MICA: SRC inhibitors as potential antipsychotics: human testing with psilocybin

本项目的目的是测试新化合物AZD0530(沙拉卡替尼)在减轻单剂量裸盖菇素后健康志愿者脑功能变化方面的疗效。裸盖菇素是一种天然存在的化合物，存在于某些种类的蘑菇中。它在结构上与大脑神经递质5-羟色胺相似--5-羟色胺与情绪和精神分裂症有关。裸盖菇素通过作用于特定的大脑受体部位--5-羟色胺2A(5-HT2A)受体而产生作用。成功阻断裸盖菇素的作用可能代表着治疗精神分裂症的一条新途径，包括治疗目前没有得到很好治疗的症状。精神分裂症是一种破坏性的疾病，包括幻觉和妄想等积极症状，冷漠等消极症状和记忆力差等认知症状。它影响了大约1%的人的一生，目前的药物虽然成功，但并不能治疗所有症状，还存在显著副作用的风险。这项研究是由最近的一项发现刺激的，即裸盖菇素和类似的药物通过脑细胞中的特定途径产生作用，并且这一途径可以被沙拉卡替尼阻断。目前阻断5-HT2a受体的药物并不是这一途径的特异性药物。这表明，这种沙拉卡替尼应该测试其在人体内阻断裸盖菇素效应的能力。使用MRI脑成像结合静脉注射裸盖菇素，我们最近发现了与主观效应有关的脑部变化。在这里，我们建议使用脑成像和主观测量来测试两种剂量的萨拉卡替尼对裸盖菇素的阻断或减弱作用的能力。24名健康的志愿者一天服用安慰剂，一天服用裸盖菇素，另外两天服用萨拉卡替尼，然后服用裸盖菇素。志愿者和研究人员都不知道给了哪些药物。如果沙拉卡替尼成功阻断了裸盖菇素效应的细胞通路，大脑的变化和主观评分应该会出现一些逆转。如果成功，这将潜在地刺激对精神分裂症的全新治疗方法的研究。

The aim of this project is to test the efficacy of a novel compound AZD0530 (saracatinib) in attenuating the changes in brain function in healthy human volunteers after a single dose of psilocybin. Psilocybin is a naturally occurring compound that is found in some species of mushroom. It is structurally similar to the brain neurotransmitter serotonin - which is implicated in mood and schizophrenia. Psilocybin produces its effects by acting at a specific brain receptor site - the serotonin 2A (5-HT2A) receptor. Successfully blocking the effects of psilocybin may represent a new avenue for the treatment of schizophrenia, including treatment of symptoms which are not well treated at the moment. Schizophrenia is a devastating disorder comprising positive symptoms such as hallucinations and delusions, negative symptoms such as apathy and cognitive symptoms such as poor memory. It affects around 1% of people across the lifespan and current medicines, while successful, do not treat the full range of symptoms and also carry a risk of significant side effects. This study is stimulated by the recent discovery that psilocybin and similar drugs produce their effects through a specific pathway in brain cells and that this pathway can be blocked by saracatinib. Current drugs that block 5-HT2A receptors are not specific for this pathway. This suggests that this saracatinib should be tested for its ability to block psilocybin effects in humans. Using brain imaging with MRI combined with intravenous psilocybin, we recently found brain changes that were related to the subjective effects. Here we propose to use brain imaging and subjective measures to test two doses of saracatinib for their ability to block or attenuate the effects of psilocybin. Twenty four volunteers who are healthy will be given placebo then psilocybin on one day, and saracatinib and then psilocybin on two other days. Neither the volunteers, nor the research staff will know which drugs are given. The brain changes and subjective ratings should show some reversal if saracatinib is successful in blocking the cell pathways mediating psilocybin effects. If successful this will potentially stimulate research into a whole new treatment approach for schizophrenia.