Interest in the use of serotonergic agonists such as psilocybin in treatment-resistant depression (TRD) has grown more quickly than the evidence on which to base a final opinion, as emphasized by McIntyre et al¹ in their review.

Psilocybin, once metabolized to psilocin, activates 5-HT2A receptors, enhancing GABA function in local circuits in the cortex and increasing connectivity between functional modules in the brain. The emergent consequences can be measured in healthy volunteers and patients by the Altered States of Consciousness Rating Scale (5D-ASC) in five domains: oceanic boundlessness, anxious ego dissolution, visual restructuralization, auditory alterations, and reduction of vigilance^{2, 3}. While the content of these experiences is very personal, their form is relatively stereotyped and very similar between various study populations. While aspects of personality or emotionality may influence the strength of effects, it is impossible to regard them as simply imaginary or the results of suggestibility.

The largest randomized control trial (RCT) of psilocybin in TRD (COMP 001) showed a striking dose-effect relationship⁴. A 25 mg dose of the investigational drug, COMP360 (a synthetic psilocybin formulation), produced an effect on depressive symptoms significantly greater than a 1 mg dose at the 3-week primary endpoint. The effect of a 10 mg dose was intermediate and tended to fade towards the 1 mg arm over time. A superiority for the 25 mg compared with the other two doses was seen up to 12 weeks. The strength of oceanic boundlessness, in particular, correlated with the outcome measured by conventional scales for mood.

The main objections to a simple interpretation that psilocybin acts to improve depressive symptoms in TRD, or in general in major depressive disorder (MDD), are summarized by McIntyre et al¹. First, the psychedelic experience is often said to be unblinding. In conventional RCTs, this implies that the active drug is identified because of some adverse effect or other cue when it should ideally be indistinguishable from placebo. In the case of psilocybin and related drugs, the actual problem is the absence of a psychedelic experience, which will reveal to patients that they have received placebo, a low dose of psilocybin, or another drug. Does such unblinding necessarily occur, and does it matter? I would argue that it may not⁵. The reason is that the psychedelic experience within the dose ranges currently in use is quite variable. The overlap between active doses due to this variability means that a dose-response relationship cannot credibly be attributed to “unblinding”, since patients and staff cannot be certain of what dose has been administered. This will be particularly the case if patients do not have previous psychedelic experience, as in over 90% of participants in the COMP 001 trial.

In addition, the problem with unblinding of an inactive dose is, in theory, the potential for a nocebo effect. Nocebo in this context refers to the possibility that unblinding leads to patients scoring lower when reporting a subjective outcome such as mood than they would if they had simply failed to respond to an active dose. This effect can be checked in all adequately sized trials by comparing the non-response profile in the placebo group with that in the active group. This is not usually done in conventional trials, but in the case of escitalopram a pooled analysis shows very clearly that responders and non-responders have very similar profiles irrespective of whether they receive drug or placebo⁶. In addition, unblinding might be expected to lead to more adverse events, including suicidality. This was not observed for the 1 mg arm in COMP 001⁴.

Second, any psychotherapy provided alongside a drug could be potentially confounding: indeed, it is common to hear the expression “psychedelic-assisted psychotherapy” overused uncritically as synonymous with psilocybin treatment. That expression is appropriate for 3,4-methylenedioxymethamphetamine (MDMA), which increases the potential for empathy and interaction with a therapist⁷. It is instead an oxymoron when applied to psilocybin, since the full psychedelic experience is largely incompatible with psychotherapy as usually understood. The psychological support that has been provided in clinical trials of psilocybin means preparation, a supportive presence on the day of drug administration, and integration soon afterwards. Preparation entails instruction, explanation and the establishment of trust. Support during a psychedelic experience is usually minimal: patients don eye shades, listen to music and are encouraged to direct their attention inwards. Integration is non-directive enquiry about the experience and how patients see it affecting their future beliefs and behavior. In most of the depression trials, it was scheduled to be two visits of up to 1 hour each.

In all the MDD and TRD studies published so far, high depression scores were registered at baseline, after preparation had occurred. Moreover, in COMP 001, the obvious mood change registered on the day after drug treatment was fully developed before integration had taken place. Hence, there is little reason to attribute clinical improvement to anything other than drug effect on the day of administration. From the perspective of mechanism of action, this is an important conclusion because, if psychotherapy provided the main mechanism of change, understanding the drug contribution would be more difficult, and its approval as a medicine could be compromised.

The assumption that psilocybin treatment is necessarily “combined with psychotherapy” has another risk. Unregulated psychotherapy practice can lead to ethical violations. The risk of such practice in “psychedelic-assisted psychotherapy” is very real and has been highlighted recently⁸. This is another reason for de-emphasizing the role of psychotherapy unless, as with MDMA, it is clearly a key part of the treatment. To refer accurately to psychological support does not diminish its importance in facilitating an optimal psychedelic experience. This support is also ethically essential as a safeguard for patients on the day of drug administration. The qualifications and training of the people providing such support must be to high standards, and a clear protocol should be used. However, the professional background of the therapist is probably less important, because what is involved is not psychotherapy. It is difficult to see how a more minimal package could be safely used as a comparator to “deconstruct” the approach and generate “an evidence base” as suggested by McIntyre et al.

The potential for psilocybin to enhance the effect of conventional psychotherapies remains of great interest. Work in animals suggests that activation of 5-HT2A receptors produces changes in synaptic function that could underpin greater behavioral plasticity⁹. The challenge for the future, along with safe delivery of the experience, appears likely to be the choice of appropriate additional treatment which may have the potential to enhance outcomes in the long term, be it pharmacological, neurostimulatory or psychotherapeutic. For the present, however, the challenge is to complete a convincing phase 3 programme leading to eventual approval of psilocybin as a medicine. We are not there yet.

^{正如 McIntyre 等人}在其综述中所强调的那样，人们对使用裸盖菇素等血清素激动剂治疗难治性抑郁症 (TRD) 的兴趣增长速度快于形成最终意见的证据。

裸盖菇素一旦代谢为裸盖菇素，就会激活 5-HT2A 受体，增强皮质局部回路中的 GABA 功能，并增加大脑功能模块之间的连接。可以通过意识状态改变评定量表 (5D-ASC) 在健康志愿者和患者中测量五个领域的紧急后果：海洋无边无际、焦虑的自我消解、视觉重组、听觉改变和警惕性降低 2, ³。虽然这些经历的内容非常个人化，但它们的形式相对刻板，并且在不同研究人群之间非常相似。虽然个性或情绪的各个方面可能会影响效果的强度，但不可能将它们视为简单的想象或暗示的结果。

TRD 中裸盖菇素最大的随机对照试验 (RCT) (COMP 001) 显示出惊人的剂量效应关系⁴。在 3 周主要终点中，25 毫克剂量的研究药物 COMP360（一种合成裸盖菇素制剂）对抑郁症状的影响显着大于 1 毫克剂量。10 毫克剂量的效果是中等的，并且随着时间的推移趋向于向 1 毫克剂量逐渐减弱。与其他两种剂量相比，25 mg 的优越性长达 12 周。特别是，海洋无边无际的强度与传统情绪尺度测量的结果相关。

McIntyre 等人总结了对裸盖菇素可改善 TRD 或一般重度抑郁症 (MDD) 抑郁症状的简单解释的主要反对意见¹。首先，迷幻体验通常被认为是不致盲的。在传统的随机对照试验中，这意味着活性药物是由于某些不良反应或其他线索而被识别的，而在理想情况下，活性药物应该与安慰剂无法区分。就裸盖菇素和相关药物而言，实际问题是缺乏致幻体验，这将向患者揭示他们接受了安慰剂、低剂量的裸盖菇素或其他药物。这种揭盲是否一定会发生，而且重要吗？我认为可能不是⁵。原因是目前使用的剂量范围内的迷幻体验变化很大。由于这种变异性，活性剂量之间的重叠意味着剂量-反应关系不能可靠地归因于“揭盲”，因为患者和工作人员无法确定所施用的剂量。如果患者以前没有迷幻经历，情况尤其如此，COMP 001 试验中超过 90% 的参与者都是如此。

此外，从理论上讲，非活性剂量揭盲的问题是潜在的反安慰剂效应。在这种情况下，Nocebo 指的是，揭盲导致患者在报告主观结果（例如情绪）时得分低于他们对主动剂量没有反应的得分。通过比较安慰剂组和活性组的无反应情况，可以在所有足够规模的试验中检查这种效果。这在传统试验中通常不会进行，但就艾司西酞普兰而言，汇总分析非常清楚地表明，反应者和非反应者无论接受药物还是安慰剂 6 都具有非常相似的^特征。此外，揭盲可能会导致更多不良事件，包括自杀。^{在 COMP 001 4}的 1 mg 组中没有观察到这一点。

其次，任何与药物一起提供的心理治疗都可能会令人困惑：事实上，经常听到“迷幻辅助心理治疗”这个词被不加批判地过度用作裸盖菇素治疗的同义词。这种表达方式适用于 3,4-亚甲二氧基甲基苯丙胺 (MDMA)，它可以增加同理心以及与治疗师互动的潜力⁷。相反，当应用于裸盖菇素时，这是一种矛盾修饰法，因为完整的迷幻体验在很大程度上与通常理解的心理治疗不相容。裸盖菇素临床试验中提供的心理支持意味着准备、给药当天的支持性存在以及随后不久的整合。准备工作需要指导、解释和建立信任。迷幻体验期间的支持通常很少：患者戴上眼罩，听音乐，并被鼓励将注意力转向内心。整合是对经历以及患者如何看待它影响他们未来的信念和行为的非指导性询问。在大多数抑郁症试验中，计划进行两次访视，每次最多 1 小时。

在迄今为止发表的所有 MDD 和 TRD 研究中，在准备工作发生后，在基线时记录了高抑郁分数。此外，在 COMP 001 中，药物治疗后第二天记录的明显情绪变化在整合发生之前就已完全发展。因此，没有理由将临床改善归因于给药当天的药物效应以外的任何因素。从作用机制的角度来看，这是一个重要的结论，因为如果心理治疗提供了主要的改变机制，那么理解药物的贡献将更加困难，并且其作为药物的批准可能会受到影响。

裸盖菇素治疗必然“与心理治疗相结合”的假设还有另一个风险。不受监管的心理治疗实践可能导致道德违规。在“迷幻辅助心理治疗”中这种做法的风险是非常真实的，并且最近已得到强调⁸。这是不强调心理治疗作用的另一个原因，除非它像摇头丸一样，显然是治疗的关键部分。准确地提及心理支持并不会削弱其在促进最佳迷幻体验方面的重要性。这种支持在道德上也是必要的，可以作为患者在用药当天的保障。提供此类支持的人员的资格和培训必须达到高标准，并且应使用明确的协议。然而，治疗师的专业背景可能不太重要，因为涉及的不是心理治疗。很难看出如何安全地使用更小的包作为比较器来“解构”该方法并生成 McIntyre 等人建议的“证据基础”。

裸盖菇素增强传统心理治疗效果的潜力仍然引起人们的极大兴趣。动物研究表明，5-HT2A 受体的激活会导致突触功能发生变化，从而增强行为可塑性⁹。未来的挑战以及安全地提供体验似乎可能是选择适当的额外治疗，从长远来看，无论是药理学、神经刺激还是心理治疗，这些治疗都有可能改善结果。然而，目前的挑战是完成令人信服的第三阶段计划，从而最终批准裸盖菇素作为药物。我们还没有到那一步。