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

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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.