Hatful of Hollow #1

Conversation with brain scientist and economist abt psilocybin, link to MDMA PTSD trial, Ann Shulgin obituary, and two cool TikTok

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Introducing Cool Stuff

“Hatful of Hollow” is what I’ve decided to call my weekly collection of links, images, my favorite TikTok videos and any essays or articles I think interesting. I’ll send it out once a week, twice at most. It’s basically things that in the last few days that caught my mind, or which have been on my mind, none of which may be important, but I want to share them anyway. This is the first entry of it hence the hashtag “#1”. I’ll try my best to number to number them. Each topic is bold line followed by some words or paragraphs, and while they may sometimes seem like they go together, they were largely written as though they don’t require reading the others.

I’m calling it “Hatful of Hollow” for two reasons. First, a hat full of hollow suggests someone’s brain is empty. This could mean either because some of these things I’m sharing are sort of pointless (like the weekly top TikTok videos I found) or because I’m dumping all of that stuff into the substack, thus emptying my brain of it. But I’m also naming it Hatful of Hollow after one of my favorite bands, The Smiths. Hatful of Hollow was one of their compilation album. Here’s the Spotify album. It holds up.

Call to Action

At the start and the finish of every Hatful of Hollow entry, I am going to make a “call to action”. A call to action is a phrase I’ve heard on Substack podcasts in which the Substack writer more or less requests that readers support the Substack writer/podcaster by subscribing either for free or if they are so inclined becoming a paying member. So if you like the explainers, if you like the podcast, and if you like Hatful of Hollow, please consider donating! Now on to the Hollow parts!

What’s in the video?

Before I dive into this week’s inaugural issue of Hatful of Hollow, let me tell you what’s in the embedded video. On June 17th, I had the pleasure of being invited to talk with Dr. David Erritzoe (MD, PhD, MRCPsych) in a talk entitled “Dual Perspective Conversation about Psychedelic Research” with my good friend Dr. Francesca Cornaglia as the moderating chair of the conversation. Dr. Erritzoe is Clinical Senior Lecturer at Imperial College where he directs the Centers for Neuropsychopharmacology and Psychedelic Research. He is part of a global group of scientists in neuroscience and psychiatry who have been studying the impact of classic psychedelics, such as psilocybin (i.e., magic mushrooms), on mental health symptoms such as depression. The video for this conversation is embedded and lasts about an hour. The first half, David provides an overview of what we know about the impact that therapist assisted psychedelics have had in the lab setting on mental health outcomes such as treatment resistant depression. The second half, starting around the 25-30 minute mark, I basically talk with him about the kinds of things that I have been thinking about following this literature over the last four years.

You’ll hear me and David talk about some of the problems of external validity from the trials, given non-random participants with heavy screening criteria to rule out people with certain conditions. You’ll also hear us talk about things like my wondering if the clinician involved in “therapist assisted psychedelics” is actually far more crucial to the molecule’s impact that is often emphasized. This goes back to the narrative I have in my mind which is that some of what we are finding in these trials is about capital and labor, not just capital. That is, it may be that trained workers are crucial to this intervention, and if that’s the case, then what does that imply about the production function of this healthcare technology? Can it in other words scale given the therapies used in these treatments have been largely forgotten? After all, these therapists are not engaging in talk therapy or CBT skills based training with patients. Is this human capital easily obtainable? If the molecules are complementary with the therapists, then scaling treatment is going to be an issue. This issue of scale and complementary capital and labor inputs in the production function is going to be something I emphasize often in the interviews.

Psychedelic therapy and history

You will notice in the weeks and months to come that some days I seem to be talking a lot about psychedelics (e.g., psilocybin). There’s a few reasons for this. The biggest reason is my research and personal interest in severe mental illness, a topic I pivoted towards back in 2018.

But what does severe mental illness have to do with psychedelics? That brings me to the second reason. Around four years ago, I somewhat randomly came across a 2015 New Yorker article by Michael Pollan discussing new scientific findings that “psychedelic therapy” had beneficial effects on severe mental health symptoms such as depression, anxiety and PTSD. The article went viral so you probably saw it too, and it ultimately led Pollan to write two books as well as a Netflix documentary adaptation/extension.

I was stunned to find this not only for the findings but that the research itself had been undertaken in a world where psychedelics were so heavily penalized and dismissed as medically harmful. But as I read more, I learned that scientists had been quietly studying the effects of psychedelics on mental health, beliefs and states of mind for decades, even after the 1970 Controlled Substance Act.

Probably the thing that really caught my eye, too, was the use of randomized controlled trials in generating these findings. I was writing my book, Causal Inference: the Mixtape, and thinking a lot about randomization, and how to communicate why it was important for causal inference, and probably that element of these findings too hit me square in the chest. Here are some of the facts that have most interested me from these studies.

  • Psilocybin (i.e., magic mushrooms) and other psychedelics were found to alleviate severe depression among people with terminal cancer by Roland Griffiths and coauthors (url).

    • From the abstract: “High-dose psilocybin produced large decreases in clinician- and self-rated measures of depressed mood and anxiety, along with increases in quality of life, life meaning, and optimism, and decreases in death anxiety. At 6-month follow-up, these changes were sustained, with about 80% of participants continuing to show clinically significant decreases in depressed mood and anxiety.”

  • Reports that the effects seemed to act more quickly than traditional psychotherapy and lasted longer. See this review by Ronald Griffiths and Charles Grob.

  • Psilocybin producing mystical experiences that seem indistinguishable to that of long-term meditators (url) which confirms an earlier study done among Harvard Divinity students by Timothy Leary and colleagues in 1962 with LSD.

  • People with chronic and untreatable PTSD saw the alleviation of their symptoms after a few therapist assisted MDMA (i.e., ecstasy) sessions (url).

  • Scientists undertook this research despite tremendous obstacles. This alone is something I have yet to fully move beyond, as the fortitude and planning required to complete this research is worthy of focused attention in my opinion.

One of the things I did early on was reach out to the Multi-disciplinary Association of Psychedelic Studies (MAPS) and see if they would share the data from their Phase 2 trials. It was 6 RCTs and around 100 participants. They indeed did share the data and I began studying it. I was initially going to include the data and topic as an exercise in my book, Causal Inference: the Mixtape, but ultimately opted to use a different dataset to illustrate the statistics behind the RCT. Seeing with my own eyes, so to speak, how large the effect sizes were in the pooled data kept me engaged with the literature, and the more I read the literature, the more I became really intrigued by the scientists themselves. I am fascinated by these scientists — what papers they’ve written, where they work, what their backgrounds are — and how they managed to pull off such bold research in such an environment as complete drug prohibition. You’re going to probably notice that theme, too, in the interviews to come as I start sharing them through the podcast.

Below I will share some of the things I am thinking about these days. First, to state the obvious, I am not a neuroscientist, psychiatrist, psychologist, nor am I trained in pharmacology. I am an applied micro economist with a historical research interest in the economics of illicit markets, drug policy (here, here, here and here) and more recently, mental health problems, including suicide. I am part health economist and one part labor economist, with an above average obsession in the nuances and details of econometrics and causal inference. So when I think about the topics I have gravitated towards in my career, it is natural that this one has caught my attention.

But I am also interested because the legal landscape is changing rapidly. Probably prompted by the success of the cannabis reform movement, psychedelic reform has been rapidly happening (in an even more condensed period of time). Cannabis reform has largely emerged as a kind of consumer product, much like drinking alcohol or smoking tobacco, though originally it evolved through a kind of medical reform too. Psychedelic reform is definitely following that model to a degree. The FDA has given “breakthrough status” to psilocybin and MDMA for instance and they are likely to be re-scheduled within the next few years. Ketamine has already been re-scheduled and is available for treating depression all over the country at “infusion clinics”, most likely in your area. And that is likely one path forward.

But another path forward is through decriminalization. Starting in 2019, and continuing to this day, approximately two dozen municipalities, including Ann Arbor, Oakland, Denver and Washington DC, have decriminalized the possession of psychedelic plants such as cacti (San Pedro and peyote which contain mescaline), fungi (mushrooms) and vines and bark containing DMT (e.g., ayahuasca). These “sacred plant” decriminalization movements have not been based on the medical reform model, but rather have been more rooted in a strategy undertaken by a non-profit group called Decriminalize Nature. Though DN is not always the driving force, they have been instrumental. These changes have come, interestingly, at low cost. Whereas the cost of getting reform through state ballots can run into the millions, DN realized that by lobbying city councils, they might be able to change enforcement of drug laws spending much much less.

There are many elements of this that I am hoping to bring attention to in the next year on here, and you will see it reflected both in Hatful of Hollow posts, but also podcast episodes. I have a two part interview with Dr. Larry Norris who was a co-founder of Decriminalize Nature in which he discusses both his own background and interests in psychedelics, as well as his own thoughts about the underlying economics (though he doesn’t use that term) of delivering psychedelics to market.

I think there are potentially questions around the market design of psychedelics around production, distribution and consumption that economists could be very impactful in studying, not to mention the fact that there have been so many reforms in such a short period of time. Over two dozen cities and the entire state of Oregon have in some form or another already decriminalized and/or legalized access to psychedelics. So part of what I’m doing on Hatful of Hollow, but also the podcast too, is to slowly drip interesting backgrounds about the science, reforms and the scientists themselves so that some entrepreneurial researcher out there, looking for a meaty project to sink her teeth into, can at the very least gather more information that in my opinion could be useful to an economist.

Scientists Go First

Scientists have been interested in the properties of psychedelics (e.g., LSD, psilocybin, mescaline) since the earlier part of the 20th century. Albert Hoffman, a chemist at Sandoz labs, discovered LSD in 1938, put it on the shelf thinking it useless, then five years in 1943 accidentally dosed himself when re-visiting the compound’s synthesis. Not expecting the dreamlike state that overtook him, he was curious and on April 19 1943 intentionally dosed himself and while the psychedelic effects of the drug began to overtake him, he hurried home on his bicycle to lay down. April 19th is now called “Bicycle Day” and is observed annually by psychonauts around the world.

This story is fascinating for several reasons, but I’ll just name one. The scientists who have continued over the years to push for more research on psychedelics have oftentimes self experimented on themselves. This is, from what I can gather, built into the worldview of the scientist herself who from the earliest stages of her education is indoctrinated to “do no harm”. So if you are to do no harm, but are equally if not more designed to understand the world around us, then who will go first in these experiments? Sometimes it’s animals, but oftentimes it has been the scientists themselves. This idea — that scientists go first — is something that has largely guided my curiosity with the emerging science of psychedelic research. I will talk a little about that in the podcasts, but I think “scientists go first” is an idea I want to put out there as to how we got from the CSA to the changes we are observing today.

Government Contradictory Interest In Psychedelics

The story is too long to tell here, so I won’t, but topping off a decade of psychedelic excess and recreational use, the United States government passed the 1970 Controlled Substance Act which placed most classic psychedelics, as well as other substances like cannabis, heroin, and cocaine, on a federal register that banned their possession, production and distribution and all but halted all research on it.

Interestingly, leading up to the CSA, scientists had been studying psychedelics for decades — as I said, going back to Hoffman himself in the early 1940s. Sandoz labs, desperate to figure out if LSD had any benefit, would basically ship it anywhere to anyone who wanted it. Over a thousand peer reviewed articles involving tens of thousands of human subjects were published up until the CSA. In therapy, it was used to treat everything from alcoholism to other mental health problems. The federal government itself, prior to the CSA, funded many of these studies, but usually for nefarious purposes. For instance, the CIA hoped they could use it as a truth serum, but as it turns out, classic psychedelics are pretty unreliable. Sometimes respondents would spill the beans; sometimes they would scream in terror and have to be sedated. To learn more about a sinister story involving the CIA, an unwilling dosing of an American scientist with LSD, followed by his murder, the coverup, and a son who cannot let the story go, see Errol Morris’s phenomenal “Wormwood” on Netflix.

Ann Shulgin’s obituary NYT

While camping in Big Bend Texas and the Grand Canyon last week, I learned that Ann Shulgin passed away. Ann Shulgin was married to the chemist Alexander (“Sasha”) Shulgin who also is no longer alive. They are both noteworthy people in the history of psychedelic therapy in part because the two of them championed and pioneered combining MDMA with therapy to treat a range of mental health problems.

They did this work somewhat clandestinely though not as as much as you might expect given the taboo nature of the subject. When Sasha re-synthesized MDMA (it had been discovered at the turn of the century by Merck), together they introduced it to a community of psychotherapists who used it openly with patients. Because it was legal (MDMA would not be added to the federal registry of banned substances until 1985), this was technically legal. What I have been learning over the years is that this kind of therapy had been more common prior to the Controlled Substances Act of 1970, largely driven by decades of productive research on the mental health benefits of psychedelic treatments for mental illness and substance use addiction, but when CSA happened, these therapists either moved to other topics in a similar space (such as Stanley Grof’s shift towards studying hyperventilation as a way to create similar kinds of mindsets found with psychedelics), they continued practicing psychedelic therapies but illegally and underground, or they stopped altogether. This history of the psychedelic therapists is something I am going to probably continue to be interested in and you’ll notice those lines of questions from time to time pop up in my podcast interviews or just on here in general.

Together, Ann and Sasha would publish two now infamous books (still in print) entitled Pihkal and Tihkal (amazon link) which were part memoir and part technical recipes for producing a range of exotic psychedelics. It was the latter that would get them into trouble with the government.

Interestingly, Sasha had a license from the DEA to produce many illicit compounds as part of consulting he did for the agency, but when the DEA began finding copies of Pihkal and Tihkal during seizures, they fined him tens of thousands of dollars and took away his license. He and Ann swore they never used the drugs listed on the actual federal register though. Because Sasha understood the chemical structure of the classic psychedelic compounds so well, he basically engaged in a kind of “rational chemistry” where he would intentionally synthesize then unknown psychedelics where he expected they were hiding. As the CSA is a list of banned substances, anything not technically on the list is not technically banned. But the DEA has discretion nonetheless in its enforcement and Sasha was basically fired from his DEA consulting when they realized he was running his own backyard lab for his own research and consumption purposes.

While Sasha was the chemist, Ann (the one who just passed away at 92) was more of the spiritualist/psychotherapist. So their partnership was interesting pairing of a chemist and a therapist. Consider her to be one of those people I mentioned who did underground and clandestine psychedelic psychotherapy after the 1970 CSA. And so her passing is interesting as we consider that she along with her husband saw the potential for treating mental illness with MDA, played a role in the research continuing through MAPS even if indirectly, and with her passing we are perhaps concluding a period of time where psychedelic therapy was only taboo and underground.

Well after the 1970 CSA, existing research on psychedelics slowed down, and new research more or less did not occur. But what I find interesting is that the therapies that had been evolving alongside the clinical studies, such as those developed by Stanley Grof at Maryland, also seemed to disappear. From what I have been able to gather, and you will catch a whiff of my interest in this in the interviews that I post (such as the one above), therapist assisted psychedelic medication did not disappear — it simply went underground. I hope to tell you more about this as I learn more through my interviews.

MDMA assisted treatment for PTSD Phase 3

MDMA, street name “ecstasy”, was banned in 1985. The story, then, of how a drug like MDMA could go from being widely used to treat mental health problems (championed by Shulgin), to banned, to where we are today is to me a fascinating story and turn of events. You can find some of that story in the page turner, The Acid Test, which tells the story mostly of MAPS and Rick Doblin and it’s too much to get into now, but interestingly enough for the crime economists out there, it tangentially involves the late Mark Kleiman when he was a professor at Kennedy. Here’s Doblin’s dissertation at Harvard and here’s Mark introducing Doblin.

So where are we now exactly? Well, from what I have read the last several years, we appear to probably be about a year away from MDMA being “rescheduled” as it will be recognized that it has medical use. Most likely off-label treatment for post-traumatic stress disorder (PTSD) at clinics across the country is imminent. Specifically, you can probably expect MDMA assisted psychotherapy to be available legally by end of 2023 and probably from the same places one can currently obtain ketamine for treating severe depression.

How does it work exactly you might ask? First let me point you to one of the latest studies, published in Nature: Medicine last year. It was only the latest RCT administered by MAPS, and if you’re curious to learn more, look at the references or some of the hyperlinks I’ve been leaving in this Hatful of Hollow post. This latest trial was, as I understand it, a somewhat decisive study (Phase 3 trial with the FDA) in which 46 volunteers were randomly assigned to receive therapist assisted MDMA and 42 a placebo. As had been found in earlier studies, individuals treated with MDMA assisted psychotherapy saw substantial alleviation in PTSD symptoms up to 2 month after their last dosage relative to the estimated counterfactual. The participants in this trial had treatment resistant PTSD. Many of them were first responders who as I understand had such debilitating PTSD that their level of daily functioning was extremely low. This is only the latest in a ring of studies, too many to list here, finding significant reduction in PTSD symptoms associated with MDMA assisted psychotherapy. You can find a great overview of these findings in The Acid Test, or by going to MAPS website and reading them yourself.

Cunningham’s explanation of how MDMA therapy works

But as for how it works, that’s more complex. To understand why psychedelic therapies have any effect on mental illness will require dusting off your AP Chemistry textbooks. As I dropped AP Chemistry pretty quickly after enrolling, I am not the go-to for that information. But let me tell you what I understand the broad theory of why MDMA has been an effective treatment for PTSD to be.

PTSD is largely a problem associated with invasive and unwanted repeated thoughts and memories. These thoughts and memories are sometimes called “intrusive”. The mind chooses its beliefs, making mental illness all the more challenging if the mental illness is an endogenous adaptation based on survival that is itself causing the traumas to persist well beyond whatever harmful events initiated it. The most effective treatments for PTSD that I have found in the literature is a kind of skills based approach called mindfulness, which is one of the elements of dialectical behavioral therapy, or DBT. Learning the skills associated with managing distress is crucial for navigating our historical lives, and mindfulness has value towards that end for people suffering from PTSD.

MDMA is interesting for this problem because of the effects that it creates. It is not a classic psychedelic though its chemical structure resembles that of mescaline (the psychedelic compound found in the peyote and San Pedro cacti) I am told. MDMA “shuts down” the “fight, flight or freeze” reflect built into the amphibian parts of our human brains. By shutting it down, the person using MDMA is able to sit nearly effortlessly within those harmful memories without experiencing any of the harms associated with the memories. MDMA also is what is sometimes called an “empathogen”, as opposed to a classic psychedelic, in that it literally produces empathy best we can understand. And so both the reduction in fight, flight or freeze combined with an overwhelming sense of love, acceptance, generosity and compassion can when working with the therapist be aimed at one’s own self and somehow through the plasticity of the brain itself through followup work with therapists to “integrate” the experience into one’s life make better sense of the traumas that happened to oneself earlier in life. To my knowledge, the best evidence is that for people with chronic PTSD, some of who haven’t had rest in decades, the MDMA therapies abated their symptoms so much that even up to two months after their last treatment, they did not technically meet criteria for PTSD any longer.

It is no wonder then that you see a tremendous amount of hope and optimism around using this to treat severe mental illness. Even former Texas governor and member of the Trump administration, Rick Perry, has become a vocal and aggressive supporter of extending MDMA treatment to veterans suffering from PTSD.

Mental illness in corrections

My main research these days is not on psychedelics though, but it is on mental illness. I study mostly severe mental illness within corrections, primarily working with jail and prison administrative data to understand the causes of self harm as well as to devise ways to predict it. A phrase worth writing down is the that corrections, due to a non-existent healthcare system for treating severe mental illness, has become the mental hospital of last resort. In most places, the local jail houses more mentally ill individuals than the local mental hospitals.

Recently, Jack Powers was released from maximum security prison where he spent the last 30 years for bank robbery. Twenty of those years he spent in solitary confinement, a housing practice as the reader knows of separating the inmate from the general population. You can read about Mr. Powers here in the NYT and here are some of his writings.

In the meantime here are some articles to better familiarize yourself with mental illness within prisons, and here is more about solitary in prison. I am sending Mr. Powers the gift of love and acceptance and welcoming him back to society. We send love in order that we can and will receive it.

What I’m Reading

This fall I have a new class prep. It’s a history of economic thought class. Baylor University, where I’m employed, has continuously taught this class since its founding. My colleague, Steve Gardner, has been teaching it for decades, but spring 2022 was his last semester and no one had been assigned the class or volunteered to teach it. Rather than let a break in the chain emerge, I asked to take it over. I love history of thought; I just don’t actually have a field in it or any training in it. But I love it and want to learn it and so the idea that a course on the history of my field that I’ve devoted my life to studying and contributing to, a field that I love so much, which has only had a handful of instructors at Baylor in the university’s entire history, one of whom was the first university president, Judge Baylor himself, will have my name attached to it is inspiring to me on top of the excitement I have towards increasing my own personal human capital around the history of the field.

To prepare for this class, I have asked to borrow some teaching materials from one of my favorite economists in the profession, the brilliant Beatrice Cherrier. She has graciously shared with me some of her own course materials, and since if all I ever could attain to was 10% of what Beatrice has managed, I felt like that would be a great thing.

The things I am most interested in are the period of developing economic thought in the 20th century. I am especially interested in post Samuelson period, but I am also interested in the history of econometrics, and about specific departments, like Chicago, Harvard and MIT. So Beatrice’s prior courses is likely to be very helpful as I feel my way through this vast landscape of the past into the present.

The first book I am reading this semester is Mary Morgan’s classic “The History of Econometric Ideas”. But I also really want to read Jeff Biddle’s history of the empirical Cobb-Douglas production function, although I’m a little deterred by that $110 price tag (yikes!). Expect things from these readings to show up on here!

Favorite New TikTok Account: @therealsurfersusie

Now to the hollow parts. Let me share with you some great TikToks I have found recently. I only just discovered @therealsurfersusie the other day and decided that her attitude towards life is what I’m shooting for every day henceforth. You can find the original TikTok link here, but until they tell me to take it down, here it is on my Vimeo too. Today’s a good day! Go out, catch your crossover step and nail it!

Favorite TikTok Video You Maybe Haven’t Seen

Man I love this video. I listen to it often. For the uninitiated, the following is called a “duet” on TikTok. One person posts a video, another person films themselves reacting to the video. This is a great example of how the whole is better than the sum of its parts. Here the band Hot Mulligan respond to @Phoenix singing an acapella version of their song “I Fell In Love With Princess Peach” while he paces in his kitchen. @Phoenix sang his version without any music, making the final version amazing. Listen to the original and compare it with this duet and rank your preferred.

Tiktok failed to load.

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