic therapy” considered above. The most common approach among these studies was to use psychedelic therapy, defined as 12-14 h after one relatively high LSD dose (200-500 mcg), during which a nurse and a therapist provide constant attention with the aim of the subject achieving a “peak or transcendental experience.”​

Setting

Regarding the physical (sensory stimuli) and interpersonal environment of subjects during the LSD treatment (see Table 2), in five trials, musical stimulation during the session was offered. Descriptions of environment were varied, finding “comfortable or tastefull furniture” or “flowers and pictures” as examples. In four of the studies, the physical environment was not described. Likewise, in two studies, the use of waist belt to bed method was mentioned to prevent subjects from leaving their position. Regarding the interpersonal environment, the fact that in the earliest study (68) subjects were unaccompanied for an indefinite period of time during the treatment is noteworthy.​

Efficacy

The efficacy of the intervention with LSD was presented by the main diagnosis where the substance was administered.​

Alcohol Use Disorder

Most clinical trials in this review evaluated the therapeutic potential of LSD in the treatment of alcohol use disorder. The main outcomes of these studies and their main statistical analysis were summarized below, by order of publication.

In the study by “Smart et al.” there was a substantial improvement in abstinence (total abstinence and longest period of abstinence) in all three groups [LSD group (800 mcg), active placebo group (60 mg ephedrine sulfate) and “no drug” group], but no significant differences were found between them. There were no significant differences between groups either in the Drinking History Questionnaire nor in number of voluntary contacts with the clinic afterwards.

The second study showed a significant improvement in the 2-month follow-up in the LSD group with respect to dextroamphetamine, based on the Drinking Behavior Scale score. No significant differences were found at 6 months follow-up, except for two specific symptoms of this scale (related to work performance), in which LSD was shown to be superior to dextroamphetamine.

Conversely, in the study by “Ludwig et al.”, results showed a significant improvement at two weeks of treatment for all four groups (three different approaches in LSD group (Hypnodelic therapy group, Psychedelic therapy group and Silent Observation group) and control group). However, no significant differences were found between them. In the same way, a significant improvement was observed in the Behavior Rating Scale values for each period (6, 12 months) in all groups, without finding significant differences between them.

In the next study, a significant improvement was found in terms of abstinence, drinking behavior and employment rate after treatment in all groups. However, no significant differences were found between them. In the same direction, in the study by “Bowen et al.”, no significant differences were found between groups.

In the study by “Denson et al.”, no significant differences were observed between groups (LSD group and control group) at follow-up, except in the Background and Follow-up Questionnaire for Non-Schizophrenic Patients data, in which the LSD treatment group showed better results in terms of general health.

In the next study, significant improvements were observed in Global Adjustment and Drinking Behavior for the LSD treatment group compared to the control group at 6 months.

Finally, in the last trial, a higher percentage of abstinence was observed among the LSD treatment group compared to the remaining groups at three months, maintaining this superiority at one year in several grades. A statistical difference was observed between the LSD group and the control group 1, but authors emphasized that the control group 1 was not representative of the best results observed in the control group 2.

In summary, it was observed a significant effect of LSD in four studies performed. However, this effect was related to quality of life and general health in some of the studies, with no clear improvements in alcohol abstinence.​

Neurotic Symptoms (Anxiety, Depression, and Psychosomatic Diseases)

Two trials evaluated LSD as a treatment of neurotic symptoms. This diagnosis was referred to as depressive neurosis, obsessive-compulsive reaction, phobic reaction, anxiety state, hysteria, psychoneurosis with somatic symptoms, character disorder and sexual neurosis. The presence of all symptomatology was not required, and a subset of neurotic symptoms was adequate. “Denson et al.” found significant differences in Questionnaire data, in which the LSD treatment group showed better results in terms of general health at 6 and 12 months. Also, in the study by “Savage et al.”, a significant improvement was observed at 6-8 weeks in most of measurements used for all three groups (LSD treatment group, active placebo (LSD) control group and “usual treatment” control group). This improvement (mainly focused on symptomatology and self-actualization) was significantly greater as an average for the LSD treatment group compared to the “usual treatment” control group, as well as for some measurements used for the active placebo (LSD) control group compared to the “usual treatment” control group. The LSD treatment group showed superiority with respect to both control groups in a sub-scale of the Minnesota Multiphasic Personality Inventory. Regarding subsequent evaluation (6 months), all groups showed significant differences in a large number of variables, but in this case the results of the statistical analysis failed to reach the defined significance level between the groups.​

Heroin Use Disorder

Only one study met the inclusion criteria in our review. Significant differences were observed in total abstinence rates in favor of the LSD treatment group at 12 months. A trend, not statistically significant, was observed in favor of the LSD treatment group in Global Adjustment Rating Scale.​

Anxiety Associated With Life-Threatening Diseases

A modern study assessed anxiety associated with chronic inflammatory disease, chronic motor disease and cancer. All patients had a score of 40 and above in the State-Trait Anxiety Inventory (STAI). A positive tendency in trait anxiety reduction in the STAI was observed at two months post ingestion, as well as a significant reduction in state anxiety in the STAI. Reduction trends in the STAI were maintained after 12 months in the LSD group, however with no significant difference.​

Aftercare Related to Experimental (LSD) Sessions

In some studies patients could be discharged after 24 h or in less time if they were able to be assisted by friends or relatives. Other studies did not specify which patients maintained subsequent therapy, or did not examine session results unless patients actively requested it. In one of these studies, a possibly inadequate follow-up of subjects was mentioned, without giving them the opportunity to receive further treatment.

One of the authors suggested that short-term changes that occurred frequently in subjects' personality could be integrated and applied to their daily-life insight with greater support and additional help after hospital discharge. In one study, patients remained hospitalized at least one week after the LSD session, being visited by their therapists repeatedly. In this study, a second session with LSD was offered to those patients who were considered suitable for second exposure (approximately 25% out of both LSD groups. In another study, a second dose was also offered to subjects in the active placebo group at months of follow-up (open- label cross-over design). Finally, in one of trials, half of each group was also treated with disulfiram (daily dose of 500 mg) after hospital discharge. Patients were strongly encouraged to take a fixed, prescribed dosage every day, instructed on the dangers of imbibing alcohol while on disulfiram, and started on the drug four days prior to hospital discharge. They were given a six-month supply of disulfiram and instructed to take one 500 mg tablet per day. Baseline to post-treatment t-tests revealed significant improvement in Behavior Rating Scale for every group at every period, while two-way analysis of covariance revealed no significant differences between groups that received disulfiram and those that did not after hospital discharge, for any of the measurements studied.​

Variables in Therapeutic Response

Some studies described efforts to predict therapeutic outcomes in relation to an acute psychedelic experience. In one of them, it was emphasized that the methodology used did not manage to measure crucial aspects of the experience that foresee subsequent benefits. In two others, a significant link was observed between values in the Global Adjustment Scale and the probability of optimal adjustment in the community in relation to the achievement of a “mystical or peak experience” during the LSD session. One of these authors identified the LSD dose as a better predictor than the type of experience in his study; although he also pointed out that there was a close link between “peak-experiences” and a higher drug dose.

On the other hand, in two studies it was observed that patients who seemed to benefit from the treatment with LSD did so optimally with more probability. A greater likelihood of complete abstinence from alcohol or optimal adjustment in the community was observed after the LSD treatment.

Finally, one of the uthors highlighted that male patients showed a clear improvement in Global Adjustment with as full dose (350 mcg) of LSD at six months post ingestion, while in females, a greater improvement was observed with low doses of 50 mcg.​

Discussion

Despite design heterogeneity among the clinical trials in this review, some positive results were observed, revealing the therapeutic potential of LSD in the reduction of psychiatric symptomatology. The vast majority of authors described important positive short-term changes in patients, although in some studies an important homogenization was observed between the LSD treatment group and the control group at long-term follow-up. Some previous studies of lower quality also exemplified a clear improvement in short-term adjustment, with a later tendency to balance results with the control group. However, this is in contrast with the results shown by some authors, in which therapeutic changes were maintained at 6–12 months after treatment. Moreover, in a follow-up study beneficial changes were found at one year of follow-up for psychedelic therapy compared with conventional psychotherapy in adolescent behavior disorders. Numerous studies in healthy volunteers have been carried out within the last decade, and some of them have showed positive effects more than a year after a LSD or psilocybin single dose.

The results of this review could conclude that alcohol use disorder patients may benefit from LSD treatment. Other studies with a lower quality control group (patients did not receive a treatment comparable to the treatment group) also found significant differences in favor of LSD treatment in alcoholism. Likewise, according to a retrospective analysis of studies published in the late 1960s, LSD is a potential therapeutic agent for the treatment of chronic alcoholism. A recent meta-analysis of six of the clinical trials chosen for this review showed the superiority of LSD over placebo in the treatment of alcoholism with an odds ratio of 1.96. This study found that a LSD single dose was comparable in terms of effectiveness with the daily intake of naltrexone, acamprosate, or disulfiram in alcoholism treatment. Other studies in our review also found promising results regarding LSD use for the treatment of heroin use disorder, anxiety, depression, psychosomatic illnesses, and anxiety in relation to life-threatening diseases. Regarding the latter, several authors emphasize the difficulty of designing placebo-controlled and double-blind trials, due to ethical reasons and the nature of te psychoactive intervention.

Regarding the disparity between some results in our review, and as noted by Pahnke et al. (62) “it is essential to keep in mind the differences in procedure among the various methods, not only because of different kinds of experiences being facilitated, but also because of conflicting results that can be correlated with the method used”. LSD invariably involves a complex interaction between drug dosage, set and setting. This link is also objectified in different studies, showing the significant relationship between the therapeutic efficacy of psychedelics and an adequate set, setting and integration of later experience. This could explain some differences between the results of these reviewed trials, in which there was a great variation between the approach of “Smart et al.”, and that of “Savage et al.” (psychedelic therapy: set, setting and aftercare related to the LSD session). Some authors argued that the accepted methods proven to generate some beneficial experience with LSD are far from those used by Smart at the 1960s. Therefore, the inherent difficulty in conducting a double blind controlled clinical trials with LSD should be mentioned. In 1964, Whitaker stated his opposition to the design of a control group with this type of substance, due to the promising responses of first patients as opposed to the control group. Due to this difficulty, widely discussed at the time, many studies previous to that carried out by “Smart et al.”, did not apply adequate measures or assessments, without a control group or properly designed statistical analysis. In this regard, Tomsovic and Edwards mentioned “the complexities and difficulties of achieving control over the placebo effect of a drug that has spectacular mind-altering properties, and where research is contaminated by expectations of benefit”.

Also, modern clinical trials are currently facing a series of problems, which could be summarized as follows (93). Firstly, subjective and objective changes experienced with LSD and the rest of psychedelics, apparent for both the subject and observer, make performing double-blind tests virtually impossible. Likewise, adequate placebo control becomes extremely difficult due to the absence of such changes in the control group. Strict control of the variables related to the therapeutic benefits of LSD is also necessary. Finally, research with these substances must overcome a series of strict ethical committees and restrictions at the legal level.

When attempting to solve difficulties in terms of blinding and adequate placebo control, a valid approach is an active placebo, using LSD at lower doses, an approach already suggested within some of clinical trials in our review. This methodology, despite possibly minimizing the effects of LSD when compared to its sole administration, is based on results by numerous researchers who have observed the link between dose and quality and intensity of the psychedelic response. Dosage and form of administration, as well as the context in which it is carried out, can be strictly controlled within a hospital setting. The possible effects of microdoses of LSD must be takin into account, possibly limiting its use.

Despite the known unpredictability of psychedelics, great efforts have been made in recent years to know which variables are associated with the therapeutic value of these substances, finding mystical-type experiences as one of the objectives to be achieved. Results of recent investigations show that mystical-type experiences are associated with positive long-term changes after a dose of psychedelics. The musical stimuli variable has also been observed as a predictor of mystical-type experiences and positive therapy outcomes.

As noted by Gasser, designing qualitative studies, not only based on pathology-oriented measurements, is also important to detect variables related to other psychopathological symptoms that can potentially be improved by LSD use (e.g. equanimity, self- assurance and mental strength). Currently, there are validated scales available to measure the quality of the psychedelic experience, such as the Mystical Experience Questionnaire (MEQ-30) and the Ego-Dissolution Inventory (EDI). The apparently unpredictable nature of these experiences makes studying them in empirical research equally difficult and necessary .

Moreover, numerous recent studies with LSD regarding changes in neural networks have been carried out. Modularity and integration networks (as observed in resting- state functional connectivity) have been shown to decrease due to effects of LSD. Patterns compared to normal waking consciousness have been demonstrated with LSD, and a correlation between subjective reports of “ego dissolution” during LSD and an increment of the overall connectivity and global integration of the brain was found. These changes at the cerebral level during the acute effects of psychedelics have been associated with the aforementioned subjective effects “ego dissolution” and “mystical-type”, and could be related to the wide therapeutic value of these substances.

Likewise, multiple modern clinical trials involving other psychedelics have been carried out in the last decade, mainly with psilocybin. Hopeful results have been found for the treatment of alcohol or tobacco addiction, anxiety in relation to advanced cancer or obsessive-compulsive disorder. Moderate doses of psilocybin (200 µg/kg) have been used in some modern studies, either with dose escalation or the same dose in various sessions, something reminiscent of the psycholithic therapy used in Europe in the past century. Some possible reasons for the greater use of psilocybin over LSD in modern trials were the shorter duration of one effects of the former (thus avoiding hospitalization) or the greater stigma that prevailed regarding the latter (making it difficult to get economic funds and the approval by ethical committees). Beyond psychiatry, the therapeutic potential of LSD in other medicine fields has recently become evident, as in the treatment of cluster headaches in neurology.

As it has been previously pointed out, the homogenization of the therapeutic approach is strictly necessary, and training programs related to research and psychotherapy with psychedelics have recently been developed. Also, there are modern guidelines available for the correct use of psychedelics in clinical research). Therefore, the reborn interest of the therapeutic potential of psychelics in modern clinical trials is evident, something proven by the remarkable increase in the number of studies carried out with these substances over the last decade.

The present review has limitations. Firstly, only articles written in English were selected; this could imply that articles in other languages were excluded despite the fact that these might have provided valuable information. Furthermore, as mentioned above, most studies were carried out during the past century. Moreover and as previously discussed, there was considerable heterogeneity in their design. Also, differences regarding patient populations, features, and diagnostic methods were noticed. Therefore, due to the lack of studies and the features exhibited by selected research, this review can contribute limited evidence on the topic of interest.

This study comes with its own set of strengths. On the one hand, to our knowledge this is the first systematic review of randomized-controlled trials to assess the therapeutic potential of LSD in psychiatry. On the other, a strict selection of studies was carried out, considering inclusion and exclusion criteria as well as confounding factors. With regards to this and in spite of the heterogeneity mentioned above, the important therapeutic value of LSD is revealed and it is observed to be related to variables controlled by the researcher, such as: set, setting and aftercare related to the LSD session. Another positive aspect of this review is that our results highlight the need for randomized-controlled clinical trials with standardized methods to accurately assess the quality of an acute psychedelic experience. Finally, this review could serve as a guide for further research involving LSD as a therapeutic agent.​

Conclusions

In conclusion, and despite some controversial results mentioned above, LSD is revealed as a potential therapeutic agent in psychiatry; the evidence to date is strongest for the use of LSD in the treatment of alcoholism. Despite the difficulty of designing double-blind clinical trials with this substance, new studies performed under modern standards are necessary in order to strengthen our knowledge, help erase the stigma that still prevails around these substances and open new doors in the future.

*From the article (including references) here :
 
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Rethinking serotonin could lead to a shift in psychiatric care

by Robin Carhart-Harris and David Nutt | Imperial College London | Science Daily

A better understanding of how a key chemical messenger acts in the brain could lead to a radical shift in psychiatric care, according to a new research paper.

Serotonin is a neurotransmitter which helps brain cells communicate with one another, playing important roles in stabilising mood and regulating stress.

Despite its importance, current models to explain serotonin's function in the brain remain incomplete.

Now, in a review paper published this month in the Journal of Psychopharmacology, researchers from Imperial College London suggest that serotonin pathways are more nuanced than previously thought.

They argue that the existing view should be updated to incorporate a 'two-pronged' model of how serotonin acts.

The researchers believe their updated model could have implications for treating recalcitrant mental health conditions, including depression, obsessive compulsive disorder and addiction, and could exploit the therapeutic potential of psychedelic drugs.

In the brain, serotonin acts via a number of sites called 'receptors' and serotonin has at least 14 of these. Brain drugs such antidepressants, antipsychotics and psychedelics are known to interact with serotonin receptors and two of these are thought to be particularly important -- the so-called serotonin 1A and 2A receptors.

For patients with depression, commonly prescribed drugs called SSRIs (Selective Serotonin Reuptake Inhibitors) can help to relieve symptoms by boosting levels of serotonin in the brain. Evidence suggests an important part of how they work is to increase activity at the serotonin 1A receptor, which reduces brain activity in important stress circuitry, thereby helping a person cope better.

In contrast, psychedelic compounds such as LSD and psilocybin (the psychoactive component of magic mushrooms), are thought to act primarily on the serotonin 2A receptor. Accumulating evidence suggests that psychedelics with psychotherapy can be an effective treatment for certain mental illnesses and, with a focus on the 2A receptor, the authors' paper attempts to explain why.

Writing in the review paper, the researchers say that while the traditional view of developing psychiatric treatments has been focused on promoting 1A activity and often blocking the 2A, the therapeutic importance of activating the 2A pathway -- the mechanism by which psychedelics have their effect -- has been largely overlooked.

"We may have got it wrong in the past," said Dr Robin Carhart-Harris, Head of Psychedelic Research at Imperial and lead author on the paper. "Activating serotonin 2A receptors may be a good thing, as it makes individuals very sensitive to context and to their environment. Crucially, if that is made therapeutic, then the combination can be very effective. This is how psychedelics work -- they make people sensitive to context and 'open' to change via activating the 2A receptor."

According to the researchers, the 1A and 2A pathways form part of a two-pronged approach which may have evolved to help us adapt to adversity. By triggering the 1A pathway, serotonin can make situations less stressful, helping us to become more resilient. However, they argue that this approach may not always be enough, and that in extreme crises, the 2A pathway may kick in to rapidly open a window of plasticity in which fundamental changes in outlook and behaviour can occur.

Growing evidence shows that in conditions such as treatment-resistant depression, obsessive compulsive disorder and addiction, certain brain circuitry may become 'stamped in' and resistant to change. The researchers suggest that in such cases, activating the 2A pathway -- such as through psychedelics -- could potentially offer a way to break the cycle, helping patients to change negative behaviours and thought patterns which have become entrenched.

By enabling the brain to enter into a more adaptive or 'plastic' state and providing patients with a suitably enriched clinical environment when they receive a drug treatment, clinicians could create a window for therapy, effectively making patients more receptive to psychotherapy.

According to the authors, their updated model of how serotonin acts in the brain could lead to a shift in psychiatric care, with the potential to move patients from enduring a condition using current pharmacological treatments, to actively addressing their condition by fundamentally modifying behaviours and thinking.

Professor David Nutt, Director of Neuropsychopharmacology in Imperial's Division of Brain Sciences, explained: "This is an exciting and novel insight into the role of serotonin and its receptors in recovery from depression that I hope may inspire more research into develop 5-HT2A receptor drugs as new treatments."

Dr Carhart-Harris added: "I think our model suggests that you cannot just administer a drug in isolation, at least certainly not psychedelics, and the same may also true for SSRIs. We need to pay more attention to the context in which medications are given. We have to acknowledge the evidence which shows that environment is a critical component of how our biology is expressed."

He added: "In psychiatry, as in science, things are rarely black and white, and part of the approach we're promoting is to have a more sophisticated model of mental healthcare that isn't just a drug or psychotherapy, it's both. I believe this is the future."

'Serotonin and brain function: a tale of two receptors'
by Robin Carhart-Harris and David Nutt is published in the Journal of Psychopharmacology.

https://www.sciencedaily.com/releases/2017/09/170904093724.htm
 
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The Psychedelic Revolution in Psychiatry

Cell Press | 3 Apr 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, 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 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.

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."

Reference
Nutt et al. (2020) Psychedelic Psychiatry’s Brave New World. Cell.
DOI: https://doi.org/10.1016/j.cell.2020.03.020

This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source.

 
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The potentially revolutionary psychiatric benefits of psychedelic drugs

by Louis Nicholas | Jun 27, 2018

Right now, across the United States, patients are being denied access to a substance that could effectively treat various diseases and help alleviate certain conditions. You likely know all about the controversy I’m referring to.

Actually, this is not a post about medical marijuana.

Thanks to the arbitrary drug control measures enacted in the Controlled Substances Act of 1970, mental health patients currently find themselves unable to pursue a therapeutic treatment - psychedelics—that could really help them.

Psychedelic psychotherapy, the clinical use of psychedelic drugs to treat mental disorders, has been affirmed by a number of clinical trials to have unique value in treating mental illnesses, with the recent breakthrough trials of MDMA-assisted psychotherapy for Post-Traumatic Stress Disorder (PTSD) being a prime example. Yet drug legislation has placed psychedelics under the highest restrictive category, Schedule I, on the grounds that they have no recognized medical value and a high abuse potential.

This unfortunate—and unsupportable — characterization, codified into law, has made the practice of psychedelic psychotherapy federally illegal and clinical research nearly impossible.

Because a great deal of cultural connotation and mystery surrounds psychedelic substances, a review of the history, neurological effects, and clinical application of psychedelics can help us understand the positive impact psychedelic psychotherapy may offer society.

Despite the common association with lab-produced hallucinogens, the practice of psychedelic psychotherapy reaches back — in more primitive forms, to be sure — into antiquity. For thousands of years, various cultures have utilized psychedelic plants for restorative purposes. Consider the use of Amanita muscaria mushrooms in Europe, DMT-containing ayahuasca in the Amazon, psilocybin mushrooms in America, and ergot rye in Ancient Greece.

These cultures recognized the medicinal potential of psychedelics, and each developed ceremonial contexts in which the substances could be safely taken for their therapeutic effects. Some of these traditions are still in practice, including the ayahuasca ceremonies of the Uniao de Vegetal church in Brazil and the Peyote rituals practiced by Native Americans.

Despite this rich tradition of worldwide psychedelic use, the class of substances remained widely unknown to the modern West until Albert Hoffman’s synthesis of LSD in 1938.

Following Hoffman’s discovery, mental health practitioners soon began developing protocol for safely and effectively administering psychedelic medicines for treatment of mental disorders. Their promising research was abruptly halted in the 1960s when politically charged drug reform legislation placed psychedelics — namely LSD, psilocybin, peyote, and DMT — under the highest restrictive category.

During this era, a large subset of psychedelic users had aligned with anti-establishment sentiment, including dissent towards U.S. intervention in Vietnam and support for the civil rights movement. Alarmed by this growing counterculture, Nixon’s administration enacted the Controlled Substances Act.

The legislation, of course, was a pretext for certain reprehensible social designs the administration wanted to achieve. Nixon’s domestic policy chief John Ehrlichman revealed to Harper’s journalist Dan Baum the underlying motivations:

"The Nixon campaign in 1968, and the Nixon White House after that, had two enemies: the antiwar left and black people. You understand what I’m saying? We knew we couldn’t make it illegal to be either against the war or black, but by getting the public to associate the hippies with marijuana and blacks with heroin, and then criminalizing both heavily, we could disrupt those communities. We could arrest their leaders, raid their homes, break up their meetings, and vilify them night after night on the evening news. Did we know we were lying about the drugs? Of course we did."

In other words, the legislation turned a blind eye to the medicinal properties of several substances in order to establish a politically expedient means of criminalizing subversive populations.

Senator Robert Kennedy, whose wife benefitted from psychedelic psychotherapy, expressed concern regarding the legislation, saying that, “to some extent we have lost sight of the fact that LSD can be very, very helpful in our society if used properly.”

Of course, we couldn’t genuinely assess Kennedy’s statement, given that it would be over 30 years before regulatory boards eased up enough to permit a select number of psychedelic studies.

Two years ago, researchers from the Imperial College London used cutting-edge neuroimaging technology to observe the neurological effects of LSD. They found that the drug facilitates a dissolution of boundaries between specialized brain networks and produces a state of highly integrated consciousness.

In this state, individual networks such as the visual cortex gain new channels of communication with other brain regions. This interconnectivity accounts for the synesthetic effects of psychedelics, during which disparate senses are blended and objects of perception are experienced on multiple levels simultaneously.



Researcher Mendel Kaelen explains the neurological effects of psychedelics by an analogy of the brain to a snowy hill and of thoughts to sleds. As sleds ride down the hill, a central groove forms in the snow. Subsequent sleds naturally glide into alignment with this groove. Psychedelics act as a temporary flattening of the snow, during which sleds may travel freely.

In short, psychedelics provide an opportunity for users to access lines of thought beyond those reinforced through years of experience.

For those with mental illness, this opportunity may amount to a new lease on life. Psychiatric disorders like PTSD, depression, and addiction are marked by an inability to disengage with negative thought patterns. These patterns reinforce themselves over time and become increasingly difficult to overcome.

When a patient is treated with psychedelic psychotherapy they have an opportunity to temporarily disengage from these habitual thoughts and assess their circumstances from a broader perspective. The goal is for the insights gained during this period to help individuals overcome profound anxieties and traumas, even ones deeply reinforced within their psyche.

Yet a key to harnessing their power productively is setting the conditions.

When taken in an improper circumstance, psychedelics may have challenging and disorienting effects on the user. This is why clinicians take special care to ensure that set and setting, the mindset of the patient and the environment surrounding them, are in proper condition before conducting psychedelic psychotherapy.

Typically, they’ll arrange sessions with the patient prior to the psychedelic experience to build rapport and trust, ensuring that the patient feels comfortable under their supervision. They arrange the treatment office or hospital room with comfortable and homey d?cor. And they encourage patients to bring photos of family and personally meaningful objects to reflect on during the experience. On the day of the treatment, the drug is administered to the patient and they are given eyeshades and a pair of headphones.

Clinicians typically do not direct the session, but rather encourage the patient to listen to music and allow the experience to wash over them. Two clinicians oversee the duration of the experience and provide support if needed. Following the session, the patient may meet with clinicians to discuss and integrate the content of their experience.

Much of the excitement surrounding psychedelic psychotherapy can be best understood by how it contrasts with conventional psychiatric medications. Typical medications for anxiety or depression must be taken daily or as needed. Constant use is often accompanied by financial burden, undesirable psychological effects, and physical dependence. Moreover, they are often palliative, working to negate symptoms of mental illness rather than treating the cause.

Psychedelics, on the other hand, can catalyze long-lasting improvements in mental health in a matter of hours. They are not psychologically or physically addictive, and do not pose any major health risks when administered in a clinical setting. Most importantly, they empower patients to confront the source of their mental illness so that they may enjoy a functional life in the absence of daily medication.

This is not to say that psychedelic psychotherapy is a catch-all miracle cure. Nor is the attempt here to suggest it’s the best, most effective therapeutic technique or practice. The point, rather, is to make a case for its wide-ranging application for difficult-to-treat mental illnesses, which should warrant regulatory approval and legislative re-appraisal.

Until this happens, untold numbers of patients will continue to be blocked from potentially benefitting from this uniquely effective treatment.

The good news is that a number of research institutions have recently cleared the formidable regulatory hurdles necessary to more closely examine psychedelic drugs. Interestingly, their findings have shown that a variety of difficult-to-treat disorders respond favorably to psychedelic psychotherapy.

A meta-analysis of six randomized clinical trials of LSD for treatment of alcoholism (536 participants) which took place between 1966–1970 found that a single dose of LSD reduced the probability of alcohol misuse almost two times that of comparison conditions. The treatment effects remained significant at a six-month follow up.

Of equal interest is a 2014 pilot study that found that psilocybin treatment for long-term, heavy tobacco smokers yielded abstinence rates of 80 percent at long-term follow-up, more than doubling abstinence rates typical of approved contemporary tobacco dependence interventions.

These studies address substance addictions with notoriously high mortality rates, and the outcomes evidence the potential of psychedelic psychotherapy to free individuals of morbidly maladaptive fixations. Such an addiction treatment would also be an invaluable asset in addressing the opioid crisis currently running riot across the United States.

Individuals who are diagnosed with life-threatening illnesses are particularly vulnerable to depression and anxiety. Unable to direct their attention elsewhere, their distress may compound and negatively impact their ability to cooperate with and respond to treatments. Three studies have demonstrated the remarkable efficacy of psychedelic psychotherapy in alleviating death anxiety in this patient population and significantly reducing the psychological suffering associated with terminal diagnosis.

At Johns Hopkins University, 51 patients with anxiety and depression relating to life-threatening cancer were treated with psilocybin. Clinician, community, and self-reported measures revealed decreased depressed mood and anxiety alongside increased quality of life, life meaning, and optimism following a large-dose psilocybin experience. These changes lasted well beyond the treatment sessions, with 80 percent of participants retaining their improvements in a six-month follow-up.

Researchers at NYU achieved similar outcomes in their study of psilocybin effects on 29 cancer patients suffering from anxiety and depression, reporting that “at the 6.5 month follow up, psilocybin was associated with enduring anxiolytic and anti-depressant effects, sustained benefits in existential distress and quality of life, as well as improved attitudes towards death.”

These effects were also replicated using LSD to treat anxiety relating to a terminal diagnosis with significant reductions in both state and trait anxiety (anxiety experienced daily, and more stable anxiety-proneness) evident at a two-month follow-up.

Of all psychedelic psychotherapy treatments, the most progress has been attained with MDMA, the chemically pure form of ecstasy, as a treatment for PTSD. Those who suffer from PTSD (approximately 7 percent of the U.S. population) experience intrusive thoughts regarding a traumatic memory of war, natural disaster, sexual abuse, violence, terrorism, or accidents.

Current medications for PTSD are effective for only a fraction of patients and with 27 percent of suicides being associated with PTSD, the psychiatric establishment is in dire need of novel treatments for this condition.

In 2000, the Multidisciplinary Association for Psychedelic Studies (MAPS) launched an international trial of MDMA as treatment for PTSD and the project has since reached the third and final phase for FDA approval, gaining an official breakthrough-treatment designation along the way. MDMA was shown to have an effect size nearly double that of the currently available PTSD medications Zoloft and Paxil, with a 12-month remission rate of 66.2 percent. For the millions of individuals and families affected by PTSD, this treatment promises an effective alternative to the costly medications that often prove ineffective.

As you can see from a review of the history, mechanisms of action, and clinical applications of psychedelic drugs, there is a case to be made for their immediate admittance into psychiatric legitimacy. We should give a serious look to anything — any substance, any practice — that holds such tremendous therapeutic potential.

Unfortunately, current drug control legislation contains false designations regarding psychedelic drugs, and this fact is preventing researchers form studying them more fruitfully. If a potentially revolutionary psychiatric intervention stands before us, it is worth, at the very least, revisiting laws whose very architects admitted were pretextually configured to solidify ideologically suspect social goals.

In the interests of those for whom conventional psychiatric treatments are ineffective, legislators must put aside their allegiance to ill-informed drug policy and lift restrictions on clinical research into psychedelic psychotherapy.

https://arcdigital.media/whos-afraid-of-psychedelic-psychotherapy-a77ce40a47b4
 
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Non-hallucinogenic psychedelic analogs could be a game changer for neuropsychiatry*

by Anna MacDonald | Technology Networks | 26 May 2021

Neuroplasticity plays an important role in a patient’s recovery from mental health conditions such as depression. However, traditional plasticity-inducing antidepressants can take a long time to provide relief, while currently available faster-acting psychoplastogens may cause undesirable effects such as addiction or hallucinations, meaning their use is restricted to a controlled clinical setting. Non-hallucinogenic psychedelic analogs could address some of these issues and provide patients with a treatment option that is both accessible and effective.

In a study recently published in Cell, a novel cellular imaging platform that predicts hallucinogenic potential was used to identify DLX-1, a non-hallucinogenic psychedelic analog with neural plasticity-promoting and antidepressant properties. To learn more about DLX-1 and its discovery, Technology Networks spoke with David E. Olson, co-author of the study and co-founder and chief scientific officer of Delix Therapeutics. In this interview, David also discusses the potential commercial, clinical and scientific implications of non-hallucinogenic psychedelic compounds.

Anna MacDonald (AM): What role does neuroplasticity play in a patient’s recovery from mental health conditions such as depression and PTSD?

David E. Olson (DO):
In healthy individuals, neurons in the prefrontal cortex communicate with other brain regions to regulate motivation, fear, and reward. However, in depression, PTSD, and related disorders, these critical neurons atrophy—their dendritic branches retract and many of their synapses are eliminated. Antidepressants fix these broken circuits by promoting neuroplasticity and re-establishing synaptic connectivity in the prefrontal cortex. However, traditional antidepressants, like SSRIs, take weeks to months to regrow these lost connections, which might explain why they need to be administered chronically before patients will start feeling better. Psychoplastogens like ketamine, psychedelics, and the non-hallucinogenic compounds we are developing, rapidly promote neuroplasticity to fix the damaged circuits in depression and related disorders.

AM: Can you give us an overview of psychoplastogens and their mechanisms of action? Are there any downsides associated with their use?

DO:
Psychoplastogens are compounds that rapidly and robustly promote structural and functional neuroplasticity in cortical neurons by ultimately turning on TrkB and mTOR signalling in the brain. These are key kinases responsible for producing the ion channels and structural proteins necessary for neuronal growth and plasticity. Several well-known psychoplastogens, such as ketamine and serotonergic psychedelics, have several downsides associated with them such as abuse liability, potential cardiotoxicity, and hallucinogenic effects. Delix is focused on developing the next generation of psychoplastogens capable of re-wiring pathological neural circuitry without these undesirable properties.

AM: You recently published a study in Cell demonstrating the therapeutic potential of a psychoplastogen without hallucinogenic effects. Can you tell us more about the study and its findings?

DO:
My colleague Lin Tian and I engineered the 5-HT2A receptor—the receptor responsible for the hallucinogenic properties of psychedelics—to light up when it binds to hallucinogenic compounds only. We then used that sensor to identify DLX-1 (also known as AAZ) as a non-hallucinogenic ligand and verified that result using an in vivo model of hallucinations. Next, we tested the ability of DLX-1 to promote neuroplasticity in neurons grown in a dish and found that it was as potent as ketamine. Finally, we tested DLX-1 in two different behavioral tests related to motivation and anhedonia—important aspects of depression. We found that despite lacking hallucinogenic effects in rodents, DLX-1 was still capable of producing robust, long-lasting antidepressant effects after a single dose.

AM: What scientific, clinical and commercial implications do non-hallucinogenic versions of psychedelic compounds, such as DLX-1, present?

DO:
Scientifically, it is important to determine whether or not the molecular and circuit-level mechanisms mediating the hallucinogenic and antidepressant effects of psychedelics are distinct so that we can better understand the neurobiology of mental illnesses and how best to treat them. From a clinical perspective, the implications are huge. While I am very hopeful that compounds like psilocybin will one day be approved for treating depression or perhaps other brain disorders, I suspect that these hallucinogenic molecules will only be used as a last resort for a variety of reasons. First, the cost associated with psychedelic-assisted therapy is likely to be extremely high given that multiple sessions with healthcare professionals are required to ensure safety. Second, psychedelic-assisted therapy is contraindicated for patients with certain comorbidities or a family history of psychotic illness. Given the overlapping genetics of neuropsychiatric diseases, this means that a large portion of the patient population will not be allowed to participate in psychedelic-assisted therapy. Finally, many patients won't want to take hallucinogenic drugs given their intense, and sometimes anxiety-inducing effects. When you consider that nearly 20% of people will suffer from a brain disorder at some point in their lifetime, it becomes clear that ketamine and psychedelics simply can't meet that demand, and thus, are perhaps best suited for patients who have tried everything else. What we really need are scalable solutions, new first-line treatments that people can take home and put in their medicine cabinets. The only way we can get there is with non-hallucinogenic compounds that lack abuse liability, and that is why I co-founded Delix Therapeutics. The Delix platform leverages non-hallucinogenic psychoplastogens to re-wire pathological neural circuitry, and we think that these compounds will really be game changers for neuropsychiatry.

AM: Can you tell us more about the discovery of DLX-1 and how Delix is working to discover additional non-hallucinatory psychedelic analogs? How is the hallucinogenic potential of compounds predicted?

DO:
DLX-1 was discovered through rational chemical design. It's important to remember that the structure of a compound dictates its function. Our medicinal chemists have deep expertise in neuropharmacology and understand what structural features are important for producing psychoplastogenic effects and what features lead to hallucinations. This has allowed us to take every major psychedelic scaffold—tryptamines, ergolines, amphetamines, iboga, etc.—and tweak these molecules just enough to eliminate the undesired properties while retaining their beneficial psychoplastogenic effects. Our library has grown substantially, and now contains over 500 novel compounds from multiple, distinct chemical scaffolds. Each scaffold has unique properties that make it better suited for certain indications. We are also investigating advanced machine learning approaches that use our in-house dataset to computationally predict the structures of novel psychoplastogens. Once we have designed and synthesized the compounds, we test them in a battery of assays to demonstrate that they are efficacious while lacking hallucinogenic effects. To measure the hallucinogenic potential of compounds, we rely on a combination of psychLight, more traditional GPCR assays, and in vivo models.

AM: What further steps are needed before non-hallucinogenic psychoplastogens could become widely available to patients?

DO:
Like all drugs, non-hallucinogenic psychoplastogens need to undergo rigorous testing to ensure both safety and efficacy. Those studies are ongoing at Delix, and we hope to have two molecules ready for clinical trials by 2022, with several additional molecules following close behind.

David E. Olson was speaking to Anna MacDonald, Science Writer for Technology Networks.

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How will psychiatrists administer psychedelic treatments?

As a new industry emerges, therapists need to be educated.

by Derek Beres | BIG THINK
  • Psychedelic therapy is predicted to become a $7 billion industry by 2027.​
  • Emerging research on psilocybin, MDMA, ibogaine, and LSD is showing a lot of promise in treating a variety of conditions.​
  • Therapists will not be able to write a script and send patients on their way, which will create a new training model.​
Psychedelic therapy is imminent. Within six years, the market for this new wave of therapeutics is predicted to reach nearly $7 billion. With advocates and investors like Tim Ferriss leading the way, protocols for implementing psilocybin, MDMA, LSD, and ibogaine into treatments for depression, PTSD, addiction recovery, and existential distress are being crafted right now.

How will psychiatrists adapt to these new substances?

This is no easy question. Unlike antidepressants currently on the market, you cannot visit a psychiatrist or general practitioner and receive a script within 10 minutes—a longstanding issue in modern psychiatry, especially given that antidepressants don’t work better than talk therapy (or as this meta-analysis shows, work better in conjunction with psychotherapy) and carry with them many physical risks. One of the most prominent side effects is weight gain, which has the potential to lead to a whole series of further physical and mental health problems.

Psychedelics are also not without risks. Early results from esketamine—this ketamine variant is not actually a psychedelic but has been generally lumped into the same category and provides a cautionary tale—have not been overly encouraging:

“Through an analysis of adverse events reported to the FDA, the authors found several adverse events related to the use of esketamine nasal spray, such as dissociation, sedation, feeling drunk, completed suicide, and especially suicidal and self-injurious ideation.”

This isn’t to write off the protocol, which has shown efficacy in trials (though not without issues either). Anecdotal reports have been positive for some depression sufferers. More importantly, the emerging ketamine clinics across North America feature robust protocols that run counter to many current antidepressant-driven psychiatric evaluations. We should continue to explore this line of therapeutics, just more carefully.

MAPS foresaw the possibility of psychedelic therapy decades ago. The organization’s founder, Rick Doblin, argued against the scheduling of MDMA in the mid-80s. The group’s training protocols for MDMA, ayahuasca, ibogaine, and LSD are holistic and include screening sessions, pre-treatment meetings, day-long sessions, and post-treatment integration.

You cannot ingest psychedelics and go about your day. Unlike SSRIs and SNRIs, they don’t take weeks for you to feel the effects. This is an entirely different model than current psychiatry protocols. If psychedelic therapy is going to be integrated into psychiatry, mental health professionals need training. They’ll have to adapt. Cutting corners will be impossible.

Besides overcoming the hurdle of federal regulations (which is quickly happening), psychedelics should be subject to Risk Evaluation and Mitigation Strategies (REMS), writes Paul Tulls in Nature. This means these novel therapies will be administered according to current FDA guidelines.

“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.”

This will not be without its challenges. As Tullis writes, some therapists have been skirting federal law by offering psychedelic therapy for 30 years, reminiscent of LSD sessions in the 1950s and MDMA therapy in the 1970s. In fact, LSD was subjected to over 1,000 studies before being criminalized, though it’s admittedly hard to offer a placebo. (Niacin has worked in some trials.) The comprehensive protocols being developed now have early pioneers to thank.

Psychedelics are also entering an industry with standard practices. Some therapists are likely to remain skeptical; others might not train properly before administering the drugs, which could create problems for the entire industry should some patients experience adverse effects. Psychotherapy will always be necessary before and after administration. In an industry where many are accustomed to writing scripts, not providing in-depth existential explorations with their patients—and many patients are accustomed to quick visits that result in refills—a giant learning curve is necessary.

While many are hopeful that psychedelic therapy will have broad appeal, the more likely result is a slow integration with specialized clinics (such as with ketamine today). There will undoubtedly be players with no history of psychedelics involved only for economic gain; we’re already seeing it with tens of millions of dollars pouring into companies. The competing forces of revenue maximization and psychedelic ritual are likely to create friction.

Regardless, this emerging industry requires funding to get off the ground. We just need to temper expectations with the real-world consequences of the psychedelic model—a hard sell in a world accustomed to quick returns. And we’ll need therapists willing to explore uncharted territory on its own terrain, not the ground they’re accustomed to walking on.



Stay in touch with Derek on Twitter and Facebook. His most recent book isHero’s Dose: The Case For Psychedelics in Ritual and Therapy.”

 
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How ecstasy and psilocybin are shaking up psychiatry*

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

by Paul Tullis | NATURE

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 remission1. Some follow-up studies after therapy, although small, have shown lasting benefits2,3.

“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.

Brave 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 tomography5 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 to N,N-dimethyltryptamine (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 animals6, 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.

"The drugs 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.”

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. The Multidisciplinary Association for Psychedelic Studies (MAPS), a non-profit organization in San Jose, California, 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. 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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DMT could revolutionize the treatment of depression*

by Scotty Hendricks | BIG THINK

As psychedelic research returns to the mainstream of medical science, several lesser known drugs are being seen as possible therapies for mental illness. One of these is DMT, which is the subject of a slew of new studies about its potential use in treating depression.

DMT is the common term for N,Ndimethyltryptamine, a powerful psychedelic drug. Its chemical structure is similar to that of serotonin and melatonin, and it is believed to bind to certain serotonin receptors in the brain.

Since the 1960s, scientists have thought that some mammals may produce DMT in their bodies. Its presence in the brains of rodents has been reported, and trace amounts have been found in the human body and cerebrospinal fluid. Exactly what naturally occurring DMT is doing remains a subject of investigation.

Because DMT is also found in a variety of plants, teas containing the drug have been consumed by many native peoples of South America for at least 1,000 years, often for religious purposes. It only received serious scientific attention as a therapeutic drug beginning in the 1950s.

Dr. Stephen Szára, a Hungarian psychologist working in the mid-20th century, was denied access to LSD by the Western companies that then produced it. At the time, LSD was considered a powerful tool with applications in spycraft, so neither communist countries nor their biomedical scientists were allowed access to it. Unable to work with that psychedelic, he turned to DMT as an alternative.

Eventually moving to the U.S., he continued to work with DMT and explored its possible applications as well as those of other psychedelics.

Effects

Unlike the more famous LSD or psilocybin, DMT trips are often quite short, sometimes lasting as little as five minutes. The short duration is more than made up in its intensity, however, with users reporting extremely vivid hallucinations. Typical doses lead to visions of complex, multicolored geometric patterns, ego death, and altered thought patterns.

DMT has another unique feature: high doses of it can lead to an occurrence called a “breakthrough,” at which point the user no longer perceives themself as being in the same plane of existence. The new location can be truly phantasmagoric, ranging from hyperspace to non-Euclidean realms. These strange places are often populated by even stranger creatures known as “machine elves.”

The machine elves, named by the ethnobotanist Terence McKenna who popularized DMT in certain circles, have been reported by users since Dr. Szára’s experiments. Reports of the elves can vary dramatically, especially in appearance, but users tend to agree that the hallucinated creatures are intelligent and benevolent. The frequency with which these beings are reported may explain the use of DMT as a religious tool for contacting the spirit world. Though some users have speculated if these beings are real, author and psychedelic authority James Kent stresses that they are hallucinations.

Legality

Generally speaking, DMT is not legal. The Convention on Psychotropic Substances, an international treaty signed in 1971, bans the drug but not the plants that contain it. Many countries have their own bans on the substance or the plants from which it can be extracted. However, many jurisdictions have exemptions for the use of DMT-containing products (like ayahuasca) by certain religious groups as part of their rituals. Some American cities have recently decriminalized the drug.

Ayahuasca

Typically, DMT cannot be consumed orally. It must be smoked or, as is common in medical studies, injected. If it is combined with a monoamine oxidase inhibitor, it can be consumed in tea. Variations of this tea, some including different hallucinogenic substances, are often known as ayahuasca from one of the names given it by indigenous South Americans.

While the production and consumption of ayahuasca go back millennia, it has only recently become popular with Western psychonauts. An entire industry of ayahuasca tourism has formed in South America, focused around northeastern Peru, with more than a few psychedelic tourists and celebrities shelling out for a chance to drink the tea in a ritual setting.

By all accounts, a trip on ayahuasca is similar to a DMT trip but with a much longer duration. It also prominently features the purging of the contents of the participants’ stomach and bowels. Some practitioners consider this part of the purification process. However, tourists looking for an “authentic” experience may be getting high on hype.

DMT as medicine

Current studies focus on how the drug works in the brain and how it might be used to treat mental illness. As Dr. Carol Routledge of Small Pharma explained to Freethink, the extreme effects of this drug might be exactly what some patients need, especially when more common drugs like SSRIs have failed:

“A lot of the mental health disorders like depression, like post-traumatic stress disorder, even OCD, have this real negative cycling thought process which leads to ingrained neuronal processes. And it’s almost impossible to get out of those, and I think that’s why SSRIs don’t really even attempt to do that. What psychedelics do is they break that pathway, they break those neuronal connections, and then they increase neuronal connectivity and synaptic connectivity.”

Early reports from Small Pharma suggest that DMT, in conjunction with therapy, can be used to help break away from undesired behavioral patterns. Other studies also suggest that it could prove useful in helping with depression and anxiety. Dr. Routledge suggests that the stimulated connectivity among neurons allows the brain to “reset.” As a result, these conditions can be more effectively treated. There is also discussion about how the mystical experiences triggered by the drug might help those with mental health problems to examine the root causes.

Whatever the outcome of this research, definitely don’t try this at home. At least a dozen tourist deaths have been associated with the consumption of improperly brewed ayahuasca. These poor souls have permanently relocated to a different plane of existence.

*From the article here :
 
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Oregon Health and Science University

Psychedelics' interaction with psych meds: More questions than answers

by Megan Brooks | Medscape | 28 Mar 2022

Psychedelics, including psilocybin and MDMA, are promising for a variety of psychiatric disorders, but there are few data showing how these drugs interact with traditional psychiatric medications, new research shows.

"Despite prolific psychedelic research and public interest, I was surprised to see little clinical research on how psilocybin and common psychiatric treatments interact," study investigator Aryan Sarparast, MD, Department of Psychiatry, Oregon Health and Science University, Portland, told Medscape Medical News.

The review was published online March 7 in Psychopharmacology.

Need for RCTs

The US Food and Drug Administration recently granted breakthrough therapy designation to psilocybin-assisted psychotherapy for major depression and treatment-resistant depression and to MDMA-assisted psychotherapy for posttraumatic stress disorder.

The investigators assessed the volume of available research on interactions between psychedelics and traditional psychiatric medications, such as antidepressants.

They found 40 studies dating back to 1958, including 26 randomized controlled trials, 11 case reports, and three epidemiologic studies.

Only one randomized clinical trial evaluated the interaction between psilocybin and the most common psychiatric treatment, selective serotonin reuptake inhibitors (SSRIs), said Sarparast.

However, this study is "reassuring and overlaps with our hypothesis that there is a low risk of psilocybin and most psychiatric drugs causing harm when combined," he noted.

Yet all of the clinical trials exclusively included young healthy adults, who were often recruited from university campuses. "We don't have data on what happens when a depressed person on an SSRI takes psilocybin," said Sarparast.

He added that he is "concerned that the lack of evidence on drug-drug interactions will lead some providers to require patients to be tapered off existing traditional psychiatric medications before initiation of psilocybin therapy."

This may force vulnerable patients to choose between their existing therapy and psilocybin.

In addition, patients who opt for the "DIY method" of tapering risk mental health relapse and medication withdrawal effects. "That's a very, very tough place to be," Sarparast said.

Ideally, said Sarparast, he would like to see a study in which depressed patients who have been receiving long-term antidepressant treatment are randomly assigned to received low, medium, and high doses of psilocybin. "This would clarify a lot of question marks," he noted.

Evidence Gap

Commenting for Medscape Medical News, Roger McIntyre, MD, professor of psychiatry and pharmacology, University of Toronto, Canada, said, "The point in this article is very well taken. Indeed, more research is needed" on potential interactions between psychedelics and traditional psychiatric medications.

"Before we embark on completing research and development for psychedelics ― or, for that matter, any psychoactive substance ― we should endeavor to identify what the potential safety and toxicity concerns are when they are co-prescribed with other prescribed medications, over-the-counter medications, and other substances (eg, marijuana) that people take,"
McIntyre said.

A case in point ― a recent study conducted by McIntyre and colleagues revealed "significant drug-drug interactions with cannabis, which never receives that much attention," McIntyre said.

Also weighing in for Medscape Medical News, Albert Garcia-Romeu, PhD, assistant professor of psychiatry and behavioral sciences, Johns Hopkins University School of Medicine, Baltimore, confirmed that there is "an evidence gap" on psilocybin's and other psychedelic drugs' interactions with other medications.

"This has not been formally studied for a number of reasons, but mainly because psilocybin has primarily been considered a drug of abuse. Psilocybin has only recently started to be looked at as a potential medication, and as such, research on drug-drug interactions is still limited, but growing," Garcia-Romeu told Medscape Medical News.

He noted that studies are underway to better understand potential interactions between psilocybin and other medications.

"This will allow us to better understand how psilocybin should be used medically and what types of interactions could occur with other drugs or medications," Garcia-Romeu added.

Psychopharmacol. Published online March 7, 2022. Abstract

 
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Will the magic of psychedelics transform psychiatry?*

by Mattha Busby | The Guardian | 7 Nov 2021

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

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 medicinal 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.

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.

“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.

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.”.

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.”

*From the article here :
 
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Psychedelics and the Future of Psychiatry

by Reid Robison, MD, MBA | Psychiatric Times | 8 Feb 2022

Over the past several years, we have witnessed a psychedelic renaissance, and a growing body of evidence suggests that several psychedelic compounds hold strong therapeutic potential for a wide array of mental health conditions.

Once dismissed as dangerous and having little therapeutic potential, psychedelic drugs are gaining mainstream acceptance. Research data continue to demonstrate that, on the whole, these medicines are not only safe, but mostly well tolerated. Although more research is needed to better understand safety, especially in the context of at-risk conditions, these favorable safety profiles are enabling deeper exploration of these medicines.

The term psychedelic was coined in the 1950s by psychiatrist Humphry Osmond, MD, and it literally means “mind-manifesting.” This class of drugs produces changes in perception, thought, and mood with minimal disorientation or confusion. Unlike alcohol, benzodiazepines, and barbiturates, psychedelics do not lead to a slowing of cognitive processes or an acceleration of cognition as seen with stimulants.

Several US states and cities are in the process of legalizing or decriminalizing psychedelics like psilocybin, MDMA), LSD, and others for therapeutic or recreational purposes. In 2020, the Oregon Ballot Measure 109 was passed, allowing licensed service providers to administer psilocybin products to individuals 21 years and older and making Oregon the first state to legalize psilocybin. The drug will not be available commercially or for home-based use, as strict regulations are in place to ensure psilocybin will be used only under the supervision of trained facilitators. This was a major milestone in psychedelic medicine, as it opened the door for more widespread access to psilocybin therapy in a safe and legal manner.

The US Food and Drug Administration (FDA) has also shown interest in prioritizing the approval of certain psychedelic drugs. Both psilocybin- assisted psychotherapy for major depressive disorder (MDD) and treatment-resistant depression, as well as MDMA-assisted psychotherapy for posttraumatic stress disorder (PTSD), have received the breakthrough therapy designation from the FDA to fast-track the approval process because of the growing clinical evidence demonstrating substantial improvement over currently available therapies.

Safety issues and scaling up

The growing research results continue to confirm that psychedelic medicines are not only safe, but well tolerated by the majority of recipients. A psilocybin study found that cases of mental health complications following a psychedelic are rare even in vulnerable populations, and rarer still with proper screening. Another study examined the classical psychedelics, LSD, psilocybin, and mescaline. It found no evidence of increased rates of mental health problems; in fact, it demonstrated psychedelic use was associated with reduced psychological distress and suicidality. Additionally, results of studies examining psychedelic substance use patterns in humans as well as self-administration in animals suggest that classic psychedelics possess little or no abuse liability and may even be antiaddictive.

Results of other studies suggest psychedelics may have protective effects when it comes to mental illness in general. Pooling more than 190,000 adults, researchers evaluated the relationship of classic psychedelic use and psychological distress and suicidality. They found that lifetime psychedelic use was associated with significantly reduced odds of past-month psychological distress, past-year suicidal thinking, past-year suicidal planning, and past-year suicide attempt.8 This offers new insight into the potential promise of psychedelics in helping to prevent suicide.

More research is still needed to fully understand safety, especially in the context of at-risk conditions and mechanisms of action. However, the favorable safety profiles are opening doors for deeper exploration of these medicines.

MDMA

MDMA-assisted psychotherapy, the psychedelic treatment closest to receiving FDA approval, is currently undergoing phase 3 clinical trials in patients with PTSD. The study included 90 patients with severe, chronic PTSD from a variety of different causes (eg, abuse, combat, sexual trauma). It is worth mentioning that this was a treatment-resistant group, meaning patients had suffered with PTSD for an average of 14 years without relief. All participants completed a 12-week treatment program composed of 3 full-day sessions, during which they received either MDMA or a placebo, plus weekly nondrug psychotherapy sessions. No serious adverse effects were detected beyond transient, mild symptoms during drug treatment such as nausea or sweating. No increases in suicide risk or potential for abuse were noted in the MDMA group relative to placebo. Two months after treatment, 67% of the MDMA cohort no longer qualified for PTSD diagnosis, compared with 32% of the placebo group. In addition, 88% of those in the MDMA group experienced a clinically significant reduction in symptoms (Figure 1).

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MDMA is unique in its ability to promote acceptance of and empathy for self and others. In addition to elevating oxytocin levels, MDMA stimulates the release of the monoamines serotonin, norepinephrine, and dopamine, resulting in improved mood and increased sociability. Brain imaging after administration of MDMA shows there is decreased amygdala activation and reduced fear response, allowing the patient to emotionally engage in therapy without becoming overwhelmed by anxiety or difficult emotions. The combination of medication plus psychotherapy represents a new frontier for the FDA, with unique challenges to be addressed such as therapeutic approaches and therapist training.

Psilocybin

Psilocybin is currently in phase 2 clinical trials for MDD. As a classic psychedelic, it is an agonist of serotonergic 5-HT2A receptors in the brain, which are particularly abundant in the cortex and regions associated with cognitive functions and social interactions. Stimulation of this receptor has been directly linked to cognitive flexibility, enhanced imagination, and creative thinking.

In pivotal study results, 71% of individuals with MDD who received 2 doses of psilocybin were treatment responders, and half of the participants entered remission (Figure 2). Some follow-up studies after therapy, although small, have shown lasting benefits.

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Concluding thoughts

Psychedelic medicine is forging ahead as a promising new treatment paradigm, in which psychedelics, paired with psychotherapy, have the potential to treat various mental health conditions. Preliminary findings show successful results for these treatments, with significant clinical improvements and few—if any—serious adverse effects. The emerging results likely have implications for future psychiatric research, education, and policy—and most importantly, they are poised to offer new therapeutic options and improve the lives of those we serve.

Dr Robison is a board-certified psychiatrist and Chief Medical Officer of Novamind. He is the co-founder of Cedar Psychiatry and serves as the Medical Director for the Center for Change, a leading eating disorders center. Dr Robison previously served as a coordinating investigator for the MAPS-sponsored MDMA-assisted psychotherapy study of eating disorders.

*From the article (including references) here :​
 
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