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The 2020s: The decade of psychedelic breakthroughs?
Clinical studies are underway. How we treat them moving forward matters.
- Michael Ehlers, a former executive at Biogen and Pfizer, has assumed an advisory role with Field Trip, a psychedelics research organization.
- Ehlers has followed the science of psychedelics for more than a decade and is excited by the potential for therapeutic applications.
- MDMA and psilocybin have been granted breakthrough therapy status by the FDA, signaling a shift in the future of mental health treatment.
Beyond the bright colors and hallucinogenic imagery of psychedelic art—the visuals of Ram Dass's 1971 book Be Here Now has never left public consciousness — there has long been a crusade to clinically research substances such as LSD, psilocybin, MDMA, DMT, and ibogaine. We've been informed, again and again and again, about the various ways that current pharmaceutical treatments in our for-profit mental health system is not only not working, but doing more damage than healing. Discussion over health care inevitably defaults to mechanisms for paying for a broken model, rarely touching upon the root causes of why so many people are depressed, sick, anxious, and suicidal in the first place.
We. Need. Better. Solutions.
In regard to psychedelics, an entire herd of elephants remain locked in a room. Thanks to the questionable (and admittedly racist) wars launched by the Nixon and Reagan administrations (first dreamed up during the Anslinger crusades), we've been denied access to these potentially therapeutic substances. Fortunately, a renaissance is occurring in psychedelics research, with ketamine being the first to be legally prescribed psychedelic for treatment-resistant depression and both psilocybin and MDMA being fast-tracked by the FDA after being labelled breakthrough therapies.
One challenge psychedelics advocates will have to face is how these drugs are treated moving through the current medical model. Regardless of personal feelings on the subject, these substances have to contend with a system that requires expensive clinical trials and will be sold in a capitalist marketplace. There will inevitably be patent issues and territorial fights. Unlike cannabis, which is a relatively mild substance with few documented consequences, psychedelics need to be rigorously evaluated and tested. While some label everyone working in medicine as minions of Big Pharma, we need to separate researchers and scientists from the shady dealings of shareholders and profiteers.
Michael Ehlers is an industry figure that has long taken an interest in psychedelics, predominantly from an outsider perspective. Now the former executive vice president for research and development at Biogen is accepting an advisory role with Field Trip Health, the psychedelics-focused organization that recently opened the world's first psilocybin research center. (You can listen to my talk with Field Trip co-founder, Ronan Levy, here.)
I chatted with Ehlers, he is also the former chief scientific officer for neuroscience at Pfizer, about his interest in psychedelics, their potential efficacy, their historical usage in ritual, and how the current model will deal with their vetting and potential applications. With every question, he was informed and honest, offering what he knows and being truthful about what he does not. There is a lot of work ahead in pharmaceuticals, yet it is undeniable the mental health industry needs a reboot, in the same way psychedelics are said to reboot the neural circuitry of the brain, making this class of substances an ideal medicine for study.
Part of my conversation with Ehlers is below; you can read the full transcript here.
Photo courtesy of Michael Ehlers
Derek: You have an accomplished career in the pharmaceutical industry. Now you've taken on an advisory role with a company specializing in psychedelics. I would love to know when you first became interested in psychedelics as a potential therapeutic tool.
Michael: I've followed this area for quite some time. I've been intensely involved in different aspects of drug discovery and development, particularly, although not exclusively, within CNS or neuroscience drug discovery, including neuropsychiatric disease. I've followed more peripherally some of the efforts both in standard pharmacology and then some of the emerging work, whether it was more acute, high-dose psychedelics or microdosing psychedelics in neuropsychiatric disease.
At the same time, I was following a lot of the work on some of the core receptor biology and neurobiology, which was really advancing in systems neuroscience. Following this field and some of the early indications of potential clinical efficacy were some of the things that really got me quite excited. I was particularly close with aspects of what's been done over the past 10 years with ketamine, which is a very different agent but also in the class, initially leading from small trials on ketamine for acute, anti-depressive actions, now to Janssen and J&J using a variation of this, esketamine, to get full-on FDA approval for the first new mechanism in depression in 20 years. The combination of these things indicated to me that there could be a new paradigm change or highly-active psychopharmacology to potentially treat some of these otherwise fairly intractable types of neuropsychiatric disorders.
There are some other things that were also on the horizon. The history of CNS drug development, particularly in neuropsychiatric disease, has been one where the empirical observations in human patients have really guided efficacious therapeutics by and large. Even though I know we like to talk a lot about rational drug discovery and development, at least in the field of neuropsychiatry, because there's still so much that is not known that we've had to rely a lot more on empirical observations in humans.
There's probably no more profound CNS pharmacology out there than that with psychedelics like psilocybin or LSD or ketamine. I've actually long thought it was just a matter of figuring out what a treatment paradigm could look like—how maybe when you dose it could you alter aspects of its dose exposure and distribution and then in what exact disease or syndrome.
Derek: You have a history of working with rare diseases. Field Trip is going to tackle a wide range of studies, but the ones that are really on everyone's mind (in terms of what psychedelics could potentially help) ranges from PTSD to treatment-resistant depression and anxiety. These are much more common diseases. Do you have any background in those diseases and, in the advisory role, what will you be doing for them?
Michael: I've got a lot of background in that. I worked for nine years in large biopharma, six years at Pfizer. I started in neuroscience and pain, but ultimately ran several divisions of Pfizer R & D, that did include rare disease, but included a bunch of other things. Then I ran R & D advising for three-and-a-half years. I've done clinical trials in depression, schizophrenia, PTSD, generalized anxiety disorder, Alzheimer's disease, and Parkinson's disease. I've done both rare diseases and a lot of common disorders: hemophilia, genetic disease, and some of the rare diseases as well. I've done stroke trials. I've had experience across a range.
One thing I like is about what Field Trip is doing and the prospect of these diseases is that they're incredibly common. Roughly 25 percent of people will have some experience with major depression in their lives. One percent of the world has schizophrenia. These are serious and significant disorders. I really love the fact that this field—and Field Trip is really part of that in a leadership role—is looking to take some of these on.
Although the lore has been that there hasn't been that much innovation, I actually think that's not true. I think we're just at the beginning of a whole new era of advances in neuropsychiatric disease. I can point to several things that indicate that. I have a feeling that if we really understand that the best way to dose and conduct trials with psychedelics like psilocybin and be able to segment patients who are the most likely to benefit, this can become quite important.
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Derek: You mentioned that pharma companies stepping away from neuropsychiatric disease. There is obviously a problem with SSRIs over the long-term. Efficacy rates tend to be high in the short-term, but over the long-term prove problematic. When you're stepping into substances that potentially could help treatment-resistant mental health diseases in one dose (or just a couple of doses), how do you think that companies are going to be able to monetize this, especially given the incredible amounts of money that have to go into R & D and clinical trials?
Michael: It's a very good question. I think we haven't solved that problem yet. There are a lot of open questions. Will some of these therapies really be single dose or short regiments and you're done? Will it have to be that there's some degree of maintenance where there's some regularity in the need for therapy? Will it really be like antibiotics or gene therapy? We don't know.
A lot of these neuropsychiatric diseases, although they're complex, have genetic features that are polygenetic but they're related. Whether you're talking about, schizophrenia, autism, bipolar disorder, ADHD, there's a complex genetic architecture that has shared features across all of those. The risk of relapse and occurrences will be there in a given population. I tend to think the likelihood of things like ketamine or psychedelic treatments for depression will be one of periodic needs.
The question you raised is an excellent one, which is what ultimately is the commercial model for that? Certainly, the hope is that it doesn't go down the road of antibiotics for which the commercial incentivization for real R & D and drug development has been catastrophic. I don't see that in this space. I just don't think it's going to be quite as simple as "one and done." The prevalence alone will be a strong incentive for investment when there's real efficacy potential.
Derek: Please correct me if I'm wrong; I'm fascinated by neuroscience, but not having an academic background my knowledge is limited. That's why I love talking to people about this. From my understanding, SSRIs work in a much different manner in terms of the serotonin release then psychedelics. Do you see any potential benefits or dangers in the ways that psychedelics deal with the serotonergic system?
Michael: It is quite different. From a simple pharmacology point of view, SSRIs are, as their name indicates, selective serotonin reuptake inhibitors: they block serotonin transporters that would normally release serotonin back up into nerve cells so that it increases serotonergic tone. Once released, it stays released in the extracellular space for longer, acting on all the different receptors in the places that it does.
The psychedelics typically act directly on serotonin receptors within serotonin transporters, but their action at different receptors has different potency. It's not a clean pharmacology. People will talk about 5-HT-2A receptors and they're clearly important, and there's been a lot of study on that, but we also know that if you just give a pure 5-HT-2A receptor an agonist you do not reproduce the effects of psilocybin or LSD.
The pharmacology is complex; it's clearly different than SSRIs. Obviously, the behavioral and therapeutic groups are very different. It just highlights that we really need to understand it better. It's going to reveal I think very important things about psychiatric disease and fundamental neuroscience.
A shaman gathers the raw materials to make ayahuasca in the jungle outside of Iquitos.
Photo by Andrew Lichtenstein/Corbis via Getty Images
Derek: One of the criticisms of the way that the industry is right now is that, why would a doctor spend an hour talking to a patient when you can see six patients in an hour and write a script? Efficacy rates are different for different people, dealing with the microbiome, for example, and the way that their gut processes drugs. It's a very complex issue. One thing I believe is going to be important is that psychotherapy is going to be tethered with psychedelics, especially if people have never done them before. Will that coupling provide a sustainable model?
Michael: Here's an aspect of what's important to understand: the field has understandably taken a cautious approach, which I think is warranted in this whole guided therapy concept and that will probably be required for certain dosing regimens. I would personally like to see this converted into what is a very standard thing in a lot of drug administration in practice or trials, which is more about medical monitoring. Change it from the notion of it's guided therapy to monitoring like you would for a lot of things. People go to IV infusion centers to get their IV drug. It's different, but there's nothing that unusual about the notion of having a monitored pharmaceutical or pharmacological drug intervention even in standard practice. This will likely be part of that.
If you're a neurologist treating MS and you've got MS patients on Alemtuzumab or Natalizumab as your IV drugs. They come in, you've got your IV clinic. They come in regularly, every month or every quarter depending on the drug, and they get their IV infusion. They get monitored while it happens because they can have an immune response. I see a future for some of these psychoactive therapeutics where you have something similar.
Now the question will be to what extent does the guided as opposed to monitoring aspect of that influence the degree of efficacy? That's something which really would need to be studied. To the extent it really requires some special type of guided activity that will be a little bit more of a limitation. To the extent that it can be ultimately the design in a more monitoring approach with education, the more widespread this can become.
Does that analogy make sense to you? There's a lot of precedence for this in other areas. The way this has gotten utilized now is still a remnant of causing people to have profound hallucinations and behavioral stuff and paranoia. Some people get afraid of that, so we need to have some monitoring.
We need to understand doses. We need to know the extent to which those experiences are part and parcel to a therapeutic response or not associated with a therapeutic response.
Derek: How much do you think anecdote is going to matter? One main issue I have with the whole cannabis legalization process is the extraction of CBD being sold for every possible ailment out there when the actual evidence is almost nothing at this point, besides epilepsy. At the same time, dealing with mental health disorders, how much are we going to rely on anecdote? If people think they're getting better, there's placebo, and it actually helps them get better.
Michael: I hope we moved beyond anecdotes, and I think that you're right about CBD, but it's interesting the way you put that because of the fact that rigorous trials have been done in rare epilepsies, like Dravet and Lennox-Gastaut syndrome, nobody disputes that. Patients in need can get insurance companies or health systems in other countries to reimburse for that. That's what I mean by saying real location impact is going to require that component of it too. You'd like to be able to generate the evidence because nothing comes without safety concerns. The nice thing about putting this all through the lens of drug discovery and development is that it allows the community—and here I mean the medical community, policymakers, others —to have a much clearer view of the benefit-risk, and where the benefit-risk is positive, in which case that's usually a required element for real access for patients.
Of course, you could argue and say, "well, if it's just out there, people can try it, we'll see and that's fine," but this doesn't allow us from a clinical scientific vantage point to really know when and where we are going to provide benefits. That's what we really need to work toward. There's enough anecdotal evidence out there to justify rigorous evaluation.
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Evolution proves to be just about as ingenious as Nikola Tesla
- For the first time, scientists developed 3D scans of shark intestines to learn how they digest what they eat.
- The scans reveal an intestinal structure that looks awfully familiar — it looks like a Tesla valve.
- The structure may allow sharks to better survive long breaks between feasts.
Considering how much sharks are feared by humans, it is a bit of a surprise that scientists don't know much about the predators. For example, until recently, sharks were thought to be solitary creatures searching the seas for food on their own. Now it appears that some sharks are quite social.
Another mystery is how these prehistoric swimming and eating machines digest food. Although scientists have made 2D sketches of captured sharks' digestive systems based on dissections, there is a limit to what can be learned in this way. Professor Adam Summers at University of Washington's Friday Harbor Labs says:
"Intestines are so complex, with so many overlapping layers, that dissection destroys the context and connectivity of the tissue. It would be like trying to understand what was reported in a newspaper by taking scissors to a rolled-up copy. The story just won't hang together."
Summers is co-author of a new study that has produced the first 3D scans of a shark's intestines, which turns out to have a strange, corkscrew structure. What's even more bizarre is that it resembles the amazing one-way valve designed by inventor Nikola Tesla in 1920. The research is published in the journal Proceedings of the Royal Society B.
What a 3D model reveals
Video: Pacific spiny dogfish intestine youtu.be
According to the study's lead author Samantha Leigh, "It's high time that some modern technology was used to look at these really amazing spiral intestines of sharks. We developed a new method to digitally scan these tissues and now can look at the soft tissues in such great detail without having to slice into them."
"CT scanning is one of the only ways to understand the shape of shark intestines in three dimensions," adds Summers. The researchers scanned the intestines of nearly three dozen different shark species.
It is believed that sharks go for extended periods — days or even weeks — between big meals. The scans reveal that food passes slowly through the intestine, affording sharks' digestive system the time to fully extract its nutrient value. The researchers hypothesize that such a slow digestive process may also require less energy.
It could be that this slow digestion is more susceptible to back flow given that the momentum of digested food through the tract must be minimal. Perhaps that is why sharks evolved something so similar to a Tesla valve.
What is Tesla's valve doing there?
Above, a Tesla valve. Below, a shark intestine.Credit: Samantha Leigh / California State University, Domi
Tesla's "valvular conduit," or what the world now calls a "Tesla valve," is a one-way valve with no moving parts. Its brilliance is based in fluid dynamics and only now coming to be fully appreciated. Essentially, a series of teardrop-shaped loops arranged along the length of the valve allow water to flow easily in one direction but not in the other. Modern tests reveal that at low flow rates, water can travel through the valve either way, but at high flow rates, the design kicks in. According to mathematician Leif Ristroph:
"Crucially, this turn-on comes with the generation of turbulent flows in the reverse direction, which 'plug' the pipe with vortices and disrupting currents. Moreover, the turbulence appears at far lower flow rates than have ever previously been observed for pipes of more standard shapes — up to 20 times lower speed than conventional turbulence in a cylindrical pipe or tube. This shows the power it has to control flows, which could be used in many applications."
A deeper dive
Summers suggests the scans are just the beginning. "The vast majority of shark species, and the majority of their physiology, are completely unknown," says Summers, adding that "every single natural history observation, internal visualization, and anatomical investigation shows us things we could not have guessed at."
To this end, the researchers plan to use 3D printing to produce models through which they can observe the behavior of different substances passing through them — after all, sharks typically eat fish, invertebrates, mammals, and seagrass. They also plan to explore with engineers ways in which the shark intestine design could be used industrially, perhaps for the treatment of wastewater or for filtering microplastics.
It could fairly be said, though, that Nikola Tesla was 100 years ahead of them.
The non-contact technique could someday be used to lift much heavier objects — maybe even humans.
- Since the 1980s, researchers have been using sound waves to move matter through a technique called acoustic trapping.
- Acoustic trapping devices move bits of matter by emitting strategically designed sound waves, which interact in such a way that the matter becomes "trapped" in areas of particular velocity and pressure.
- Acoustic and optical trapping devices are already used in various fields, including medicine, nanotechnology, and biological research.
Sound can have powerful effects on matter. After all, sound strikes our world in waves — vibrations of air molecules that bounce off of, get absorbed by, or pass through matter around us. Sound waves from a trained opera singer can shatter a wine glass. From a jet, they can collapse a stone wall. But sound can also be harnessed for delicate interactions with matter.
Since the 1980s, researchers have been using sound to move matter through a phenomenon called acoustic trapping. The method is based on the fact that sound waves produce an acoustic radiation force.
"When an acoustic wave interacts with a particle, it exerts both an oscillatory force and a much smaller steady-state 'radiation' force," wrote the American Physical Society. "This latter force is the one used for trapping and manipulation. Radiation forces are generated by the scattering of a traveling sound wave, or by energy gradients within the sound field."
When tiny particles encounter this radiation, they tend to be drawn toward regions of certain pressure and velocity within the sound field. Researchers can exploit this tendency by engineering sound waves that "trap" — or suspend — tiny particles in the air. Devices that do this are often called "acoustic tweezers."
Building a better tweezer
A study recently published in the Japanese Journal of Applied Physics describes how researchers created a new type of acoustic tweezer that was able to lift a small polystyrene ball into the air.
Tweezers of Sound: Acoustic Manipulation off a Reflective Surface youtu.be
It is not the first example of a successful "acoustic tweezer" device, but the new method is likely the first to overcome a common problem in acoustic trapping: sound waves bouncing off reflective surfaces, which disrupts acoustic traps.
To minimize the problems of reflectivity, the team behind the recent study configured ultrasonic transducers such that the sound waves that they produce overlap in a strategic way that is able to lift a small bit of polystyrene from a reflective surface. By changing how the transducers emit sound waves, the team can move the acoustic trap through space, which moves the bit of matter.
Move, but don't touch
So far, the device is only able to move millimeter-sized pieces of matter with varying degrees of success. "When we move a particle, it sometimes scatters away," the team noted. Still, improved acoustic trapping and other no-contact lifting technologies — like optical tweezers, commonly used in medicine — could prove useful in many future applications, including cell separation, nanotechnologies, and biological research.
Could future acoustic-trapping devices lift large and heavy objects, maybe even humans? It seems possible. In 2018, researchers from the University of Bristol managed to acoustically trap particles whose diameters were larger than the sound wavelength, which was a breakthrough because it surpassed "the classical Rayleigh scattering limit that has previously restricted stable acoustic particle trapping," the researchers wrote in their study.
In other words, the technique — which involved suspending matter in tornado-like acoustic traps — showed that it is possible to scale up acoustic trapping.
"Acoustic tractor beams have huge potential in many applications," Bruce Drinkwater, co-author of the 2018 study, said in a statement. "I'm particularly excited by the idea of contactless production lines where delicate objects are assembled without touching them."
Australian parrots have worked out how to open trash bins, and the trick is spreading across Sydney.
- If sharing learned knowledge is a form of culture, Australian cockatoos are one cultured bunch of birds.
- A cockatoo trick for opening trash bins to get at food has been spreading rapidly through Sydney's neighborhoods.
- But not all cockatoos open the bins; some just stay close to those that do.
Dumpster-diving trash parrots
In a study about these smart birds just published in Science, researchers define animal culture as "population-specific behaviors acquired via social learning from knowledgeable individuals."
Co-lead author of the study Barbara Klump of the Max Planck Institute of Animal Behavior in Konstanz, Germany says, "[C]ompared to humans, there are few known examples of animals learning from each other. Demonstrating that food scavenging behavior is not due to genetics is a challenge."
An opportunity presented itself in a video that co-author Richard Major of the Australian Museum shared with Klump and the other co-authors. In the video, a sulphur-crested cockatoo used its beak to pull up the handle of a closed garbage bin — using its foot as a wedge — and then walked back the lid sufficiently to flip it open, exposing the bin's edible contents.
Major has been studying Cacatua galerita for 20 years and says, "Like many Australian birds, sulphur-crested cockatoos are loud and aggressive." The study describes them as a "large-brained, long-lived, and highly social parrot." Says Major, "They are also incredibly smart, persistent, and have adapted brilliantly to living with humans."(Research regarding some of the ways in which wild animals adapt to the presence of humans has already produced some fascinating results and is ongoing.)
Clever cockie opens bin - 01 youtu.be
The researchers became curious about how widespread this behavior might be and saw a research opportunity. After all, says John Martin, a researcher at Taronga Conservation Society, "Australian garbage bins have a uniform design across the country, and sulphur-crested cockatoos are common across the entire east coast."
Martin continues, "In 2018, we launched an online survey in various areas across Sydney and Australia with questions such as, 'What area are you from, have you seen this behavior before, and if so, when?'"
Word gets around
Credit: magspace/Adobe Stock
Although the cockatoos' maneuver was reported in only three suburbs before 2018, by the end of 2019, people in 44 areas reported observing the behavior. Clearly, more and more cockatoos were learning how to successfully dumpster dive.
As further proof, says Klump, "We observed that the birds do not open the garbage bins in the same way, but rather used different opening techniques in different suburbs, suggesting that the behavior is learned by observing others." One individual bird in north Sydney invented its own method, and the scientists saw it grow in popularity throughout the local population.
To track individual birds, the researchers marked 500 cockatoos with small red dots. Subsequent observations revealed that not all cockatoos are bin-openers. Only about 10 percent of them are, and they are mostly males. The other cockatoos apparently restrict their education to a different lesson: hang around with a bin-opener, and you will get supper.
Thanks to the surveys, the researchers consider the entire project to be a valuable citizen-science experiment. "By studying this behavior with the help of local residents, we are uncovering the unique and complex cultures of their neighborhood birds."
The few seconds of nuclear explosion opening shots in Godzilla alone required more than 6.5 times the entire budget of the monster movie they ended up in.