Psychedelics re-engineered for potential use in the clinic
TL;DR: An analogue of the psychedelic drug ibogaine has been developed as mentioned in this paper, which has fewer side effects and is much simpler to synthesize than the original drug and can treat addiction and depression in animal models.
Abstract: An analogue of the psychedelic drug ibogaine has been developed. The analogue mirrors ibogaine’s ability to treat addiction and depression in animal models, has fewer side effects and is much simpler to synthesize. A safer analogue of the psychedelic compound ibogaine.
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TL;DR: The authors showed that axonal serotonin release in the medial prefrontal cortex (mPFC) directly inhibits the major mPFC output neurons and found endogenous activity signatures pre-reward retrieval and at reward retrieval during a cognitive flexibility task.
Abstract: The medial prefrontal cortex (mPFC) regulates cognitive flexibility and emotional behavior. Neurons that release serotonin project to the mPFC, and serotonergic drugs influence emotion and cognition. Yet, the specific roles of endogenous serotonin release in the mPFC on neurophysiology and behavior are unknown. We show that axonal serotonin release in the mPFC directly inhibits the major mPFC output neurons. In serotonergic neurons projecting from the dorsal raphe to the mPFC, we find endogenous activity signatures pre-reward retrieval and at reward retrieval during a cognitive flexibility task. In vivo optogenetic activation of this pathway during pre-reward retrieval selectively improved extradimensional rule shift performance while inhibition impaired it, demonstrating sufficiency and necessity for mPFC serotonin release in cognitive flexibility. Locomotor activity and anxiety-like behavior were not affected by either optogenetic manipulation. Collectively, our data reveal a powerful and specific modulatory role of endogenous serotonin release from dorsal raphe-to-mPFC projecting neurons in cognitive flexibility.
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TL;DR: The current state of animal models of mental illness, with a focus on schizophrenia, depression and bipolar disorder, is reviewed and it is argued for areas of focus that might increase the likelihood of creating more useful models, at least for some disorders.
Abstract: Modeling of human neuropsychiatric disorders in animals is extremely challenging given the subjective nature of many symptoms, the lack of biomarkers and objective diagnostic tests, and the early state of the relevant neurobiology and genetics. Nonetheless, progress in understanding pathophysiology and in treatment development would benefit greatly from improved animal models. Here we review the current state of animal models of mental illness, with a focus on schizophrenia, depression and bipolar disorder. We argue for areas of focus that might increase the likelihood of creating more useful models, at least for some disorders, and for explicit guidelines when animal models are reported.
1,765 citations
TL;DR: Preliminary support for the safety and efficacy of psilocybin for treatment-resistant depression is provided and motivates further trials, with more rigorous designs, to better examine the therapeutic potential of this approach.
842 citations
TL;DR: Psilocybin was associated with enduring anxiolytic and anti-depressant effects in patients with cancer-related psychological distress, sustained benefits in existential distress and quality of life, as well as improved attitudes towards death.
Abstract: Background:Clinically significant anxiety and depression are common in patients with cancer, and are associated with poor psychiatric and medical outcomes. Historical and recent research suggests a...
823 citations
TL;DR: Recent behavioural and neuroimaging data show that psychedelics modulate neural circuits that have been implicated in mood and affective disorders, and can reduce the clinical symptoms of these disorders.
Abstract: After a pause of nearly 40 years in research into the effects of psychedelic drugs, recent advances in our understanding of the neurobiology of psychedelics, such as lysergic acid diethylamide (LSD), psilocybin and ketamine have led to renewed interest in the clinical potential of psychedelics in the treatment of various psychiatric disorders. Recent behavioural and neuroimaging data show that psychedelics modulate neural circuits that have been implicated in mood and affective disorders, and can reduce the clinical symptoms of these disorders. These findings raise the possibility that research into psychedelics might identify novel therapeutic mechanisms and approaches that are based on glutamate-driven neuroplasticity.
491 citations
TL;DR: MDMA-assisted psychotherapy can be administered to posttraumatic stress disorder patients without evidence of harm, and it may be useful in patients refractory to other treatments.
Abstract: Case reports indicate that psychiatrists administered ±3,4-methylenedioxymethamphetamine (MDMA) as a catalyst to psychotherapy before recreational use of MDMA as ‘Ecstasy’ resulted in its criminalization in 1985. Over two decades later, this study is the first completed clinical trial evaluating MDMA as a therapeutic adjunct. Twenty patients with chronic posttraumatic stress disorder, refractory to both psychotherapy and psychopharmacology, were randomly assigned to psychotherapy with concomitant active drug (n = 12) or inactive placebo (n = 8) administered during two 8-h experimental psychotherapy sessions. Both groups received preparatory and follow-up non-drug psychotherapy. The primary outcome measure was the Clinician-Administered PTSD Scale, administered at baseline, 4 days after each experimental session, and 2 months after the second session. Neurocognitive testing, blood pressure, and temperature monitoring were performed. After 2-month follow-up, placebo subjects were offered the option to re-en...
460 citations