Critical Period Plasticity as a Framework for Psychedelic-Assisted Psychotherapy

The authors of this paper (2021) offer a novel framework for investigating the neurobiological basis of psychedelic-assisted psychotherapy. The authors propose that psychedelics may reopen “critical periods” in neurodevelopment whereby the brain is particularly sensitive (neuroplasticity) to environmental input.


As psychedelic compounds gain traction in psychiatry, there is a need to consider the active mechanism to explain the effect observed in randomized clinical trials. Traditionally, biological psychiatry has asked how compounds affect the causal pathways of illness to reduce symptoms and therefore focus on analysis of the pharmacologic properties. In psychedelic-assisted psychotherapy (PAP), there is debate about whether ingestion of the psychedelic alone is thought to be responsible for the clinical outcome. A question arises how the medication and psychotherapeutic intervention together might lead to neurobiological changes that underlie recovery from illness such as post-traumatic stress disorder (PTSD). This paper offers a framework for investigating the neurobiological basis of PAP by extrapolating from models used to explain how a pharmacologic intervention might create an optimal brain state during which environmental input has enduring effects. Specifically, there are developmental “critical” periods (CP) with exquisite sensitivity to environmental input; the biological characteristics are largely unknown. We discuss a hypothesis that psychedelics may remove the brakes on adult neuroplasticity, inducing a state similar to that of neurodevelopment. In the visual system, progress has been made both in identifying the biological conditions which distinguishes the CP and in manipulating the active ingredients with the idea that we might pharmacologically reopen a critical period in adulthood. We highlight ocular dominance plasticity (ODP) in the visual system as a model for characterizing CP in limbic systems relevant to psychiatry. A CP framework may help to integrate the neuroscientific inquiry with the influence of the environment both in development and in PAP.

Authors: Lauren Lepow, Hirofumi Morishita & Rachel Yehuda



The psychedelic treatment paradigm is an alternative to the prevailing model of psychopharmacology, in which a medication is used to bring about symptom reduction by providing corrective neurochemical effects on faulty pathways implicated in psychiatric disorders.

A prevailing model of chronic stress in the brain is that rapid-acting antidepressant compounds such as ketamine can reverse pathological atrophy of cortical neurons in the prefrontal cortex, thus abolishing the patient’s psychiatric symptoms.

Clinical researchers working with psychedelics have emphasized the importance of extra-pharmacologic factors, yet the common recreational use of psychedelics is accompanied by lack of spontaneous psychiatric illness remission, and even potential psychological harm.

To understand the neurobiology of psychedelic assisted psychotherapy, we suggest investigating the interaction of the psychopharmacology and its context. This requires adopting a new theoretical approach to design studies to help explain mechanism.

Advances in psychiatric treatment may result from the discovery of interventions that “release the brakes that retard” adult neuroplasticity to induce the heightened sensitivity to the environment observed during specific periods of development.

The brain has a heightened plasticity during the critical period, which creates both a vulnerability to environmental insults and a remarkable ability to quickly and robustly acquire skills. The nature and the underlying mechanisms of the critical period are distinct from adult types of neuroplasticity.

This paper highlights advancements in visual science and discusses the biological underpinnings of CPP, which may help explain how encounters with salient environmental stimuli during a sensitive period of development alter functional neurocircuitry.

While ketamine has psychedelic-like properties, it has not been packaged together with psychotherapy for FDA approval as have 3,4-Methylenedioxymethamphetamine (MDMA) and psilocybin.


Developmentally sensitive periods occur in which the brain is particularly sensitive to environmental input. Adverse experiences or deprivation during a sensitive period can affect lifelong psychological functioning.

The development of the emotional brain likely consists of many different overlapping sensitive periods, and adversity differentially affects the developing brain during critical periods. Targeted enrichment in developmental domains is most effective during well-characterized temporal windows of opportunity.


A period of rapid physical growth in late childhood corresponds with the opening and closing of the visual critical period, which is reflected in the representation of the left versus right eye inputs into striate ocular dominance columns in the primary visual cortex (V1).

Pharmacologic intervention has made it possible to re-open visual CPP in rodent models of amblyopia. The intervention creates the molecular conditions whereby the brakes of CPP are released, and a specific environmental input can exert abiding effects.

The excitatory/inhibitory balance of interneurons, myelin-related nogo receptor signaling, and Lynx family proteins, which are involved in visual CPP, may also be relevant in limbic circuits.


Visual CPP has been revisited by many, and certain psychotropic medications have been highlighted for their unexpected induction of juvenile-like neuroplasticity in the visual system.

Chronic fluoxetine treatment was shown to reinstate ODP in the adult amblyopic rat, and ketamine treatment similarly restored ODP. These studies have helped to better understand the molecular components involved in the opening and closing of ODP critical periods.

The reopening of a critical period in the fear circuit by fluoxetine and ketamine is similar to the reopening of a critical period in the ODP circuit by fluoxetine.

SSRIs and ketamine have both been evaluated in the framework of ODP, but PAP is the first novel treatment to implement ODP.


In a CPP framework, psychedelics might put the brain in a CP “open state”, while the psychotherapeutic aspect might retrieve appropriate engrams, such as traumatic memories, for modification.

MDMA can reopen a psychosocial critical period in mice by binding to the serotonin transporter and triggering a cascade leading to a metaplastic upregulation of oxytocin receptors and reopening of the social critical period and long-term depression at excitatory synapses.

The 5-HT2AR is often cited as a mechanism for psychedelic-induced plasticity, but there is also evidence that psychedelics may have a mechanism independent of 5-HT2AR.

MDMA and other psychedelics might reopen ocular dominance CPP as ketamine does, and this would have implications for visual science and psychiatry.


Neuroplasticity is a process in which neural networks are exquisitely sensitive to environmental inputs. Ocular dominance CPP may provide a theoretical framework for biological investigation of the synergistic effects of the psychopharmacologic and psychological properties of psychedelic-assisted-psychotherapy on clinical outcomes.

Building on a body of literature, we suggest that ocular dominance plasticity (ODP) is a potentially helpful framework for psychiatry, and that it may orient future work to a different level of observation missing from psychedelic research.

While the ODP critical period has been the most well-characterized, other critical periods have also been studied. It is possible that psychedelics may be a tool for better characterizing neuropsychiatric critical periods, as was begun with the critical period for social learning.

If psychedelics induce CPP, translational research studies should consider the many extra-pharmacologic factors that influence a patient’s clinical and biological outcome. This will help us understand what halts and what enables the brain to adapt to its environment.


All authors contributed to the article, which was written by LL and RY with edits by HM.

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