Newsletter / Issue No. 19

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17 Oct, 2024
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Dear Aventine Readers, 

Given the success of using psychedelic therapies for certain mental health conditions in clinical trials, it was a blow to advocates when the FDA declined to approve MDMA for the treatment of PTSD in June. Surprisingly, however, many researchers we spoke to who study the use of psychedelics in mental health believe the ruling was a good thing. Read on to find out why psychedelic-based treatments are almost impossible to compare to traditional drug regimens and are therefore so difficult to assess. 

Also in this issue: The last coal-fueled power plant closed in the U.K., a revolutionary new schizophrenia drug is now available in the U.S., why building robots is hard and three Nobel Prizes explained!

Thanks for reading, 

Danielle Mattoon
Executive Director, Aventine

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Five Ways to Think About

Psychedelic-Assisted Therapy


In just a few short years, psychedelics have gone from a category of purely recreational illicit drugs to the purported next frontier in treating mental health conditions. Drugs like MDMA, psilocybin and LSD have demonstrated the potential in clinical trials to help patients with post-traumatic stress disorder (PTSD), substance use disorders, depression and more.

Last year a study investigated the benefits of psychotherapy coupled with MDMA for 104 people with moderate to severe PTSD. After 18 weeks, with three separate dosing sessions, more than 71 percent of participants no longer met the criteria for a PTSD diagnosis, compared with 48 percent for those who received psychotherapy with a placebo. Another study of individuals with major depressive disorder found that a single dose of psilocybin administered with psychological support was associated with a rapid and sustained antidepressant effect. 

The success of such studies fueled hope that these drugs would soon be approved for wider use, but proponents experienced a major setback in June when the U.S. Food and Drug Administration (FDA) declined to approve MDMA therapy for PTSD, requesting an additional clinical trial to further study its safety and efficacy. 

A significant challenge facing the new therapies is that psychedelic-based psychiatric treatments are difficult to compare to traditional drug regimens. More information is needed on issues such as how to prescribe accompanying psychotherapy and measure its role, how to account for the difficulty of effectively blinding studies (establishing that participants do not know if they are being given MDMA or a placebo) and how to manage the lack of information on the long-term effects of treatment.  


Aventine spoke with five researchers about what the FDA decision means and the challenges that must be overcome in order to bring psychedelics into the mainstream of mental health care. 

It’s very rare that you’re approving a drug in conjunction with therapy, and that therapy isn’t regulated by the FDA. Once the drug is approved, there’s no prescription for how that therapy must be performed. To put that into perspective, you could have a patient that responded well, not because the drug helped them, but because they had a fantastic therapist. Or you could have a situation where the drug did help them, but the therapy did not. And when you look at the totality of the data, how do you figure out which one that it was?

The FDA also wanted the sponsor to look at long-term rates of abuse and addiction. Even though MDMA doesn’t have the same abuse potential as, for example, fentanyl or other opioids, it does have some abuse potential. Did participants continue using the drug outside of therapy? Because that would be an unintended consequence that the sponsor didn’t study. Ultimately, if we're going to approve these drugs, I think it’s very important that we do our due diligence.”
Maryann Amirshahi, co-medical director at the National Capital Poison Center and a temporary member of the FDA’s Psychopharmacolgic Drugs Advisory Committee

Lykos really tried to do something new, and in doing so have sort of tested the bounds of the FDA. One way of looking at the rejection is as an enormous act of philanthropy to the broader field of psychedelics, in that we now have a much clearer idea of what the FDA is looking for and what constitutes evidence. The next question will be, what can other groups learn from this to improve the odds of getting one of these treatments over the finish line?

Also, there are lots of companies developing analogs and derivatives — so while MDMA may never be approved, an MDMA-like drug may well be. Now that we have a better understanding of how to study these drugs, it seems very likely to me that there will eventually be an approval of a psychedelic-class drug for mental health conditions.
Boris Heifets, associate professor of anesthesiology, perioperative and pain medicine at Stanford University and a researcher in psychedelic medicine

The primary challenge is determining how well psychedelic-assisted therapy actually works compared to current first-line treatments. To make a strong case for licensing psychedelic therapies, we need to concretely establish that psychedelics have substantially greater long-term efficacy and carry equivalent or lower risk of adverse effects than current treatment approaches, particularly given the extra obstacle presented by their legal status. We also need to know more about the mechanisms via which psychedelics improve mental health, their long-term effectiveness, variance of treatment response, and the relative incidence of adverse responses compared to existing pharmacotherapies.

People are desperate for new treatment approaches in mental health, which is completely justified given that current treatments do not work for a large proportion of patients. There is a great deal of hype surrounding psychedelics, but before touting them as 'game changers’ in mental health, they need to meet the same rigorous standards of evidence as any other, less ‘fashionable’ drugs.”
Ravi Das, professor of psychopharmacology at University College London

The MDMA and other psychedelic treatment models use just a few doses with psychological support before, during and after each drug administration. The FDA is not empowered to adjudicate on the value and veracity of psychotherapy, and several different types of therapy were allowed in the Lykos studies. The FDA were concerned that it would not be possible to ensure veracity of psychotherapy treatment in real clinical practice, which undermined their confidence in giving it a license.

But it is possible to deal with this concern by using standardized treatment manuals or even computerized applications of therapy. Most of the ongoing psychedelic trials are doing this. All is not lost for MDMA as the FDA has requested a further phase 3 trial which hopefully will control therapy in a manner that will then allow them to offer marketing authorization if the clinical results remain positive.”
David Nutt, Edmond J. Safra Professor of Neuropsychopharmacology and director of the Neuropsychopharmacology Unit in the Division of Brain Sciences at Imperial College London

The biggest challenges that the psychedelic science research community must overcome to be accepted for clinical use are multifaceted. First, we must get creative with our study designs to overcome the issue of effective control conditions. Because psychedelics have profound effects, concealing them in research studies is very challenging. Thus, we must find creative ways to study these substances that may not adhere to this gold standard practice. Second, clinical trials to date are severely lacking in diverse representation. Diverse representation allows researchers to understand the application to a broader population, ensures that the benefits of the treatments will be distributed equitably, and will help identify and address health disparities.

Third, what we know about the durability of these treatments is limited as most of our clinical trial data only extends 6 to 12 months after the psychedelic treatment. Therefore, we cannot say with confidence how long we expect someone who benefits from treatment how long their improvement will last. Fourth, there is still a lot left to learn about how these substances impact the brain at a biological level. Understanding these mechanisms of action will allow for more therapeutic precision, increase safety, and allow us to better predict long-term effects.”
Stacey Armstrong, senior researcher and associate director at the Center for Psychedelic Drug Research and Education at The Ohio State University

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Learn about the past, present and future of artificial intelligence on our latest podcast, Humans vs Machines with Gary Marcus.

Quantum Leaps

Advances That Matter

Cooling towers from the U.K.'s last coal-fueled power plant in Ratcliffe-On-Soar, which was shut down at the end of September. andylewisphoto / iStock

The UK has quit coal for electricity production. In 1882, the world’s first coal-fired power plant opened in London. Almost a century and a half later, the country shut down its one remaining coal-fired power station in Ratcliffe-on-Soar. The closure makes the U.K. the first G7 nation to end its use of coal for commercial electricity production and is the culmination of a 2015 promise made by Britain’s former prime minister David Cameron to stop using coal to generate electricity by 2025. (Coal is still used in other U.K. industries like steelmaking, though the volume used is small compared to that used to produce electricity.) In 2013 coal accounted for a bit over 40 percent of energy production in the U.K., with renewable energy accounting for just 14.6 percent and gas and nuclear contributing most of the remainder; today, renewable electricity accounts for 51 percent of the nation’s power generation, with the rest still coming from gas and nuclear. But while this is a milestone, it's just one step on Britain's journey to reach net-zero emissions by 2050. The country is struggling with oppressive electricity prices, which are among the highest in the developed world and more than double the cost of electricity in the U.S. Though many factors contribute to this, including the spike in gas prices caused by Russia's invasion of Ukraine, the cost of the transition to clean energy sources has undoubtedly played a role. And what comes next may be even more difficult: weaning the nation from gas, which still accounts for 32 percent of energy production and provides the always-on power that current renewables can’t deliver. The challenge is enormous, requiring increased nuclear capacity, the use of green hydrogen in gas power plants and huge quantities of grid storage, all of which are extremely expensive right now. Nevertheless, the closure of the Ratcliffe-on-Soar plant is a critical first step in reducing the country’s carbon emissions. 

A revolutionary schizophrenia drug gained FDA approval. The medication, called KarXT, is arguably the most innovative schizophrenia drug to be developed in several decades, producing far fewer side effects than existing medications. As Nature reports, the medication, which is now licensed for use in the U.S., is a combination of two existing drugs, xanomeline and trospium. The first activates so-called muscarinic receptors to dampen the effects of dopamine, an important chemical messenger in the human brain that is present in higher levels among schizophrenia patients. The second stops xanomeline from affecting any part of the body other than the brain. (Because there are also muscarinic receptors in the gut, xanomeline used alone causes severe gastrointestinal complaints.) In trials, the drug — taken as a twice-daily pill — has been shown to be effective at relieving the symptoms of schizophrenia without causing the weight gain, sedation or movement issues, such as spasms and tremors, that are common side effects of many antipsychotics. Yet the drug is not a guaranteed success. First, drugs with high-frequency dosing schedules like KarXT are difficult for many people with schizophrenia to adhere to. (For this reason some antipsychotics are now injectable and administered only a few times annually.) Second, the new drug is expected to cost uninsured patients $20,000 per year. While the medication is expected to be supported by private insurance, along with Medicare and Medicaid, many of the most vulnerable sufferers of schizophrenia don’t have access to insurance, according to the Financial Times, putting the new drug out of their reach. 

The most sophisticated map of a brain ever made. The humble fruit fly may not seem like a particularly complex creature, but its brain is made up of around 140,000 neurons, all working to help it fly, fight, communicate and more. And while its brain is far simpler than that of a human, with its 86 billion or so neurons, it is still an important model for biologists seeking to understand brain function in more detail. Now, researchers at Princeton University have published a full 3D model of the neurons in a female fruit fly’s brain, mapping more than 54.5 million synaptic connections between 139,255 neurons in what is commonly referred to as a connectome. The map was created using AI tools that allowed the researchers to stitch together data from images of slices of the fly’s brain made with an electron microscope. The results, published in nine different papers in the journal Nature, also included identifying 8,453 unique types of neurons in the fruit fly’s brain, 4,581 of which were newly discovered. The findings have already expanded researchers’ understanding of the insect, including the way it senses tastes and walks. But, as The Economist reports, the greatest value of this work may be in the improvement of the technology required to construct the connectomes, which could allow bigger brains to be mapped and — over time — help drive down the cost of the process. While a connectome of the entire human brain remains a distant possibility, research such as this increases the odds of achieving it.

Innovators

Nobel Roundup

Every October, committees in Sweden and Norway name the winners of the Nobel Prizes, celebrating achievements in sciences, literature, economics and peace work. Here, we give you a quick rundown on the winners of the three scientific categories — medicine, physics and chemistry — and explain why they are important. Particularly notable this year: the emphasis on artificial intelligence, which sparked debate in the scientific community about the role that computational methods should play in cutting-edge research.

The Physics prize was awarded jointly to John Hopfield and Geoffrey Hinton for their contributions to the creation of artificial neural networks, which underpin modern AI. Both used ideas borrowed from physics to develop tools that can identify patterns in data. Hopfield used physics that describes the properties of atoms to build a network that could save and reconstruct information; Hinton built on Hopfield’s work and used statistical physics to build networks that could identify patterns. The advances, which they introduced in the early 1980s, are embedded in many modern AI systems, like image recognition and recommendations for films and music. The awards recognize the work the men did at a time when AI was a nascent field of research, not the commercial juggernaut it’s become. Since then, Hinton and Hopfield have expressed concern about both the pace of advances and the direction of modern AI; Hinton went so far as to quit a senior position at Google that he’d held for 10 years to speak out about his concerns. On that point, Hinton told The New York Times that he hoped having the Nobel Prize would mean that people might take his concerns “more seriously.”

The Chemistry prize was awarded half to David Baker and half to the team of Demis Hassabis and John Jumper for advancing our understanding of proteins. In the early 2000s, Baker developed software that enabled him to specify protein structures and compute their so-called amino acid sequences, enabling him to design an entirely new protein. Later, in 2020, Hassabis — a cofounder of Google DeepMind — and Jumper developed an AI tool called AlphaFold2 that solved the decades-old reverse problem: predicting protein structures from their amino acid sequences. It is hard to understate the importance of these results, given how fundamental proteins are to all the processes that take place inside living organisms. Our increased understanding of their structures has and will continue to expand our ability to understand diseases, treatments and all kinds of other biological nuances.

The Medicine prize was awarded jointly to Victor Ambros and Gary Ruvkun for the discovery of microRNA, a type of molecule that helps determine how cells develop and function. The tiny molecules — which resemble unusually short versions of more typical RNA molecules but without the section of code responsible for protein production — were first identified in worms and later in all multicellular organisms. The pair showed that microRNA binds to other forms of RNA to block protein production, meaning that they regulate complex genetic behavior in living creatures differently than previously understood RNA. Since its discovery in 1993, abnormalities in microRNA have been shown to contribute to illnesses including cancer, congenital hearing loss and skeletal disorders, providing researchers with another vantage through which to tackle disease in humans.

Long Reads

Magazine and Journal Articles Worthy of Your Time

Inside Google’s 7-Year Mission to Give AI a Robot Body, from Wired
4,400 words, or 18 minutes

Hans Peter Brondmo knows exactly how difficult it is to build a great robot because, for over seven years, that was his job. As part of Google’s moonshot division (known as X) and then at Everyday Robots, also overseen by Google, Brondmo led teams assigned to build robots that could perform everyday tasks like tidying desks, wiping down tables and sorting trash. Yet the challenge was so great that, ​​in January 2023, Google shut down the whole operation. In this essay, Brondmo describes the problems that plague robotics, describes what he thinks is required to build machines that are genuinely useful and lays out his concerns about the commitment of the technology industry to solve the big hairy problems that remain. “I have concerns that Silicon Valley, with its focus on ‘minimum viable products’ and VCs’ general aversion to investing in hardware, will be patient enough to win the global race to give AI a robot body,” he writes. “And much of the money that is being invested is focusing on the wrong things.”

The Searchers, from The Washington Post
7,100 words, or 28 minutes

If you’ve ever wondered what kind of person devotes one’s life to a highly technical, entirely essential yet easily overlooked element of a space program, look no further. This is a story from the Post’s excellent “Who Is Government?” series, which introduces readers to the people working in public service who are responsible for some of the government’s most remarkable achievements. This story is focused on the team building a core part of the technology for NASA’s forthcoming Nancy Grace Roman Space Telescope which will, it’s hoped, help discover planets around the universe where other life may exist. But really, the Roman telescope is just a route into a more important narrative about the scale of ambition, depth of teamwork and overwhelming humility of the teams, particularly at the Jet Propulsion Laboratory near Pasadena, Calif., whose job it is to make projects like this a reality.

How to fine-tune AI for prosperity from MIT Technology Review
4,800 words, or 19 minutes

“To uphold Moore’s Law, which predicts that the number of transistors on a chip will double roughly every two years, the semiconductor industry needs 18 times more researchers than it had in the early 1970s,” writes David Rotman in this story. “The ambition is not only to supply various tools that will make the lives of scientists easier, like automated literature search, but for AI itself to come up with original and useful scientific ideas that would otherwise evade researchers. In that vision, AI dreams up new compounds that are more effective and safer than existing drugs, and astonishing materials that expand the possibilities of computation and clean energy.” The question that Rotman tries to get to the bottom of here is: Could AI actually achieve that? There is, predictably, no simple answer to that question, but the story is vital for anyone trying to grapple with the topic.

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