Phase I, Randomized, Double-Blind, Placebo-Controlled, Single Ascending Dose Study to Assess the Safety, Tolerability, and Pharmacokinetics of Oral MG001

This research study is the first time the new medication MG001 is being tested in people. MG001 is a formulation of mitragynine, a compound that comes from a plant called Mitragyna speciosa (sometimes known as kratom), which some people use on their own to help manage symptoms of opioid withdrawal. The purpose of this study is to understand how safe MG001 is, how well it is tolerated, and how the body processes it. About 32 healthy adult volunteers, both men and women, will take part. Before joining, participants will undergo screening tests up to four weeks in advance to make sure they are eligible and healthy enough. On the day before dosing, participants will be admitted to the clinic for final health checks, and those who qualify will be randomly assigned-by chance, like flipping a coin-to receive either a single dose of MG001 or a placebo (an inactive substance). Neither the participants nor the staff giving the medicine will know which one is given. The study drug will be administered after at least 10 hours of fasting, and participants will then remain in the research clinic under close medical observation for three nights, until Day 4. During this time, doctors and nurses will monitor participants' health, look for any side effects, and collect blood samples to see how MG001 moves through the body. A follow-up clinic visit on Day 7 will provide one last check-in and blood test. This design helps researchers gather important first information on the safety and tolerability of MG001, while protecting the health and well-being of participants.

开始日期2026-09-01

申办/合作机构

National Institute on Drug Abuse

[+2]

IRCT20230707058707N1

/ Completed临床1期IIT

Evaluating the safety of Administration of Adenosine, Lidocaine, and Mg(ALM) cocktail among Multiple Trauma Patients receiving Massive Transfusion with dose escalation A phase I, clinical trial

开始日期2023-12-22

申办/合作机构

Shiraz University of Medical Sciences

TCTR20250717004

/ Completed临床3期IIT

Efficacy and safety of Mitragynine gel in primary osteoarthritis knee ; Randomized controlled trial

开始日期2023-05-01

申办/合作机构

National Research Council of Thailand

100 项与 Mitragynine 相关的临床结果

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100 项与 Mitragynine 相关的转化医学

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100 项与 Mitragynine 相关的专利（医药）

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项与 Mitragynine 相关的文献（医药）

2026-12-01·TALANTA

Electrochemical behavior of mitragynine and its determination by HPLC with dual-channel coulometric detection

Article

作者: Maier, Vitezslav ; Jirovsky, David ; Hrbac, Jan ; Belbasi, Zeynab

This study provides the first report on the intrinsic electrochemical behavior of mitragynine, the principal alkaloid of Mitragyna speciosa (kratom). Voltammetric analysis revealed that mitragynine undergoes a pH-dependent anodic oxidation at relatively low potentials (Epa = 530 mV vs Ag/AgCl at pH 7), with a Nernstian slope of 59 mV per pH unit, suggesting a proton-coupled electron transfer mechanism involving the indole moiety. Under the studied experimental conditions, the mitragynine anodic feature is irreversible and diffusion-limited. Based on these electrochemical findings, a sensitive HPLC method with dual-channel coulometric detection (HPLC-ECD) was developed for the determination of mitragynine without requiring any prior derivatization steps. Under optimized conditions at +700 mV vs Pd/H₂, the method achieved a superior limit of detection (LOD) of 1.8 ng mL^-1 and a limit of quantification (LOQ) of 5.5 ng mL^-1, maintaining excellent linearity (R² = 0.999) across the concentration range of 20-200 ng mL^-1. The utility of the dual-channel configuration was demonstrated through the adaptive optimization of selectivity: while +700 mV ensured maximum sensitivity for kratom plant extracts (yielding 13.5 mg g^-1), a lower potential of +300 mV effectively suppressed co-eluting endogenous interfering species in complex human plasma matrices. The use of dual-channel detection enabled not only the selectivity optimization, but also confirmation of analyte identity based on the consistency of signal ratios at different detection potentials. The proposed approach represents a simple, cost-effective, and reliable strategy for the determination of mitragynine and highlights the potential of electrochemical detection for the analysis of electroactive alkaloids in complex matrices.

2026-07-01·PHYTOCHEMISTRY

Quantitative analysis of 7-hydroxymitragynine in commercial kratom products and its stability under chemical and physiological conditions

Article

作者: Pandey, Pankaj ; Avula, Bharathi ; Ali, Syed Kashif ; Khan, Ikhlas A ; Cheepilla, Lochana ; Katragunta, Kumar ; Tatapudi, Kiran K ; Khan, Shabana I ; Chittiboyina, Amar G ; Ali, Zulfiqar ; Husain, Islam

7-Hydroxymitragynine (7-OH), a minor alkaloid in kratom (Mitragyna speciosa (Korth.) Havil.) (Rubiaceae) and an active metabolite of mitragynine, is a critical transient precursor to mitragynine pseudoindoxyl, which exhibits >2-fold μ-opioid receptor-biased agonism and improved isoform selectivity relative to its precursors. Although present only in trace amounts in kratom leaves, a recent survey identified hundreds of consumer products with semisynthetic 7-OH and mitragynine pseudoindoxyl. Their high potency, ease of access, and risk of addiction have prompted the US FDA to recommend scheduling 7-OH as a Schedule I controlled substance. To address this public health crisis and the associated analytical challenges, a comprehensive analysis of commercially available kratom products was performed. The results revealed substantial inconsistencies between the quantities claimed on the products' labels and the actual 7-OH amount detected in several of these products. Along with 7-OH and mitragynine pseudoindoxyl, several (over)oxidized byproducts were detected, providing crucial insights into their synthetic origins. Analysis of >98% of 7-OH-labeled products indicated a semisynthetic origin, with labeled doses ranging from 0.001 to 33.6 mg per serving. Furthermore, consistent with the prior report, 7-OH degrades into the potentially toxic byproduct 3-dehydromitragynine under simulated gastric conditions. These findings underscore significant safety concerns over oral 7-OH products and necessitate validated analytical monitoring to guide regulatory oversight and consumer protection.

2026-06-07·SUBSTANCE USE & MISUSE

Kratom Beverages Online: Marketing Narratives, Content, Dosing, and Potential Risks

Article

作者: Chin, Sayorn ; Perry, Teresa

BACKGROUND:

In the past five years, the market for pre-made kratom, or Mitragyna speciosa, drinks has expanded rapidly. They are now sold in retail stores, convenience stores, grocery stores, specialty tobacco shops, and online. Despite their rapid market expansion, significant gaps remain in our understanding of their online marketing strategies, reported kratom content, dosing information, and serving sizes.

OBJECTIVES:

To examine the online marketing practices of pre-made kratom beverages sold in the United States, with a focus on transparency, dosage information, and public health risks.

METHODS:

We analyzed the front labels and websites of 107 ready-to-drink kratom products using Python-based web scraping and manual image inspection. We examined marketed benefits, ingredient lists, dosage recommendations, and the presence of warnings or Food and Drug Administration (FDA) disclaimers.

RESULTS:

Kratom content ranged from 20 mg to 500 mg per drink and was reported using inconsistent terms such as "extract," "alkaloids," or "mitragynine." Serving suggestions varied from one to fifteen servings per drink, and the recommended dose ranged from 17.5 mg to 350 mg. Marketing of the product most emphasized natural or organic qualities and wellness related claims.

CONCLUSIONS:

The considerable variation in reported kratom content, dose, and serving size, together with its frequent framings as a "health-based" product, points to a need for stronger regulation. Policies should include evidence-based dosing recommendations, standardized and transparent online descriptions and warnings, and clear marketing guidelines for kratom beverages promoted as natural or wellness products.

项与 Mitragynine 相关的新闻（医药）

2026-07-02

·PRNewswire

Statement from Shatterproof on DEA's Temporary Scheduling of 7-Hydroxymitragynine (7-OH) and Related Substances

WASHINGTON, July 2, 2026 /PRNewswire/ -- Shatterproof applauds the U.S. Drug Enforcement Administration's decision to temporarily schedule 7-hydroxymitragynine (7-OH) and related substances. This is an important and long-overdue step toward addressing the rapid proliferation of highly potent, chemically modified kratom-related products that have outpaced existing regulatory safeguards. For too long, consumers, especially young people, have had access to products marketed as "natural" despite containing concentrated, semi-synthetic or synthetic compounds with opioid-like effects and significant risks. Yesterday's action reflects growing recognition that these products warrant a stronger federal response. While this action represents meaningful progress, it is not the finish line. Continued federal leadership is needed to: evaluate the broader landscape of synthetic, semi-synthetic, and highly concentrated kratom-related substances, as well as other emerging drugs; establish clear product standards; strengthen enforcement against unsafe and misleading products; support rigorous scientific research on safety, efficacy, and appropriate use to inform long-term policy and ensure whole leaf kratom and mitragynine only products, which still possess psychoactive effects, are included in research and regulatory efforts Shatterproof remains committed to advancing evidence-based policies that protect youth. We will continue working with federal and state partners to build comprehensive policies that limit youth access to emerging substances, increase transparency to product safety, and ensure public policy is informed by the best available science. Our recent analysis in Health Affairs and educational webinar on kratom further explore the risks posed by today's evolving marketplace and the policy solutions needed to better protect consumers. and provide transparency into the safety of these products. SOURCE Shatterproof 21% more press release views with Request a Demo

2026-05-21

·神经科的那些事

前沿进展--CAR T细胞治疗重症肌无力的研究进展

一、重症肌无力的病理生理与治疗现状 1.1 免疫学发病机制重症肌无力（MG）是一种由自身抗体介导、补体参与、T细胞依赖的获得性神经肌肉接头传递障碍性疾病。约85%患者存在抗乙酰胆碱受体（AChR）抗体，这些抗体通过三种主要机制导致突触后膜破坏：①直接阻断AChR的乙酰胆碱结合位点，干扰神经递质传递；②通过补体经典途径激活膜攻击复合物（MAC），导致突触后膜褶皱溶解和AChR密度降低；③加速AChR的内吞和降解，缩短其半衰期。约5-8%患者存在抗肌肉特异性酪氨酸激酶（MuSK）抗体，这类患者通常不依赖补体介导的损伤机制，而是通过直接干扰MuSK-DOK7信号通路影响AChR聚集。约1-3%患者存在抗低密度脂蛋白受体相关蛋白4（LRP4）抗体，LRP4作为agrin-MuSK信号通路的关键共受体，其自身抗体同样干扰突触后分化（Liu et al, Rev Neurol, 2026）。 1.2 传统治疗的局限性现有MG治疗策略主要围绕症状控制和非特异性免疫抑制展开。胆碱酯酶抑制剂（如溴吡斯的明）仅改善神经肌肉传递效率，对疾病本身的免疫病理过程无影响。糖皮质激素和传统免疫抑制剂（硫唑嘌呤、吗替麦考酚酯、他克莫司、环孢素）通过广谱免疫抑制控制疾病活动，但需长期维持使用，伴随显著的累积毒性，包括骨质疏松、代谢综合征、感染风险增加和恶性肿瘤风险。约10-15%患者对上述治疗无充分应答，发展为难治性MG（rMG），这部分患者面临持续的疾病活动和进行性残疾风险（Liu et al, 2026）。近年来靶向生物制剂为rMG带来了新的治疗选择。补体C5抑制剂依库珠单抗（Eculizumab）在AChR抗体阳性gMG中显示出疗效，显著改善MG-ADL评分（Guan et al, Syst Rev, 2025）。FcRn拮抗剂艾加莫德（Efgartigimod）通过加速IgG分解代谢降低致病性自身抗体水平，在ADAPT试验中达到主要终点。IL-6受体抑制剂托珠单抗在部分难治性患者中显示出前景。然而，这些生物制剂仍需持续给药，部分患者应答不充分或出现继发性失应答，且长期使用带来的感染风险和卫生经济学负担不容忽视。利妥昔单抗（抗CD20单抗）在MuSK-MG中疗效明确，但在AChR-MG中的疗效数据有限，其无法清除长寿命浆细胞是疗效受限的重要原因之一（Gu & Zhao, Intractable Rare Dis Res, 2026）。 1.3 从免疫抑制到免疫重建的范式转变传统治疗的核心局限在于其"免疫抑制"而非"免疫重建"的本质——它们压制免疫系统的功能，但不消除致病性免疫细胞克隆，停药后疾病极易复发。CAR T细胞疗法作为"活体药物"，通过基因工程改造自体T细胞，使其表达靶向特定抗原的嵌合抗原受体（CAR），精准识别并清除表达靶抗原的细胞群体。与传统抗体疗法不同，CAR T细胞可在体内扩增、迁移至淋巴组织和中枢神经系统，穿透血脑屏障，并在清除靶细胞后分化为记忆T细胞，维持长期的免疫监视功能。这种"一次治疗、长期获益"的潜力使其代表了从慢性免疫抑制向免疫重建的范式转变（Dalakas, Ther Adv Neurol Disord, 2026；Katsaros & Mougiakakos, Ther Adv Neurol Disord, 2025）。二、CAR T细胞构建类型与靶点选择 2.1 CD19靶向CAR T细胞 CD19是B细胞谱系广泛表达的跨膜糖蛋白，从早期前B细胞到浆母细胞阶段持续表达，是B细胞耗竭的理想靶点。抗CD19 CAR T细胞（如Kyverna Therapeutics开发的KYV-101）通过清除CD19+ B细胞群体，消除包括自身反应性B细胞克隆在内的整个B细胞库。在血液恶性肿瘤中，CD19 CAR T已证明深度和持久的B细胞耗竭能力。在自身免疫性神经系统疾病中，CD19 CAR T已显示出令人瞩目的疗效。 Ayzenberg等报告了一例具有代表性的难治性病例：62岁女性，抗GAD抗体阳性的僵人综合征（SPS）合并抗AChR阳性MG，14年病史，经历静脉注射免疫球蛋白、血浆置换、糖皮质激素、硫唑嘌呤和利妥昔单抗等多种治疗均告失败。患者病情进行性加重，步行距离不足10-15米，左上肢持续僵硬伴疼痛性肌痉挛发作。在同情用药的框架下接受抗CD19 CAR T（KYV-101）治疗后，从第3个月起步行距离显著改善，第6个月可步行500米，抗GAD滴度从1:320降至1:32，MG症状同步缓解。安全性方面仅出现Grade 2 CRS和短暂性白细胞减少，无ICANS或严重感染。该病例证明了CD19 CAR T在同一患者中同时靶向两种不同自身免疫性疾病的能力（Ayzenberg et al, Neurol Neuroimmunol Neuroinflamm, 2025）。 2.2 BCMA靶向CAR T细胞 BCMA（B细胞成熟抗原，又称TNFRSF17）特异性表达于浆细胞和浆母细胞表面，是自身抗体产生的核心效应细胞。与传统CD20靶向治疗（如利妥昔单抗）不同，BCMA靶向策略可以直接清除长寿命浆细胞，这些细胞不表达CD20，是传统B细胞耗竭疗法无法覆盖的"盲区"。在MG中，浆细胞是抗AChR、抗MuSK和抗LRP4自身抗体的直接来源，因此BCMA靶向具有独特的理论优势。 Descartes-08（Cartesian Therapeutics）是一种RNA编码的自体抗BCMA CAR T细胞疗法，其技术路线与传统DNA整合型CAR T存在根本差异。①非整合性：RNA通过电转导入T细胞，不整合入宿主基因组，消除了基因组插入突变风险；②自限性表达：CAR蛋白随细胞分裂逐渐稀释，降低了长期B细胞耗竭的风险；③门诊给药：无需住院管理和持续静脉输注；④无需淋巴清除：不依赖氟达拉滨/环磷酰胺预处理，减少了预处理相关的血液学毒性和感染风险。在Phase 2b RCT（NCT04146051, MG-001研究）中，26例gMG患者随机接受Descartes-08（n=15）或安慰剂（n=11），给药方案为6次每周静脉输注（52.5×10⁶ CAR⁺ cells/kg/次）。主要终点（MGC改善≥5分）在Descartes-08组达到66.7%（10/15），显著优于安慰剂组27.3%（3/11，P=0.0472）。在AChR抗体阳性亚组中，差异更为显著（63.6% vs 12.5%，P=0.0258）。至第6个月，33%的患者达到最小症状表达（MSE，MG-ADL ≤1），这一比例在生物制剂初治患者中高达55.6%，并在第12个月维持不变。至第12个月，83%的Descartes-08治疗患者维持持续且临床有意义的应答（Vu et al, Nat Med, 2026）。 Chahin等进一步报告了MG-001研究7例接受6次每周输注患者的12个月随访数据。所有患者在第3个月均表现出MGComposite、MG-ADL、QMG和MG-QoL 15r评分的显著改善，且无显著毒性。至第9个月，所有患者仍维持显著的临床改善。在第12个月，5/7患者维持应答，3例出现疗效丧失（约在第6个月后复发）。值得注意的是，3例复发患者均接受了Descartes-08再治疗，其中2例在第8周即达到最小症状表达，并维持至再治疗后12个月；第3例也获得了与首次治疗相似的临床评分改善。这些数据证明了BCMA-CAR T再治疗的安全性和有效性，为复发管理提供了策略支持（Chahin et al, Ann Clin Transl Neurol, 2025）。 2.3 BCMA/CD19双靶点CAR T细胞双靶点策略同时覆盖CD19+ B细胞和BCMA+浆细胞，理论上实现更彻底的B细胞谱系清除。Zhang等在徐州医科大学附属医院开展的单臂Phase 1试验（ChiCTR2200061267）中，18例难治性gMG患者接受抗BCMA/CD19双特异性CAR T细胞单次输注（剂量梯度：1.0、3.0、5.0×10⁶ CAR⁺ T cells/kg）。结果显示82%（15/18）患者达到最小症状表达，88%（16/18）停用糖皮质激素，47%（8/17）实现抗AChR抗体血清学转阴。MG-ADL评分平均改善-8.6分（95% CI -10.2至-7.0），QMG评分平均改善-15.4分（95% CI -17.6至-13.2）。安全性方面，仅39%患者出现Grade 1 CRS，无ICANS报告。最常见的Grade 3+不良事件为短暂性血液学毒性：3例白细胞减少、3例中性粒细胞减少、1例贫血和1例血小板减少，均可控可恢复（Zhang et al, EClinicalMedicine, 2025）。 Ruan等采用类似的双靶点策略但无需淋巴清除预处理，治疗6例难治性gMG患者。5/6患者在输注后第90天达到MG-ADL=0（最小症状表达），全部患者停用糖皮质激素。CAR T细胞在体内扩增峰值出现在输注后8-22天，持续性约28至180天。通过单细胞RNA测序和流式细胞术纵向分析，该研究揭示了B细胞重建后BCR信号减弱、骨髓微环境抑制性信号增强、T/B细胞克隆扩增显著减少，以及重建的B细胞以初始B细胞为主且AChR特异性降低。这些发现共同支持CAR T治疗后发生的是"系统性免疫重置"而非简单的B细胞耗竭（Ruan et al, Med, 2026）。 2.4 下一代精准靶向策略（1）CAAR T细胞（嵌合自身抗体受体T细胞）：Oh等设计了表达AChR α亚基胞外域（A210，210个氨基酸）的CAAR T细胞，通过CD137-CD3ζ胞内域引导T细胞毒性特异性针对抗AChRα B细胞。研究发现A210-CAART结合CD8α跨膜域（TMD8α）虽有功能但表面表达不稳定，部分可通过抑制溶酶体降解恢复。而结合CD28跨膜域的A210-CAART实现了持续的表面表达，不依赖TMD二聚化基序。在小鼠异种移植模型中，A210.TMD8α-CAART早期控制了抗AChR B细胞扩增但随后出现反弹和表面CAAR表达丢失；相反，A210.TMD28-CAART实现了持续的表面CAAR表达和靶细胞清除。该研究证明了CD28跨膜域对CAAR稳定性和体内功能的关键作用，为AChR-MG的精准细胞免疫治疗奠定了基础（Oh et al, Sci Adv, 2026）。Trinh和Fairclough（2025）进一步开发了人AChR主免疫原区（MIR）的肽模拟物（H39MIR），可作为CAAR靶向元件或Fc融合蛋白的靶向部分，用于清除抗MIR记忆B细胞。（2）CAR-Treg细胞：将调节性T细胞（Treg）与CAR技术结合，使Treg在疾病局部高浓度聚集，创造免疫耐受微环境，避免全身性免疫抑制。这一策略在器官特异性自身免疫疾病中可能更具优势。（3）同种异体"现货"CAR T：通过基因编辑消除移植物抗宿主病（GvHD）风险，实现即用型CAR T产品，大幅降低制备成本和时间。（4）体内CAR T工程化：通过LNP递送CAR编码mRNA直接在体内工程化T细胞，消除体外制备环节，是实现CAR T可及性的潜在革命性策略（Wu et al, Front Immunol, 2025；Yao et al, Immun Inflamm Dis, 2025）。图1. CAR T细胞构建类型关键维度比较（基于靶点覆盖深度、特异性、安全性、持久性和可及性综合评分）三、临床证据汇总与数据分析 3.1 关键临床试验结果目前公开的CAR T治疗难治性gMG的临床数据来自4项病例系列和1项Phase 2b随机对照试验。Hegelmaier等（2026）系统梳理了截至2025年7月的文献，确认5项独立病例系列共7例患者接受CAR T治疗，靶点涵盖CD19、BCMA和双特异性抗原。所有患者均表现出一致的临床改善。CAR T细胞体内扩增峰值出现在输注后8-22天，持续时间为28至约180天。安全性方面优于肿瘤适应症，主要为Grade 1-2 CRS，罕见ICANS，无严重或危及生命事件。7项注册临床试验（>260例患者）正在进行中，预计2026-2029年完成（表1）。图2. CAR T细胞疗法治疗MG的MG-ADL评分最大改善幅度（负值表示改善）图3. CAR T细胞疗法治疗MG的临床应答率与免疫学指标（MSE、激素停药、AChR抗体转阴） 3.2 不同抗体亚型的疗效差异 AChR抗体阳性患者是CAR T治疗MG研究中最大的亚群。Vu等（2026）的Phase 2b RCT亚组分析显示，AChR抗体阳性患者中Descartes-08治疗组63.6%（7/11）达到主要终点，而安慰剂组仅12.5%（1/8），差异具有统计学意义（P=0.0258），且在数值上优于总体人群（P=0.0472），提示AChR阳性亚组可能是CAR T治疗的最优获益人群。这一发现与AChR-MG的自身抗体产生高度依赖BCMA+浆细胞的病理机制一致。 MuSK-MG患者的CAR T治疗数据有限，但基于其自身抗体（抗MuSK IgG4亚型）同样来源于浆细胞的机制，理论上BCMA靶向策略同样适用。LRP4-MG方面，Schreiber等（2025）报告了一例难治性LRP4+ MG患者使用Teclistamab（BCMA×CD3双特异性T细胞衔接抗体，非CAR T但同为BCMA靶向策略）的成功案例：47岁女性，轮椅依赖，接受teclistamab治疗后出现轻度CRS和自限性淋巴细胞减少，残存循环B细胞被清除，抗LRP4抗体变为不可检测，临床评分显著改善，恢复行动能力并维持短期缓解。该案例为BCMA靶向策略在罕见MG亚型中的应用提供了概念验证（Schreiber et al, Mol Ther, 2025）。 3.3 免疫学机制深度解析 Ruan等的单细胞RNA测序研究提供了CAR T治疗后免疫重置的最深入分子层面证据。CAR T细胞在体内扩增导致B细胞和浆细胞深度耗竭。B细胞重建后表现出BCR信号减弱和来自骨髓微环境的抑制性信号增强，T细胞和B细胞的克隆扩增显著减少。重建的B细胞以初始B细胞为主，AChR特异性降低，功能能力减弱。Olink蛋白组学分析进一步显示抗炎因子（IL-10、TGF-β等）上调和促炎分子（IL-6、TNF-α等）下调。这些发现共同支持CAR T治疗后发生的是一种"系统性免疫重置"，而非简单的B细胞耗竭（Ruan et al, Med, 2026）。 Huang等（2026）的研究进一步揭示了复发机制：在1例复发患者中，单细胞测序发现年龄相关B细胞（ABCs）扩增，差异基因分析显示Fc受体样5（FCRL5）表达在ABCs中显著上调。而在CAR T应答者中，FCRL5呈下调趋势。值得注意的是，在利妥昔单抗治疗后复发的MG患者中也观察到类似的ABC扩增和FCRL5上调，提示FCRL5可能是MG复发的一种共同的、此前未被识别的靶点。这一发现具有重要的临床转化意义：FCRL5靶向可能成为预防CAR T治疗后复发的潜在策略（Huang et al, Sci Adv, 2026）。 Fedak等（2026）对Descartes-08 Phase 2b试验的生物标志物分析进一步揭示了免疫重置的精确机制。通过流式细胞术、血清蛋白分析、多重细胞因子检测和批量/单细胞转录组学分析比较Descartes-08治疗组（n≤19）与安慰剂组（n≤15），发现BCMA+浆细胞和浆细胞样树突状细胞活性下降，疾病相关细胞因子（如IL-6）减少，同时自我反应性抗体和T细胞受体库发生改变。值得注意的是，这些效应不伴随免疫抑制——疫苗特异性抗体滴度未下降，无低丙种球蛋白血症。这些发现揭示了一种新型的"精确免疫重调"（precision retuning of self-reactivity），支持BCMA靶向RNA细胞疗法作为自身免疫性疾病更易获取的治疗选择（Fedak et al, Nat Med, 2026）。图4. CAR T治疗后免疫重置的生物学标志物（左：经综合后的B细胞重建示意时间线，仅作参考；右：经综合后的浆细胞重建示意时间线）图5. CAR T治疗后免疫重置的生物学标志物（左：B细胞亚群组成变化；右：AChR抗体滴度下降轨迹）四、安全性特征 CAR T治疗自身免疫性疾病的毒性特征与肿瘤适应证存在根本差异，这是其能够在神经自身免疫领域快速推进的关键前提。以下从四个维度系统分析现有安全性数据。 4.1 细胞因子释放综合征（CRS） CRS是CAR T治疗最常见的急性毒性，由CAR T细胞激活后大量释放炎性细胞因子（IL-6、IFN-γ、TNF-α等）引起。在肿瘤适应证中，Grade 3+ CRS发生率可达20-30%。然而在MG的CAR T治疗中，CRS发生率显著降低且严重程度明显减轻。Zhang等报告39%患者出现Grade 1 CRS；Ruan等所有患者均无CRS（可能与无需淋巴清除预处理有关）；Vu等报告80%出现输液相关反应（多数为Grade 1-2），66.7%出现Grade 1-2 CRS；Huang等仅报告Grade 1 CRS；Ayzenberg等出现Grade 2 CRS（SPS合并MG患者）。所有研究中均无Grade 3+ CRS或危及生命的CRS事件（Zhang et al, 2025; Ruan et al, 2026; Vu et al, 2026; Huang et al, 2026; Ayzenberg et al, 2025）。图6. CAR T细胞疗法治疗MG的CRS安全性分布（按研究分层的CRS分级比例） 4.2 免疫效应细胞相关神经毒性综合征（ICANS） ICANS是肿瘤CAR T治疗中最受关注的神经毒性，表现为失语、意识障碍、癫痫和脑水肿等。在所有已报告的MG CAR T治疗案例中，无ICANS事件。这可能与自身免疫疾病患者的靶细胞负荷远低于肿瘤患者有关，导致CAR T细胞扩增幅度较低，炎性细胞因子释放水平有限。Alqaisi等（2026）的系统综述也证实，在神经自身免疫CAR T应用中毒性谱与血液肿瘤显著不同，需要建立适应证特异性的风险评估框架（Alqaisi et al, Ann Clin Transl Neurol, 2026）。 4.3 血液学毒性最常见的Grade 3+不良事件为血液学毒性。Zhang等报告18例患者中出现3例白细胞减少、3例中性粒细胞减少、1例贫血和1例血小板减少，均为短暂性和可控的。Ayzenberg等报告了中度白细胞减少。这些血液学毒性可能与CAR T治疗或潜在的淋巴清除预处理有关，但在自身免疫适应证中普遍较轻，无需特殊干预（Zhang et al, 2025; Ayzenberg et al, 2025）。 4.4 感染风险深度B细胞耗竭理论上增加感染风险，但在现有CAR T治疗MG的数据中，无严重感染报告。Descartes-08的免疫学分析显示疫苗特异性抗体滴度未下降，无低丙种球蛋白血症，提示其免疫重置具有选择性，不损害基础体液免疫功能（Fedak et al, Nat Med, 2026）。五、讨论与展望 CAR T细胞疗法在难治性MG中的初步临床证据令人瞩目，但将其从研究性治疗转化为常规临床实践仍面临多重挑战。Dalakas（2026）在系统综述中强调，CAR T治疗代表了神经自身免疫疾病治疗算法的潜在范式改变，但需要在最佳患者选择、毒性管理和长期随访方面建立循证指南。以下从五个维度讨论未来研究方向。 ① 最佳治疗时机的确定：Dalakas（2026）强调CAR T应在患者达到早期活动性/难治性状态时尽早应用，而非等待晚期疾病进展导致不可逆的神经功能缺损。这需要建立精确的疾病活动度评估工具（如MG-ADL、QMG、MGC的动态监测）和分层标准，以识别最可能从CAR T治疗中获益的患者亚群。过早治疗可能使本可用传统药物控制的患者承受不必要的风险，而过晚治疗则可能错失免疫重建的窗口期。目前正在进行的7项注册临床试验将提供更大样本的数据，为治疗时机决策提供循证依据。 ② 长期疗效与复发机制的阐明：现有随访数据最长约12-18个月，B细胞重建后的疾病复发模式尚不明确。Chahin等（2025）报告3/7患者在Descartes-08首次治疗后约第6个月复发，但再治疗均获得成功（2/3在W8达MSE，1/3获得相似的临床评分改善）。Huang等（2026）发现的FCRL5/ABC通路提示了复发的一种可能机制——年龄相关B细胞（ABCs）在B细胞重建过程中异常扩增并高表达FCRL5，这些细胞可能携带自身反应性。FCRL5作为B细胞共受体，已在多种B细胞恶性肿瘤中被报道，但在自身免疫复发中的作用此前未被充分重视。这一发现为预防CAR T治疗后复发提供了潜在的新靶点。此外，需要更大样本的前瞻性队列来验证FCRL5作为复发生物标志物的预测价值。 ③ 安全性优化的持续探索：尽管现有数据安全性良好，但随着更多患者接受CAR T治疗，迟发性不良反应的风险需要在大规模队列中评估，包括继发性恶性肿瘤（基因组插入突变相关的克隆性造血或淋巴瘤）、长期免疫缺陷（反复感染风险）、以及B细胞耗竭对疫苗接种应答的影响。非整合型mRNA CAR T（Descartes-08）、同种异体"现货"CAR T和CAAR T等新技术路线可能进一步改善安全性。特别是CAAR T，通过精确靶向致病性B细胞克隆而非全B细胞谱系，有望在保持疗效的同时最大限度保留正常体液免疫功能（Oh et al, 2026）。 ④ 卫生经济学与可及性：CAR T治疗的单次费用高达数十万美元，远超大多数MG患者和医疗系统的承受能力。同种异体"现货"CAR T、体内CAR T工程化和简化制备流程是降低成本的潜在策略。此外，需要建立专门的CAR T治疗中心，培训神经内科医师掌握CAR T治疗的患者筛选、疗效监测和并发症管理能力。Luo等（2026）在JAMA Neurol综述中指出，CAR T在神经病学中的应用需要神经科医师的深度参与，从患者选择到神经毒性管理都需要神经科专长（Ismail et al, JAMA Neurol, 2025）。 ⑤ 精准靶向策略的临床转化：CAAR T和CAR-Treg代表了从"广谱B细胞清除"向"精准免疫调控"的演进方向。AChR-CAAR T和MuSK-CAAR T的临床开发将实现真正的抗原特异性治疗，在消除致病性自身反应性B细胞的同时保留正常的体液免疫功能。Oh等（2026）证明了CD28跨膜域对CAAR稳定性和体内功能的关键作用，为A210-CAAR T的临床转化奠定了技术基础。Wu等（2025）综述了五种CAR T优化策略：CD19靶向、长寿命浆细胞靶向、自身抗体特异性靶向、器官特异性CAR-Treg和mRNA工程化CAR T，指出建立及时的适应证应用共识指南和风险分层策略对于提升治疗个性化和降低不良反应至关重要。未来3-5年内，随着Phase 3试验结果的公布和CAAR T的首次人体试验，CAR T治疗MG的临床路径有望更加清晰（Wu et al, Front Immunol, 2025）。图6. CAR T细胞疗法在自身免疫性神经病学中临床证据的发展时间线参考文献： [1] Zhang Y, Liu D, Zhang Z, et al. Anti-BCMA/CD19 CAR T cell therapy in patients with refractory generalized myasthenia gravis: a single-arm, phase 1 trial. EClinicalMedicine. 2025; PMID: 41245531 [2] Ruan Z, Ning F, Zhang W, et al. Single-cell profiling of immune reset in patients with refractory generalized myasthenia gravis receiving autologous CD19/BCMA CAR-T cell therapy. Med. 2026; PMID: 41747738 [3] Vu T, Durmus H, Rivner M, et al. BCMA-directed mRNA CAR T cell therapy for myasthenia gravis: a randomized, double-blind, placebo-controlled phase 2b trial. Nat Med. 2026;32(3):1131-1141; PMID: 41514038 [4] Fedak RR, Ruggerie RN, Shan Y, et al. BCMA-directed mRNA CAR-T cell therapy for myasthenia gravis: exploratory biomarker analysis of a placebo-controlled phase 2b trial. Nat Med. 2026;32(3):1118-1130; PMID: 41514039 [5] Huang X, Zhang Z, Liu D, et al. BCMA/CD19 CAR T cell therapy for refractory myasthenia gravis: Proteomic signatures and single-cell transcriptomics of disease flares. Sci Adv. 2026;12(1):eaeb6424; PMID: 41481736 [6] Chahin N, Sahagian G, Feinberg MH, et al. Durability of Response to B-Cell Maturation Antigen-Directed mRNA Cell Therapy in Myasthenia Gravis. Ann Clin Transl Neurol. 2025;12(11):2358-2366; PMID: 40856088 [7] Ayzenberg I, Aloizou AM, Lohmann C, et al. Anti-CD19 CAR T-Cell Therapy in Advanced Stiff-Person Syndrome and Concomitant Myasthenia Gravis. Neurol Neuroimmunol Neuroinflamm. 2025;12(6):e200479; PMID: 41052399 [8] Hegelmaier T, Duscha A, Desel C, et al. Chimeric Antigen Receptor T-Cells in Myasthenia Gravis: Advances, Safety Challenges, and Future Directions. Muscle Nerve. 2026;73(6):942-951; PMID: 41958278 [9] Dalakas MC. The prospects of CAR T-cell therapies in changing the therapeutic algorithm of neurologic autoimmunities. Ther Adv Neurol Disord. 2026;19:17562864261429570; PMID: 41884016 [10] Dalakas MC. Promising Effects of CAR T-Cell Therapy in Refractory Stiff Person Syndrome and a Hopeful Future for All Neuroautoimmunities. Neurol Neuroimmunol Neuroinflamm. 2026;13(1):e200511; PMID: 41248446 [11] Katsaros DE, Mougiakakos D. CAR T-cell therapy for neurological disorders: scientific rationale and mechanistic insights. Ther Adv Neurol Disord. 2025;18:17562864251396039; PMID: 41394288 [12] Kaminski HJ, Kusner LL. Autologous CD19/BCMA CAR-T cell therapy for myasthenia gravis: Advancing care for those with severe disease. Med. 2026;7(4):101036; PMID: 41966710 [13] Oh S, Khani-Habibabadi F, O'Connor KC, Payne AS. Composition and function of AChR chimeric autoantibody receptor T cells for antigen-specific B cell depletion in myasthenia gravis. Sci Adv. 2026;11(9):eadt0795; PMID: 40020066 [14] Schreiber S, Al-Dubai M, Vielhaber S, et al. 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细胞疗法免疫疗法ASH会议临床研究

2026-05-06

·EINPresswire

The 'Natural' Supplement That Acts Like an Opioid: A Clinical Warning on Kratom

With 3,434 poison control reports in 2025 and no permanent regulation in sight, physicians warn kratom's most dangerous form could return to Florida shelves. FL, UNITED STATES, May 6, 2026 / EINPresswire.com / -- Kratom -related poison control calls have surged 1,200% in a decade, and a Florida emergency ban on its most potent form is set to expire June 30, 2026, after lawmakers failed to make it permanent. A board-certified addiction medicine physician explains what’s at stake. Kratom (Mitragyna speciosa) is marketed as a safe, “natural” herbal supplement, sold openly at gas stations, smoke shops, and online retailers. But behind the wellness branding lies a pharmacologically active and dangerous substance whose primary alkaloids—mitragynine and especially 7-hydroxymitragynine (7-OH)—act as partial agonists, producing dose-dependent effects: stimulant-like alertness at low doses and opioid-like sedation, analgesia, and euphoria at higher doses. Although some individuals begin use innocently, drawn by accessibility, Kratom’s opioid-receptor activity carries substantial risks of tolerance, dependence, and substance use disorder. The FDA has repeatedly warned that Kratom is not approved for any medical use and can cause serious adverse effects, including liver toxicity, seizures, respiratory depression, and addiction. Unregulated products often vary widely in potency and may contain contaminants or concentrated extracts that amplify dangers, increasing Risks in Florida and Nationally. Recent national data show a dramatic rise in Kratom-related harm. Poison control center reports for Kratom exposures increased approximately 1,200% from 2015 to 2025, reaching a record high of 3,434 reports in 2025. 3,434 poison control reports in 2025, a 1,200% increase over the past decade, documented by the CDC’s National Poison Data System. This surge reflects both greater accessibility of Kratom products and the growing potency of concentrated formulations, particularly those high in 7-hydroxymitragynine. In areas where such products remain readily available in many retail settings, clinicians are seeing a corresponding uptick in patients presenting with dependence and withdrawal. Concentrated or semi-synthetic 7-OH products are especially concerning. These bind more potently to opioid receptors and have driven regulatory action. In August 2025, Florida Attorney General James Uthmeier issued an emergency rule classifying isolated/concentrated 7-OH (above specific concentration thresholds) as a Schedule I controlled substance, leading to the removal of thousands of packages from shelves due to addiction and overdose risks. However, as of April 2026, proposed legislation to strengthen consumer protections and make 7-OH restrictions permanent did not pass before the legislative session ended. The emergency rule is set to expire June 30, 2026, leaving high-potency products in a legal gray area, while traditional kratom leaf products remain generally legal for adults 21+ under the existing Kratom Consumer Protection Act framework. "At Banyan Treatment Centers , we are seeing more patients whose 'innocent' start with Kratom has progressed to daily dependence, tolerance escalation, and withdrawal that disrupts work, relationships, and health, often compounding existing mental health or prior SUD challenges."-Dr. Darrin Mangiacarne. Key Risks and Pharmacology Opioid-like dependence: Chronic use leads to physical dependence. 7-hydroxymitragynine is significantly more potent than mitragynine (roughly 10–40x at mu-opioid receptors in some studies). This helps explain why extracts can lead to faster dependence. Withdrawal (onset 12–48 hours, peaking 1–3 days) includes muscle aches, insomnia, anxiety, irritability, gastrointestinal distress, and intense cravings, sometimes comparable to mild-to-moderate opioid withdrawal. However, severity varies with dose and product potency. Toxicity and medical complications: Liver injury, seizures, cardiovascular effects, and rare fatalities (frequently in combination with other substances). Unregulated nature: Variable alkaloid content, potential adulterants, and the rise of potent extracts or gummies/shots make dosing unpredictable and riskier. Kratom does not treat opioid use disorder safely or effectively; it often trades one dependence for another and may delay evidence-based care. When Individuals Should Seek Help: Encourage patients, families, and communities to seek professional evaluation if they notice. Escalating doses due to tolerance or inability to cut back. Withdrawal symptoms when stopping or reducing use. Continued kratom use despite negative impacts on health, relationships, work, or mental well-being. Cravings or using kratom to manage emotions, pain, or prior substance issues. Early intervention matters. At Banyan, we provide a comprehensive assessment for kratom use disorder alongside any co-occurring mental health or substance use conditions. Clinical Management and Treatment. There are no FDA-approved medications specifically for kratom dependence, but individualized care is effective. Supervised withdrawal: Gradual tapering or supportive care (e.g., clonidine for autonomic symptoms, antiemetics, hydration) is often preferred over abrupt cessation. Medication options: Buprenorphine (or buprenorphine/naloxone) has shown success in case reports and clinical practice for managing cravings and withdrawal, particularly when opioid-receptor effects are prominent or comorbid opioid use disorder exists. Behavioral and residential support: Cognitive-behavioral therapy (CBT), contingency management, and structured programs address underlying drivers like chronic pain, anxiety, or trauma. Residential inpatient care at facilities like Banyan offers a safe, supportive environment for detox, stabilization, and skill-building when outpatient care is insufficient. Holistic recovery: Screen for liver function, polysubstance use, and mental health; connect to long-term outpatient follow-up and community resources. Patients should understand that Kratom is not a harmless natural remedy; it is a chemical with real addiction potential. Evidence-based treatment works and offers a clear path to sustained recovery. How Banyan Treatment Centers Treats Kratom Addiction: Banyan Treatment Centers offers a structured, evidence-based approach to Kratom addiction that addresses every stage of recovery. Because Kratom dependence involves opioid-receptor pathways, Banyan’s clinical team treats it with the same rigor applied to traditional opioid use disorders, beginning with a thorough medical and mental health evaluation to develop an individualized treatment plan. Treatment typically begins with medically supervised detox , where patients are safely guided through withdrawal under 24/7 medical oversight. Clinicians use supportive medications, such as clonidine for autonomic symptoms, antiemetics, and sleep aids, to manage discomfort and may introduce buprenorphine when clinically appropriate to reduce cravings and stabilize opioid-receptor activity. This supervised setting is especially critical for patients using high-potency kratom extracts or 7-OH products, whose withdrawal can be more intense and unpredictable. Following stabilization, patients transition into residential inpatient care, where the focus shifts to understanding and addressing the root causes of addiction. Banyan’s programs incorporate cognitive-behavioral therapy (CBT), dialectical behavior therapy (DBT), individual and group counseling, and trauma-informed modalities. Because many Kratom users initially turned to the substance to self-manage chronic pain, anxiety, depression, or prior opioid dependence, Banyan’s dual-diagnosis approach treats co-occurring mental health conditions simultaneously, ensuring that underlying issues do not go unaddressed and fuel relapse. Banyan also provides multiple levels of care to support patients at every phase of recovery. After completing residential treatment, patients may step down to partial hospitalization (PHP), intensive outpatient (IOP), or virtual intensive outpatient programming, maintaining therapeutic continuity while gradually reintegrating into daily life. With locations across multiple states, Banyan is equipped to provide accessible, comprehensive kratom addiction treatment tailored to each individual’s needs. Final Thoughts. In Florida’s evolving regulatory landscape, marked by accessibility, recent 7-OH restrictions, and ongoing debates over consumer protections, clinicians and families must stay vigilant. If you or someone you know is struggling with Kratom, do not wait for a crisis. Reach out to Banyan Treatment Centers or call SAMHSA’s National Helpline at 1-800-662-HELP for confidential guidance. Banyan remains committed to delivering medically grounded, compassionate care that cuts through hype and focuses on real recovery. About Banyan Treatment Centers: Banyan Treatment Centers is a leading provider of mental health and substance use disorder treatment, offering a full continuum of care, including detox, residential treatment, partial hospitalization, intensive outpatient, and Telehealth services across the United States. Brittany Hepple Banyan Treatment Centers +1 888-230-3122 email us here Legal Disclaimer: EIN Presswire provides this news content "as is" without warranty of any kind. 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