Critical Period Plasticity as a Framework for Psychedelic-Assisted Psychotherapy

Abstract

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.

Models of Psychedelic-Assisted Psychotherapy: A Contemporary Assessment and an Introduction to EMBARK, a Transdiagnostic, Trans-Drug Model

“…Some may also develop a clarified sense of their deeply held values, which may form the basis for beneficial post-treatment actions ( Watts and Luoma, 2020 ). At the neural level, it has been suggested that the plasticity brought about by many psychedelic medicines may signal the reopening of a social reward critical learning period for weeks after administration, suggesting that pro-therapeutic changes may take root during a time period that extends beyond the end of what is typically considered integration ( Nardou et al, 2019 ; Dölen, 2021 ; Dölen and Briggs, 2021 ; Lepow et al, 2021 ). The EMBARK approach recognizes this unique opportunity.…”

“…Although some actors in the field are seeking to develop drugs that replicate the putatively therapeutic neuropharmacology of classic psychedelics while eliminating their subjective effects ( Dong et al, 2021 )—and thereby the need for supportive therapy ( Yakowicz, 2021 )—the potential efficacy of this approach remains speculative ( Yaden and Griffiths, 2020 ; Olson, 2021 ). In fact, it may be more likely that the widely touted increases in neuroplasticity induced by some psychedelics reflect a pluripotent state that requires therapeutic framing to bring about enduring beneficial outcomes ( Vollenweider and Kometer, 2010 ; Carhart-Harris et al, 2018a ; Dölen, 2021 ; Lepow et al, 2021 ). As such, the first wave of psychedelic medicines in psychiatry will almost certainly hold as axiomatic that psychedelic medicines are best administered within a well-considered context of psychotherapy.…”

The conundrum of therapeutic intoxication

“…Psilocybin and MDMA, but not cocaine, seem to support enduring and complex possibilities for self-learning that can be harnessed with psychological interventions. 5 Such data indicate granularity and suggest that positively experienced intoxication is not alone sufficient for therapeutic growth. Similarly, ketamine and its derivatives are not routinely administered in contexts that include psychotherapy, but the combination may facilitate new insights and ways of being for people.…”

“…Likewise, in a smaller study, olanzapine 25 mg/day was associated with response in only 5% of a treatmentresistant group, and 41% of the same patients subsequently responded to clozapine. 5 Some studies have shown benefit for non-clozapine antipsychotics in resistant patients, but these trials are methodologically flawed and subject to funder bias. 6 Most clinicians accept that clozapine is uniquely effective in refractory schizophrenia.…”

MDMA for the Treatment of Negative Symptoms in Schizophrenia

“…3,4-Methylenedioxy methamphetamine (MDMA) is a schedule I substance with a controversial history and resulting stigmatization. In recent years, it has emerged as a novel therapeutic given its ability to enhance social interactions, generate empathy, and induce a state of metaplasticity in the brain [ 13 , 14 ]. MDMA has been shown to be an effective treatment for PTSD and is currently in phase III clinical trials [ 15 ].…”