Disulfiram

Pictured: Bottles wrapped in an Iboga plant/Taylor Tieden for BioSpace Notoriously difficult to treat, substance use disorders are devastating individuals and healthcare systems across the globe. They are also a primary target of psychedelic drug developers who believe these novel therapeutics can help turn the tide. In 2018, the total medical costs of substance use disorder among people with U.S. employer-sponsored insurance came to an estimated $35.3 billion. Current treatment options include 12-step groups, detox programs and medicines such as disulfiram and acamprosate for alcohol use disorder (AUD) and buprenorphine for opioid use disorder (OUD). Despite the availability of such treatments, 3.2 million people died globally from SUD-related causes in 2019 alone. Several biopharma companies are placing bets that psychedelic therapies can help curb SUD. There are currently eight psychedelic candidates in development for SUDs, including AUD and OUD, according to Psychedelic Alpha, spanning modalities such as ketamine, psilocybin and DMT. Albert Garcia-Romeu, an associate professor of psychiatry and behavioral sciences at Johns Hopkins University School of Medicine who studies psilocybin for addiction and other conditions, said the data generated so far “absolutely suggests” that psychedelics can be more effective than traditional treatments for SUDs. But as the field awaits the first FDA approval of a psychedelic for psychiatric use, substantial hurdles remain to development of the drugs for these conditions. Ketamine, LSD and Ibogaine In the 1950s and 1960s, before being outlawed, LSD was studied “heavily” as a potential treatment for SUDs, and “showed some promise in treating alcohol and opioid dependence,” Garcia-Romeu told BioSpace. However, he said, therapeutic research with classic psychedelics then stalled until the 2000s, “and most of the work since that time has really focused on psilocybin,” the active component of magic mushrooms. Other substances, including ketamine and ibogaine, have also shown some promise in treating addiction, he noted. New York–based MindMed is developing MM120, or LSD D-tartrate, for generalized anxiety disorder, among other therapeutic areas. Chief Medical Officer Daniel Karlin told BioSpace that while LSD has historically shown evidence of efficacy in SUD, its mechanism is not fully explained. But, he said, “LSD is neat because it has both a psychiatric psychological mechanism and it has a neurobiological mechanism,” with an acute neurobiological effect leading to an acute psychological experience. “We exist as a story we tell ourselves about ourselves,” Karlin said, “and for some people, that organization leads to neurotic unhappiness,” manifesting in anxiety, depression, or addiction. With LSD treatment, the mind’s organizational structures “come offline,” he explained. “This story you tell about yourself gets disorganized.” During this experience, people have the opportunity to see their narrative differently, Karlin said. After LSD treatment, the organization comes back online, but it comes back differently. Elsewhere, Toronto-based Awakn Life Sciences is in Phase III trials in the U.K. with AWKN-001, an s-ketamine–based therapy to be used in conjunction with cognitive behavioral therapy for severe AUD. “There’s a strong dissociative effect with ketamine delivered . . . at the doses we’re delivering it,” explained Anthony Tennyson, co-founder and CEO of Awakn. During a preparative therapy session, the reasons why an individual became addicted and the addiction’s effects on others surface, and ketamine then enables a different perspective on these experiences. “Getting a different perspective and a different view on things during this dissociative effect can help some people forgive themselves and forgive other people in a much more rapid and efficient way than just talk-based therapy by itself,” Tennyson told BioSpace. Ketamine also disrupts memories, which Tennyson said are “very often triggers for relapse.” Awakn pairs its ketamine therapy with a cognitive behavioral manual that is specifically designed to help people deal with the ketamine experience. In Phase II, treatment with the regimen led to an average of 86% abstinence over the six months following treatment versus 2% prior to the trial, Awakn reported. Meanwhile, Berlin and U.S.-based atai Life Sciences is tackling opioid use disorder with ibogaine, a psychoactive compound that comes from the iboga tree and has long been used in spiritual ceremonies by indigenous people in West Central Africa. Data have shown “marked benefits” of ibogaine on opioid use disorder, including on withdrawal and persistent changes in mood and craving behavior, Srinivas Rao, chief scientific officer at atai, told BioSpace. In a review of clinical results from an open-label case series of human volunteers seeking to detoxify from opioids or cocaine, ibogaine therapy diminished withdrawal symptoms and reduced drug cravings. Atai expects to begin a Phase I/IIa trial with an intravenous form of ibogaine, IBX-210, in the second half of this year. While atai considered other molecules, including LSD, the company decided to go with ibogaine because of “compelling” aggregate data in opioid use disorder. Like Awakn, Atai is planning to deliver IBX-210 with psychological support to help participants prepare for the dosing session and integrate it into their experience afterward. ‘Not a Cure-All’ While treatments like AWKN-001 and IBX-210 are intended for people with addictive personalities, “you need to consume [ketamine] in a very significantly greater quantity and on a far more regular and ongoing basis than our treatment cycle and treatment program requires” in order for addiction to be an issue with the drug, Tennyson said. Garcia-Romeu said that substances like psilocybin are not addictive in the sense that they don’t produce withdrawal and tolerance, but acknowledged that they can create a form of psychological dependence where people seek out the drug. In general, he said, “The drugs are pretty self-limiting.” Rao added that psychedelic therapies in development are intended to be administered in a supervised medical setting to mitigate their risks. “Regardless of whatever likeability any of these compounds have, none of them are being developed for at-home therapy, so that’s an important element.” Many treatment protocols—including Awakn’s AWKN-001—are combined with talk therapy, something Todd Berrios, a Veteran of the U.S. Army Special Forces who was wounded in combat was diagnosed with both alcohol dependency and post-traumatic stress disorder, told BioSpace is critical. In August 2023, through a grant sponsored by VETS, Berrios was treated with ibogaine and 5-MeO-DMT, a psychedelic found in a wide variety of plant species and secreted by the glands of at least one toad species. Since then, “I haven’t had the urge, want or need to drink alcohol, which I thought was pretty impressive,” he said. However, he emphasized that ibogaine and 5-MeO-DMT are not a “cure-all” and that patients need to put in work. “There’s never an end game, there’s never a finish line. It’s constant work,” said Berrios, who participates in weekly men’s calls, mindful medication calls and men’s calls hosted by VETS. And the psychedelic experience is not positive for everyone. In a mixed-method study published in PLOS ONE last year, 608 participants reported extended difficulties following psychedelic experiences, including feelings of anxiety and fear, existential struggle and social disconnection. The Road Ahead While the research appears promising, psychedelic therapies still have an uphill climb. Psilocybin and LSD are experimental, Garcia-Romeu said, and they are not legal in the U.S. or “in most countries.” Rao also acknowledged that working with Schedule 1 drugs adds “a lot more paperwork,” including with importation and exportation. Additionally, Garcia-Romeu said, “We don’t really know how it works. We also are kind of in this process of understanding what types of treatments are best paired with the psychedelic because it’s not just the drug that seems to help exert these effects, but it’s almost always incorporated within some form of counseling or psychotherapy.” The other main hurdle, Garcia-Romeu said, will be accessibility. “This will likely be an expensive type of treatment, because it’s very labor intensive,” he said, noting that a course of psychedelic therapy takes around three months to complete and requires hours of psychotherapy. “So even if this becomes an approved medicine, people’s ability to access these treatments may be slow, I would say, and probably limited to people of means.” Rao also noted the stigma, or “sociological overlay,” around psychedelics. “There’s just a lot of additional baggage.” Psychedelic therapies would also require a different kind of paradigm shift, he said. “Whether it’s depression or substance use disorder, we’re really looking at intermittent therapy rather than daily therapy.” Some of the baggage could be lessened this summer if Lykos Therapeutics wins FDA approval for its midomafetamine (MDMA) capsules to treat post-traumatic stress disorder. The FDA has set a PDUFA date of August 11, 2024. Heather McKenzie is a senior editor at BioSpace. You can reach her at heather.mckenzie@biospace.com. Also follow her on LinkedIn.

When white blood cells, meant to protect the body from infection, are overly activated, they eject their DNA into nets, further disrupting the immune system and making patients more likely to develop a potentially severe reaction to immunotherapy. A new study from the University of Michigan Health Rogel Cancer Center reveals a connection between the most common type of white blood cells, which act as a first defense in the body's immune system, and a severe complication of CAR T-Cell immunotherapy. The findings, out now in Blood Advances, show that a process called NETosis, in which neutrophils eject their DNA to create webs, may contribute to the development of cytokine release syndrome (CRS), a potentially life-threatening hyper-activation of the immune system. Further, the team, led by Muneesh Tewari, M.D., Ph.D., Ray and Ruth Anderson-Laurence Sprague Memorial Research Professor in the Department of Internal Medicine, and Sung Won Choi, M.D., M.S., Edith S. Briskin and Shirley K. Schlafer Foundation Research Professor of Pediatrics, identified certain proteins that are biomarkers of NETosis and could predict which patients are likely to develop CRS before they develop symptoms. Tewari explains that there are FDA-approved drugs that can be used to affect neutrophils, like disulfiram used to treat alcohol abuse. Though typically prescribed for other conditions, these drugs could be leveraged to inhibit NETosis and prevent CRS. "We identified biomarkers that are part of the 'nets' the neutrophils cast, and an indication that CRS is likely to occur," Tewari said. "In addition to this strong correlation, we hypothesize that NETosis is also contributing to the development of CRS. We want to test this idea in preclinical models, and eventually in clinical trials, to see if we can inhibit the net formation and reduce the risk of CRS in patients." Over 70% of patients develop cytokine release syndrome; about 15%-20% of those cases are severe and could require admission to an intensive care unit because of low blood pressure, increased heart rate, shortness of breath, or major organs shutting down. Patients can develop cytokine release syndrome within a week after receiving CAR T-cell infusions. Tewari explains that little is known about the mechanisms happening during that first week, before CRS symptoms are present. Given this lack of knowledge, the research team used proteomics analysis to measure hundreds of proteins in blood samples from patients who underwent CAR T-cell therapy, both those who went on to develop CRS and those who didn't. "We found dozens of proteins that seem to be different in patients who go on to develop CRS versus those who don't. We also found less than 10 proteins that seemed to be different before patients developed CRS, even before they got the treatment," Tewari explained. The team also analyzed what proteins in the blood plasma change over time as CRS developed. "We noticed that neutrophil-related proteins were coming up. That tipped us off to think more about neutrophils specifically, which let us to NETosis," Tewari said. The process of NETosis is like its name suggests. When neutrophils are triggered, which normally might happen at the onset of a bacterial infection, for example, they eject their DNA, which is packed tightly inside the nucleus, into structures resembling "nets" that can capture and contain the bacteria. In patients that go on to develop CRS, Tewari explains that while there is "no bacteria, per se," the neutrophils are confused and act as though there's an invader. "We don't yet know why, but in some patients, their neutrophils are already triggered and on high alert. They're already forming these nets, which activates the entire immune system and makes their bodies more prone to over-react by making a flood of cytokines, producing CRS." In addition to pursuing clinical trials to see if certain FDA-approved drugs can help suppress NETosis, Tewari says this study could help reveal how stress affects the body on a cellular level. "We're seeing more and more how a triggered immune system makes a difference in terms of outcomes, especially with cytokine release syndrome," Tewari said. "There's early data to suggest that psychological stress can affect neutrophil function. This study is another piece of the puzzle that could lead to more insights into how stress can negatively impact the body and contribute to illness."