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Psychedelics reopen the social reward learning critical period

Psychedelics are a broad class of drugs defined by their ability to induce an altered state of consciousness1,2. These drugs have been used for millennia in both spiritual and medicinal contexts, and a number of recent clinical successes have spurred a renewed interest in developing psychedelic therapies3,4,5,6,7,8,9. Nevertheless, a unifying mechanism that can account for these shared phenomenological and therapeutic properties remains unknown. Here we demonstrate in mice that the ability to reopen the social reward learning critical period is a shared property across psychedelic drugs. Notably, the time course of critical period reopening is proportional to the duration of acute subjective effects reported in humans. Furthermore, the ability to reinstate social reward learning in adulthood is paralleled by metaplastic restoration of oxytocin-mediated long-term depression in the nucleus accumbens. Finally, identification of differentially expressed genes in the ‘open state’ versus the ‘closed state’ provides evidence that reorganization of the extracellular matrix is a common downstream mechanism underlying psychedelic drug-mediated critical period reopening. Together these results have important implications for the implementation of psychedelics in clinical practice, as well as the design of novel compounds for the treatment of neuropsychiatric disease.

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Classically, psychedelics have been defined to include drugs such as lysergic acid diethylamide (LSD), mescaline, phenylcyclohexyl piperidine (PCP), ibogaine, 3,4-methylenedioxymethamphetamine (MDMA), psylocibin and ketamine, because each of these compounds produces alterations to sensory, self, time and space perception that are “so alien to everyday experience that they shed new light on the workings of these everyday mental functions”1. Although more recent attempts have been made to subcategorize psychedelics10 on the basis of the subjective character of the altered state that they induce (for example, hallucinogenic, empathogenic, oneirogenic or dissociative), their chemical structure (for example, tryptamines, phenethylamines or arylcyclohexamines), or their principal binding target (for example, serotonin receptor 2A (5-HT2AR), monoamine transporter, κ-opioid receptor (KOR) or N-methyl-D-aspartate receptor (NMDAR)), the importance of these categories for therapeutic applications remains unclear, since psychedelics that span the diversity of classification systems have shown remarkable promise for the treatment of addiction4,5, post-traumatic stress disorder6,7 (PTSD) and depression3,8,9. Thus, identification of a common neurobiological mechanism that can account for the shared therapeutic effects of psychedelics is an obvious priority for translational neuroscience.

During specific periods of brain development, the nervous system exhibits heightened sensitivity to ethologically relevant stimuli, as well as increased malleability for synaptic, circuit and behavioural modifications. These mechanistically constrained windows of time are called critical periods and neuroscientists have long sought methods to reopen them for therapeutic benefit. Recently, we have discovered a novel critical period for social reward learning and shown that the empathogenic psychedelic MDMA is able to reopen this critical period11. This mechanism shares a number of features with the therapeutic effects of MDMA-assisted psychotherapy for the treatment of PTSD, including rapid onset, durability and context dependence6,7. At the same time, cocaine does not reopen the social reward learning critical period11, and since cocaine does not share the psychedelics’ therapeutic profile12, these results lend further support for the view that the reinstatement of social reward learning in adulthood underlies the therapeutic efficacy of MDMA.

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