Pictured: Psychedelic plants in front of blue squiggly lines/Taylor Tieden for BioSpace

A highly heterogeneous disease, depression has long challenged drug developers. While effective treatments exist for some patients, many are still left behind by current regimens. Now, with the global depression treatment market projected to top $16 billion by 2027, psychedelic drug developers have their sights set on the space, with six programs currently in clinical development, according to Psychedelic Alpha..

抑郁症是一种高度异质性的疾病，长期以来一直困扰着药物开发人员。虽然对一些患者存在有效的治疗方法，但目前的治疗方案仍有许多患者落后。现在，全球抑郁症治疗市场预计到2027年将达到160亿美元，迷幻药开发商将目光投向了这个领域，根据迷幻药Alpha的数据，目前有六个项目正在临床开发中。。

The current standard of care for depression comprises selective serotonin reuptake inhibitors (SSRIs) such as Eli Lilly’s Prozac and Pfizer’s Zoloft, along with depression-focused psychotherapy. However, at least 30 percent of people with major depressive disorder fail to respond to two or more antidepressants, a condition called treatment-resistant depression (TRD).

目前抑郁症的护理标准包括选择性5-羟色胺再摄取抑制剂（SSRIs），如礼来公司的百忧解和辉瑞公司的Zoloft，以及以抑郁症为重点的心理治疗。然而，至少30%的重度抑郁症患者对两种或两种以上的抗抑郁药没有反应，这种情况称为治疗抵抗性抑郁症（TRD）。

Less than 15% of patients with TRD reach remission with the standard of care, according to Theis Terwey, CEO and co-founder of GH Research, which is developing the psychedelic drug 5-MeO-DMT for the treatment of TRD..

GH Research的首席执行官兼联合创始人泰斯·特维（Theis Terwey）表示，只有不到15%的TRD患者达到了标准治疗的缓解，GH Research正在开发用于治疗TRD的迷幻药5-MeO-DMT。。

There is precedent for using psychedelics to treat TRD. Johnson & Johnson won approval for Spravato (esketamine) for TRD in 2019, though the company does not consider the nasal spray to be a classic psychedelic. Carlene MacMillan, an interventional psychiatrist and chief medical officer at the mental health treatment and research technology platform Osmind, explained that Spravato is not a classic psychedelic because it does not cause a hallucinatory effect and because of how it acts in the brain.

使用迷幻药治疗TRD有先例。强生公司（Johnson＆Johnson）于2019年获得了用于TRD的Spravato（esketamine）的批准，尽管该公司不认为鼻喷雾剂是典型的迷幻药。心理健康治疗与研究技术平台Osmind的介入性精神病医生兼首席医疗官卡琳·麦克米伦解释说，Spravato不是一种典型的迷幻药，因为它不会引起幻觉，也因为它在大脑中的作用。

In clinical trials, patients who received Spravato saw “superior” and “sustained” improvement in their depression symptoms compared to those who received a placebo and an oral antidepressant, according to J&J..

据J＆J称，在临床试验中，与接受安慰剂和口服抗抑郁药的患者相比，接受Spravato治疗的患者的抑郁症状得到了“更好”和“持续”的改善。。

Companies like GH and Compass Pathways are now seeking to improve on those results with 5-MeO-DMT and psilocybin—with the hallucinogenic qualities intact. There are currently no other psychedelic drugs on the market, though MDMA, being developed by Lykos Therapeutics for post-traumatic stress disorder (PTSD) and up for FDA approval in August, could set the stage for more psychedelic-based treatments for mental health..

。目前市场上没有其他迷幻药，尽管由Lykos Therapeutics为创伤后应激障碍（PTSD）开发并于8月获得FDA批准的MDMA可能为更多基于迷幻药的心理健康治疗奠定基础。。

In depression, in particular, psychedelics stand to offer something new, MacMillan told BioSpace. “Most of the medications that we have on the market, and have had on the market for several decades, are all just variants of kind of the same thing, acting on serotonin in some way, taking weeks to months to work,” she said.

麦克米伦告诉BioSpace，特别是在抑郁症中，迷幻药可以提供一些新的东西。她说：“我们市场上的大多数药物，以及市场上几十年来的大多数药物，都只是同一事物的变体，以某种方式作用于血清素，需要数周至数月才能起作用。”。

The potential for psychedelics to treat TRD in a much more rapid way is “really very, very high.”.

迷幻剂以更快速的方式治疗TRD的潜力“真的非常非常高”。

Psilocybin Leads the Way in Compass’ Phase III for TRD

Psilocybin在Compass的TRD第三阶段中领先

London–based Compass is in Phase III TRD trials with psilocybin, a serotonin receptor agonist that occurs naturally in some mushroom species.

总部位于伦敦的Compass正在进行裸盖菇素的III期TRD试验，裸盖菇素是一种血清素受体激动剂，在某些蘑菇物种中天然存在。

Psilocybin binds to the 5-HT2A receptor for serotonin, explained Guy Goodwin, chief medical officer at Compass, provoking “a series of downstream changes.” While he acknowledged that researchers don’t know which of these changes is functional, he said a change in connectivity is seen on the MRIs of patients treated with psilocybin..

Compass首席医学官盖伊·古德温（GuyGoodwin）解释说，裸盖菇素与血清素的5-HT2A受体结合，引发了“一系列下游变化”。虽然他承认研究人员不知道这些变化中的哪一个是功能性的，但他说，裸盖菇素治疗患者的核磁共振成像（MRI）显示连通性发生了变化。。

“Normally, at rest, the brain has a number of modules, which seem to prefer to fire together, dotted around the brain, and one of them is sometimes called the default mode network.” When a patient takes psilocybin, “that kind of breaks down, and these strict, kind of separated modules become much more interconnected,” he explained.

“通常，在休息时，大脑有许多模块，这些模块似乎更喜欢一起发射，散布在大脑周围，其中一个有时被称为默认模式网络。“当患者服用psilocybin时，“这种故障，这些严格的，分离的模块变得更加相互关联，”他解释道。

“It’s sort of as if you have a kind of breaking of the existing strict topography of the brain into something that is much more fluid and much more potentially malleable.” The hypothesis is that the brain is then able to see situations and problems “in a different way.”.

“这有点像是大脑现有的严格地形被打破，变成了更具流动性和潜在可塑性的东西。”假设是大脑能够“以不同的方式”看到情况和问题。

MacMillan agreed. “The psychedelics allow you to teach an old dog new tricks.” She said that this can be helpful in treating depression and specifically pointed to psilocybin’s potential. “Psychedelics, particularly psilocybin, have shown great promise at helping people who are not traditionally helped, and faster.”.

麦克米伦同意了。“迷幻药可以让你教给老狗新把戏。”她说，这可能有助于治疗抑郁症，并特别指出了裸盖菇素的潜力。“迷幻药，特别是裸盖菇素，在帮助传统上没有得到帮助的人方面表现出了巨大的希望，而且速度更快。”。

In Phase IIb trials, Compass’ candidate, COMP360, showed “a highly statistically significant reduction in depressive symptoms after three weeks” following a single 25-mg or 10-mg dose in combination with psychological support, with the response lasting up to 12 weeks, according to COMPASS. The control group received the same therapeutic support together with a 1-mg dose of COMP360.

在IIb期试验中，Compass的候选人COMP360显示，在单次25毫克或10毫克剂量联合心理支持后，“三周后抑郁症状的统计学显着降低”，根据Compass，反应持续长达12周。对照组接受相同的治疗支持以及1mg剂量的COMP360。

A Phase III trial is underway, with a study completion date of May 2025. .

第三阶段试验正在进行中，研究完成日期为2025年5月。

Compass isn’t alone in pursuing psilocybin for the treatment of depression. Braxia Scientific is investigating a psilocybin-assisted therapy in Phase II for TRD.

Compass并不是唯一一家寻求裸盖菇素治疗抑郁症的公司。Braxia Scientific正在研究psilocybin辅助治疗TRD的II期。

DMT Close Behind in Phase II from GH Research

DMT在GH研究的第二阶段紧随其后

Dublin-based GH is developing a novel formulation of 5-MeO-DMT, a psychedelic tryptamine found in several plant species. The candidate, GH001, is currently being studied in a Phase IIb trial for TRD, for which the company expects topline data in the third or fourth quarter of 2024.

总部位于都柏林的GH正在开发一种新型的5-MeO-DMT配方，这是一种在几种植物中发现的迷幻色胺。候选人GH001目前正在TRD的IIb期试验中进行研究，该公司预计2024年第三或第四季度将公布该试验的最终数据。

5-MeO-DMT was particularly attractive to GH due to its rapid and short-acting nature when inhaled. Terwey said this can address some of commercial feasibility issues inherent in longer-acting compounds like psilocybin and LSD. Such longer-acting drugs often also involve additional visits for psychotherapy or psychological support, he said, adding that this can be challenging to incorporate into an eventual label and commercial model..

。特维说，这可以解决一些长效化合物（如裸盖菇素和LSD）固有的商业可行性问题。他说，这种长效药物通常还需要额外的心理治疗或心理支持，并补充说，要将其纳入最终的标签和商业模式，可能会面临挑战。。

5-MeO-DMT represents a pure pharmacological approach, Terway said. As a trial participant, “you’re really present with your ego during the experiment,” he explained. “So it’s not much to process or not really a lot of memories in context of a narrative. It’s more a deep feeling that develops and that we felt could be given without those cumbersome preparation and integration visits.”.

Terway说，5-MeO-DMT代表了一种纯粹的药理学方法。作为试验参与者，“在实验过程中，你真的表现出了你的自我，”他解释道。“因此，在叙述的背景下，处理或实际上不需要太多的记忆。这是一种更深刻的感觉，我们觉得不需要那些繁琐的准备和整合访问就可以得到它。”。

MacMillan disagreed, however, saying that the experience with 5-MeO-DMT is “extremely intense” and has a much more significant risk profile than psilocybin, LSD, mescaline and MDMA.

然而，麦克米伦不同意，他说5-MeO-DMT的经验“非常强烈”，并且比裸盖菇素，LSD，美司卡林和MDMA具有更大的风险。

In addition to GH, Beckley Psytech is in Phase IIb trials with a 5-MeO-DMT formulation for TRD. Meanwhile, Biomind Labs and Viridia Life Sciences (atai Life Sciences) are each studying a related compound simply called DMT, which occurs in many plants and animals, including humans, for TRD.

除GH外，Beckley Psytech正在进行IIb期试验，使用5-MeO-DMT配方进行TRD。与此同时，Biomind实验室和Viridia Life Sciences（atai Life Sciences）正在研究一种相关化合物，简称DMT，它存在于包括人类在内的许多动植物中，用于TRD。

Targeting Difficult-to-Treat Depression

针对难治性抑郁症

While still investigational, psychedelics could be an effective treatment for those with more difficult-to-treat depression, MacMillan said.

麦克米伦说，虽然仍在进行研究，但迷幻药可能是治疗抑郁症难度较大的患者的有效方法。

Patients whose depression stems from life circumstances will generally respond better to traditional medicines and traditional psychotherapy than will patients with a genetic predisposition to depression, she noted. Additionally, many patients with TRD have comorbidities “that are making it harder” to treat, she said, highlighting personality disorders like narcissism and obsessive-compulsive disorder..

她指出，与具有抑郁症遗传易感性的患者相比，生活环境导致的抑郁症患者通常对传统药物和传统心理治疗的反应更好。此外，她说，许多TRD患者合并症“越来越难”治疗，突出了自恋和强迫症等人格障碍。。

“Those patterns are not really addressed at all by the traditional antidepressants,” MacMillan said. As psilocybin or MDMA open new ways to learn, “I think it stands to reason that somebody that has a personality disorder and then gets related therapy for that disorder after a psychedelic experience could potentially actually change some of those underlying things as well.” .

麦克米伦说：“传统的抗抑郁药根本没有解决这些模式。”。随着psilocybin或MDMA开辟了新的学习方式，“我认为有理由认为，患有人格障碍的人，在经历迷幻经历后，然后接受相关的治疗，实际上也可能改变一些潜在的东西。”。

MacMillan indicated she would be comfortable using certain psychedelic therapies in her practice, providing a strong Risk Evaluation and Mitigation (REMS) program is in place. “As a psychiatrist, I think that we are well positioned to work with patients that have more complex psychiatric concerns.”  .

麦克米伦表示，如果有一个强有力的风险评估和缓解（REMS）计划，她在实践中使用某些迷幻疗法会很舒服。“作为一名精神病医生，我认为我们能够很好地与患有更复杂精神疾病的患者合作。”。

While MacMillan expressed optimism about the potential of psychedelics, she noted that other rapid-acting neuromodulation treatments like transcranial magnetic stimulation are also showing promise. “I think it’s important that we see broadly treatments for TRD and not get overly focused on psychedelics being the only way, because it’s just a different time in our field now.” .

虽然麦克米伦对迷幻剂的潜力表示乐观，但她指出，其他快速作用的神经调节治疗（如经颅磁刺激）也显示出前景。“我认为重要的是，我们要广泛了解TRD的治疗方法，不要过分关注迷幻药是唯一的方法，因为现在我们的领域已经不一样了。”。

Heather McKenzie is a senior editor at BioSpace. You can reach her at heather.mckenzie@biospace.com. Also follow her on LinkedIn.

希瑟·麦肯齐是BioSpace的高级编辑。你可以通过heather.mckenzie@biospace.com.也可以在LinkedIn上关注她。