RESEARCH | +80 articles

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Imperial College London

Your brain on LSD: A guide*

by David Nutt | Science Focus | 28 Jan 2021

David Nutt is a professor of neuropsychopharmacology in Imperial College London. In this extract from his book, Drugs without the hot air, he explains how psychedelic drugs can be used for treating a variety of mental health conditions, and can even help with problem-solving.

Since the first edition of this book there has been a veritable explosion of research on psychedelics, with brain-imaging studies on psilocybin, ayahuasca and even LSD, and several landmark clinical trials. Many of these have come from the team led by Robin Carhart-Harris in my unit.

In collaboration with the Beckley Foundation we have conducted three imaging studies with psilocybin, two using fMRI, one using MEG (mag- netoencephalography), and the first-ever imaging study of LSD. Other groups have conducted similar studies – in Barcelona (with ayahuasca) and in Zurich (with psilocybin and LSD).

These have confirmed the first findings with psilocybin reported earlier in this chapter [that psilocybin administered in a controlled environment can help to treat depression].

Psychedelics produce a profoundly altered state of consciousness which can be explained by a marked loosening of the normal constraints on brain functioning. In the psychedelic state the brain is less constrained, more flexible and more interconnected.

This explains the emergence of complex hallucinations and altered feelings such as being at one with the Universe. To paraphrase the words of William Blake, which were used by Aldous Huxley to explain his psychedelic experiences: The doors of perception are opened, so man can see everything as it is – infinite.

Along with these new insights into the neuroscience of psychedelics has come the use of psilocybin to help dying people be reconciled to their imminent death, or help patients with major psychiatric problems (such as resistant depression) come to terms with their condition.

There have also been pilot studies on using psilocybin to treat smoking and alcohol dependence, and above we referred to our team’s 2016 controlled trial of psilocybin for resistant depression. We are now repeating this study but this time comparing the effect of psilocybin with that of escitalopram (a strong SSRI). This study funded by the Alexander Mosley Charitable Trust will allow us to compare whether the two treatments are the same in terms of their brain mechanisms or, as we suspect, rather different.

Also at the end of 2016 the two largest placebo-controlled clinical trials of psilocybin ever conducted were reported by Roland Griffiths of Johns Hopkins and Stephen Ross of New York University, both in the US. The designs were similar so they each provided a form of validation for each other.

Both showed a significant benefit of psilocybin – again at a single 25 mg dose – to reduce the anxiety and depression that people who are facing death from untreatable medical conditions usually experience.

These results were well received, with several past-presidents of the American Psychiatric Association writing in favour of more research with psychedelics. On the basis of this enthusiasm and the efficacy demonstrated in two independent and sizeable studies, there is now a plan to push to have psilocybin licensed for treating depression, and this approach has been endorsed as viable by the FDA (Food and Drug Administration) in the US.

What it will take is a major multi-centre study and this is now underway, being conducted by COMPASS Pathways using the same 25 mg oral dose that we used. The results should be available in 2021 and, if positive, psilocybin might be allowed as a medicine a couple of years after that.

Should scientists take LSD?​

One line of enquiry which was being studied before LSD was made illegal was its use in problem-solving. This may seem surprising because most people find it hard to focus when tripping, and it’s certainly true that people taking LSD don’t perform particularly well on standard psychological tests.

As psychologist Arthur Kleps explained in 1966, “if I were to give you an IQ test and during the administration one of the walls of the room opened up giving you a vision of the blazing glories of the central galactic suns, and at the same time your childhood began to unreel before your inner eye like a three-dimensional colour movie, you would not do well on the test.”

However, psychedelics can induce creativity, by lowering the psychological defences around “getting something wrong” and helping to see problems from new angles. With the right set and setting, this can be directed towards familiar problems, sometimes with spectacular results.

This approach seems to work best when the problem is one that has been considered many times while sober, and the setting includes notes, lots of paper and pens to record your thoughts, and a guide to help you through the initial disorientation and remind you of what your aim is.

Although most people who have tried psychedelics might find it hard to believe that it would be possible to concentrate on a task during a trip, that’s probably because they’ve taken them in circumstances where they were easily distracted – and they’ve probably also been surrounded by other people on drugs at the same time.

In a calm setting it’s much easier to focus, and in fact people on LSD are so suggestible that if they have a guide who tells them that they will have no difficulty concentrating, this will probably be the case.

Taking LSD in this way has been known to deliver moments of inspiration to designers, architects and engineers. There are many stories about near-perfect technical designs which have suddenly become obvious while contemplating the problem on the drug.

In LSD – the Problem Solving Psychedelic, written in 1967, the authors recount several examples of this. One was a furniture designer who completed a chair design while on LSD which was successfully modelled into a functional dining chair with no substantial changes from the original concept. (These pieces of furniture are extremely difficult to create and the designer was used to new chairs taking two months and ten trial models to complete.)

Another example was an engineer who worked in Naval Research and had been trying to design a special detection device for five years without success. Within minutes of contemplating the problem on LSD he had found the solution and the device was then patented and used by the US Navy.

A third example was an architect who took the drug to help him design a shopping centre and was able to visualise it in its entirety: “Suddenly I saw the finished project. I did some quick calculations… it would fit on the property and not only that… it would meet the cost and income requirements… I began to draw… my senses could not keep up with my images.” The image stayed with him just as sharply after the drug experience had ended, and his design was accepted and constructed.

Even in the less-obviously creative fields of hard science, LSD can be profoundly beneficial. In fact, it played a role in the two biggest discoveries in biology of the 20th Century.

Francis Crick, who discovered the double helix structure of DNA with James Watson, and Kary Mullis, who invented the polymerase chain reaction (PCR), had both taken the drug, and attributed some of their understanding and insights to it.

Mullis has gone so far as to say: “would I have invented PCR if I hadn’t taken LSD? I seriously doubt it… having taken LSD I could sit on a DNA molecule and watch the polymers go by. I learnt that partly on psychedelic drugs.”

Both Crick and Mullis received Nobel prizes for their work. Now that LSD is illegal few scientists would dare to use it, and even fewer would own up to taking it. Perhaps scientific progress in many areas has been hindered by this state of affairs!

*From the article here :

Your brain on LSD: a guide through the most mind-blowing psychedelics research

In an extract of his acclaimed book Drugs without the hot air, David Nutt explains recent scientific discoveries – and how substances like LSD have influenced creative breakthroughs.

www.sciencefocus.com

 

[mr peabody]

FT-104, Field Trip's next generation psychedelic molecule*

Psilocybin Alpha | 29 Oct 2020

Field Trip’s novel psychedelic molecule, FT-104, is found to be similar in potency to psilocybin but with a shorter duration of psychoactivity. The half-life of the molecule is roughly one third of psilocybin’s.

This makes it a potentially preferable option for related therapies.

This is further to the results announced in late September, which demonstrated successful GLP synthesis and that the molecule is a serotonin 5HT2a receptor agonist.

We asked Executive Chairman Ronan Levy two questions:

The 89% bioavailability cited is based on subcutaneous delivery. Does the team envisage this being the delivery method that is ultimately used? If not, how might different delivery methods affect this?

Ronan Levy: The structure of the active molecule of FT-104 gives us flexibility on the method of delivery, of which subcutaneous injection is an option, but oral administration is an option as well. As with most alternative forms of administration, bioavailability and onset may be changed depending on the format.

When can we expect to see clinical studies for this molecule?

Ronan Levy: We expect to be in Phase 1 human trials before the end of next year.

Results confirm that Field Trip’s novel psychedelic molecule is similar in potency to psilocybin but with shorter duration of psychoactivity making it a potentially preferable option for psychedelic therapies

Field Trip, a leader in the development and delivery of psychedelic therapies, today provided an update on its in-vivo and in-vitro studies on FT-104, its lead drug candidate.

Further to its announcement confirming both the successful GLP synthesis of FT-104 and that FT-104 is a serotonin 5HT2A receptor agonist (the serotonin receptor believed responsible for psychedelic experiences), Field Trip announced that FT-104 is a potent psychedelic molecule with rapid onset and a short duration.

Notably, Field Trip reported:

- FT-104’s binding constant (Ki) for the 5HT2A receptor is 120 nM, which indicates a potency similar to psilocybin1;

- A 2mg/kg subcutaneous dose of FT104 to rats resulted in peak concentrations (Cmax) of the active agonist of 150+/-51 ng/ml at 60 min (Tmax) and bioavailability of 89%.

- The elimination of FT-104 from the bloodstream has a half-life (t1/2) of 40min, which compares to psilocybin with a half-life on the order of 120min2;

- A head twitch response (“HTR”) was observed after administration of FT-104. The intensity of the HTR correlated well with plasma levels of the active which suggests that the EC50 (50% effective concentration) for the HTR is in the range of 100 ng/ml. It has been shown that the HTR in rodents is related to the intensity of psychedelic activity of a psychedelic substance, and thus, is an indicator of its potential for use as a catalyst to treat mood disorders.

In summary, these experiments demonstrate that: (i) FT-104 is a near equipotent 5HT2A receptor agonist to psilocybin that can be delivered with high bioavailability; and (ii) FT-104 will likely produce a reliably short-duration of psychedelic experience in the range of two to four hours, which is approximately half the duration of psilocybin.

“As we formulated our drug development strategy, we focused on new molecules (NCEs) that: (i) offer shorter duration of psychedelic experiences to make them more practical and convenient for use in the clinic; (ii) had similar potency to psilocybin or MDMA; (iii) had low potential for addiction; and (iv) would be simple to synthesize while differentiated and structurally distinct from psilocybin or other existing 5HT2A receptor agonists,” commented Dr. Nathan Bryson, Field Trip’s Chief Science Officer. “After significant research and due diligence, we initiated synthesis of a battery of small molecules, from which FT-104 was selected as our lead molecule. I am excited to take FT-104 into the next phases of our drug development program.”

FT-104 is a novel, synthetic psychedelic molecule developed by Field Trip inspired by the chemical structures of known psychedelic substances. FT-104 was selected for its simplicity as well as its potential to distinguish itself with respect to its pharmacological features relative to naturally-derived substances, such as psilocybin, DMT and LSD.

“Drugs like psilocybin and MDMA are showing significant efficacy in treating conditions like depression and PTSD,” said Dieter Weinand, Field Trip Board Member and former Chairman and CEO of Bayer Pharmaceuticals AG. “However, the relatively slow onset, and long duration of those drugs, which can result in treatment times lasting from 6 to 10 hours or more, makes them less attractive to patients and clinicians because of the time and treatment infrastructure required. Not to mention, they are not, generally speaking, protectable by intellectual property.”

“If the results suggested by these preliminary studies for FT-104 are confirmed in clinical studies, FT-104 will address several notable limitations of psilocybin and MDMA. Plus, it would be more convenient,” added Weinand, “which could make it a first choice for clinicians and a better treatment option than psilocybin.”

Ronan Levy, Field Trip’s Executive Chairman noted, “Since inception, our philosophy at Field Trip has been that any psychedelics company needs to focus on both the development of psychedelic medicines and the delivery of psychedelic therapies. We’ve always known that the Field Trip Health centers rolling out across North America would give us a competitive advantage in understanding and meeting the challenges of psychedelic medicine. Now, the latest results with FT104 suggest that Field Trip will also be the leader in the development of new psychedelic therapeutics.”

*From the article here :

Field Trip Health Ltd. Provides Update on FT-104, Its Next Generation Psychedelic Molecule in Development - Psilocybin Alpha

Field Trip's novel psychedelic molecule, FT-104, is found to be similar in potency to psilocybin but with a shorter duration of psychoactivity. The half-life of the molecule is roughly one third of…

psilocybinalpha.com

 

[mr peabody]

​

Scientists zero in on the ideal dose of LSD to use in psychiatric treatment

by Eric Dolan | PsyPost | 10 Mar 2021

New research published in Neuropsychopharmacology provides insight into the acute dose dependent effects of LSD. The findings will help in the planning of clinical trials examining the use of the psychedelic drug in patients with psychiatric conditions.

Previous research has provided initial evidence that LSD might be a viable treatment for certain mental disorders when combined with psychotherapy. But these studies have compared a placebo against a single dose of LSD. The authors of the new research set out to scientifically test the effects of LSD across a range of different doses.

“We wanted to generate clinical data on LSD for its later use as medication in patients,” said research Matthias E. Liechti of University Hospital Basel. “The new study provides information on the acute effects of different doses of LSD. This will help to select the right dose for future trials in patient to treat anxiety and depression.”

During six experimental sessions, which occurred under double-blind conditions in a controlled laboratory setting, eight men and eight women received a placebo, four different doses of LSD, and a high dose of LSD combined with ketanserin, a serotonin 2A antagonist that blocks the effects of LSD.

The researchers found that all four doses of LSD — 25 µg, 50 µg, 100 µg, and 200 µg — increased experiences of “oceanic boundlessness” and “visionary restructuralization” compared to placebo. But only the 50, 100, and 200 µg doses of LSD were associated with “ego dissolution,” the experience of losing one’s sense of self.

There was also evidence of a ceiling effect. The positive subjective effects of LSD increased from the lowest dose to 100 µg, but there was no difference in positive drug effects between the 100 and 200 µg doses. Similarly, ratings of oceanic boundlessness and visionary restructuralization also increased from the lowest dose to 100 µg before leveling off.

But the 200 µg dose of LSD produced significantly greater ego dissolution and was the only dose that significantly increased ratings of anxiety compared with placebo.

“Based on the available data, the following dosing terminology may be useful for future LSD research: ‘microdose’ (1–20 µg), ‘minidose’ (21–30 µg), and ‘psychedelic dose’ (>30 µg). Within the psychedelic LSD dose range, good effects likely predominate at doses of 30–100 µg (good-effect dose), whereas ego dissolution and anxiety increase at doses above 100 µg (ego-dissolution dose),” the researchers said.

Some physiological effects were also observed. LSD increased blood pressure at doses of 50 µg and higher, and increased heart rate at 100 and 200 µg

As expected, administration of ketanserin caused significant reductions in the effects of LSD. “Retrospective reports showed that ketanserin and LSD together were identified correctly by the participants or mistaken as a low dose of LSD but never mistaken for a high dose of LSD,” the researchers explained.

Although the findings help to zero in on the ideal dose to use in psychiatric settings, scientists are likely to further fine tune dosages in additional research.

“Only a limited amount of doses were tested,” Liechti said. “Thus an ideal dose may be between two selected doses. Additionally, the ultimate right doses need to be tested and selected in patients and there are patient characteristics that may result in dose adjustments.”

The study, “Acute dose-dependent effects of lysergic acid diethylamide in a double-blind placebo-controlled study in healthy subjects“, was authored by Friederike Holze, Patrick Vizeli, Laura Ley, Felix Müller, Patrick Dolder, Melanie Stocker, Urs Duthaler, Nimmy Varghese, Anne Eckert, Stefan Borgwardt, and Matthias E. Liechti.

Psychedelics research: Scientists zero in on the ideal dose of LSD to use in psychiatric treatment

New research published in Neuropsychopharmacology provides insight into the acute dose dependent effects of LSD. The findings will help in the planning of ...

www.psypost.org

 

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UCSF launches Translational Psychedelic Research Program

by Colin Newton | LUCID | 9 Apr 2021

The newly christened Translational Psychedelic Research (TrPR) Program is launching a unique multidisciplinary network of scientists and healthcare providers who work together to research psychedelic-assisted therapies.

The TrPR Program, which is based at UCSF, is distinguishing itself from other university research groups through its distinctively inclusive approach to psychedelic medicine. Members of the TrPR network study psychedelic therapies that may benefit patients with conditions considered higher risk or overlooked by other researchers in the field, such as bipolar disorder, Parkinson’s and back pain.

TrPR includes investigators from both clinical and research disciplines based at medical centers from the San Francisco Bay Area to Seattle, says Dr. Joshua Woolley Associate Professor of Psychiatry at the UCSF Weill Institute for Neurosciences and Director of the Translational Psychedelic Research Program.

“I think our unifying goals are to understand if these treatments work, who they work for and how they work,” says Woolley.

Dr. Joshua Woolley

Dr. Ellen Bradley, associate director of TrPR, says the program’s interdisciplinary team includes different perspectives that will help strengthen the research. “It’s kind of ever evolving,” says Bradley. “We’re really lucky we have a group that spans multiple medical specialties.”

The TrPR Program includes researchers with expertise in psychology, neurology, epidemiology, animal science, molecular science, even primary care and nursing. “It’s really exciting,” says Bradley. “I think it gives us a great advantage of how to design some of the studies and answer some really interesting questions.”

The TrPR team is reaching out to other programs and institutions. Bradley says that she is excited to see the UCSF Neuroscape neuroscience center begin to research psychedelic therapies and hopes to work with these investigators on future studies. Woolley says he has been talking with Neuroscape Director of Psychedelics Division, Robin Carhart-Harris, about possible collaborative projects.

“What brings everyone together is the motivation to really deepen our understanding of how psychedelic compounds impact the body and to figure out how psychedelic therapies can help patients living with a wide range of health issues,” says Bradley. “There’s just a ton of science to be done in this space, so the more folks who can roll up their sleeves and jump in, the better!”

A pivotal study on AIDS survivors

Some members of TrPR were investigators in a pivotal study published in late 2020 that examined the effectiveness of psilocybin-assisted group therapy for demoralized older long-term AIDS survivors. "The open-label safety and feasibility pilot study, which laid the groundwork for TrPR, looked at grief, guilt, and loss of purpose and meaning among participants," says Woolley.

The study focused on gay men who had been diagnosed with AIDS before 1996. “The people were older than many of the other trials, and there was more variability of severity of illness,” says Woolley. “It was more naturalistic.”

According to Woolley, there were a number of reasons to integrate group therapy into the study of older AIDS survivors. It was a more time and cost efficient way to integrate talk therapy, but it also followed indigenous practices in which people use psychedelics in a group setting. “There might be power in that, a group of people going through it together,” says Woolley. “They could talk about that experience with each other.”

Woolley notes that participants in studies at John Hopkins University investigating psychedelic-assisted therapies had wanted to talk to other participants in the same study. “In a Prozac study, that never happened,” says Woolley.

The study of AIDS survivors gave Woolley and his team significant momentum in the psychedelic research space. The TrPR Program is currently working with the Usona Institute on a clinical trial to study the medical and safety effects of psilocybin on patients with Major Depressive Disorder (MDD). This Phase 2 clinical trial is also taking place at seven other sites across the U.S.

The Usona clinical trial may be the highest profile investigation the TrPR Program has in progress, but the team is also pursuing other cutting edge research. According to Woolley, an upcoming open-label study of psilocybin for depression in bipolar II disorder is a strong example of the program’s philosophy toward working with patients with different risk profiles.

“One thing we are doing that is a little different than other groups is working on populations that are a little bit higher risk,” says Woolley.

Studying psilocybin treatment for Bipolar Disorder

Bipolar II disorder is a mental health condition which includes both depression and mania. According to Woolley, depression sometimes has a larger impact on people with bipolar disorder than the episodes of mania.

Psilocybin has been shown in studies to be a promising antidepressant. But Woolley notes that there are concerns about possible negative effects if psilocybin is used to treat people with bipolar disorder because of its potential effect on mania. Accordingly, people with bipolar disorder, as well as people with relatives who have bipolar disorder, have been excluded from modern psilocybin studies.

After completing a survey study to address these questions, the TrPR team concluded that while there are cases of bad outcomes from people with bipolar depression using psilocybin, these outcomes are limited to just a few cases over decades, says Woolley.

The mixed-methods study, which included a survey of about 600 people with bipolar disorder who used psychedelic mushrooms, was conducted in collaboration with Dr. Erin Michalak of the University of British Columbia’s Department of Psychiatry. The survey was followed by interviews with participants to obtain more qualitative information. The TrPR team even combed through relevant subforums on Reddit for anecdotal accounts.

“That community driven aspect is key,” says Bradley. “We’re not just doing a top-down, academic study. We’re trying to combine our team of specialists, but also rely on how people are already using these substances in the community.”

Bradley notes that the members of the TrPR team are well positioned to examine how psilocybin is presently used for self-medication and include this information while researching its therapeutic applications. “These treatments are not formalized in our healthcare system, but people are using these treatments out in the world,” says Bradley. “People are figuring out what works for them, what’s safe for them. That’s really, really important to listen to. It’s valuable to integrate those perspectives.”

The mixed-methods study is informing upcoming research investigating the use of psilocybin on depression in bipolar II disorder, conducted by the TrPR team in collaboration with Dr. David Gard, director of the Motivation and Emotion Research Lab at San Francisco State University. Safeguards will include overnight observation of participants, a support person who sees participants daily and investigators checking on them routinely in a controlled environment.

“This has never been tried before, and there is some risk, but we think the potential for benefits is very high,” says Woolley. Bradely adds that the TrPR team is committed to seeking therapies for a broad range of people with mental health conditions. “We can’t just cherry pick the people who are the most healthy,” says Bradley. “We want to see people that are at risk potentially, but also could really benefit.”

Seeking therapies for higher risk groups

Another example of TrPR’s commitment to researching treatments for higher risk groups is the upcoming open-label trial of psilocybin for treating depression and anxiety in patients with Parkinson’s disease. This study is being conducted in collaboration with Dr. Jill Ostrem, medical director and division chief of the UCSF Movement Disorders and Neuromodulation Center.

As with people suffering from bipolar disorder, those with Parkinson’s can also experience a decreased quality of life. They are impacted by depression and anxiety more than one might realize, says Bradley. “I spend my time working with patients who have Parkinson’s,” says Bradley. “We don’t have great treatments for these patients, and a lot of them are suffering and frustrated by that.”

The TrPR Parkinson’s research will also be carefully monitored, with overnight observation and participants receiving a low test dose before getting a full dose. “It’ll be a small, open-label pilot, and it will involve quite a few precautions,” adds Bradley. “Something really important is a serial assessment of [participants’] motor skills to make sure there are no negative effects there.”

Another unexpected clinical trial launched by TrPR is a study of psilocybin as a possible treatment for lower back pain. “This population is not a particularly high risk population, but it is a novel population,” says Woolley.

According to Woolley, chronic lower back pain is a condition without a fully effective treatment for how people experience this pain. The study will look at how psilocybin might change the relationship between patients and their discomfort rather than seeking to reduce the pain itself. “We’re agnostic as to its effects on the intensity of the pain, but we’re hoping that will go down as well,” says Woolley.

“The pain study is really exciting because the development of chronic pain is not well understood,” says Bradley. “It’s physical, it’s conceptual, it’s emotional, it’s all of these things rolled together.”

Bradley notes that while psilocybin shows promise as a therapy that could potentially rewire neurocircuitry that’s gone awry, there are still many biomechanical questions that must be answered. The back pain study will give the TrPR Program the ability to look at the condition from a variety of perspectives, from psychological to molecular.

"The bipolar II disorder, Parkinson’s and chronic back pain studies have all received UCSF Institutional Review Board (IRB) approval, which is required by the FDA to review and monitor biomedical research involving human subjects," says Woolley. "These studies are expected to begin in the spring or summer of 2021."

An inclusive approach to funders and volunteers

The most significant financial support for the TrPR Program is a $2 million donation from a donor who wishes to remain anonymous, says Woolley. TrPR also received an additional $1 million in funding from Usona for its participation in the Institute’s psilocybin trial.

"The TrPR team is presently in talks with academic and industry partners for future financing," says Woolley. As the academic study of psychedelics is still relatively new, he says these investigations do not get the types of government funding that other forms of medical research receive. Some of the funding for TrPR comes from smaller contributions from individual donors.

One individual donor to TrPR is Cassie Nielsen, who contributed funds and volunteered to assist the program by creating a database of researchers investigating psychedelics. Nielsen is a Talent Partner at VMG Partners, a private equity firm focused on consumer products. “He created an environment where I, as a random outsider, could join,” says Nielsen of Woolley. “It felt like I could have a voice in his room.”

Nielsen says she began her own personal research into psychedelic-assisted medical therapies because she has a family member who battles alcoholism. She began investigating podcasts, books and conferences on the subject until she found an article about Woolley and his team. “I reached out cold and said, I’m not sure how I can be supportive or if there’s ways I can volunteer with what you’re doing,” says Nielsen.

At first, Nielsen says the TrPR team was surprised that someone outside of the research or medical community was interested in volunteering, but they were happy to accept her support. Nielsen in turn says she was surprised and delighted. That was two years ago, and Nielsen is still helping to support the TrPR Program. In addition to helping create a database of researchers, she has also offered suggestions on how the team can present job descriptions and broaden the program’s exposure.

“I believe in Woolley and his team. He’s built an incredible team around him,” says Nielsen. “He gives his folks a lot of autonomy. He’s receptive to their ways of thinking.”

Nielsen has contributed $15,000 in unrestricted donations to the TrPR Program – $5,000 in 2019 and $10,000 in 2020 – and she expects her contributions to increase. Nielsen says she is encouraged that medical research into psychedelic-assisted therapies is increasingly visible.

Efforts to decriminalize psychedelics are also having a positive impact on access to these therapies by veterans, people of color and other underserved communities that have medical conditions psychedelic-assisted therapies could treat, says Nielsen. From her perspective, the inclusivity of TrPR is another sign of progress.

UCSF Launches Translational Psychedelic Research (TrPR) Program - Lucid News

TrPR Program takes an interdisciplinary and inclusive approach to investigating psychedelic-assisted therapies for higher risk patients.

www.lucid.news

 

[mr peabody]

Cambridge

Scientists using AI to develop new psychedelic drugs

Using supercomputers and machine learning, the next generation of psychedelics may look like nothing we've ever seen before.

by Troy Farah | Doubleblind | 26 Apr 2021

In the near future, drugs like psilocybin, MDMA and LSD may be considered passé, surpassed by the next generation of psychedelics. Some venture capitalists and researchers are banking on yet-to-be developed drugs that they feel greatly “improve” upon the so-called “classic” psychedelics in that they won’t cause hallucinations and may potentially be more effective in treating depression, addiction, and mental health.

While research is still in the early stages, scientists are making massive advancements by deploying artificial intelligence and machine learning to sift through hundreds of millions of different drugs, analogs and derivatives of psychedelics. Usually drug companies focus on developing one drug for one condition at a time. But using advanced computer science, some researchers are instead developing dozens of potential psychedelics—or drugs that resemble them—all at once.

The medications that are designed next may look unlike anything seen in psychiatry before—at least, if these predictions can be backed up by science. The use of AI not only holds promise to push new psychedelic molecules through clinical trials faster, but it could also radicalize the way we think about mental health.

MagicMed Industries, a biotech startup based in Calgary, Alberta is building what it calls its “Psybary,” a large portfolio of patented molecules based on psychedelics. According to Green Market Report, the Psybary includes 12 filed patents related to nine different drug categories covering 125 million individual molecules.

That seems like a lot of drugs, and it is, but most of them are the smallest atomic variation on already established psychedelics like psilocybin. It’s not yet clear if the majority of these analogs would even be psychoactive, let alone effective at treating mental health. And to be clear, these patents haven’t been awarded yet. But using supercomputing and machine learning, companies like MagicMed are gambling that they can find effective new drugs in record time.

“A big part of the idea here with this AI is to cut that [timeline to clinical trials] significantly,” explains Dr. Joseph Tucker, a drug development veteran and CEO of MagicMed. He says to think of the base structure of the molecule, such as psilocybin, like a key blank. A skillful locksmith—or in this case, biochemist—can develop an almost endless number of permutations.

“We’re trying to get the house key, all the different teeth. Now let’s try them all until you find the right one,” Tucker tells DoubleBlind. The “house” they want to enter is effective treatment for pretty much anything, not just the mental health issues that can be addressed by psilocybin, for example. “We actually start with a target indication in mind. And then we go and say, ‘What receptors are the right receptors? What physiological biomarkers are we looking for in animal models and in humans?’ And let’s try to design a drug out of the Psybrary that best addresses that.”

In early March, MagicMed launched their PsyAI program, recruiting Dr. Eric Nyberg, a professor at Carnegie Mellon University who helped develop the original IBM Watson computer system, which famously won on the gameshow Jeopardy! MagicMed hopes to wield Nyberg’s technology to sift through these millions of chemical designs to find medications that might work like psychedelics for treating a variety of ailments.

“We’re essentially moving the molecules much more rapidly by doing stuff in silico,” Tucker says, referring to the Latin phrase for computer simulation. And like other machine learning programs, the more it does its job, the better it gets at finding new drugs. “Comparing it to real data that we generate [through clinical trials], we can improve the predictive capability of this PsyAI, so that it becomes more and more intelligent, more successful in its predictive capabilities.”

Other efforts using AI to generate new psychedelic drugs include the work of molecular pharmacologist Dr. Bryan Roth, at the University of North Carolina-Chapel Hill. As previously reported by DoubleBlind, Roth is was recently awarded $27 million by the U.S. military’s secretive developmental wing DARPA (the Defense Advanced Research Projects Agency) to develop drugs that resemble psychedelics, but don’t cause hallucinations or a trip.

Roth’s lab uses a computational program called Ultra Large Scale Docking (Ultra LSD) that generates millions of permutations of different chemical structures, then predicts how the molecules would fit into the serotonin 2A receptor, which is largely associated with how some psychedelics generate their unique mental effects. LSD, psilocybin and DMT all bind to the serotonin 2A receptor, and Roth has done some of the world’s most groundbreaking research on how these drugs, such as LSD, interact at these receptors.

“We have basically a three-dimensional model of the [serotonin] receptor [where] there are sites for drugs to bind. The computer takes each drug one by one and puts it in there,” Roth explains. If the drug clicks into the serotonin 2A receptor, that’s an indication that it will work like a psychedelic. “The library has been expanded considerably and we’re planning on docking, I think, 5 billion compounds in the summer.”

Roth’s lab has been slowly picking chemicals that seem like promising new medications and working with a lab that then synthesizes them. Finally, a robot tests the drugs by squirting them at human cells to make sure what the computer predicted matches up with reality.

“The project is to make drugs that interact with the same receptor that LSD does, and have the beneficial, putative effects of LSD without having a psychedelic effect,” Roth explains. This is accomplished by picking drugs that have slightly different binding profiles than classic psychedelics, but have removed the downstream effects that cause hallucinations and visuals.

Therefore, these drugs can’t really be called psychedelics. Some in the industry call these new compounds “neurotransformational medicines” because they are a new class of drugs altogether that psychiatry has never encountered before. That raises big questions if they would actually work, but the implications are huge.

Already, Roth and his colleagues have narrowed down a few promising new drugs and begun testing them in mice using a battery of tests that can determine if a drug is psychoactive in animals. For people with debilitating conditions like heart problems or schizophrenia, the powerful sway of psychedelics may not be therapeutic—it may even be harmful. A drug that can ease depression as rapidly as a psychedelic without the introspective distortion would be very useful for certain patients.

But making a drug that looks like LSD without the hallucinogenic aspects is just part of the equation. Roth’s lab still has to determine if these medications will have the same alleged benefits of psychedelics, such as improving mood, erasing suicidal thoughts, or easing the symptoms of post-traumatic stress disorder. However, some argue that the “journey is the medicine” and that without the visual distortions—even “bad” or uncomfortable trips—non-psychedelic psychedelics won’t work as well.

Tucker’s lab will encounter the same issue: It’s nice to generate millions, or even billions, of psychedelic drugs using a computer program, but unless that translates into useful medications, it’s not very practical.

Nonetheless, artificial intelligence and machine learning is rapidly changing drug development, not just for psychedelics, but for the entire pharmaceutical industry. Late last November, DeepMind, (a subsidiary of Alphabet Inc., the company that owns Google), solved protein folding, a longtime puzzle that has plagued biology for around 50 years.

Protein folding involves using computers to predict a protein’s three-dimensional structure based on its amino acid sequence, which is a lot harder than it sounds. But now that it’s been solved, it will likely accelerate drug development unlike anything previously seen by making it easier to predict how new medications will interact with receptors.

It’s a major step forward in drug development and related efforts in the psychedelic sphere are no less impressive. As Roth previously told me, his project may fail and “we may just end up with better psychedelics.” Better, of course, is subjective.

“Our goal is to ultimately alleviate human suffering,” Roth says. “That’s what we’re doing this for. And I hope we’re successful. It would be wonderful.”

Scientists are Using AI to Develop New Psychedelic Drugs

Using supercomputers and machine learning, the next generation of psychedelics may look like nothing we've seen. Read on at DoubleBlind.

doubleblindmag.com

 

[mr peabody]

Scientists show how LSD opens the doors of perception*

Study analysing brain scans of people finds psychedelic drug lowers barriers that constrain thoughts.

by Ian Sample | The Guardian | 19 May 2021

When Aldous Huxley emerged from a mescaline trip that veered from an obsession with the folds in his trousers to wonder at the “miraculous” tubularity of the bamboo legs on his garden chairs, he offered an opinion on how the drug worked.

Writing in The Doors of Perception, his 1954 book that took its name from a William Blake poem, Huxley declared that the psychedelic “lowers the efficiency of the brain as an instrument for focusing the mind on the problems of life.”

Even for Huxley, the assessment now seems remarkably prescient. In new research, scientists have found evidence that LSD, another psychedelic, lowers the barriers that constrain people’s thoughts. In doing so, it frees the mind to wander more easily and experience the world anew.

“Normally, our thoughts and incoming information are filtered by our prior experience,” said Parker Singleton, a PhD candidate at Cornell University in New York. “But if you take that filtering and suppression away, you are looking at the world with new eyes. You get a totally new perspective.”

Singleton and his colleagues set out to test the so-called Rebus model of psychedelics. Standing for “relaxed beliefs under psychedelics,” it frames the brain as a prediction engine. Under the model, the brain takes thoughts and information from the senses and shapes them according to its understanding of the world. This makes the brain highly efficient: armed with prior beliefs, the noise and uncertainty of perception and thought are swiftly hammered into coherent reality.

But the brain works differently on psychedelics. According to Rebus, substances such as LSD weaken the influence of prior beliefs that the brain uses to make sense of the world. In one sense, the drugs rewind the brain’s clock to a time before it learned that walls tend not to move and furniture is rarely threatening.

“You can imagine you might experience altered perceptions,” said Amy Kuceyeski, a senior author on the study at Cornell. “If your prior belief is that walls don’t move and your prior belief melts, then that wall may appear to move.”

The scientists analysed fMRI brain scans of people on placebo or LSD. These revealed four distinct states, or patterns of activity, that the brain switched between when the volunteers were resting in the scanner. Two of the brain states were largely driven by sensory parts of the brain, while the other two involved the kind of top-down processing the brain performs to make sense of the world. On LSD, the brain spent less time on higher-level processing and more on the sensory-driven activities.

By comparing scans of the brain on LSD versus placebo, the researchers found that the drug reduced the amount of energy the brain needed to switch from one brain state another. Dr Kuceyeski likens it to flattening the landscape over which the brain can roam. Normally, the brain’s activity is constrained by the mountains and valleys of our prior beliefs, but on LSD these obstacles are flattened out. “It allows us to move more freely and have more dynamic brain activity,” she said.

Writing in a preprint, which has yet to be peer-reviewed, the researchers go on to show how the distribution of a particular receptor called 5-HT2a, the primary target for LSD, enables the drug to have such a profound levelling effect.

David Nutt, professor of neuropsychopharmacology at Imperial College London, who was not involved in the research, said that “flattening the landscape” allowed parts of the brain to talk to each other for the first time since early childhood.

“The whole process of child development and education is to take your brain, which is extremely malleable, and force it to be like everyone else’s brain. Under psychedelics, you go back to a state where bits of the brain that haven’t spoken since you were a baby can cross-talk. And it’s that increased connectivity that allows people to get new insights into old problems,” he said.

The ability of LSD to free up brain activity may explain why psychedelics can help people with depression, anxiety and other mental health disorders such as post-traumatic stress disorder.

“In depression, people get locked into a way of thinking that is repetitive and ruminative. It’s like tramline thinking,” said Nutt. “Psychedelics disrupt those kinds of processes so people can escape from it.”

*From the article here :

Acid test: scientists show how LSD opens doors of perception

Study analysing brain scans of people finds psychedelic drug lowers barriers that constrain thoughts

www.theguardian.com

 

[mr peabody]

Tolerance, Tachyphylaxis, and psychedelic drug action

Understanding this interplay is essential in psychedelic drug research.

by Alaina Jaster, BS | Psychedelic Science Review | 7 Jun 2021

Psychedelic drugs are a unique class of compounds. They affect sensory processing, perception, and cognition. But these effects can be blunted with repeated dosing, causing tolerance.

Tolerance vs. Tachyphylaxis

Tolerance is when higher doses of a drug are required to produce a given response.1 Behavioral tolerance to a drug can be rapid or chronic. Rapid tolerance means tolerance develops within 24 hours and chronic tolerance develops over a longer stretch of time like days or weeks. Psychedelics typically produce rapid tolerance that dissipates within a few days while other drug classes have a chronic tolerance. For example, a typical recreational dose of lysergic acid diethylamide (LSD) is 100-250 micrograms (µg). If a person took 200 µg one day and then within the next few days wanted to take another 200 µg dose, this dose may have less of an effect or none at all, and a higher dose is needed to produce the same behavioral or perceptual response. It has been shown that most people can build up a complete tolerance to the same dose within a week.

Tachyphylaxis describes a rapid decrease in response to repeated doses of a drug over a short period of time.4 This is similar to rapid tolerance. One study by Buchborn and colleagues investigated the tolerance and tachyphylactic effects of 25CN-NBOH* on the head twitch response (HTR) in mice. They applied the drug twice at 1 and 1.5-hour intervals and found a rapid loss of responsiveness to the second injection, which is thought to be attributed to cellular signaling mechanisms. This is comparable to other studies with DOI**, where HTR frequency decreased following repeated injections between 2-8 hours.

* 4-[2-[(2-hydroxyphenyl)methylamino]ethyl]-2,5-dimethoxybenzonitrile

** 2,5-Dimethoxy-4-iodoamphetamine

The neuroscience behind these effects

These phenomena are common with many pharmacological classes of compounds. The development of this rapid tolerance and tachyphylaxis is thought to be due to changes in the receptors these compounds activate. In the case of psychedelics, it’s the serotonin 2A receptor (5-HT2AR).

Internalization, down-regulation, and desensitization are all ways these receptors are altered to produce less of an effect. Desensitization involves phosphorylation of the 5-HT2ARs at a specific area that diminishes evoked responses and typically happens within milliseconds to minutes of drug exposure. This makes it so the receptor can’t keep producing a signal with more agonist exposure. Internalization and down-regulation occur after a longer exposure to the agonist. Internalization is when a receptor is taken from the surface of the cell via a process called endocytosis. Following internalization, the receptor is either recycled back into the cell surface for activation or is degraded and no longer active. The down-regulation of receptors is when the total number of receptors decreases due to that degradation. The changes in the receptors alter the ability of psychedelics to activate the 5-HT2AR to exert their effects

Implications in therapeutics

The development of rapid tolerance with psychedelics is also important for further development as treatments for psychiatric disorders. Unlike other pharmacotherapies like selective serotonin reuptake inhibitors (SSRIs), psychedelics cannot be given daily due to the rapid development of tolerance. Although SSRIs also cause internalization and down-regulation of receptors, this is seen over longer periods of administration like weeks to months. It is also important to note that even small doses of psychedelics may produce tolerance or tachyphylaxis.

Further research is necessary to figure out how this pharmacological mechanism may play a role in the future of psychedelic medicine.

Alaina Jaster is a PhD student in pharmacology at Virginia Commonwealth University. Her research focuses on behavioral changes and circuitry of psychedelics involved in preclinical models of addiction and depression.

Tolerance, Tachyphylaxis, and Psychedelic Drug Action

Understanding this interplay is essential in psychedelic drug research.

psychedelicreview.com

 

[mr peabody]

Relaxed beliefs under psychedelics: The REBUS Model*

by George Blackburne | Psychedelic Science Review | 10 Jun 2021

Dr. Robin Carhart-Harris‘s REBUS model has received much attention for its purportedly unifying account of the effects of psychedelic drugs on global brain dynamics. REBUS is an eloquent marriage of the entropic brain hypothesis and hierarchical predictive coding. The entropic brain hypothesis proposes a kernel function of the brain to be the restriction of entropy associated with spontaneous neural activity. Importantly, it states perhaps the defining act of psychedelic drugs is the elevation of this entropy, eliciting a corresponding increase in the richness of the content of conscious experience.

Predictive coding is the view that the brain is a hierarchically organised system that functions as a prediction engine. Under predictive coding, our perception is a generative mental model that is algorithmically optimised through a prediction error minimisation scheme. Prediction errors are the difference between the higher-level priors (expectations) a brain has about the world and the conflicting bottom-up information about the world the brain receives through sensory channels.

REBUS postulates that the 5-HT2A receptor, the holy grail of classical psychedelic pharmacology, possesses a perhaps unique expression profile on cells across cortical regions deemed to be at the uppermost ranks of the brains hierarchy. As shown above, it crucially suggests psychedelics act by deweighting the precision of higher-level priors, which concomitantly liberates the influence of information ascending the hierarchy, resulting in a situation where the functional hierarchy is flattened. In other words, the brain becomes anarchic, and a corollary of this is deemed to be that the variational free-energy landscape of the brain is flattened. That is to say that the brain is able to explore its repertoire of possible states with greater ease, as suggested by more temporally diverse or entropic brain activity.

Tentative support for REBUS has come from recent work demonstrating that DMT significantly decreases top-down alpha-band rhythms, supposedly corresponding to the decreased influence of predictions. This study also showed that DMT significantly increased bottom-up forward waves, supposedly corresponding to the increased influence of prediction errors. Additionally, LSD has been shown to decrease coupling between structural and functional connectivity, thus facilitating the brain to access states less constrained by anatomical connections.

Furthermore, LSD and psilocybin have been shown to reduce the hierarchical differentiation of the transmodal versus unimodal cortex. Nonetheless, the idea that the energy requirements for brain-state transitions are reduced under psychedelics had remained untested, until a recent prodigious study performed by Stephen Parker Singleton and colleagues.

LSD flattens the brain’s functional hierarchy and energy landscape via 5-HT2A

The study clustered brain activity into recurrent states and sought to characterise how the LSD changes the temporal dynamics of how the brain occupies these states. Singleton et al. showed that LSD induces a decrease in the persistence (occupation over time) of states dominated by activity in frontoparietal networks, networks associated with executive functions. This effect was accompanied by an increase in the persistence of states dominated by activity in somatomotor and ventral attention/salience networks, networks associated with the effective sampling of sensory data. These results are fascinating since they correspond to REBUS’ designation of top-down and bottom-up activity respectively, and thus the effective flattening of the brain’s functional hierarchy.

Next, Singleton et al. leveraged recent developments in network control theory (NCT) to quantify the minimum energy required to transition between pairs of brain states. Remarkably, they showed LSD lowered the transition energy between every possible combination of initial and final brain states. Moreover, using positron emission tomography (PET) maps for 5-HT2A expression, they showed that energy injection at these specific locations in the placebo data set could induce a flattened energy landscape. The mechanistic pertinence of this specific receptor was further demonstrated by the fact that the same protocol performed for other targets of LSD, such as 5-HT1A, did not flatten the energy landscape to the same extent.

Lastly, Singleton, et al. showed that the flattened energy landscape induced by LSD resulted in a heightened frequency of brain-state transitions and that these transitions did not compile into a predictable sequence. In fact, they demonstrated that the greater a subject’s energy landscape was flattened the more entropic their brain-state time series became, thus providing support for another key tenet of REBUS.

Conclusions

Rounding off, while the study corroborates a number of claims made by REBUS, there are a number of outstanding questions. For example, the LSD fMRI data set used in the study is the same LSD data set that was no doubt used to aid in the formulation of REBUS. Ultimately there are only 15 participants in the data set, thus greater data acquisition is imperative to see how well REBUS’ claims generalise.

Moreover, the study found no significant correlations between energy landscape flattening and the intensity of the subjective experience. It also provided no analysis on how energy landscape flattening might be statistically associated with specific features of psychedelic experiences.

Another aspect of REBUS that future research would do well to flesh out is the “improved ability to see the bigger picture” logically implied by energy landscape flattening.1 Additionally, the phenomenon of fact-free learning is relevant to energy landscape flattening, that is learning not by the accumulation of new information but by the acquisition of a novel frame of reference on already attained information.

Notwithstanding, this paper is a wonderful addition to the roster of recent receptor-informed whole-brain computational models investigating the effect of psychedelics on global brain dynamics. Fundamentally, it is a beautiful exposition of what is perhaps the most prominent and comprehensive model of psychedelic drug action to date, showing it to pass the initial test on one of its most pivotal claims.

*From the article here :

LSD and the Anarchic Brain

LSD flattens the brain’s functional hierarchy and energy landscape via 5-HT2A…

psychedelicreview.com

 

[mr peabody]

University of Denmark in Copenhagen

Researchers closer to understanding how psilocybin impacts the brain

by Kristi Pahr | LUCID | 21 Apr 2021

A recent study may have brought us closer to understanding how psilocybin impacts the brain. Researchers in Denmark examined the brains of pigs after psilocybin administration and discovered that a single dose of the psychedelic substance increased neuroplasticity, and had marked and long-lasting antidepressant effects.

Several studies have proven that psilocybin has a positive impact on mood and decreases depressive symptoms, but the mechanism of action was never determined.

“The fact that there are therapeutic properties in psilocybin is not a doubt anymore,” said study author Nakul Ravi Raval of the University of Denmark in Copenhagen. “Though, the understanding behind its neurobiology remains unclear. There are many hypotheses and models that some people have defined, but they are still not proven. This is a small step at understanding the effects that can be seen directly in the brain.”

Researchers administered psilocybin to 12 pigs and a saline placebo to 12 pigs, and then examined the brains of the subjects. Six of the pigs were euthanized and examined one day after administration of psilocybin, and six were euthanized and examined 7 days after administration.

The brains of the pigs that had been given psilocybin had markedly increased amounts of SV2, synaptic vesicle glycoprotein 2A, a protein associated with the density of synaptic nerve endings. The seven-day samples also showed an increase in SV2A indicating that the changes associated with psilocybin are longer-lasting than previously thought.

It may be worth noting that SV2A is found in decreased quantities in patients diagnosed with major depressive disorder.

While it might seem strange to use pigs in a psychedelics study, they are the only large mammal with similar brain structure to that found in the human brain.

“Believe it or not, they are much closer to humans than other laboratory animals. For instance, they have a gyrated brain like humans. Physiological too, they are more similar to humans,” says Raval. “They are also very genetically different from one another, just like us humans. Though, genetic variability is a double-edged sword. On the other hand, they are great as a tool for neuroimaging. Our lab has tested and optimized many positron emission tomography tracers in pigs before human trials. Pigs also have giant brains compared to rodents. The size of the brain allows for multiple studies from a single batch of an experiment.” He adds that the steep price of housing pigs often prevents such studies from being frequently conducted.”

"Depression and related disorders are correlated with neural atrophy, meaning there are “lesser connections” of functional neurons. In vitro studies, or test-tube experiments, show that when neurons (in cell cultures) are treated with psychedelics, there is an increase in structural and functional plasticity,” Raval says.

“What this means is that there is an apparent increase of connections in the neuronal cell. We believe the immediate and prolonged antidepressive effect of psilocybin is due to this increase in connections and function.”

Because the animals used in the study were all healthy and not depressed, the researchers had to make the connection between psilocybin’s neurological effects, and its antidepressant qualities. “Just like the in vitro studies, we can only add one to one,” says Raval. “However, this is the first time that such an effect is seen in a large animal study. Unfortunately, with the lack of good large animal models for depression, this study has to be performed on healthy animals.”

Raval says this research has paved the way for multiple studies in their laboratory, and others.

“We are trying to translate these findings into humans. Research never stops; one question is always followed by another. [But] it will surely help in the understanding of the neurobiology of psychedelics.”

Researchers Are Closer to Understanding How Psilocybin Impacts the Brain - Lucid News

Researchers in Denmark shed light on psilocybin’s neurological effects after administering the substance to pigs in a recent study.

www.lucid.news

 

[mr peabody]

Harm Reduction in Psychedelic Research​

by Abigail Calder, MSc | Psychedelic Scvience Review | 16 Jul 2021

Psychedelic science operates with an abundance of caution.

Psychedelics are not tame substances. Their therapeutic benefits are becoming better known, but they are also perfectly capable of mayhem. This leaves sober-minded people with a dilemma: what do we do with drugs famously capable of sending people to both heaven and hell?

If you’re a scientist, you come up with a long list of safety precautions to keep hell at bay. Most of the scientific knowledge we have about psychedelics comes from clinical trials, perhaps the safest possible setting in which to take them. As something of an insider, I hope I can help people appreciate the depth of the precautions we take in research, as well as what that means for interpreting study results and implementing psychedelic therapy in different settings. As with rock climbing, new cars, and trampoline parks, a lot of thought goes into safety behind the scenes.

First, a basic question: what are safety precautions trying to prevent? In essence, three things. The first and easiest is a dangerous physical reaction to the drug, which with psychedelics is exceedingly rare; one influential researcher called LSD and psilocybin “freakishly safe” when it comes to physical toxicity. The second is an acute negative reaction – a “bad trip” – especially one that is either so strong or so prolonged that it is not likely to turn beneficial. The third is the most dire: a sustained negative reaction, at worst a prolonged psychological crisis. Though also incredibly rare, the fact that this is theoretically possible means we take it seriously.

Not everyone should take psychedelics

Safety begins with the belief that some people, at some points in their lives, should not take psychedelics. This is obviously not a radical idea; most people have at least heard that those with schizophrenia should not tempt hallucinogenic fate. But researchers also typically exclude participants with any history of psychotic episodes, bipolar disorder, or personality disorders, as well as anyone with a close relative suffering from schizophrenia (it has a strong genetic component). In studies with healthy volunteers, any psychological disorder at all may be disqualifying, as is the intake of psychoactive medications.

Beyond a psychiatric history, some studies require participants to pass a general medical screening, which particularly looks for abnormalities in the cardiovascular system (psychedelics modestly elevate heart rate and blood pressure). Pregnant women are always out, and frequent psychedelic fliers usually are. And though less common, researchers may also look for certain personality traits in their participants. In general, the ideal study participant is emotionally stable and not averse to novelty; the kind of person who won’t scream at the guy who cuts them off in traffic on their way to a new sushi restaurant. A few studies have even screened out people who score high in neuroticism, a core personality trait that describes someone’s predisposition to experience negative emotions and may predispose people to unpleasant trips.

Participants aren’t the only ones to get this extreme vetting. The professionals who are responsible for safety, whether they be therapists, guides, or unassuming grad students, must have particular characteristics as well. Participants in studies are always supervised by trained professionals, often a pair of psychologists, who are not only knowledgeable about psychedelics and altered states but also highly empathetic and able to create a trusting atmosphere with a participant in a relatively short period of time. Though they often have formal training, their interpersonal abilities and knowledge of the psychedelic state are widely considered more important than a degree.

Preparing person, space, and substance

Before taking any drugs, participants in clinical trials undergo extensive preparation for the psychedelic experience. The aforementioned trained guides take time to get to know the participants and build trust, and to educate them on what they might experience in a psychedelic session. They also advise people on the possibility of difficult experiences and how to handle them. This preparation can take up many hours spread out over several weeks so that by the end of it, the participant has asked all of their questions and ideally feels absolutely safe with those supervising them.

At least some of these preliminary appointments take place in the psychedelic session room. Even in clinics, the sterile hospital look is switched out for a comfy, living room-like aesthetic. Couches, pillows, and serene decorations are common, as is soft lighting and the occasional mushroom statue. This is a private, safe place to give up control, and it greatly reduces the risk that unexpected events might intrude on the trip.

Last but not least, the drug itself is prepared beforehand: a moderate to high dose of a pure, top-quality substance, often from a government-sanctioned lab. This takes the risk of contaminants and inaccurate dosing out of the equation.

An ever-present guide

Before the session starts, many of the risk factors for negative reactions have already been greatly reduced. Once the trip begins, medical personnel are available in case of emergency and at least one guide is always present in the room while participants are under the influence. These guides are able to respond in case of distress and nip a potential bad trip in the bud, as well as stop participants from doing anything harmful (or embarrassing). The trusting relationship they have built greatly enhances their ability to do this.

In case participants start to feel distressed, guides are trained to radiate a sense of empathetic calm, not only with comforting words but also with their tone and body language. They are the anchor to reality, and their calm demeanor in crisis can communicate to participants that even a frightening experience is not really going to hurt them. Music is also almost universally used in psychedelic sessions, and it can be instrumental (sorry) in helping participants feel safe and calm. Even an escalating negative reaction can often be impeded with the right words or music, a comforting touch, and a reminder that the participant is safe and their experience is transient.

As a last resort, guides can administer an antidote (usually a benzodiazepine) to weaken or end the trip, although this is rarely necessary. Indeed, the fact that participants know they can get off the ride makes them less likely to want to. At the root of many bad trips is a fear of losing control, and the presence of an antidote gives people a sense of control even if they never use it.

Integration

The final cornerstone of psychedelic safety is integration or discussing and processing the experience together with the guides after it is over. Often, integration also means taking any perceived lessons from the experience and applying them to one’s life in hopes of improving well-being. Participants benefit from at least one integration session, but the integration period may be longer if needed and feasible.

Integration’s primary value as a safety measure is checking for persistent negative effects that might appear after a psychedelic experience, and if need be, preventing them from getting worse. Especially if the experience was challenging, therapists and guides consider it highly important to support participants afterwards and give them space to discuss these strange and potentially life-changing experiences. They specifically ask whether any negative effects have lingered, including persistent perceptual changes (e.g. flashbacks), dissociative symptoms, or signs of psychosis, and can make sure participants get the help they need for such symptoms.

Credible reports of negative effects after psychedelic use in recreational settings exist, although they are still relatively rare. But in studies with modern safety standards – so, in the past 25 years – none of these long-term reactions have been observed: a powerful testament to the effectiveness of safety procedures in psychedelic research.

What about other settings?

Clearly, scientists do a lot for safety. It may also be clear that many of their safeguards are hard to implement in other settings. Does this mean that other environments are more dangerous?

To answer this question, let’s review how scientists prevent adverse reactions in trials. Studies take place in a private, safe environment, with clean substances and moderate doses, screened participants, sufficient preparation, competent guides, and integration afterwards. Any setting which has this basic profile is probably about as safe as a clinical trial. Religious psychedelic use within many indigenous communities checks these boxes, as does regulated psychedelic therapy outside of research (e.g. in compassionate use exemptions). Other settings are riskier to the extent that they neglect these basic safeguards, with more neglect probably meaning higher risk.

This does not mean that people are guaranteed a horror trip in less controlled settings. It rather means that if one starts to build, there are fewer things that can stop or transform it, and it may be more likely to negatively affect the person after it’s over. The precise risk of a malignant bad trip is difficult to judge. On the one hand, psychedelics are still relatively safe and prolonged adverse reactions are not common. On the other, many recreational users report having had difficult experiences that at least temporarily exceeded their coping mechanisms or affected them negatively for some time afterwards.

People can consider this when evaluating retreats, clinics, and other settings in which they might plan on taking psychedelics. If guests are not well-screened, if the preparation is minimal, if the session monitors are not well-trained or numerous enough to handle a crisis, and if there is little follow-up after the experience, one cannot assume the same level of safety seen in studies. The acceptable level of risk is a personal decision, but it should be made with the best information.

Judging the risks of psychedelics is a balancing act between avoiding an unrealistic account of their dangers, yet taking rare adverse effects seriously. The clear success of clinical trials in ensuring participant safety shows that it is possible to reap the benefits of psychedelics while reducing the risk of severe adverse effects, especially prolonged ones, to nearly zero. Understanding how scientists manage this can improve people’s ability to judge the safety of different settings and contribute to a culture of safety around the use of these powerful substances.

Abigail is a doctoral candidate in medical neuroscience at the University of Fribourg, Switzerland. Her research concerns various effects of LSD on the brain in healthy people, including both acute drug effects and enduring neuroplastic changes.

*From the article here :

How Scientists Keep People Safe in Psychedelic Research - Rules for Harm Reduction

Are psychedelics safe? In research, four harm reduction rules greatly reduce the risk of bad trips.

psychedelicreview.com

 

[mr peabody]

Real-world Research in Psychedelic Science

by Nate Seltenrich | Psychedelic Science Review | 6 Jul 2021

Researchers see value in a naturalistic approach to psychedelic studies.

In a recent webinar, psychedelic researcher Robin Carhart-Harris of Imperial College London made an offhand remark regarding naturalistic studies. Neither he nor anyone else followed up on it. Perhaps that’s because the comment didn’t quite gel with his status as a leading expert in the neuroscience of psychedelics — nor for that matter with what many of us may view as the gold standard of psychedelic research: clinical studies employing strict controls and sophisticated technologies.

What Carhart-Harris expressed was a call for more of the opposite: psychedelic research studying drug use outside the lab, in the real world, by regular people, either alone or in groups, at home or retreat centers or wherever they happen to be. And while Carhart-Harris’ May talk for DoubleBlind magazine, titled “Psychedelics in the Brain,” predictably focused on neuroscience, in recent months his lab has emerged as a leader in the oft-overlooked area of naturalistic psychedelic research.

Microdosing study

Its highest-profile offering was a March 2021 study on microdosing effects among users of LSD and magic mushrooms1 (which contain the compounds psilocybin and psilocin). Thanks to an innovative design that allowed for self-blinding among the 191 participants, it was the largest placebo-controlled trial on psychedelics to date. The study — and its core finding that anecdotal benefits of microdosing can be explained by the placebo effect — received a fair amount of attention.

“Clinical studies are an artificial setting that is not representative of how most medicine is practiced, and this can lead to distortions,” says Balázs Szigeti, a research associate within the Centre for Psychedelic Research at Imperial College who served as lead author of the study. “First, medicine is always prescribed open-label, meaning that the patient knows he/she will get the active medicine, [with] no chance for placebo. Furthermore, generally, there is a much more intense patient-doctor relationship in a trial, which is likely to boost outcomes, as a warm, caring attitude from doctors has been shown to boost results.”

The bottom line, he argues, is that because clinical studies do not reflect real-world conditions, they are not the bulletproof arbiters of truth we often want or expect them to be. “The microdose study is a good example of a pragmatic trial where the context is much more similar to how microdosing is done in real life by real people,” Szigeti says.

Accessing cultural knowledge

The very same month that study was published, Carhart-Harris’ lab also produced — yet much more quietly — the largest prospective (meaning, in this case, that baseline survey responses were collected from participants) naturalistic study to date addressing psychedelic retreat settings. Lead author Hannes Kettner, a Ph.D. student and research assistant under Carhart-Harris with a focus on naturalistic settings, says the study and others like it serve as a counterweight to more reductionist investigations into psychedelics.

“There is a narrative emerging from multiple points that portray psychedelic-assisted treatments as a historically isolated phenomenon developed and housed within the Western medical system, discounting the influence of underground practices and/or indigenous usage,” Kettner told Psychedelic Science Review in an email. He added,
​

With naturalistic studies we try to access this culturally accumulated knowledge around psychedelic use and show that it may contain elements that might have merit even within modern treatments, such as the group component.​

To put it another way, as the Western medical system continues to subsume psychedelics, it ignores the big picture at its own peril, Kettner argues. “If psychedelics will be conceptualized purely as pharmacological treatments with no regard to context, there is a risk that when adopted in real-world clinical practice they might just be found to be ineffective, or even detrimental. Samples of 20 to 50 participants that all undergo their sessions in strictly curated and uniform laboratory conditions poses some serious limitations.”

Other naturalistic research papers to come from Carhart-Harris’ lab this year include “Sustained, multifaceted improvements in mental well-being following psychedelic experiences in a prospective opportunity sample” and “Psychedelics alter metaphysical beliefs.”

Complementing clinical studies

Of course, Carhart-Harris’ isn’t the only psychedelic-science lab producing rigorous naturalistic research alongside more clinical or reductive work. In 2019 9 and 2020, 10 Johns Hopkins University professor of psychiatry and neurosciences Roland Griffiths led a pair of studies that used online surveys to investigate entity- and God-encounter experiences among users of psychedelic drugs. (“It’s official,” read the headline in Vice, “DMT makes you believe in God”).

Also in 2019, Griffiths served as senior author of another naturalistic study that found the use of 5-MeO-DMT was associated with unintended improvements in depression and anxiety — a particularly meaningful result given the attention given in recent years to treating these potentially debilitating conditions with psychedelics. Indeed, the authors stress that their findings should inform future “controlled clinical pharmacology studies” to assess the safety and efficacy of using the drug to relieve depression and anxiety.

“I think of naturalistic studies as a complement to clinical studies,” agrees Szigeti. “I think that’s one key point which is often missing from the discussions of the topic.” This perspective suggests that together the two approaches can provide a clearer idea of what psychedelics do and how they do it — and a better sense of how to maximize their benefits while minimizing potential harms — than can either on its own.

Naturalistic Research in Psychedelic Science

Researchers complement clinical trials with naturalistic studies and citizen science on psychedelics.

psychedelicreview.com

 

[mr peabody]

Psychedelic Research Institutions in North America*​

by James Stephen | Truffle Report | 13 Sep 2021

Psychedelics are making a comeback. We’ve been fortunate enough to meet and speak with some great people in the process of studying psychedelics, and to expand our knowledge of the field as it charts a new course in mental healthcare.

We’ve put together a list of departments, programs, and centres that are affiliated with prominent universities and research institutions, all of which we’ve covered in the past here at Truffle Report. We should also add that this list isn’t meant to be exhaustive. Please feel free to reach out with suggestions for any we may have missed. We’d love to hear from you, and to speak to more experts in the field.

We hope this will be an education.

Johns Hopkins

The Johns Hopkins Center for Psychedelic and Consciousness Research is, quite possibly, the premiere academic research centre for psychedelics in the world.

Renowned psychedelic researchers such as Doctors Roland Griffiths and Matthew Johnson have been studying psychedelics at Johns Hopkins far longer than the prestigious university hospital has had a dedicated wing. JHU’s team has generated dozens of peer-reviewed articles, with initial studies into the effects of psilocybin on depression in terminally ill cancer patients, smoking cessation, and religious/spiritual experiences being the catalyst for much of the current psychedelic renaissance.

Harvard

Once the sight of some serious academic infamy on the subject, Harvard now has a hospital affiliate and a branch of their prestigious law school studying psychedelics.

Massachusetts General

An affiliate of Harvard Medical School, Massachusetts General Hospital is now home to the Center for the Neuroscience of Psychedelics. Their current studies, led by director Jerrold Rosenbaum, seek to understand the impact of psilocybin on rumination, a phenomenon linked to many mental health conditions, and — in partnership with MAPS — the effects of MDMA-assisted mindful self-compassion on loneliness in treatment-resistant PTSD.

POPLAR

Studying psychedelics isn’t just limited to the lab. Outside of the medical and scientific fields, we’re already witnessing the beginning of profound social changes as a result of these substances making their way into the mainstream of our society. We can only expect this to continue as evidence of their success mounts, and Harvard Law School’s Petrie-Flom Center for Health Law Policy, Biotechnology, and Bioethics has launched POPLAR, the Project on Psychedelics, Law, and Regulations, to stay ahead of the curve.

Issues of ethics in research and practice, intellectual property, and the establishment of regulatory frameworks are already piling up in the new space. POPLAR is beginning by hosting academic events and roundtable discussions, inviting stakeholders from the industry, while also carrying out a rigorous review of psychedelic research and its social implications. In its most recent case, this has taken the form of a partnership with state health authorities in Oregon.

NYU Langone

The NYU Langone Center for Psychedelic Medicine focuses on psychiatry, medicine, and preclinical research. What makes it unique is its research training program for junior faculty and postdoctoral fellows.

“We focus strongly on clinical applications, such as the development of therapeutic uses of psychedelics,” director Dr. Michael Bogenschutz told Truffle Report in a previous interview. “We do this primarily through clinical research, although we are developing a program of preclinical research as well, which aims to identify promising therapeutic effects and elucidate therapeutic mechanisms.”

“A robust training program supports the development of junior faculty members and post-doctoral fellows to become independent investigators in the field of psychedelic medicine. The center provides an environment in which highly trained scientists, clinicians, trainees, and staff collaborate to ensure that the momentum created by the modern psychedelic renaissance is sustained and continues to yield medical breakthroughs, backed by sound science.”

USCF’s TrPR

Based at the University of California’s San Francisco campus, the Translational Psychedelic Research Program, or TrPR, is headed up by Doctors Joshua Woolley and Ellen Bradley, and focuses on the use of psychedelics in the treatment of conditions that would normally function as exclusion criteria for clinical trials, such as depression related to Bipolar II disorder and Parkinson’s Disease.

TrPR is also investigating the potential for psilocybin in treating chronic low-back pain, is likewise involved in the Usona Institute’s depression study and has private sector partnerships with both Silo Pharma and Filament Health, respectively investigating psilocybin for the treatment of various aspects of inflammation, and psilocybin vs ketamine for the treatment of depression.

University of Wisconsin, Madison

The University of Wisconsin, Madison School of Pharmacy is home to the Psychoactive Pharmaceutical Investigation Program, the first Master’s program of its kind.

“It was born out of our observation, as a working group, that the field of psychedelics was moving quickly beyond the academic research space. I was fortunate enough to join a large group of investigators here at Madison, who have already been working with psychedelics for many years. Together, we wanted to design a program that would meet the needs of the field as it expanded into the industrial and pharmaceutical research settings, as well as providing services for not-for-profits, and even potentially services for areas outside of that core science arena, such as support for public policymakers,” explained Program Director Professor Cody Wenthur in a previous interview with Truffle Report.

More recently, the UW-Madison School of Pharmacy also launched The Transdisciplinary Center for Research in Psychoactive Substances, with a focus on expanding participation from research subjects of diverse and underrepresented backgrounds.

University of Ottawa

The University of Ottawa’s Faculty of Arts is now offering a virtual microprogram on Psychedelics and Spirituality Studies. The program is being taught by Dr. Ann Valley of the Department of Classics & Religious Studies and Dr. Monnica Williams, Associate Professor at the School of Psychology, and will explore the intersection of cultural, ceremonial, and therapeutic practices throughout the history of psychedelic plant medicine.

Other Institutions

Both the palliative psychedelic nonprofit TheraPsil and the privately-owned ATMA Journey Centres have initiated training programs for qualified candidates looking to become psychedelic therapists. Through Section 56 exemptions, TheraPsil has completed the training of its first cohort of therapists using psilocybin itself.

James Stephen
James Stephen is a content contributor at Truffle Report. He studied Politics and International Development at Trent University and completed his Postgraduate Certificate in Book, Magazine, and Electronic Publishing at Centennial College. He has previously worked as a chef, and in his spare time is an author and freelance writer.

*From the article here :

Studying Psychedelics Pt I: North American Research

Prominent universities and institutions are now studying psychedelics, opening research centres and beginning training programs.

www.truffle.report

 

[mr peabody]

Psychedelics and Perception, Part 1: Visual Effects

Reviewing early research (1895-1975) on changes in visual perception.

by Joshua Falcon, MA | Psychedelic Science Review | 21 Jun 2021

Psychedelic drugs have long been associated with temporary alterations in perception. These changes include, but are not limited to, auditory, visual, and sensory distortions or hallucinations, alterations in body image, and modifications in one’s sense of time. Although early studies are often overlooked due to recent advances in scientific methods and technologies, valuable research was conducted on the physiological changes that psychedelics produce at the visual, auditory, and sensory levels and how these are associated with phenomenological changes in perception.

In a recent review article, Aday et al. provide a novel synthesis of scientific literature drawn from the first era (1895-1975) of psychedelic research. While the early research was predominantly concerned with changes in visual perception, there was also research conducted on auditory processing, changes in body schema and tactile processing, and alterations in the perception of time. The following article summarizes Aday et. al.’s review of psychedelics’ effects on visual perception by drawing out some of its key findings and areas where further research is needed.

Physiological Changes in Vision

Upon reviewing the first era of studies, Aday et al. suggest that there remains a longstanding debate that has heretofore fallen by the wayside over whether psychedelic-induced changes in visual perception stem from alterations in the brain versus the peripheral eye. On the one hand, early animal studies from the 1950s and 1960s exhibited elevated levels of LSD found in the iris of monkeys. Additional research from this period found that LSD produced spontaneous firing in the sclera, visual cortices, and optic nerves of cats, leading some to hypothesize that changes in visual perception may stem from physiological changes in the retina and peripheral eye.

On the other hand, research conducted between the 1950s and 1970s suggests that changes in visual perception may instead stem from the brain insofar as studies on both blind individuals and in animal models exhibit neurological changes at the cortical and subcortical levels of the visual system.

Despite this era of research being technologically limited to electroencephalography (EEG), notable findings show that changes in cortical activity are more pronounced than changes in the lateral geniculate nucleus (LGN) under the effects of psychedelics. This hypothesis is not only thought to be consistent with contemporary claims which posit that the effects of psychedelics are primarily exerted through the 5-HT2A receptors, but it also lends credence to the idea that modifications in brain activity are more pertinent, robust, and dynamic than those located in the peripheral eye and the retina. Given certain discrepancies in the data, however, further research is needed on the brain versus peripheral eye debate as well as in other areas where discrepancies are found such as changes in alpha activity.

Changes in Simple Visual Processing

The visual changes provoked by psychedelics are thought to stem from changes in elementary visual imagery (EVI), or changes in motion, form, and depth. In studies conducted during the 1950s with participants who had their eyes open, it was found that LSD changed perception in apparent horizon and apparent verticality, as well as elevations in low-level visual thresholds, while psilocybin contracted the perception of nearby visual space. These findings suggest that transformations in visual perception may ultimately be influenced by alterations in low-level visual processing; a point that appears to be at odds with recent studies, signaling the need for further research.

In studies from the 1940s where participants had their eyes closed, reports of geometric and kaleidoscopic patterns appearing in one’s visual field were reported and grouped together by researchers according to their phenomenological descriptions. These groupings included dynamic patterns such as tunnels, cobwebs, spiral designs, and cones to name a few.

Alterations in the perception of color can also be found in several of the first era of studies based on reports of increased color saturation or vividness. One study from the 1960s, in particular, found that LSD, psilocybin, and mescaline equally impaired color discrimination performance and suggested that each drug may affect the perception of different hues.

Complex Visual Imagery

Apart from changes in low-level visual perception, early studies also show that psychedelics tend to provoke intricate and evolving visionary experiences. Today’s researchers describe these changes in perception in terms of complex visual imagery (CVI), and individuals often describe these experiences as being dreamlike or vivid. Both anecdotal reports and self-experimental studies published during the first half of the twentieth century have long attested to the ability of psychedelics to produce these enduring, changing, and internal visions; however, these experiences prove difficult to quantify. Nevertheless, psychedelic experience reports are rife with references to internally experienced dynamic visions dating back to the early stages of psychedelic science. Although the nature of CVI has proved elusive, it is suggested that researchers should be on the lookout for cognitive factors that may be related to CVI, such as increases in creativity and metaphoric thinking.

Summary

The first era of research (1895-1975) into the effects of psychedelics on perception contains valuable findings that can be useful to researchers today. These include debates on how psychedelics produce physiological changes in the brain, the peripheral eye, and the retina to provoke changes in visual perception, as well as how alpha activity is affected by psychedelics.

Researchers during the mid-twentieth century found that psychedelics produced changes in low-level visual perception, increased vividness in color perception, as well alterations in the perception of certain hues. The significant visionary effects that are often produced by psychedelics were also investigated during the first era but proved difficult to quantify, signaling the need for contemporary research into the cognitive factors associated with the more profound and complex changes in visual perception.

Psychedelics and Perception, Part 2: The First Era of Research

Reviewing early research (1895-1975) on changes in auditory perception.

Psychedelic drugs have historically been recognized for their ability to produce changes in various aspects of perception. Upon examining early research conducted on psychedelics and changes in perception, Aday et al.’s recent review article synthesizes evidence drawn from the first era (1895-1975) of psychedelic research. Part 1 of this article above provides a summary of the first section of Aday et al.’s review, focusing on research conducted on changes in visual perception.

This article, Part 2, surveys a second portion of their review by examining the early evidence on psychedelics and changes in auditory perception. It highlights key findings drawn from the first era of research on psychedelics and changes in non-visual perception, while it also brings this evidence into conversation with contemporary studies where either resonances or discrepancies in the data exist.

Changes in Auditory Processing

Apart from investigating how psychedelics produce changes in the sphere of visual perception, researchers from the first era of psychedelic science also examined alterations in auditory perception. Behavioral studies conducted during the 1960s and 1970s, for example, found that LSD and other psychedelics reduced auditory sensitivity and led to increases in stimulus generalization. In contrast, other research conducted during this time period using animal models claimed that, in general, psychedelics produced fewer responses and reaction times overall, while they also appeared to have no effect on stimulus generalization. These observations of delayed reactions to auditory stimuli were also frequently reported across studies on psychedelics from the 1950s to the 1970s.

Around the same time, other experiments directed at studying the neural correlates of auditory alterations showed that mescaline, in a dose-dependent manner, increased the amplitude, latency, and peak area of the N1 and P1 auditory evoked potential (AEP) components in cats. Another notable study from 1971 compared how DMT and LSD differentially affect AEPs, suggesting that while LSD appeared to have no effect, peak DMT sessions showed a disappearance of AEP’s that tended to gradually resurface as the effects of DMT diminished. Aday et al. interpret the latter findings as being consistent with more recent studies on DMT, where individuals commonly report increased dissociation from their immediate surroundings.

Auditory hallucinations are another area of research investigated during the first era of psychedelic science; whereas some insisted on auditory hallucinations being common occurrences during psychedelic experiences, others considered them to be rare. Of the few early studies which quantitatively investigated the occurrence of auditory hallucinations, their frequency was considered to be uncommon. Instead of interpreting these changes in auditory perception as auditory hallucinations, some researchers during the 1930s and 1950s respectively suggested that these were perceptual distortions of objective stimuli. Aday et al. believe these results to resonate with contemporary studies wherein alterations in auditory perception have been examined.

Lastly, in undertaking investigations on the effects of music on psychedelic experiences, the first era of research produced several insights that would later be confirmed in more recent studies. In 1970, for instance, researchers suggested that music eased patients’ ability to “let go” during psychedelic therapy sessions, allowed patients to more fully explore their inner mental experiences, and reliably provoked intense emotions. Another study published in 1972 study showed that patients benefited more from the music they were most familiar with and that they also considered romantic and religious music as the most significant. In addition, it was discovered that music could, at times, “guide” the experience of the patient. These early insights on how music affects mental imagery and emotions during psychedelic experiences, and how these, in turn, are associated with increases in therapeutic value, have been validated in more recent studies, one of which was the subject of a Psychedelic Science Review article earlier this year.

Conclusions

The effects of psychedelics on perception have proven to be a longstanding area of interest to psychedelic researchers. This article summarized findings drawn from Aday et al.’s review of the first era of psychedelic research (1895-1975) and focused on the effects of psychedelics on auditory perception in particular. Behavioral studies predominantly from the 1960s and 1970s found divergent findings with regards to how psychedelics affect responses to auditory stimuli; however, they more reliably showed that there were delayed reactions to auditory stimuli across both animal and human models. Early investigations on the neural correlates of psychedelic-induced changes in auditory perception found increases in the amplitude, latency, and peak area of the N1 and P1 auditory evoked potential (AEP) components in cats. Other studies on the neural correlates of auditory changes during psychedelic states suggested that peak DMT experiences temporarily reduced AEP altogether, which can be seen as both anticipating and corroborating contemporary research on DMT.

While some first-era studies maintained opposing stances on the rarity of the phenomenon of auditory hallucinations, other investigations fell more in line with contemporary research which considers auditory hallucinations as pseudo hallucinations that stem from perceptual distortions of objective stimuli. Significant insights on the relationship between music and psychedelic experiences were also produced during the first era of psychedelic science, with many of these insights being validated by current research on music and psychedelic psychotherapy.

Psychedelics and Perception Part 2: The First Era of Research

Reviewing early research (1895-1975) on changes in auditory perception.

psychedelicreview.com

The Science of Psychedelic Visuals

How does LSD make you hallucinate? Early research on why psychedelics change visual perception already addressed this question.

psychedelicreview.com

 

[mr peabody]

Ketanserin’s contributions to Psychedelic Research

Blocking the 5-HT2A receptor helps researchers understand psychedelics.

by Melody Pezeshkian, BS | Psychedelic Science Review | 30 Apr 2021

When thinking of psychedelic medicine, the drugs that come to mind are often the classic psychedelics like LSD and psilocybin. Research chemicals like 4-HO-MET or 2-CB may also fall into this line of thinking. But people often overlook the importance of non-psychedelic drugs like ketanserin that aid in further discoveries in the field.

Ketanserin isn’t a psychedelic drug; in fact, it diminishes the effects of psychedelics. Its relevance arises out of the ability to block the binding of the neurotransmitter serotonin and some psychedelic compounds at the serotonin 2A receptor (5-HT2AR), giving researchers the ability to study the effects of serotonin-specific psychedelics.

Ketanserin synthesis and pharmacology

Ketanserin was discovered at Janssen Pharmaceuticals in 1980 as a small molecule quinazoline derivative that acts selectively at S2 receptors (5-HT2Rs). Ketanserin is currently prescribed as an antihypertensive drug via antagonism activity at the alpha-1 receptor. Alpha-1 receptor antagonists, referred to as alpha-blockers in some cases, bind to inhibit alpha-adrenergic receptors and can reduce symptoms of hypertension. Ketanserin’s antihypertensive effects are comparable to popular antihypertensive drugs metoprolol and propranolol.

By antagonizing 5-HT2ARs, ketanserin induces platelet aggregation. Its platelet aggregating capacity, however, is not directly what distinguishes it in psychedelic research. Ketanserin’s strong, selective inhibitions at 5-HT2ARs allows researchers to understand what drug effects are based on 5-HT2AR activity. In addition, ketanserin helps researchers understand the activity and effects of other serotonin receptors such as 5-HT1AR.

Two serotonin pathways

In the 1980s, scientists discovered that Ketanserin shows the most activity at the 5-HT2 receptor. They also observed that ketanserin had 1.5 times lower binding affinity at 5-HT1Rs than 5-HT2Rs. Its stronger affinity at 5-HT2Rs made it the first selective serotonin antagonist. Research has since delineated receptor subtypes, with a major focus on 5-HT2AR activity in the treatment of depression. It is proposed that psychedelics’ therapeutic action occurs primarily at the 5-HT2A receptor site, whereas antidepressants act primarily upon the 5-HT1A receptor site. Understanding the difference between these two pathways is of critical importance in understanding the role of the 5-HT2AR in psychedelic studies. Thus, ketanserin antagonism at 5-HT2ARs is essential to the study of psychedelic drugs.

Selective serotonin uptake inhibitors (SSRIs) enhance extracellular levels of serotonin through reuptake inhibition, increasing postsynaptic 5-HT1AR signaling. This results in decreased stress, aggression, and anxiety. Psychedelics increase signaling at 5-HT2ARs, which is associated with a decrease in rigid thinking, pessimism, and an increase in adaptability. Researchers studying psychedelics use ketanserin to delineate which effects of psychedelics are attributed to activity at 5-HT2ARs, versus at other serotonin receptor subtypes.

Psychedelic research using Ketanserin

As a 5-HT2AR antagonist, ketanserin is used to study the specific effects of classic psychedelics such as LSD and psilocybin. Only eight years after its synthesis, in 1998, researchers revealed ketanserin’s ability to mitigate negative side effects of psilocybin such as psychosis-like syndromes. They attributed ketanserin’s ability in blocking antipsychotic side effects of psilocybin to its inhibition at the 5-HT2AR.

A more recent study conducted in 2017 revealed that the positive effects of LSD are strongly correlated with 5-HT2AR activity. The general subjective effects of LSD were fully inhibited by the administration of ketanserin.

When LSD was administered in conjunction with ketanserin, typical LSD-induced effects such as the experience of unity, blissful states, and imagery, decreased, scored using the 5-D Altered States of Consciousness (5-D ASC) scale. The ketanserin group showed significantly lower, near-zero, scores for mystical experiences, autobiographical experiences, and spiritual experiences related to the therapeutic effects of LSD. Ketanserin administration in conjunction with LSD attenuated meaningful experiences overall. These findings suggest that 5-HT2ARs play a large role in mediating the general subjective experience of LSD.

A separate study surveying the role of serotonin on psilocybin found that psilocybin-induced effects are attenuated by ketanserin. Researchers administered ketanserin alone (40 g), psilocybin alone (260 µg/kg), or ketanserin + psilocybin combined. Interestingly, they found that cognitive deficits declined in the ketanserin+psilocybin treatment group. Ketanserin administration alongside psilocybin decreased the number of errors on a cognitive test (Stroop Task) than when psilocybin was administered alone. The Stroop Task is a measure of cognitive flexibility, response inhibition, and attentional control where participants are told to name the ink color of words but ignore denotation. Response time was significantly elevated in all trials when only psilocybin was administered than when ketanserin and psilocybin were combined.

When ketanserin was administered in combination with psilocybin, researchers noticed significant changes in response time on the Stroop Task (Figure 2). Most of the hallucinogenic effects of psilocybin were neutralized by ketanserin as well.

Conclusion

Ketanserin is of prime importance in psychedelic research because of its ability to selectively inhibit 5-HT2A receptors with much less activity at 5-HT1A receptor sites. By using a selective serotonin inhibitor, researchers are able to infer what neural regions are dependent on 5-HT2AR mediated processes. Current research emphasizes the importance of the 5-HT2AR subtype of serotonin receptors in mediating the effects of psychedelics in humans. Specifically, as pointed out by the Preller et al. study, the 5-HT2AR subtype is critical for the generation of meaning during a psychedelic experience. Ketanserin studies further the understanding of the neural underpinnings of subjective, therapeutic effects of psychedelics.

Ketanserin’s Contributions to Psychedelic Research

Blocking the 5-HT2A receptor helps researchers understand psychedelics.

psychedelicreview.com

 

[mr peabody]

Ketamine-Assisted Psychotherapy – Online?

by Veronika Gold, LMFT and Eric Sienknecht, PsyD | PSYCHEDELIC SUPPORT | 30 Nov 2020

Is the COVID pandemic presenting us with a new opportunity in the field of psychedelic-assisted psychotherapy? Can we collaborate with patients to offer virtual sessions safely and effectively? If so, what are the implications of this new way of providing treatment? Join Dr. Eric Sienknecht, PsyD and Veronika Gold, LMFT in an exploration of offering ketamine-assisted psychotherapy during social distancing.

In mid-March 2020, as the Shelter-In-Place order was put into effect in San Francisco, nearly all businesses and services ground to a halt. We stayed home, canceled all plans and appointments, foraged for the meager supplies remaining in stores, and waited. Our ketamine-assisted psychotherapy clinic, Polaris Insight Center, was closed for business, indefinitely. As fears of infection spread, along with the virus, we worried about our many patients, some of whom were suffering from Treatment-Resistant Depression and Anxiety while others reported newly emergent symptoms, exacerbated by the stress of the pandemic.

The question on hand became: How could we best respond to this potential healthcare crisis?

After several meetings, and as Telemedicine and HIPAA regulations were relaxed, we decided to begin offering virtual ketamine-assisted psychotherapy (KAP) sessions. Although our physicians regularly provide suitable patients with prescriptions for ketamine lozenges for at-home use during maintenance phases of treatments, we typically require in-office medical and psychological evaluations and several in-office KAP sessions before transitioning to at-home regimens. In this new COVID era, we would now be conducting evaluations, determining treatment plans, and facilitating the self-administration of ketamine lozenges at home via Zoom, all without ever meeting the patient in person.

Readers with an understanding of the powerful, often transformative, effects of psychedelic medicine may be skeptical and may wonder, “How is this possible?” and “Is this safe?” We also had similar questions, which informed the development of a new protocol for virtual services that included additional requirements to maximize safety and support.

Consider these three dimensions of virtual ketamine-assisted psychotherapy:

1. Accessibility

Upsides

Virtual KAP is more affordable compared to in-office treatment: Standard KAP treatment is a significant time investment. Typical treatments will include, at minimum, 1/2 hour with the physician, 1-hour intake with the therapist, 1 – 3 hours of preparation, several 2- to 3-hour experiential sessions, and 1 or more 1-hour integration therapy sessions. Because off-label use of ketamine is not usually reimbursed by insurance companies, the 10 – 20 hours or more of treatment are typically paid out of pocket. Virtual sessions allow for savings on rent in clinics and allow clinicians to see more patients, as there is less time spent between sessions (in the waiting room, in transition between session and transportation, changing sheets, and resetting the room).

Virtual KAP is more accessible compared to coming in person to the clinic: People who live in remote areas and places where there are no Ketamine-Assisted Psychotherapy clinics can now have access to this treatment.

KAP is most often used to target Treatment-Resistant Depression. One of the common challenges with depression for people is finding the motivation to engage in treatment, i.e. planning for sessions, leaving the house, and driving to and from appointments. With virtual sessions, these roadblocks are removed, facilitating access to, engagement in, and delivery of treatment.

The home setting can be more convenient for supporting the inner process and reducing side effects: Patients can stay with their process without interruption beyond the time of the session. Ketamine can elicit non-ordinary states of consciousness and, even when patients return to their normal state of consciousness, the physical effects of the medicine can continue beyond the time of the session. For this reason, many clinics, like ours, have “recovery areas” where patients wait, and patients are required to have arranged a ride home. When treatment is done at home, the patient can stay in their bed or on their sofa for as long as they need, and there is no pressing need to shift the state and commute home. One of the most common side effects of ketamine therapy is nausea, which is exacerbated by movement, and so this is greatly decreased during at home sessions where the patient can stay in a comfortable position as long as they need.

Downsides

Due to limitations of the online format, there is a greater need to communicate instructions clearly. During in-office sessions, the therapist/physician team are responsible for creating the setting and co-creating the set of the sessions. During online sessions, the patient has to prepare the set and setting themselves. As such, additional communication around details of preparation – from interacting with the compounding pharmacy, to learning how to use the lozenges, to setting up the music, to navigating online platforms – are needed. Instructions need to be explicitly spelled out and often repeated. In short, more energy and effort are required by the provider on the front end to facilitate a smooth, safe, and supportive experience.

2. Safety

Upsides

Virtual sessions in the familiarity of the home environment are experienced as safer for some patients, allowing for the possibility of greater vulnerability and increased capacity to fully let go into the therapeutic process. As human beings, we are wired for relationships and in healthy individuals, personal contact and connection facilitates relaxation, feelings of joy, and openness. However, for many people who suffer with depression, anxiety, and PTSD, personal contact and/or being in clinical settings can increase their discomfort, thereby creating an obstacle to depth exploration.

Downsides

Safety concerns for our patients and legal concerns for our clinic required us to spend more time and energy upfront anticipating risks and creating contingency plans. We developed new informed consents, including a telehealth consent and an at-home lozenge-use consent, describing in detail set and setting requirements, safety plans, and the importance of support systems. Additionally, since we would be expanding our services to people outside the Bay Area, we created new contact lists for local emergency services for various areas in California.

3. Support System

Upsides

Particularly since the pandemic, there has been a greater need for connection with others and as well with those who are familiar with KAP. . We have found ourselves sharing more community online resources with our patients and discussing the importance of Ketamine Integration groups. We have seen much more interest in virtual support groups such as the weekly Psychedelic Integration Circles with Tam Integration and Polaris Insight Center and the weekly Ketamine Integration Circles with Sage Integrative Health.

Downsides

The patient’s support system is even more important if they are engaging in virtual sessions. Time and energy are needed to communicate with the patient’s support system. In cases involving extreme social isolation, inability to communicate with others and/or absence of a support system could be a major obstacle to this kind of treatment.

Compared to in-person sessions where the therapist/physician is physically present and can provide verbal and physical support, patients can sometimes find it harder to take in the support in a virtual session. As such, having a sitter present during the session, in the same or separate room, or at least someone who is aware that the patient is taking a journey and who can be on-call if needed, should be arranged.

---

The favorable outcomes we have witnessed thus far with this new method of collaboration between providers and patients have broader implications for our healthcare system. Patients treated at home might be less dependent on the system for their healthcare needs, resulting in greater self-empowerment and agency, and less strain on the healthcare system. Furthermore, with at-home sessions being significantly less expensive than in-office treatments, access to care would widen.

As at-home sessions are being provided by more clinics, it will be important to track safety and efficacy in an ongoing way, and protocols will need to be revised accordingly. Nevertheless, after successfully facilitating many at-home treatments, it is our belief that virtual KAP sessions can be provided safely and effectively when paired with sufficient screening, preparation, and support.

Ketamine-Assisted Psychotherapy - Online? - Psychedelic.Support

Is the COVID pandemic presenting us with a new opportunity in the field of ketamine-assisted psychotherapy? Join us as we explore remote medicine.

psychedelic.support

 

[mr peabody]

​

Canada’s first Psychedelic Psychotherapy Research Centre for Mental Health*

by Solarina Ho, Avis Favaro, Avis Favaro, Elizabeth St. Philip | CTV News | 25 Oct 2021

TORONTO -- Canadian tech entrepreneur and venture capitalist Sanjay Singhal was in his early 30s when he was first diagnosed with bipolar disorder. It had been a lifelong struggle -- one moment feeling great, then suddenly mentally paralyzed and unable to get out of bed for three straight days.

“When I went manic, I would make bad decisions ... spend money unreasonably,” he said. “Up until age 38, my life was a roller coaster.”

Today, Singhal is 56 and on a mission to transform mental health care. He is the philanthropist behind Canada’s first psychedelic psychotherapy research centre for mental health at Toronto’s University Health Network (UHN). Starting with a $5 million donation made through the Nikean Foundation that he founded, Singhal hopes researchers at the centre can unlock the potential of psychedelic medicine and find answers on how psilocybin and a so-called “God molecule” can help transform mental health care.

The founder of several start-ups, including Audiobooks.com, Singhal spoke to CTV National News about his struggles with mental health even as he built several successful businesses.

“I was very aware of what mental illness can do,” he said in his very first on-air interview about the subject and his personal struggles with it.

But it is not just about him. He also has a daughter, Nikki, who has struggled with anorexia since childhood that he also wants to help. She was hospitalized at the age of eight, and again when she was 16. Now a third year resident in psychiatry at the University of Toronto, she has done well but continues to navigate through her struggles.

A chance presentation several years ago by Robin Carhart-Harris, one of the world’s leading researchers on psychedelic medicine that mentioned psilocybin as a potential treatment for anorexia piqued Singhal’s interest. Carhart-Harris is the head of the Centre for Psychedelic Research, a division of Brain Sciences with the Faculty of Medicine at the Imperial College London.

“I thought, oh my God, I have to go listen to this guy and see what's going on...I spoke to him afterwards, drove him to the airport, and then a couple of weeks later, my daughter and I both flew to London … we were amazed at the possibilities of what this could do.”

But Singhal is quick to note that at the Canadian research centre, psychedelic medicine will only be used alongside therapy in a controlled setting.

“I don't want people to do this on their own,” he said. “I don't want this to become recreational play.”

A POTENTIAL PARADIGM SHIFT

The potential of psychedelic therapy goes as far back as the 1950s when several pioneering psychiatrists experimented with LSD as a possible treatment for mental health disorders. Some of the earliest groundbreaking experiments and research happened in Saskatchewan. But studies into these drugs ended by the 1960s amid social and political backlash.

For scientists, the new research centre represents potential for transformational change in mental health therapies and offers new hope for many patients.

“I was thrilled beyond belief because psychiatry hasn't had a real paradigm shift or a new opportunity at treatment in a long time,” said Dr. Susan Abbey, psychiatrist-in-Chief for the Centre for Mental Health at UHN, in an interview.

“There truly is a signal that there is something to this. And, really, every major academic center in mental health in the world is trying to begin to conduct research in psychedelic, particularly psychedelic assisted psychotherapy.”

There are many disorders, including post-traumatic stress disorder and end-of-life distress, that are treatment resistant, says Abbey.

Dr. Emma Hapke, a staff psychiatrist with UHN and lecturer at the University of Toronto agrees.

“We haven’t had a lot of new treatments in psychiatry in a long time. There seem to be more people suffering…struggling and there is an appetite for something new that might work,” Hapke told CTV National News in a phone interview.

"Traditional medications prescribed for mental health care typically suppress symptoms," Hapke said. While much more research is needed, there are suggestions that psychedelics work differently and do not require ongoing use.

The centre is planning six to eight research projects, including psilocybin therapy for end-of-life grief, grief suffered by caregivers, families who have lost a child, and body dysmorphic disorder.

It also hopes to research a separate psychedelic called 5-MeO-DMT, also called “The God Molecule'' due to the profound psychoactive effects on the user, as a potential therapy for PTSD. Found in a wide variety of plants, it is also secreted by the glands of the Sonoran Desert Toad. It is illegal in the United States but unregulated in Canada. BuzzFeed News once described it as “the most powerful psychedelic on the planet.”

The centre is also looking at training programs for licensed therapists to learn how to work with psychedelics, since treatments will likely also involve therapy for patients to understand the insights that emerge with treatment.

TRYING PSILOCYBIN AND THE ‘GOD MOLECULE’

Singhal grew up in a tumultuous household, and from a young age, built emotional walls around himself without even realizing. If he encountered someone who clearly needed emotional comfort, his automatic response was escape.

“I was afraid of other people’s emotions,” Singhal said. After three psilocybin sessions, everything changed.

“Now, my instant thought is, I need to sit down with this person and comfort them, find out what's going on. That has been tremendously beneficial for my relationships.”

Singhal’s original intent when he decided to try psilocybin as a therapy was to find out why he sometimes drank too much and to get a handle on that aspect of his life. He had already been seeing a therapist for 20 years, and while it has helped him get through some of the most depressed periods of his life, psilocybin was different. Suddenly, he felt liberated, he said.

“The psilocybin took me on this circuitous journey of, no, let's explore what's really going on here,” he said.

But Singhal is perhaps even more interested in the potential of 5-MeO-DMT, which is still in the drug development process phase and likely years away from clinical trial use.

One of the challenges with psilocybin and MDMA is that they are expensive treatments, Singhal explained. It takes four to six hours in a room with one or two trained therapists, licensed professionals, so a single treatment can run upwards of $2,000 or more.

"5-MeO-DMT lasts just 15 minutes, which makes potential treatment significantly more affordable," he said.

”You're not aware you're conscious, but you're not aware of what's going on so when you come back from that trip, all you know is something beautiful happens. And all of a sudden you feel better,” Singhal said.

While much of the new research involving these psychedelics are still considered very early stage, Singhal’s experience and newfound peace gives him hope.

“The apparent lack of adverse effects is reassuring and consistent with what we know about these compounds more generally – that when administered in a responsible manner, to suitable and prepared individuals, they are almost invariably well-tolerated,” according to a research commentary on 5-MeO-DMT published in 2019 in The American Journal of Drug and Alcohol Abuse.

But it also added that “any conclusions pertaining to the antidepressant efficacy of 5-MeO-DMT must wait until the appropriate clinical trials are conducted.”

UHN doctors agree all the compounds need rigorous scientific study.

"We need to take a very careful approach... so that we don't just get so swept away with potential excitement, but that we're really understanding how medications work what they do for people," said Abbey.

Singhal acknowledges that much of the evidence that psychedelics could be used to help with anorexia or other mental disorders is anecdotal, but it is enough that he is willing to write a big check to fund the research necessary.

“We're all traumatized children running around in adult bodies, and these medicines can help us all,” Singhal said.

“I would say, now, three years later, my daughter has tried various treatments, and she's still struggling, but she has hope. And if … this gives somebody hope, that's a tremendous gift.”

*From the article here :

Canadian entrepreneur gifts $5 million to help create psychedelic research centre for mental health

Canadian tech entrepreneur and venture capitalist Sanjay Singhal gives $5 million to help launch a new psychedelic psychotherapy research centre for mental health at Toronto's University Health Network.

www.ctvnews.ca

 

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Psychedelic Research ​

Beyond Depression & Trauma​

by Cristela Tello Ruiz | TRUFFLE REPORT | 26 Oct 2021

In the past few years, psychedelic research into therapeutic treatments for mental health conditions has increased significantly. It is no longer a secret that people are using substances such as MDMA, psilocybin, and ketamine to treat their depression, trauma, and addiction. At the same time, prestigious research centres and universities are conducting multiple clinical trials, one of which is now federally funded, regarding psychedelic use for mental health purposes. However, a lot of these studies tend to pursue these same indications.

While an abundance of good science is never a problem, it can lead to the mistaken impression that psychedelic research is very limited. Yes, most of the studies that are easily found online involve common conditions such as depression, PTSD, or generalized anxiety, but there is also plenty of research involving rare diseases and less common mental health indications.

Seelos Therapeutics: Trehalose for Sanfilippo Syndrome

Seelos Therapeutics is a New York-based clinical-stage biopharmaceutical company that focuses on the development of novel therapeutics to address the unmet medical needs of patients with central nervous system (CNS) disorders, as well as other rare diseases. Their pipeline includes several late-stage clinical assets targeting psychiatric and movement disorders, including orphan diseases, as well as psychedelic research involving substances such as ketamine.

One of the substances that Seelos Therapeutics is using in their research is SLS-005, or Trehalose, which is a sugar consisting of two glucose molecules. While not a psychedelic itself, this compound was first identified in the same ergot fungus that is used to produce LSD, and can be found in some bacteria, plants, fungi, and invertebrate animals that synthesize it as a source of energy. When administered directly to the bloodstream, it can be naturally autophagy-promoting. Seelos’ trehalose studies are ongoing for both ALS and Sanfilippo Syndrome.

Sanfilippo Syndrome is a rare genetic disorder characterized by the loss or dysfunction of enzymes that play a key function in the breakdown of a group of sugar molecules called glycosaminoglycans. The accumulation of these molecules causes progressive damage. As the disease progresses, patients slowly lose the ability to speak, walk, and eat, causing a form of childhood dementia. Unfortunately, there’s no cure for Sanfilippo syndrome, and the average life expectancy of sufferers ranges from 10 to 20 years.



In August of 2019, the FDA accepted Seelos’ investigational new drug application for SLS-005, which allowed them to initiate a Phase 2b/3 trial to test SLS-005’s safety, tolerability, and efficacy in patients with Sanfilippo syndrome type A or B. Previous preclinical studies in a Sanfilippo type B mouse model showed that trehalose extended the lifespan, eased inflammation in the brain, and lessened nerve cell degeneration. The mice also showed less hyperactivity and anxiety-related behaviour at the early stages of the disease.

Additionally, a collaboration between Seelos and Team Sanfilippo Foundation (TSF) prompted a separate study to include patients with Sanfilippo types C and D, and patients with types A or B who do not meet the Phase 2b/3 trial eligibility criteria. Upon approval by the FDA, TSF will begin a Phase IIb/III clinical trial in up to 20 patients with Sanfilippo syndrome with Seelos providing the clinical supply of trehalose.

Ketamine Infusion for Pediatric Sickle Cell

Sickle cell disease is a group of disorders that affect hemoglobin, the molecule in red blood cells that delivers oxygen to cells throughout the body. People with this condition have atypical hemoglobin molecules called hemoglobin S, which can distort red blood cells into a sickle shape. It is also referred to as sickle cell anemia. Pediatric sickle cell disease is very prevalent in sub-Saharan Africa and it carries a high morbidity and mortality risk.

A trial by Cameroon Baptist Convention Health in collaboration with Muhimbili National Hospital in Tanzania and Carolinas Medical Center in North Carolina aims to evaluate the efficacy and safety of non-dissociative intranasal ketamine as an inexpensive, easily available and easily administered adjunct to standard pain therapy. This will be a multi-centred, randomized, double-blind, and placebo-controlled trial involving children 4–16 years of age with sickle cell disease, and who are suffering from painful vaso-occlusive pain crises.

Patients randomized to the treatment arm will receive 1 mg per kg of bodyweight of intranasal ketamine, while placebo arm participants will receive volume-matched intranasal normal saline. Primary outcomes will be the changes in self-report pain scales at 30, 60, and 120 minutes after the infusion. Secondary outcomes will include hospital length of stay, total analgesic use and quality of life assessment two to three weeks after the intervention.

The trial was registered in 2015 and was expected to be concluded in 2019, but no results have been posted.

Mount Sinai: Intravenous Ketamine for Drug-Resistant Epilepsy

Ketamine is often used as an anesthetic and as a painkiller. Recently, it was also approved as a therapeutic for treatment-resistant depression using non-anesthetic doses. In hospital settings, intravenous anesthetic doses of ketamine are also often used to treat violent seizures in comatose patients; however, ketamine in subanesthetic doses has not yet been attempted as a treatment for drug-resistant seizures in the outpatient setting.

In an open-label pilot study conducted at the Icahn School of Medicine at Mount Sinai Hospital in New York, researchers will evaluate the effectiveness of a sub-anesthetic dose (0.5mg/kg) of IV Ketamine in patients dealing with drug-resistant epilepsy. The study will consist of three phases.

The first phase will be screening. A seizure diary will be prospectively filled for four weeks and participants must have at least four seizures in 28 days to proceed to the second phase for treatment. This phase will consist of six study visits in which patients will receive 0.5mg/kg of racemic ketamine IV over 40 minutes three times a week for two consecutive weeks. The third and final phase will be the post-treatment phase. This phase will consist of five post-infusion safety assessments and three post-treatment assessments. This study is not recruiting participants yet.

MAPS and UCLA: MDMA-assisted Therapy for Social Anxiety in Autistic Adults

Studies suggest that autistic adults are at greater risk for social anxiety. Currently, there are no FDA-approved medications to treat social anxiety in autistic adults, but off-label prescriptions of selective serotonin reuptake inhibitors (SSRIs) are on the rise in this population. However, there is no particular treatment that has proven to be significantly effective to treat social anxiety in autistic adults. This leads researchers to wonder if perhaps MDMA could offer a viable alternative, due to its known prosocial effects.

A double-blind, randomized, placebo-controlled exploratory pilot study conducted by MAPS and UCLA assessed the viability of MDMA-assisted therapy for social anxiety in adults on the autism spectrum. A total of 12 subjects were selected to participate in two blinded experimental sessions in which they were administered either MDMA (75 to 125 mg) or a placebo. Each session lasted seven hours. Before each experimental session, the participants underwent three separate hour-long preparatory sessions to learn what to expect and complete pre-treatment assignments. After each experimental therapy, participants received three separate hour-long integrative sessions to help integrate their experiences and insights.



The participants who received the active treatment showed some improvement in social anxiety markers compared to the placebo group. Overall, the trial showed that MDMA could be a viable treatment option for autistic adults dealing with social anxiety, as well as demonstrating rapid improvement of social anxiety symptoms in this population. However, these initial outcomes need to be researched in larger samples to reach more definite conclusions.

Psychedelic Research Beyond Depression & Trauma

- While many psychedelic studies involve common conditions such as depression, there is also plenty of research involving rare diseases.

www.truffle.report

 

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Psychedelic Research ​

Beyond Depression & Trauma, part II​

by Cristela Tello Ruiz | TRUFFLE REPORT | 2 Nov 2021

Last week, Truffle Report covered psychedelic research (above) involving rare diseases such as Sanfilippo Syndrome and underserved populations such as autistic adults. This week, we’re looking at several other clinical trials that explore the potential use of psychedelics to treat less common mental health indications. Again, an abundance of good science around conditions such as depression and PTSD is never an issue, but it can lead to the mistaken impression that psychedelic research is very limited.

Safety and efficacy of Psilocybin for Body Dysmorphic Disorder

A psychedelic research trial sponsored by the New York State Psychiatric Institute and conducted in collaboration with UCLA and COMPASS Pathways aims to evaluate the viability of psilocybin for the treatment of body dysmorphic disorder (BDD). BDD is a mental health disorder in which a person is consumed with thoughts about an imagined or slight defect in their body that others cannot see. The sufferers perceive an altered image of their bodies when they see themselves in the mirror. As a result, people with this disorder see themselves as “ugly” and tend to avoid social exposure or turn to excessive plastic surgery or other extreme and potentially harmful behaviour to try to improve their appearance. This obsession interferes with their everyday life and can severely impact their quality of life.

In this pilot study, 12 adult outpatients diagnosed with BDD that have not responded to at least one treatment of antidepressants will be treated openly with a single oral dose of psilocybin. The participants will receive intensive preparation and support from two therapists, including an eight to nine-hour active substance session. Follow-up visits to monitor safety and clinical outcomes will be conducted one day, one week, one month, two months and three months post-administration. Resting-state functional magnetic resonance imaging (fMRI) will be conducted before and one day after psilocybin administration to assess the effect of the substance on brain circuits. This trial is expected to be finalized in August of 2022.

LSD Microdosing trial for Adult ADHD

In May of 2020, MindMed announced that it had entered into a clinical trial agreement with Maastricht University to conduct a Phase 2a clinical trial for LSD in adult patients with Attention Deficit Hyperactivity Disorder (ADHD). As part of the agreement, Maastricht University will provide the facilities and personnel for the multicentre, randomized, double-blind, and placebo-controlled clinical trial.



The study aims to evaluate the effects that microdising LSD has on multiple clinical outcomes in adults with ADHD, including:​

• Cognitive performance​
• Sleep quality​
• Mood​
• Neuroplasticity​
• Emotion regulation​
• Quality of life​
• Immune system response​

According to MindMed’s website, the trial was expected to begin at the end of 2020. However, no further information has been published yet.

Ketamine Infusion for Sickle Cell Pain Crisis

While far from a complete clinical trial or formal psychedelic research, a case report published by the journal Annals of Hematology offers some insights regarding the use of ketamine infusions in conjunction with opioids for sickle cell pain crises. This was the case study of a 31-year-old African-American male with a diagnosis of sickle cell disease, who was presented to the emergency department of Abington Memorial Hospital in Abington, Pennsylvania, complaining of chest tightness, multiple joint pain, and headache for the past week.

He was treated for severe pain crises and pneumonia with intravenous fluids, supplemental oxygen, and intravenous levofloxacin. The patient was also placed on fentanyl, patient-controlled analgesia (PCA), oxycodone, ketorolac, and methadone with co-analgesic gabapentin, and venlafaxine. During his hospitalization, his chest pain subsided, but the joint pain persisted. He was then transferred to the ICU and was discharged after seven days of ketamine infusion when the pain was finally relieved. According to the case study, ketamine is a noncompetitive antagonist at the N-methyl-D-aspartate (NMDA) receptor which has been shown to modulate opioid tolerance and opioid-induced hyperalgesia. While this is one single case, ketamine is effective when treating other kinds of pain.

There have been very few published reports on the use of low-dose ketamine in sickle cell pain management, and this particular case study is from 2014. However, it sets an important foundation into what future research could look like. It is important to note that sickle cell disease is more prevalent in Black people, a population that has been historically underserved.

Multiple sclerosis (MS) is an inflammatory and degenerative disease of the central nervous system. Signs and symptoms of MS can be very different depending on each patient and also depend on the amount of nerve damage and which nerves are affected. Some people with severe MS may lose their ability to walk without a walking aid or even at all. Others may experience long periods of remission without any new symptoms. However, a symptom that seems to be consistent with most patients is fatigue. Unfortunately, despite fatigue being a common and debilitating symptom of MS, no effective pharmacological treatment is available yet.

Ketamine for Treatment of Multiple Sclerosis Fatigue

A study conducted by Johns Hopkins University aimed to determine the tolerability, safety, and efficacy of low-dose ketamine infusion for MS-related fatigue. In this double-blind, randomized, active-placebo-controlled trial, 18 participants living with MS and reported fatigue received a single intravenous infusion of either ketamine (0.5 mg/kg) or midazolam (0.05 mg/kg). The primary outcome was a change in Daily Fatigue Severity (DFS) for seven days following the infusion. Secondary outcomes included Fatigue Severity Scale (FSS) and Modified Fatigue Impact Scale (MFIS) measured up to day 28 post-infusion.

No changes were observed in DFS after seven days, however, the researchers observed reduced FSS scores after one week and a clinically and statistically significant reduction in MFIS score at day 28. This led them to conclude that not only were ketamine infusions safe and well-tolerated by this population, they could also provide a reduction of long-term fatigue severity in patients with MS.

Visual Surround Suppression and Perceptual Expectation under Psilocybin

A study conducted by the University of Minnesota aims to address the critical need for more accurate characterizations in psychedelic research of the critical visual effects of the psilocybin by measuring the impact of severe psilocybin intoxication on a perceptual task known as visual surround suppression, compared to active placebo control.

For this interventional and randomized clinical trial, 75 participants will be randomized into two experiment arms. On the first one, participants will be administered a single dose of a 25 mg capsule of psilocybin followed by a 100 mg capsule of niacin. On the second arm, participants will receive the niacin first, followed by the psilocybin. Following administration, visual psychophysics tasks will be conducted. These will consist of perceptual judgments such as having the participant reporting which of two visual stimuli presented appears to have higher contrast.

This trial started in August of 2021 and is expected to be completed by May of 2024. The data collected in the proposed will make important contributions to the knowledge of how psilocybin impacts contextual processing in the brain. While this trial does not investigate a condition per se, it will offer results that can be used when studying conditions in which visual alterations are a symptom.

Psychedelic Research Beyond Depression & Trauma Part II

Truffle Report covers several psychedelic research trials that explore the potential use of psychedelics to treat less common conditions.

www.truffle.report

 

[mr peabody]

Texas launches Center for Psychedelic Research and Therapy*

by Greg Gilman | Psychedelic Spotlight | 29 Dec 2021

Research will focus on how various psychedelics can be used under proper supervision and guidance to treat severe depression, anxiety and PTSD.

Six months after Governor Greg Abbott (R) signed a bill that requires the state to study the risks and benefits of psilocybin, MDMA, and ketamine for veterans, the Dell Medical School at the University of Texas at Austin announced the launch of the Center for Psychedelic Research and Therapy — the first center of its kind in Texas.

Center co-lead Charles B. Nemeroff, professor and chair of Dell Med’s Department of Psychiatry and Behavioral Sciences, said its “research will bring further scientific rigor and expertise to study psychedelic therapy.” Researchers will conduct clinical studies with the aim of exploring potential for psychedelic-assisted therapy to treat depression, anxiety and post-traumatic stress disorder (PTSD), using substances such as psilocybin, MDMA, ibogaine and ayahuasca.

Initial focus will be on military veterans living with PTSD — a population state senators were particularly interested in helping when the Texas State Senate voted to approve the previously mentioned legislation last May. The Lone Star State has the nation’s second-largest veteran population with about 1.6 million, and previous studies and testimonies demonstrating psychedelics’ abilities to heal their trauma is no doubt fueling the widely conservative state’s commitment to this progressive area of study.

The Heroic Hearts Project, a non-profit organization that has been busy spearheading a psilocybin research program to treat veterans suffering from traumatic brain injury (TBI) with psychedelics, will be among the center’s first program partners, along with The Mission Within, a clinical psychedelic retreat provider in Rosarito, Mexico creating specialized treatments for PTSD, mTBI, depression, anxiety, and personal growth.

“This work has the potential to change the paradigm in mental health and firmly stamps UT Austin at the forefront of psychiatric innovation,” said UT alumnus Paul Barnhart III, one of the early donors supporting the center, which will also cater to adults experiencing prolonged grief disorder or depression, as well as those who have experienced childhood trauma.

Greg Fonzo, an assistant professor in Dell Med’s Department of Psychiatry and Behavioral Sciences, will co-lead the center with Professor Nemeroff. Now that the center has secured funding to launch its initial work, Fonzo will investigate how psilocybin and transcranial magnetic stimulation work together to provide lasting relief for stress-related depression and anxiety.

“A key ingredient in how psychedelic therapies promote mental health may be their ability to enhance neural plasticity, the process that allows the brain to adapt to new experiences — which when combined with brain modulation therapies may promote maximum benefit,” Fonzo said. “The potential implications are far-reaching for people with these conditions and their families, and also for the future of mental health treatment and care.”

The Center for Psychedelic Research and Therapy is one of several academic institutions springing up around North America in wake of renewed interest in psychedelics, which were first brought to mainstream attention and study in the mid 1950s before America’s War on Drugs forced research underground by the early 1970s.

The University of Wisconsin-Madison School of Pharmacy become the first school in the United States to offer master’s program in psychedelic medicine earlier this year, and then launched the UW-Madison Transdisciplinary Center for Research in Psychoactive Substances to coordinate its ongoing research and education related to psychedelic compounds. Meanwhile in Canada, the University of Ottawa offers a psychedelic studies program, as well as a master’s program.

*From the article here :

Texas's First-Ever Psychedelic Research Center Launches at UT Austin

The Center for Psychedelic Research and Therapy at the University of Texas in Austin will focus on military veterans living with PTSD.

psychedelicspotlight.com

 

[mr peabody]

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NYU’s Langone Health joins the psychedelic research renaissance*

by B. David Zarley | FreeThink | 6 Mar 2021

Another august institution is throwing its weight behind the psychedelic research renaissance: NYU is launching a Center for Psychedelic Medicine.

Established with $10 million in funding, the Center for Psychedelic Medicine — under the direction of Michael Bogenschutz, professor of psychiatry at NYU Grossman School of Medicine — will “support health-focused research across the translational spectrum,” as the university release puts it, from basic science to phase 3 clinical trials.

NYU joins a quickly crowding field, as centers dedicated to psychedelic medicine and research have recently opened their doors — and opened minds — at Johns Hopkins and Mount Sinai.

But NYU Langone, in New York City, is no stranger to the field; previous studies out of NYU have examined using psychedelics to treat distress in patients with cancer, addiction, and PTSD, as well as research on more exotic drugs, like ibogaine.

Psychedelic medicine startup MindMed is providing the lion’s share of the funding, kicking in $5 million. The company — which is developing psychedelic medicines — was founded by J.R. Rahn, who came to psychedelic medicine, as so many others do, from a place of deep need.

“To the outside world, I was doing really well, but inside me I was struggling,” Rahn told the New Yorker’s Nathan Heller. He turned to a bottle of wine to sleep, cocaine to party, benzodiazepines for his anxiety.

“A friend recommended I have a psychedelic experience, to piece together a solution,” he told Heller. He tried psilocybin and LSD, which helped him to process his traumatic memories of discovering the body of his mother, who died during a vacation in the Dominican Republic when Rahn was eight.

MindMed’s contribution is earmarked for funding the Center’s Psychedelic Medicine Research Training Program, which NYU believes is a differentiator from the other research centers forming psychedelics’ academic ecosystem.

That program is designed to develop postdocs and early career faculty members into independent psychedelic medicine researchers.

“This is a new era in psychopharmacology,” Yale professor of psychiatry and neuroscience John Krystal — whose lab pioneered the medicinal use of ketamine as a treatment for depression — told me via email.

“With the approval of esketamine by the FDA for the treatment of patients with treatment-resistant forms of depression and depression in the context of high suicide risk, we have the need for a new type of expert psychopharmacologist.”

The kind the Center for Psychedelic Medicine’s program is looking to train. The Psychedelic Medicine Research Training Program will provide clinical investigators with training and salary support, as well as funding four research positions.

“These initiatives will provide an environment in which scientists, clinicians, trainees, and other staff contribute in meaningful ways to ensure that the momentum created by the modern psychedelic renaissance is sustained and continues to yield medical breakthroughs backed by sound science,” Bogenschutz said in the release.

*From the article here :

NYU is launching a center for psychedelic medicine

NYU’s Center for Psychedelic Medicine will serve as the nexus for the school’s psychedelic research, as well as provide training to budding researchers.

www.freethink.com