瑞典试验：单剂裸盖菇素数日内改善抑郁，一年后与安慰剂差异消退

这项试验做了什么

研究由卡罗林斯卡学院的Hampus Yngwe等人开展，论文发表在JAMA Network Open。参与者是35名瑞典成人，均处于中重度复发性抑郁症的发作期，平均41岁，其中21名女性；入组时没有人用过致幻剂，也没有人正在服用抗抑郁药或接受心理治疗。他们通过社交媒体和网络广告招募而来。

参与者被随机分到两组：17人服用25毫克裸盖菇素，18人服用100毫克烟酸作为活性安慰剂。烟酸是维生素B3的一种形式，会引起潮红等身体感觉，设计意图是让参与者更难判断自己吃的是哪一种。两组在17天内都接受了五次心理治疗性支持会谈，包括准备会谈、给药当天的会谈和三次随访。

效果出现得快，消退得也明确

主要结局是给药后第8天由临床医生用蒙哥马利-阿斯伯格抑郁评定量表（MADRS）评估的症状变化。结果显示，裸盖菇素组的评分比烟酸组多下降约7分，这是试验预设的主要比较。第15天和第42天，裸盖菇素组仍保持领先，但到第365天，这一差异不再具有统计学显著性。

参与者自评的结果时间线不同：第2天就出现组间差异，并持续到第102天，也就是三个多月。缓解率方面，第8天裸盖菇素组有8人达到缓解，烟酸组2人，这一差异未达统计显著；第42天两组缓解率分别为53%和6%；一年后为53%和41%，作者认为这个差距小到可能只是偶然。裸盖菇素组的缓解率从第一周起基本稳定，烟酸组则从12%升到41%，作者提出这与抑郁症本身的发作—缓解波动有关，包括自发缓解的可能。随访一年内，两组各有6人和7人开始服用抗抑郁药。

耐受性与盲法问题

副作用多为暂时性的头痛、焦虑和幻觉，没有与药物相关的严重不良事件。但裸盖菇素组有两名参与者在给药后出现持续数周的严重焦虑，需要医疗处理。作者在结论中写道，单剂裸盖菇素与快速抗抑郁效果相关，自评指标上的效果持续三个月以上，总体耐受良好，但部分人给药后需要额外支持；他们建议进一步研究重复给药或联合治疗策略。

盲法基本失败是解读结果时必须考虑的限制。研究结束时，裸盖菇素组94%的参与者和烟酸组所有答对的人正确猜出了自己的分组，临床评分者也在多数参与者上猜对。抑郁通过访谈和自评测量，知道分组可能影响参与者和评分者对症状的判断；通过社交媒体招募也可能吸引了对治疗抱有较高期待的人。

这项研究能说明什么

这项试验补充了裸盖菇素抗抑郁潜力的证据，尤其是自评指标上较快且持续数月的变化。但它只有35人，效应必须相当大才能被检测到；试验也不是为得出长期效果的确定结论而设计的。因此，更稳妥的读法是：在这批特定参与者中，单剂裸盖菇素在短期内与更明显的症状下降相关，而一年后主要临床指标上的组间差异已经消失。至于重复给药能否延长效果、哪些人更适合这类治疗，材料只提出需要进一步研究，没有给出答案。

A randomized clinical trial conducted in Sweden found that a single 25-mg dose of psilocybin produced rapid antidepressant effects in patients with moderate to severe recurrent major depressive disorder. On a self-report measure, the effects appeared as early as the second day after dosing and lasted for more than three months, although by one year the difference between groups had faded on the main clinician-rated measure. The paper was published in JAMA Network Open.

Depression, or major depressive disorder, is a mental health condition characterized by persistent low mood, loss of interest or pleasure, and other emotional, cognitive, and physical symptoms that can substantially interfere with daily life. When a person experiences repeated episodes of major depression separated by periods in which symptoms improve or disappear, such a condition is called recurrent depression.

Antidepressant medications such as selective serotonin reuptake inhibitors (SSRIs) are widely used to treat major depressive disorder. However, about two-thirds of patients do not achieve remission with their first SSRI, and some remain depressed despite several treatment attempts. Mainstream antidepressant medications may also take several weeks to produce effects. They frequently need to be taken for years to reduce the risk of relapse, while adverse effects can make long-term treatment difficult. These limitations have increased interest in faster-acting treatments that might produce improvement after only one or a few administrations.

Psilocybin, a classical psychedelic, has attracted particular attention because some studies suggest that a single dose can produce antidepressant effects lasting for several weeks or longer. Researchers are especially interested in whether such effects might also reduce the risk of future depressive episodes and lessen the need for continuous daily medication.

However, evidence for long-term benefits remains limited because many previous studies lacked suitable control groups, used suboptimal designs, or could not fully separate treatment effects from the natural course of depression and other treatments. Psilocybin’s strong effects can also make it easy for participants to tell whether they received the drug, which can undermine blinding.

Study author Hampus Yngwe of the Karolinska Institutet and his colleagues conducted a randomized clinical trial to test the short-term antidepressant effects of a single, oral, 25-mg dose of psilocybin in people with major depressive disorder. They also followed participants for 12 months to examine longer-term effects and tolerability, and tested how well the study’s blinding held up.

Study participants were 35 adults in Sweden with moderate to severe recurrent depression who were in a depressive episode at the time of recruitment and were recruited through social media and online ads. Their average age was 41, and 21 were women. None had used psychedelics before, and none were taking antidepressants or receiving psychotherapy when they entered the study.

Participants were randomly assigned to receive either 25 mg of psilocybin (17 participants) or an identical-looking capsule containing 100 mg of niacin, a form of vitamin B3 (18 participants). Niacin served as an active placebo, a substance that produces noticeable bodily sensations, such as flushing, and was intended to make it harder for participants to tell which capsule they had received. The study was double-blind, meaning that neither participants nor the researchers assessing them were told who received which capsule. Both groups also received five psychotherapeutic support sessions over 17 days, including a preparation session, the dosing session, and three follow-up sessions.

Depressive symptoms were assessed by a clinician using the Montgomery-Åsberg Depression Rating Scale (MADRS) on the dosing day and again on days 8, 15, 42, and 365. Participants also rated their own symptoms using a self-report version of the scale, daily during the first week and then at regular intervals for a year, along with measures of disability, quality of life, and anxiety. Participants who were still depressed at day 42 were referred for standard treatment.

On the clinician-rated measure, depressive symptoms fell by about 7 points more in the psilocybin group than in the niacin group by day 8, the study’s main outcome. The psilocybin group remained ahead on days 15 and 42, but the difference was no longer statistically significant at day 365. On the self-report measure, the psilocybin group showed a greater reduction in symptoms as early as day 2, and the difference persisted through day 102, or more than three months.

By day 8, 8 participants in the psilocybin group had reached remission, compared with 2 in the niacin group, a difference that was not statistically significant. By day 42, remission rates were 53% in the psilocybin group and 6% in the niacin group. After one year, remission rates were 53% and 41%, respectively, a difference small enough that it could reflect chance. Remission in the psilocybin group held steady from the first week onward, while in the niacin group it rose from 12% to 41% over the year, which the authors suggest reflects the episodic nature of depression, including the potential for spontaneous remission.

Similar numbers of participants in the two groups (6 and 7) started antidepressant medication during the follow-up year. Psilocybin was generally well tolerated, with mostly temporary side effects such as headache, anxiety, and hallucinations, and no serious adverse events linked to the drug. However, two participants in the psilocybin group experienced severe anxiety that persisted for weeks after dosing and required medical attention.

“In this randomized clinical trial of MDD [major depressive disorder], a single dose of psilocybin was associated with rapid antidepressant effects, observed by day 2 and persisting for more than 3 months on secondary outcomes; psilocybin was generally well tolerated, but some individuals required additional support after dosing due to anxiety,” study authors concluded.

“These results suggest that psilocybin may provide a rapid and relatively long-lasting antidepressant effect on major depressive disorder, warranting further investigation into repeated dosing or adjunctive treatment strategies.”

The study contributes to the scientific knowledge about the antidepressant potential of psilocybin. However, it should be noted that the study was conducted on a very small group of participants, so any effects needed to be quite large to be detected, and the trial was not designed to draw firm conclusions about long-term effects.

Blinding also largely failed. At the end of the study, 94% of participants in the psilocybin group and all of those in the niacin group who answered correctly guessed which treatment they had received, and the clinicians rating symptoms guessed correctly for most participants as well. Because depression was measured through interviews and self-reports, knowing which treatment they had received may have influenced how participants and raters judged symptoms, and recruitment through social media may have drawn people with high expectations for the treatment.

The paper, “Short-Term and Late-Term Effects of Psilocybin on Symptoms in Major Depression: A Randomized Clinical Trial,” was authored by Hampus Yngwe, Pontus Plavén-Sigray, Carl Johan Ekman, Eva Henje, Anders Berglund, Mikael Tiger, Maria Beckman, and Johan Lundberg.