Acamprosate Calcium

▎药明康德内容团队编辑 喝酒伤身，这可不是一句空话。长期大量饮酒可导致酒精使用障碍的发生，患者对酒精使用的控制力削弱，导致生理依赖，耐受性增加以及心理、社会功能和身体的损害。相关研究显示，酒精使用障碍的终生患病率为9%，男性患病率是女性的48倍之多。心理社会支持治疗是酒精使用障碍治疗的基石，药物治疗数据比较有限，但整体也是有效的。既往动物实验发现，胰高血糖素样肽-1受体激动剂（GLP-1 RA）可减少酒精的使用，这提示GLP-1 RA或有潜力作为降低酒精危害的治疗方式。 近日，JAMA Psychiatry发表一项研究，结果以简短报告的形式发布，表明GLP-1 RA中的司美格鲁肽和利拉鲁肽有助于减少酒精使用障碍患者的饮酒量，降低住院风险。 截图来源：JAMA Psychiatry 这是一项观察性研究，纳入年龄16~64岁确诊为酒精使用障碍的患者22万多例，其中63.5%为男性，36.5%为女性，平均年龄40岁。中位随访8.8年间，其中6276例患者使用GLP-1 RA（主要为利拉鲁肽、艾塞那肽、度拉糖肽和司美格鲁肽），7.5万例患者接受酒精使用障碍药物（主要为disulfiram、acamprosate和纳曲酮）治疗。共有13万多（58.5%）的酒精使用障碍患者住院接受治疗。 研究结果显示，接受GLP-1RA治疗的患者中，使用司美格鲁肽的患者风险最低，其中因酒精使用障碍住院风险降低了36%（aHR=0.64，95%CI：0.50~0.83），因任何物质使用障碍（指使用精神活性物质导致的任何精神障碍）住院风险降低了32%（aHR=0.68，95%CI：0.54~0.85）。 其次是利拉鲁肽，其因酒精使用障碍住院风险降低了28%（aHR=0.72，95%CI：0.57~0.92），因任何物质使用障碍住院风险降低了22%（aHR=0.78，95%CI：0.64~0.97）。使用任何治疗酒精使用障碍的药物均可适当降低因酒精使用障碍住院风险和因任何物质使用障碍住院风险。 ▲使用不同药物的患者，因酒精使用障碍住院风险（A）和因任何物质使用障碍住院风险（B）差异（图片来源：参考文献[1]） 此外，研究人员还发现，司美格鲁肽和利拉鲁肽可分别使因躯体症状住院风险降低22%（aHR=0.78，95%CI：0.68~0.90）和21%（aHR=0.79，95%CI：0.69~0.91），但并不能降低患者企图自杀的风险。 研究第一作者兼通讯作者，来自东芬兰大学的Markku Lähteenvuo教授表示：“我们的研究结果表明，GLP-1RA不仅能够治疗糖尿病和肥胖，还可能有助于治疗酒精使用障碍和物质使用障碍，当然，这一发现仍需在随机对照试验中进一步验证”。 点击文末“阅读原文/Read more”，即可访问JAMA Psychiatry官网阅读完整论文。 推荐阅读 欢迎投稿：学术成果、前沿进展、临床干货等主题均可，点此了解投稿详情。 参考资料 [1]Lähteenvuo M, Tiihonen J, Solismaa A, Tanskanen A, Mittendorfer-Rutz E, Taipale H. Repurposing Semaglutide and Liraglutide for Alcohol Use Disorder. JAMA Psychiatry. Published online November 13, 2024. doi:10.1001/jamapsychiatry.2024.3599 [2] 王岚,王冉,王学义.酒精使用障碍的危害及风险[J].神经疾病与精神卫生，2024，22（4）：229-233. [3]University of Eastern Finland. Obesity-fighting drugs may reduce alcohol consumption in individuals with alcohol use disorder.13-Nov-2024.https://www.eurekalert.org/news-releases/1064676 免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。 版权说明：本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「医学新视点」微信公众号留言联系。 如有其他合作需求，请联系wuxi_media@wuxiapptec.com 分享，点赞，在看，传递医学新知

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.