Lysergic acid diethylamide

根据国际指南，焦虑障碍药物治疗中证据等级最高的选项包括： 社交焦虑障碍：选择性5-羟色胺再摄取抑制剂（艾司西酞普兰、帕罗西汀、舍曲林）以及5-羟色胺和去甲肾上腺素再摄取抑制剂文拉法辛。 惊恐障碍：SSRIs（西酞普兰、艾司西酞普兰、帕罗西汀、舍曲林）和SNRI文拉法辛。 广泛性焦虑障碍：SSRIs（艾司西酞普兰、帕罗西汀）、SNRIs（文拉法辛、度洛西汀）以及钙通道调节剂普瑞巴林。 由于苯二氮䓬类药物具有较高的滥用和依赖潜力，因此应仅临时使用。 临床挑战 尽管这些获批并推荐用于焦虑障碍的药物治疗效果尚可，但其疗效的标准化均值差在0.33至0.44之间，仅有约50%至67%的患者显示出充分的临床反应。至少30%患者的治疗抵抗导致焦虑障碍显著慢性化，这反映在其在全球疾病"伤残生存年"排名中位列第6位。 超说明书用药 一些药物，如抗抑郁药米氮平、阿戈美拉汀或非典型抗精神病药喹硫平，并未获批用于治疗焦虑障碍。然而，基于随机对照、开放标签研究或病例报告，这些药物构成了特别是GAD，也包括PD或SAD的替代性且可及的药物治疗选择。 例如，一项针对27名门诊PD患者的米氮平与氟西汀双盲随机弹性剂量试验证明，米氮平的疗效不劣于氟西汀，并能诱导显著的临床改善。米氮平的改善睡眠副作用可能对常共病失眠的焦虑障碍尤其有益。 阿戈美拉汀，一种褪黑素受体激动剂和5-HT2C受体拮抗剂，在临床前研究中显示出抗焦虑特性，并且在数项为期12周至6个月的双盲随机对照试验中被证明对GAD有效。 多项随机对照试验发现喹硫平对GAD有效，近期一项荟萃分析显示其在治疗头四周内对症状改善具有良好的效应值。 具体到难治性焦虑障碍，随机对照试验提示仅有极少数其他物质可用于（超说明书）治疗，如表1所总结，这凸显了对创新化合物进行更多研究的必要性。 表1：难治性焦虑障碍（超说明书）药物治疗的随机对照试验证据GAD：广泛性焦虑障碍；SAD：社交焦虑障碍；PD：惊恐障碍。 药物类别 GAD PD SAD 抗精神病药 喹硫平 利培酮 奥氮平 抗抑郁药 西酞普兰 氯米帕明 帕罗西汀 抗焦虑药 普瑞巴林 抗惊厥药 氯硝西泮 其他 氯胺酮 吲哚洛尔 氯胺酮 研发管线 此外，一些作用于经典神经递质系统（如单胺能或γ-氨基丁酸/神经甾体系统）的新型化合物正在被优化和改进。其中包括： 5-羟色胺能致幻剂，如裸盖菇素、LSD、CYB004 以及 entactogen MDMA。 其他单胺能药物，如 AVN-101、ITI-1284、托鲁文拉法辛、buagafuran 或 SEP-363856。 GABA能药物，如 ENX-102、darigabat 和 fasedienol。 同时，针对具有新型抗焦虑作用机制的物质的I-III期研究正在规划或进行中，这些物质靶向例如谷氨酸能、大麻素、神经肽或胆碱能系统。这些药物列于表2，并将在下文中示例性综述。 图1：旨在对焦虑障碍产生急性和/或持久治疗效果的部分临床研发中的药物。 1、致幻剂： LSD是一种经典的致幻剂，作为部分激动剂与5-HT2A受体相互作用。一项采用双盲、安慰剂对照、随机交叉设计的研究纳入了42名DSM-IV诊断的焦虑障碍患者（无论是否伴躯体疾病），结果显示，与安慰剂相比，LSD在第一个治疗期显著减轻了焦虑。最大效应在第二次LSD会话后两周达到，并持续长达16周。 此外，用于GAD的III期多中心随机对照试验研究的LSD酒石酸盐（MM120）已获得FDA突破性疗法认定。 2、GABA / 神经甾体系统： GABA能信号传导已被确定为焦虑障碍遗传风险的潜在机制之一，并且是已获批具有急性抗焦虑作用药物的主要靶点。 苯二氮䓬类药物作为GABA-A受体的正性变构调节剂。其剂量依赖性副作用（如镇静、运动障碍以及依赖性）促使药物研发转向新型化合物，它们作用于特定的GABAA受体亚基，从而在最小化副作用的同时促进抗焦虑作用。 针对α1亚基影响小、选择性作用于α2/3/5亚基的GABAA受体PAMs——ENX-102和darigabat，目前正分别针对GAD和PD进行II期试验。 另一类作为内源性GABAA受体PAMs的药物是神经活性甾体。神经甾体fasedienol被提议作为信息素激活与大脑情绪调节区域相连的嗅球神经元。在一项随机、多中心研究中显示出对抗SAD症状的快速起效有益效果后，这些结果正在针对SAD的当前III期试验中进行跟进，该试验以鼻喷雾剂形式给予。 3、谷氨酸系统： 氯胺酮，一种电压依赖性NMDA谷氨酸受体拮抗剂，似乎能在多种临床环境下提供快速且持续的抗焦虑症状缓解，其抗焦虑效果在给药后12小时内出现，并可保持有效1-2周。 关于氯胺酮在焦虑障碍分类实体中的应用，正在进行的研究涉及SAD和GAD。迄今为止，仅完成了两项针对SAD的小型随机对照研究。对这些非常小型研究的荟萃分析显示，剂量≥0.5 mg/kg体重的氯胺酮显著优于安慰剂。 4、大麻素系统： 尽管内源性大麻素系统在临床前焦虑研究中得到深入研究，但迄今为止，来自随机对照研究的关于使用大麻或其衍生物治疗焦虑障碍的证据尚不充分。 初步证据表明，大麻二酚强化治疗（200-800毫克/天）对任何难治性焦虑障碍患者（15-25岁）可能有效。然而，在最近的一项随机对照试验中，大麻二酚（300毫克）作为增强SAD和PD体内暴露疗法的强化策略并未被证明有效。 5、神经肽系统： 几种神经肽，如催产素、食欲素、神经肽Y、促肾上腺皮质激素释放激素、加压素、P物质、胆囊收缩素或神经肽S，在临床前研究中被认为是焦虑障碍药物开发的潜在靶点。然而，目前仅有催产素在临床试验中被作为靶点进行研究。 6、胆碱能系统： α7-nAChR负性变构调节剂BNC210已被证明在动物模型中能减少焦虑和应激相关行为，并增加恐惧消退。在临床方面，小型研究显示其可降低GAD个体的自我报告焦虑，并减少对威胁的杏仁核反应。 BNC210已获得FDA快速通道资格，目前正在一项III期研究中作为SAD焦虑的"按需急性治疗"进行调研。 表2：临床研发中用于治疗焦虑障碍的化合物概览 靶点系统 GAD PD SAD 焦虑（泛指） 致幻剂与MDMA MM-120 (III) 裸盖菇素 (II) CYB004 (II) MDMA (II) EMP-01 (II) 裸盖菇素 (I-II) 其他单胺系统 AVN-101 (III) ITI-1284 (II) Buagafuran (III) SEP-363856 (II/III) Toludesvenlafaxine (III) GABA/神经甾体系统 ENX-102 (II) Darigabat (II) Fasedienol (III) 谷氨酸系统 氯胺酮 (II) 氯胺酮 (II) 氯胺酮 (I) 大麻素系统 大麻二酚 (III) 大麻二酚 (III) 大麻二酚 (III) ONO-1110 (II) 大麻二酚 (II) 神经肽系统 催产素 (II) 催产素 (II) 胆碱能系统 BNC210 (III) 营养制剂 HB-1 (II) *表中各化合物的临床研发阶段（I-III期）标注在括号内。粗体表示已获得FDA突破性疗法或快速通道认定的化合物。 推荐阅读 它能成为抑郁症患者的“更优解”吗？新药头对头研究揭示潜在答案 发病年龄、FT4与睾酮水平：双相抑郁自杀意念的新风险信号 辅助三重时间疗法治疗青少年重度抑郁症 大话精神编译，转载请联系编辑部。 投稿请联系：dahuajingshen@126.com  长按二维码，关注大话精神

Generalized anxiety disorder affects millions, often trapping sufferers in cycles of fear and isolation that conventional medications barely relieve. At UCSF, neuroscientist Jennifer Mitchell is testing a pharmaceutical form of LSD called MM120, which has shown striking results in reducing symptoms by promoting neuroplasticity and easing rigid thought patterns. In clinical trials, a single dose significantly outperformed standard treatments, offering hope to those who have found little relief elsewhere. Roughly one in twenty adults in the United States lives with generalized anxiety disorder (GAD). For those with severe symptoms, daily life can become overwhelming. Many avoid leaving home, struggle to maintain employment, and find it difficult to build meaningful social connections. Unfortunately, traditional medications often provide little relief. At the University of California, San Francisco (UCSF), neuroscientist Jennifer Mitchell, PhD, is leading research into innovative treatments for conditions such as anxiety, depression, PTSD, impulsivity, stress, and addiction. She believes a new approach could help where standard therapies fall short -- and early results are encouraging. This potential breakthrough treatment? A carefully developed pharmaceutical form of LSD. What is generalized anxiety disorder? Generalized anxiety disorder is a persistent and excessive form of anxiety that feels out of proportion to actual events or situations. It interferes with daily functioning, affecting relationships, work, and overall quality of life. People living with GAD may struggle to focus, make decisions, or remember information, making it difficult to manage responsibilities at work or home. The condition can also lead to fatigue, irritability, and secondary depression. Many individuals hesitate to leave their homes for fear of feeling trapped, embarrassed, or helpless in social or public settings. How is it different from day-to-day anxiety? A hallmark of generalized anxiety disorder is that it manifests as physical symptoms. Persistent worry activates the body's fight-or-flight response, triggering stress hormones that cause physical effects. Patients may have muscle tension and rapid breathing, and report symptoms like headaches and insomnia, ringing in the ears, and cardiovascular, respiratory, and gastrointestinal issues. How is generalized anxiety disorder treated? It's usually treated with medications like Zoloft and Paxil that boost and stabilize the neurotransmitter serotonin, leading to reduced anxiety and enhanced emotional well-being. These medications have been found to reduce symptoms by an average of 1.25 points on the 56-point anxiety scale -- insufficient to make significant difference for at least some patients. Why LSD? LSD as well as other psychedelics, have tremendous potential to shift mood and emotions when used in a controlled, therapeutic setting. We have seen this in a previous trial of Ecstasy to treat PTSD. The pharmaceutical formulation of LSD is MM120. Its primary mechanism is to promote neuroplasticity in the brain, potentially altering negative thought patterns. It also increases communication between brain regions that may address the rigid thinking that underlies GAD. How effective is MM120? In an earlier phase of the study, published in JAMA, the effects of a single dose of MM120 were evaluated over a 12-week period in approximately 200 participants with moderate-to-severe generalized anxiety disorder. The drug significantly alleviated symptoms, reducing them by five to six points on the anxiety scale in addition to the effects of placebo. That's quite significant and enough to reclassify moderate generalized anxiety disorder as mild in some cases. Were there side effects? Participants were carefully monitored by medical staff during the period after the drug was administered. Side effects were generally mild or moderate and included hallucinations, visual distortions, nausea, and headache. It's important to note, these were more prevalent using the highest dosage -- which we will not be using since it was found to be no more effective. Nausea is a common side effect with psychedelics, but this was reduced by restricting participants to a light breakfast and treating them proactively with an anti-nausea medication. What challenges do you face recruiting participants for the study? We are looking for people with moderate-to-severe general anxiety disorder, so typically those with disabling symptoms who are reluctant to leave their home. Ironically, people who would best qualify are least likely to show up. Participants are screened by very skilled clinicians who probe and observe body language and carefully build a rapport. We hope this builds trust and enables participants to be vulnerable and reflective.