A psychedelic drug is one that “produces thought, mood and perceptual changes otherwise rarely experienced except in dreams, contemplative and religious exaltation, flashes of vivid involuntary memory, and acute psychosis”¹. It does so “without causing physical addiction, craving, major physiological disturbances, delirium, disorientation or amnesia”¹.

The “classic psychedelics” include mescaline, psilocybin, lysergic acid diethylamide (LSD), dimethyltryptamine (DMT), and plant‐based substances such as ibogaine and ayahuasca. Their chemical structures differ, but they all act on the 5‐HT2A serotonin receptor¹. 3,4‐methylenedioxy​methamphetamine (MDMA) is also included, although it does not produce the perceptual effects of the classic psychedelics².

Over the past two decades, there has been a revival of clinical research on the therapeutic use of psilocybin and MDMA^{2, 3}. This research has been encouraged by the US Food and Drug Administration (FDA) because in phase 2 trials these drugs have produced substantial benefits, respectively, in patients with treatment‐resistant depression and post‐traumatic stress disorder (PTSD)³. Funding for psychedelic research has largely been philanthropic, because the pharmaceutical industry is not interested in drugs that are off patent.

The new psychedelic research that is being done in leading universities in the US and Europe includes randomized controlled trials conducted to the standard required for FDA approval³. Psilocybin has been chosen rather than LSD, because it has a shorter period of action (4‐6 hours vs. 8‐12 hours), its pharmacology is better understood, it is less likely to produce “bad trips”, and it does not carry the cultural baggage of LSD³. Clinical trials have also been done on MDMA‐assisted psychotherapy in PTSD.

If phase 3 trials confirm the results of phase 1 and 2 studies, psilocybin is likely to be approved for treatment‐resistant depression, and for depression and anxiety in patients with terminal cancer. MDMA‐assisted psychotherapy may also be approved to treat PTSD.

A major challenge in conducting randomized placebo‐controlled trials of psychedelics is that it is impossible for patients and therapists not to be aware of who has been given a psychedelic drug⁴. Recent trials have used an “active placebo”, such as methylphenidate or dextroamphetamine, or used low, moderate and high doses of the psychedelic drug to see if treatment effects are related to dose⁵.

It has been argued⁶ that psilocybin has a low abuse potential, because it does not produce euphoria in humans or self‐administration in animals, and there are much lower rates of regular use of this drug in population surveys than for cannabis, cocaine and opioids. Furthermore, users rapidly develop tolerance to its effects and so do not persist in using it.

Studerus et al⁴ reported very few acute, subacute and long‐term effects of psilocybin in 110 participants in laboratory studies followed up for 8‐16 months. This was a select group in that persons with a family or personal history of psychiatric disorders were excluded and 40% had used a psychedelic drug at least once. The short‐term adverse effects were minor: fatigue, headache, lack of energy, and difficulty concentrating the day after. Eleven individuals reported “negative changes in psychological well‐being and/or mental functions” after the psilocybin session. One reported “persistent emotional instability, anxiety and depressive feelings” that he “attributed to suppressed memories” released by the drug. He recovered after receiving psychotherapy.

Psilocybin has been described as a “disruptive” treatment because a single dose produces an immediate clinical response – unlike selective serotonin reuptake inhibitors (SSRIs) that require two weeks of treatment – and its benefits are sustained for six months in a substantial proportion of patients^{2, 3}. It also appears to act by different mechanisms than SSRIs and serotonin and norepinephrine reuptake inhibitors (SNRIs)².

The major limitations of the current evidence for psychedelic drugs are interconnected. In the absence of pharmaceutical industry interest, limited support from philanthropic sources has funded the research, restricting trials to relatively small samples of patients because of the cost of doing larger studies. The persons who have done the research believe in the therapeutic value of psychedelic drugs. This is to be expected, given the history of psychedelics and the reputational challenges in conducting clinical research on them.

If psychedelic drugs are introduced in clinical practice, there is a risk that their use will get ahead of the evidence on their safety and efficacy, in much the same way that “medical cannabis” has done⁷. If psilocybin is approved for treatment‐resistant depression, patients and prescribers are likely to demand its use as a first‐line treatment for severe depression rather than requiring that patients first fail to respond to SSRIs and other antidepressants. It is unclear whether the FDA and other drug regulators will require trials of psilocybin as a first‐line treatment. There may also be demands to use psilocybin off‐label to treat anxiety disorders. If MDMA‐assisted psychotherapy is approved to treat PTSD, there may be demands to use MDMA off‐label to treat other anxiety and depressive disorders. If the criteria for who is a qualified therapist are relaxed, MDMA may be used to treat unhappiness, anxiety and existential angst.

The evidence may be used to argue for compassionate access to other psychedelic drugs, such as LSD, mescaline and DMT. It is uncertain if the use of psychedelics will remain under medical supervision for approved disorders, or whether their use will be advocated for spiritual and other nonmedical purposes. A combination of libertarian and utilitarian arguments may be used to justify the legalization of adult use of these drugs for any purpose, because they cause little harm to users and have a low abuse potential⁸.

There may also be demands for compassionate access to plant‐based psychedelic drugs in advance of any research evidence. US states may pass citizen‐initiated referenda to legalize the medical use of psychedelic mushrooms and plants, such as ibogaine and ayahuasca, by appealing to the putative “entourage” effects of whole plants and the misconception that medicines derived from plants are safer than “synthetic” pharmaceuticals⁹.

For all these reasons, we need public funding of independent evaluations of the efficacy of psychedelic drugs. Trials should involve larger numbers of patients who are representative of those clinical disorders for which these drugs may be used, and should include longer‐term follow‐up evaluations of safety and sustainability of favorable outcomes.

迷幻药物是一个“生产思想，情绪和感知变化否则很少经历除了在梦想，沉思和宗教的提高，生动的不自主记忆闪烁，急性精神病” ¹。这样做“不会造成身体上瘾，渴望，严重的生理紊乱，ir妄，迷失方向或健忘症” ¹。

“经典迷幻药”包括美斯卡林，倍半胱氨酸，麦角酸二乙酰胺（LSD），二甲基色胺（DMT）以及基于植物的物质，例如伊博加因和阿育吠陀。它们的化学结构不同，但都作用于5-HT2A血清素受体¹。3,4-亚甲基二氧基甲基苯丙胺（MDMA）也包括在内，尽管它不产生经典迷幻药²的知觉效果。

在过去的二十年中，关于倍半孢菌素和MDMA ^2、3的治疗用途的临床研究正在复兴。美国食品和药物管理局（FDA）鼓励这项研究，因为在2期试验中，这些药物分别对耐治疗性抑郁症和创伤后应激障碍（PTSD）^3的患者产生了实质性益处。迷幻研究的资金主要来自慈善事业，因为制药行业对不属于专利的药物不感兴趣。

在美国和欧洲领先的大学中进行的新的迷幻研究包括按照FDA批准要求的标准进行的随机对照试验³。之所以选择了赛洛西宾而不是LSD，是因为它的作用时间较短（4-6小时vs. 8-12小时），其药理作用得到了更好的理解，不太可能产生“不良旅行”，并且它不会携带LSD的文化包³。在PTSD中，还进行了有关MDMA辅助心理治疗的临床试验。

如果3期试验证实了1期和2期研究的结果，则psilocybin可能会被批准用于治疗性抑郁症以及晚期癌症患者的抑郁症和焦虑症。MDMA辅助的心理治疗也可能被批准用于治疗PTSD。

进行迷幻药的随机安慰剂对照试验的一个主要挑战是，患者和治疗师不可能不知道是谁服用了迷幻药⁴。最近的试验使用了一种“活性安慰剂”，例如哌醋甲酯或右旋苯丙胺，或使用了低，中，高剂量的迷幻药，以查看治疗效果是否与剂量^5有关。

有人提出⁶，psilocybin的滥用可能性很低，因为它不会在人类中引起欣快感或在动物中自我给药，并且在人口调查中经常使用这种药物的比率比大麻，可卡因和阿片类药物低得多。 。此外，用户迅速发展出对其效果的容忍度，因此不坚持使用它。

Studerus等人[ ^4]报道，在实验室研究中随访了8-16个月的110名参与者中，鹦鹉螺菌素对急性，亚急性和长期的影响很小。这是一个选择人群，因为有家族性或精神病史的人被排除在外，有40％的人至少使用过一次迷幻药。短期不良影响较小：疲劳，头痛，精神不振以及第二天难以集中精力。鹦鹉螺菌素治疗后，有11个人报告“心理健康和/或心理功能发生了负性变化”。有人报告说，他“归因于药物释放的抑制性记忆”，“持续的情绪不稳定，焦虑和抑郁感”。他接受了心理治疗后康复了。

胶凝霉素被描述为“破坏性”疗法，因为单剂可立即产生临床反应（与需要两周治疗的选择性5-羟色胺再摄取抑制剂（SSRIs）不同），并且在相当大比例的患者中其获益可维持六个月^{2 ，3}。它似乎也以不同于SSRIs和5-羟色胺和去甲肾上腺素再摄取抑制剂（SNRIs）^2的机制起作用。

迷幻药当前证据的主要局限性是相互联系的。在没有制药业兴趣的情况下，来自慈善机构的有限支持为该研究提供了资金，由于进行大型研究的成本，试验仅限于相对较小的患者样本。从事这项研究的人相信迷幻药的治疗价值。考虑到迷幻药的历史以及在进行迷幻药临床研究时所面临的声誉挑战，这是可以预料的。

如果将迷幻药物引入临床实践，则存在使用风险会超过其安全性和有效性的证据的风险，这与“医用大麻”的行为几乎一样⁷。如果将psilocybin批准用于治疗性抑郁症，则患者和开药者可能会要求将其用作严重抑郁症的一线治疗方法，而不是要求患者首先对SSRI和其他抗抑郁药无反应。尚不清楚FDA和其他药物监管机构是否需要将psilocybin作为一线治疗药物进行试验。可能还需要使用非处方psilocybin来治疗焦虑症。如果MDMA辅助心理疗法被批准用于治疗PTSD，则可能需要使用MDMA非处方药来治疗其他焦虑症和抑郁症。如果放宽了谁是合格治疗师的标准，则可以使用MDMA来治疗不满，焦虑和生存焦虑。

该证据可用于辩护同情地使用其他迷幻药，例如LSD，麦斯卡林和DMT。尚不确定是否会对批准的疾病使用迷幻药继续接受医学监督，或者是否会出于精神和其他非医学目的而提倡使用迷幻药。自由主义和功利主义论点的结合可以用来证明成人出于任何目的使用这些药物的合法性，因为它们对使用者几乎没有危害，而且滥用可能性低⁸。

在任何研究证据之前，可能还需要同情地获取基于植物的迷幻药。美国各州可能会通过公民发起的全民公决，以使迷幻蘑菇和植物（如伊博加因和阿亚瓦斯卡）的医疗使用合法化，从而引起人们对整个植物的假定“诱使”作用，以及人们误解认为源自植物的药物比“合成的”药物更安全”药品⁹。

由于所有这些原因，我们需要公共资金对迷幻药的功效进行独立评估。试验应包括更多代表可使用这些药物的临床疾病的患者，并应包括对安全性和良好结局可持续性的长期随访评估。