Innovations in medicine: psychedelic drugs to treat depression

 Here's an editorial in JAMA that accompanies a report on treating some depressive patients using psilocybin therapy.

Psychedelic Therapy—A New Paradigm of Care for Mental Health, by Rachel Yehuda, PhD Amy Lehrner, PhD JAMA. Published online August 31, 2023. doi:10.1001/jama.2023.12900

"An increasing number of clinicians and researchers have become interested in the potential of psychedelic drugs for the treatment of mental health disorders, including depression, anxiety, posttraumatic stress disorder, eating disorders, and addictions.1,2

"Currently, most psychedelic compounds are illegal under federal law. They were placed on the most restrictive class of drugs, Schedule I, in the 1970s as part of the “war on drugs,” meaning that they were considered to have high potential for abuse with no accepted medical use.2 However, the ever-growing global mental health crisis, coupled with the shortage of effective therapeutic strategies, has given rise to a reconsideration of the therapeutic potential of these compounds in recent years.

...

"The study by Raison et al provides an excellent example of the promise of this new approach using psilocybin therapy for patients with major depressive disorder.3 Although the trial was relatively small, it demonstrated that a single dose of psilocybin in the context of a 6-week period that included active psychotherapy resulted in a rapid, robust, and sustained reduction in depressive symptoms.

"Psilocybin is a naturally occurring compound belonging to a class of compounds known as tryptamines, similar to lysergic acid diethylamide (LSD), dimethyltryptamine (DMT), and mescaline. Understanding its therapeutic efficacy requires an appreciation of the context in which it is used, and not just its pharmacological profile or biological mechanism of action. The psychotherapy that occurs with the psychedelic medication is a critical component of this approach.4

...

"The social, economic, and public health impacts of untreated mental disorders demand solutions. If psychedelic therapies do prove to have enduring effects after just a single or a few administrations in the context of a few sessions for preparation and integration, they have the potential to offer not just a new approach to mental health care, but an entirely new paradigm of care."

Innovations in addiction technology--illicitly manufactured fentanyl (IMF) combined with xylazine

 The fight against addictions is complicated by the fact that those who sell addictive goods can be innovative on many levels. (In the case of legal addictive substances such as nicotine, we are becoming accustomed to that competition, e.g. in connection with the growth of non-combustible vaping.)

Here's an article about innovation involving illegal opioids.

The emerging fentanyl–xylazine syndemic in the USA: challenges and future directions, by David T Zhu, Joseph Friedman, Philippe Bourgois, Fernando Montero, Suzanne Tamang, Lancet, August 24, 2023 DOI:https://doi.org/10.1016/S0140-6736(23)01686-0

"Xylazine, a non-opioid analgesic and sedative approved only for non-chronic veterinary use, is spreading across unregulated North American drug markets and becoming increasingly implicated in opioid overdoses. Between 2018 and 2021 in the USA, estimated fatal drug poisonings involving xylazine, often co-occurring with synthetic opioids such as fentanyl, increased from 260 to 3480 cases.1 This use of xylazine takes place in the context of the ongoing US opioid overdose crisis, which is expected to claim an estimated 1·2 million additional lives by 2029, barring urgent substantial policy reforms.2 The White House Office of National Drug Control Policy identified fentanyl adulterated or associated with xylazine (FAAX) as an emerging threat and in July, 2023, issued a response plan leveraging the Emerging Threats Committee and other vital stakeholders.3 Although this is a welcome strategy that sets out the federal government's plan to address xylazine, further non-punitive efforts and public health interventions are needed from health-care systems, policy makers, and community leaders to address the longer-term structural factors driving this crisis.

...

"Although more evidence is needed about why xylazine is combined with fentanyl, some reports suggest that by adding xylazine as an adulterant for synthetic opioids such as IMF, manufacturers can potentially maximise profits and distinguish their brand in the market, attracting a wider customer base.6,  7 This has most notably been observed in Philadelphia, PA, USA—regarded as an epicentre of the emerging xylazine crisis in mainland USA—where over 90% of the city's street opioid supply has shifted to FAAX.8 Further, xylazine has been described by people who use drugs as lengthening the sedative effects of IMF—solving the disadvantage of fentanyl's short duration of effect—thereby postponing craving and physical withdrawal symptoms"

The underbelly of the global art market (NYT)

 Art is not just art, it's also an investment opportunity, and one that evades many of the regulations that apply to investments recognized as securities.

The NY Times has the story, which is long and interesting throughout.  It follows an investigation begun by the lawyer Claude Dumont Beghi .

The Inheritance Case That Could Unravel an Art Dynasty/How a widow’s legal fight against the Wildenstein family of France has threatened their storied collection — and revealed the underbelly of the global art market.  By Rachel Corbett

"First, she drew up a list of known assets, which soon zigzagged into a chart of far-flung bank accounts, trusts and shell corporations. Over the course of several years, she would fly around the world to tax havens and free ports, prying open the armored vaults and anonymous accounts that mask many of the high-end transactions in the $68 billion global art market. Multimillion-dollar paintings can anonymously trade hands without, for example, any of the requisite titles or deeds of real estate transactions or the public disclosures required on Wall Street. She would learn that the inscrutability of the trade has made it a leading conduit for sanction-evading oligarchs and other billionaires looking to launder excess capital. 

...

"Independent of any national jurisdiction, free ports allow traders to ship and store property without paying taxes or customs duties. If a dealer buys a painting in one country, he can ship it to a free port without paying import taxes; then, when he is offered the right price, he can sell it there too, without paying capital gains. It has been estimated that $100 billion worth of art and collectibles are held in the Geneva free port alone, to say nothing of those in Zurich, Luxembourg, Singapore, Monaco, Delaware or Beijing.

...

"many of their practices are commonplace in high levels of the art trade, which a 2020 U.S. Senate subcommittee called the “largest legal, unregulated market.” Unlike financial institutions, art businesses are not expressly subject to the Bank Secrecy Act, which requires firms to verify customers’ identities, report large cash transactions and flag suspicious activity. A study from the U.S. Department of the Treasury last year cited a figure estimating that money laundering and other financial crimes in the art market may amount to about $3 billion a year. (Britain and the European Union, however, have implemented anti-money-laundering regulations that require stricter due diligence in art transactions there.)

"According to a report by Art Basel and UBS, auction houses did about $31 billion in sales last year. They say that they know who their clients are, but those may just be the names of art advisers or other intermediaries. And collectors’ insistence on anonymity, long framed as genteel discretion, hasn’t budged. The buyer of the most expensive artwork ever sold at auction, Leonardo da Vinci’s $450.3 million “Salvator Mundi,” registered at Christie’s a day before bidding with a $100 million down payment, identifying himself as one of 5,000 princes in Saudi Arabia. A few weeks later, it was revealed that the true buyer was Crown Prince Mohammed bin Salman — who was reportedly displaying the painting on his superyacht — and that a little-known cousin of his bought it as a proxy." 

Minimal envy mechanisms, by Julien Combe

 Here's an article I missed when it came out online:

Reallocation with priorities and minimal envy mechanisms, by Julien Combe, Economic Theory volume 76, 551–584 (2023)

"Abstract: We investigate the problem of reallocation with priorities where one has to assign objects or positions to individuals. Agents can have an initial ownership over an object. Each object has a priority ordering over the agents. In this framework, there is no mechanism that is both individually rational (IR) and stable, i.e. has no blocking pairs. Given this impossibility, an alternative approach is to compare mechanisms based on the blocking pairs they generate. A mechanism has minimal envy within a set of mechanisms if there is no other mechanism in the set that always leads to a set of blocking pairs included in the one of the former mechanism. Our main result shows that the modified Deferred Acceptance mechanism (Guillen and Kesten in Int Econ Rev 53(3):1027–1046, 2012), is a minimal envy mechanism in the set of IR and strategy-proof mechanisms. We also show that an extension of the Top Trading Cycle (Karakaya et al. in J Econ Theory 184:104948, 2019) mechanism is a minimal envy mechanism in the set of IR, strategy-proof and Pareto-efficient mechanisms. These two results extend the existing ones in school choice."

OB-GYN doctors will use a new application system to apply to residency programs (but will continue to go through the NRMP resident match)

 Before new doctors can participate in the resident match (by engaging with the NRMP), they first have to apply to residency programs, and arrange interviews.  This process has been experiencing congestion, and the specialty of Obstetrics and Gynecology has now decided to switch application services. 

However, participation in the NRMP will not change: the Association of Professors of Gynecology and Obstetrics (APGO) FAQ states "Obstetrics and gynecology applicants will use the National Residency Match Program (NRMP) for the Match. This new application does not change how the applicant or programs interact with the NRMP Match system."

Medpage Today has the story:

Ob/Gyn Switching to Independent System for Residency Applications— This is the last year ob/gyn will use ERAS, despite helping to pilot the program  by Rachael Robertson, Enterprise & Investigative Writer, MedPage Today August 25, 2023

"Beginning next year, ob/gyn programs will start using an independent system for processing residency applications, rather than the Electronic Residency Application Service (ERAS).

"The joint decision to switch to the new system was made by the American College of Obstetricians and Gynecologists (ACOG), the Association of Professors of Gynecology and Obstetrics (APGO), and the Council on Resident Education in Obstetrics and Gynecology (CREOG). The new system will be managed by Liaison International, which uses "Centralized Application Service (CAS) technology," according to the company's website.

...

"A joint statement on the APGO website opens in a new tab or window

said that the new system "will be user friendly and efficient, less expensive for applicants, and will directly decrease the burdens faced by program directors, program managers, and applicants alike," and "will incorporate the entirety of interview season functions, from application submission, review, interview offers and interviews, to rank list submission."

ACOG explained that the decision to pull the ERAS stemmed from the Right Resident, Right Program, Ready Day One initiativeopens in a new tab or window, noting that the new system is mobile-friendly and "will include immediate fee reduction," as detailed on their FAQ pageopens in a new tab or window.

In response, the Association of American Medical Colleges (AAMC), which runs ERAS, issued a statementopens in a new tab or window attributed to President and CEO David J. Skorton, MD, and Alison J. Whelan, MD, the chief academic officer, saying they were "surprised and dismayed" by the decision. 

...

"Bryan Carmody, MD, of Eastern Virginia Medical School in Norfolk, shared information  opens in a new tab or window

about the change on social media, writing on his blogopens in a new tab or window that ob/gyn program directors helped to pilot ERAS when it was first rolled out in the mid-90s.

Carmody told MedPage Today that he anticipates the biggest downsides will fall on applicants, such as those who want to apply to another specialty in addition to ob/gyn.

"Those applicants will have to use one system to apply to ob/gyn and another to their other specialty," he explained. "The same thing applies to applicants who fail to match. They'll have to use ERAS to apply to another specialty during SOAP [Supplemental Offer and Acceptance Program] since few, if any, ob/gyn positions are typically available."

*************

OB-GYN will continue to employ signaling  (very loosely modeled on the signaling used in the Econ PhD job market, but asking applicants to submit 3 "gold" signals and 15 "silver" signals): 

Program Signaling for OBGYN Residency Application Background and FAQs

**************

Earlier:

Friday, April 21, 2023

Transition from medical school to residency: defending the parts that work well (namely the NRMP Resident Match)

Unclaimed bodies and medical school anatomy classes.

 There's a long history of unclaimed bodies being used in medical school anatomy classes. (I think the historical availability of such cadavers is one of the reasons that the Harvard Medical School is in Boston rather than Cambridge.*)  Here's an update on the practice, in Texas.

Unclaimed Bodies and Medical Education in Texas, by Eli Shupe, PhD1; Serena Karim2; Daniel Sledge, PhD, JAMA.  online August 24, 2023

"The use of unclaimed bodies (bodies not claimed by next of kin for burial or cremation) in gross anatomy education in the US has declined substantially since the middle of the 20th century owing to increases in voluntary donations and escalating ethical concerns.1-3 Nonetheless, in most US jurisdictions, counties can donate unclaimed bodies to science without consent from the deceased or their next of kin, with some medical schools still accepting such donations. The current scope and magnitude of the use of unclaimed bodies in the US is underresearched, although one 2019 study found that anatomy course leaders at 12.4% of surveyed US medical schools indicated possible use of unclaimed bodies at their institutions.4 The objective of this study was to examine the trends in use of unclaimed bodies in medical education in Texas.

...

"We found that during 2017-2021, 6 of the 14 medical schools in our sample (42.9%) either engaged in the direct procurement and use of unclaimed bodies (2 schools, 14.3%) or received transferred cadavers from schools that did (4 schools, 28.6%). The remaining 8 schools (57.1%) had no possible use of unclaimed bodies."

###########

*Here's a related story from the Harvard Crimson:

Harvard's Habeas Corpus: Grave Robbing at Harvard Medical School, BY NURIYA SAIFULINA, September 28, 2017

"Harvard’s corpse legacy began in late 18th century, when the newly opened Medical School began hiring grave diggers—not to bury bodies, but to exhume them. According to a 2015 history of the so-called “resurrection men” in Synthesis, an undergraduate history of science journal, the diggers snuck into Boston’s burial grounds in search of new graves, stealthily dug up some of the most “fresh” residents, and refilled the graves to avoid arousing suspicion.

...

"Around 1770, Joseph Warren founded an illicit secret society called the “Spunker Club,” also known as the “Anatomical Club.” His older brother, John Warren—the founder of Harvard Medical School—was also a member. Some of the club’s most notable members included a William Eustis, the future governor of Massachusetts, and Samuel Adams’ son.

...

"As “resurrection men” and body-snatching enthusiasts continued to ransack Boston graveyards, civil indignation incited the Act to Protect the Sepulchers of the Dead in 1815, making disturbance of buried bodies illegal and prompting a citywide patrol of graveyards and burial grounds.

"This legislature forced Harvard Medical School to “import” the cadavers from New York instead, where body snatchers were “emptying at least six hundred or seven hundred graves annually,” according to an article in the Boston Gazette.

"After the Massachusetts Medical Society published a plea in 1829 claiming that medical students had no other choice but to pursue their studies “in defiance of the law of the land,” the school’s need for illegally-obtained cadavers waned. Massachusetts passed the Anatomy Act of 1831, which allowed for dissection of the unclaimed bodies of the indigent, insane and imprisoned."

THE 18TH CONGRESS OF ASIAN SOCIETY OF TRANSPLANTATION (CAST) 25 -28 August 2023 • Hong Kong

Tonight, Sunday, at 5:30pm California time, I'll be opening the Monday morning session in Hong Kong of the THE 18TH CONGRESS OF ASIAN SOCIETY OF TRANSPLANTATION 25 -28 August 2023.

Keynote Lecture

28 Aug 0815-0915 Theatre 1 Keynote Lecture III

Chairs : Albert CY CHAN, Hong Kong, China

Hai-Bo WANG, Mainland China

Topic 1. Transplant economics Alvin ROTH USA

Topic 2. Organ transplantation reform in China: The synergy of Chinese cultural traditions and WHO guiding principle  Jie-Fu HUANG Mainland China

Challenge trials for a Hepatitis C vaccine

 The Journal Clinical Infectious Diseases has a special supplement on challenge trials (human infection trials) of a Hep C vaccine (now that Hep C is a curable disease):

Volume 77, Issue Supplement_3, 15 August 2023

Controlled Human Infection Model for HCV Vaccine Development

SUPPLEMENT ARTICLES

Controlled Human Infection Model for Hepatitis C Virus Vaccine Development: Is It Time to Be Real? 

T Jake Liang and others

Clinical Infectious Diseases, Volume 77, Issue Supplement_3, 15 August 2023, Page S215, https://doi.org/10.1093/cid/ciad343

• Hepatitis C virus (HCV) elimination has been a goal of the public health and scientific communities since its identification in 1989. Despite the advance and availability of highly effective antiviral regimens to treat HCV infection, it is unlikely that global HCV elimination can be achieved without an effective preventive vaccine. Because of the lack of appropriate animal models for preclinical testing and the perception that highly effective treatments would suffice in addressing the global burden of HCV, HCV vaccine development has not been a high priority. To accelerate vaccine development, the concept of a controlled human infection model (CHIM) for HCV has been proposed, in which healthy human volunteers would be deliberately infected with HCV for the purpose of testing the efficacy of candidate vaccines. This concept of challenge studies is not new and has been applied to more than 25 infectious agents, including the cholera vaccine, for which all efficacy data that served as the basis for regulatory approval were obtained from CHIM studies. Without a CHIM strategy, HCV vaccine development may not be feasible. In a recent phase 2 randomized controlled trial, over 900 people who inject drugs were screened to enroll 548 individuals to receive a T-cell–based HCV vaccine candidate or placebo. After a monumental effort that took over 6 years to complete, the trial documented 75 incident HCV infections overall, with only 45 included in the final analysis, and showed no protection against initial infection or progression to chronicity with the vaccine. While this study demonstrated that vaccine testing in the at-risk population can be done, future testing of additional HCV vaccine candidates using a similar pathway may be impractical in light of the duration and cost. With the ability to cure those who do not clear the virus, HCV CHIM is now a conceivable approach that could be a critically important, if not necessary, intermediate stage of vaccine development. HCV CHIM could de-risk vaccine candidates, accelerate development, reduce cost, and allow the selection of more promising candidates for further testing in larger clinical trials. CHIM may conceivably be used for larger phase 2/3 efficacy trials as a basis for clinical approval. In developing such a model, many challenges and questions must be addressed. In this Supplement issue, we, the editors of this Supplement commissioned various articles written by respective subject matter experts who provide their perspectives and opinions on these challenges and questions, ranging from the source of viral inoculum and the safety of transient HCV infection to the perspective of potential volunteers and the ethics of CHIM. While we strive to be data-driven and evidence-based, some of the opinions represent the views of the authors of each article and may be controversial. Ultimately, we hope these perspectives will enable fulsome discussion about the feasibility of HCV CHIM and lead to the development of well-designed clinical protocols.

  Supplement sponsorship. This article appears as part of the supplement “Controlled Human Infection Model for HCV Vaccine Development,” sponsored by Toronto General Research Institute, United States National Institutes of Health, Johns Hopkins University, the Canadian Institutes of Health Research (CIHR), and the Canadian Network on Hepatitis C (CanHepC). CanHepC is funded by a joint initiative of CIHR (HPC-178912) and the Public Health Agency of Canada.

• View article

Ethics of Controlled Human Infection Studies With Hepatitis C Virus 

Annette Rid and others

Clinical Infectious Diseases, Volume 77, Issue Supplement_3, 15 August 2023, Pages S216–S223, https://doi.org/10.1093/cid/ciad382

• Global elimination of hepatitis C virus (HCV) will be difficult to attain without an effective HCV vaccine. Controlled human infection (CHI) studies with HCV were not considered until recently, when highly effective treatment became available. However, now that successful treatment of a deliberate HCV infection is feasible, it is imperative to evaluate the ethics of establishing a program of HCV CHI research. Here, we evaluate the ethics of studies to develop an HCV CHI model in light of 10 ethical considerations: sufficient social value, reasonable risk–benefit profile, suitable site selection, fair participant selection, robust informed consent, proportionate compensation or payment, context-specific stakeholder engagement, fair and open collaboration, independent review and oversight, and integrated ethics research. We conclude that it can be ethically acceptable to develop an HCV CHI model. Indeed, when done appropriately, developing a model should be a priority on the path toward global elimination of HCV.

• View article 
• Supplementary data

Volunteering for Infection: Participant Perspectives on a Hepatitis C Virus Controlled Human Infection Model 

Jake D Eberts and others

Clinical Infectious Diseases, Volume 77, Issue Supplement_3, 15 August 2023, Pages S224–S230, https://doi.org/10.1093/cid/ciad350

The perspectives of former challenge study participants and a survey of other potential volunteers can inform the design of hepatitis C virus controlled human infection models, including on topics such as transparency, volunteer safety and risk, and compensation.

• Ethical human subjects research requires participants to be treated safely and respectfully, yet much bioethical debate takes place without participants. We aim to address this gap in the context of controlled human infection model (CHIM) research. Based upon our own experience as study participants, and bolstered by a survey of 117 potential hepatitis C virus CHIM participants, we present ideas to inform efficient, ethical, and scientifically useful study design. We advocate for full protocol transparency, higher compensation, commitment to the rapid dissemination of study results, and proactive efforts to detail risk-minimization efforts as early as possible in the recruitment process, among other measures. We encourage researchers to proactively partner with volunteer advocacy organizations that promote collective representation of volunteers to maximize their agency, and guard against ethical issues arising from healthy human subjects research.

• View article 
• Supplementary data

First Do No Harm? Modeling Risks and Benefits of Challenge Trials for Hepatitis C Vaccine DevelopmentGet access

Alyssa Bilinski and others

Clinical Infectious Diseases, Volume 77, Issue Supplement_3, 15 August 2023, Pages S231–S237, https://doi.org/10.1093/cid/ciad379

• Background

  In 2019, about 58 million individuals were chronically infected with hepatitis C virus. Some experts have proposed challenge trials for hepatitis C virus vaccine development.

  Methods

  We modeled incremental infections averted through a challenge approach, under varying assumptions regarding trial duration, number of candidates, and vaccine uptake. We computed the benefit-risk ratio of incremental benefits to risks for challenge versus traditional approaches. We also benchmarked against monetary costs of achieving incremental benefits through treatment.

  Results

  Our base case assumes 3 vaccine candidates, each with an 11% chance of success, corresponding to a 30% probability of successfully developing a vaccine. Given this probability, and assuming a 5-year difference in duration between challenge and traditional trials, a challenge approach would avert an expected 185 000 incremental infections with 20% steady-state uptake compared to a traditional approach and 832 000 with 90% uptake (quality-adjusted life-year benefit-risk ratio, 72 000 & 323 000). It would cost at least $92 million and $416 million, respectively, to obtain equivalent benefits through treatment. BRRs vary considerably across scenarios, depending on input assumptions.

  Conclusions

  Benefits of a challenge approach increase with more vaccine candidates, faster challenge trials, and greater uptake.

• View article 
• Supplementary data
• **********
  Earlier:

  Monday, May 15, 2023

  Eliminating Hepatitis C, now that there's a cure (even though it's expensive

  and here are my posts on challenge trials (and Covid vaccines).