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Our technology-supported approach to psychedelic integration enables patients to harness the limited window of neuroplasticity after treatment to make practical, positive changes for long-term outcomes.


Opening the window of neuroplasticity

Pivotal Mental States


Journal of Psychopharmacology, 2020


Abstract: This paper introduces a new construct, the ‘pivotal mental state,’ which is defined as a hyper-plastic state aiding rapid and deep learning that can mediate psychological transformation. We believe this new construct bears relevance to a broad range of psychological and psychiatric phenomena. We argue that pivotal mental states serve an important evolutionary function, that is, to aid psychological transformation when actual or perceived environmental pressures demand this.

Leveraging Neuroplasticity to Enhance Adaptive Learning: The Potential for Synergistic Somatic-Behavioral Treatment Combinations to Improve Clinical Outcomes in Depression


Biological Psychiatry, 2019


Abstract: Until recently, therapeutic development in psychiatry was targeted solely toward symptom reduction. While this is a worthwhile goal, it has yielded little progress in improved therapeutics in the last several decades in the field of mood disorders. Recent advancements in our understanding of pathophysiology suggests that an impairment of neuroplasticity may be a critical part of the development of neuropsychiatric disorders. Interventions that enhance or modulate neuroplasticity often reduce depressive symptoms when applied as stand-alone treatments. Unfortunately, when treatments are discontinued, the disease state often returns as patients relapse. However, treatments that enhance or modulate plasticity not only reduce symptom burden, but also may provide an opportune window wherein cognitive or behavioral interventions could be introduced to harness a state of enhanced neuroplasticity and lead to improved longer-term clinical outcomes.

Psychoplastogens: A Promising Class of Plasticity-Promoting Neurotherapeutics

Journal of Experimental Neuroscience, 2019


Abstract: Neural plasticity — the ability to change and adapt in response to stimuli — is an essential aspect of healthy brain function and, in principle, can be harnessed to promote recovery from a wide variety of brain disorders. Many neuropsychiatric diseases including mood, anxiety, and substance use disorders arise from an inability to weaken and/or strengthen pathologic and beneficial circuits, respectively, ultimately leading to maladaptive behavioral responses. Thus, compounds capable of facilitating the structural and functional reorganization of neural circuits to produce positive behavioral effects have broad therapeutic potential. Several known drugs and experimental therapeutics have been shown to promote plasticity, but most rely on indirect mechanisms and are slow-acting. Here, I describe psychoplastogens — a relatively new class of fast-acting therapeutics, capable of rapidly promoting structural and functional neural plasticity. Psychoplastogenic compounds include psychedelics, ketamine, and several other recently discovered fast-acting antidepressants.

Psychedelics Promote Structural and Functional Neural Plasticity


Cell Reports, 2018


Abstract: Atrophy of neurons in the prefrontal cortex (PFC) plays a key role in the pathophysiology of depression and related disorders. The ability to promote both structural and functional plasticity in the PFC has been hypothesized to underlie the fast-acting antidepressant properties of the dissociative anesthetic ketamine. Here, we report that, like ketamine, serotonergic psychedelics are capable of robustly increasing neuritogenesis and/or spinogenesis both in vitro and in vivo. These changes in neuronal structure are accompanied by increased synapse number and function, as measured by fluorescence microscopy and electrophysiology. The structural changes induced by psychedelics appear to result from stimulation of the TrkB, mTOR, and 5-HT2A signaling pathways and could possibly explain the clinical effectiveness of these compounds. Our results underscore the therapeutic potential of psychedelics and, importantly, identify several lead scaffolds for medicinal chemistry efforts focused on developing plasticity-promoting compounds as safe, effective, and fast-acting treatments for depression and related disorders.

Integration — “the critical period” 

Critical period as a framework for psychedelic -assisted therapy


Frontiers in Neuroscience, 2021


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.

Oxytocin-dependent reopening of a social reward learning critical period with MDMA


Nature, 2019


Abstract: A critical period is a developmental epoch during which the nervous system is expressly sensitive to specific environmental stimuli that are required for proper circuit organization and learning. Mechanistic characterization of critical periods has revealed an important role for exuberant brain plasticity during early development, and for constraints that are imposed on these mechanisms as the brain matures. In disease states, closure of critical periods limits the ability of the brain to adapt even when optimal conditions are restored. Thus, identification of manipulations that reopen critical periods has been a priority for translational neuroscience. Here we provide evidence that developmental regulation of oxytocin-mediated synaptic plasticity (long-term depression) in the nucleus accumbens establishes a critical period for social reward learning. Furthermore, we show that a single dose of (+/-)-3,4-methylendioxymethamphetamine (MDMA) reopens the critical period for social reward learning and leads to a metaplastic upregulation of oxytocin-dependent long-term depression. 

Harnessing neuroplasticity for habit change

Every patient’s treatment plan will include daily integration “homework” to help them create new, practical habits that support incremental progress toward long-term therapy goals.


A wealth of research indicates a direct relationship between homework adherence and positive clinical outcomes in cognitive behavioral therapy (CBT). In particular, various smaller studies suggest enhanced efficacy of CBT in the “critical period” following ketamine treatment.

Cognitive Behavior Therapy May Sustain Antidepressant Effects of Intravenous Ketamine in Treatment-Resistant Depression


Psychotherapy and Psychosomatics, 2017  


Abstract: Ketamine has shown rapid though short-lived antidepressant effects. The possibility of concerning neurobiological changes following repeated exposure to the drug motivates the development of strategies that obviate or minimize the need for longer-term treatment with ketamine. In this open-label trial, we investigated whether cognitive behavioral therapy (CBT) can sustain or extend ketamine’s antidepressant effects…[Results indicated that] CBT may sustain the antidepressant effects of ketamine in treatment-resistant depression. Well-powered randomized controlled trials are warranted to further investigate this treatment combination as a way to sustain ketamine’s antidepressant effects.


Can Exposure-Based CBT Extend IV Ketamine’s Effects in Obsessive-Compulsive Disorder? An Open-Label Trial



Journal of Clinical Psychiatry, 2016


Abstract: A single subanesthetic intravenous (IV) dose of ketamine leads to rapid anti-obsessional effects in obsessive-compulsive disorder (OCD) patients with near-constant intrusive obsessions, but these effects usually do not persist. We tested whether a brief course of exposure-based cognitive behavioral therapy (CBT) could extend ketamine’s effects in a two week pilot open trial and if this effect was maintained (without additional treatment) two weeks later. Our rationale was: 1) ketamine is reported to enhance plasticity and extinction learning in rodents, and 2) enhanced extinction learning may facilitate CBT gains, as reported in trials that combined CBT with medication thought to facilitate extinction learning (e.g. D-cycloserine). Mimicking those trials, CBT was abbreviated (i.e. 10 one-hour exposure sessions) but delivered during the putative time interval when ketamine facilitates extinction learning (within 14 days). 

Homework Compliance Counts in Cognitive Behavioral Therapy


Cognitive Therapy and Research, 2012


Abstract: Prior research has demonstrated that there is some association between treatment engagement and treatment outcome in behavioral therapy for anxiety disorders. However, many of these investigations have been limited by weak measurement of treatment engagement variables, failure to control for potentially important baseline variables, and failure to consider various treatment engagement variables simultaneously. The purpose of the present study is to examine the relationship between two treatment engagement variables (treatment expectancy and homework compliance) and the extent to which they predict improvement from cognitive-behavioral therapy (CBT) for anxiety disorders.

The Relationship Between Homework Compliance and Therapy Outcomes: An Updated Meta-Analysis


Cognitive Therapy and Research, 2010


Abstract: The current study was an updated meta-analysis of manuscripts since the year 2000 examining the effects of homework compliance on treatment outcome. A total of 23 studies encompassing 2,183 subjects were included. Results indicated a significant relationship between homework compliance and treatment outcome suggesting a small to medium effect (r = .26; 95% CI = .19–.33). Moderator analyses were conducted to determine the differential effect size of homework on treatment outcome by target symptoms (e.g., depression; anxiety), source of homework rating (e.g., client; therapist), timing of homework rating (e.g., retroactive vs. contemporaneous), and type of homework rating (e.g., Likert; total homeworks completed). Results indicated that effect sizes were robust across target symptoms, but differed by source of homework rating, timing of homework rating, and type of homework rating. Specifically, studies utilizing combined client and therapist ratings of compliance had significantly higher mean effect size relative to those using therapist only assessments and those using objective assessments.

Clinical collaboration is key

A strong therapeutic alliance — the relationship between clinician and patient — is integral to positive treatment outcomes. To foster the therapeutic alliance, treatment goals must be developed collaboratively between patient and clinician.  

A Meta-Analysis of the Relation between Therapeutic Alliance and Treatment Outcome in Eating Disorders


International Journal of Eating Disorders, 2017 


Abstract: The therapeutic alliance has demonstrated an association with favorable psychotherapeutic outcomes in the treatment of eating disorders (EDs). However, questions remain about the inter-relationships between early alliance, early symptom improvement, and treatment outcome. We conducted a meta-analysis on the relations among these constructs, and possible moderators of these relations, in psychosocial treatments for EDs. Twenty studies met inclusion criteria and supplied sufficient supplementary data. Results revealed small-to-moderate effect sizes…indicating that early symptom improvement was related to subsequent alliance quality and that alliance ratings also were related to subsequent symptom reduction…In sum, early symptom reduction enhances therapeutic alliance and treatment outcome in EDs, but early alliance may require specific attention for younger patients and for those receiving nonbehaviorally oriented treatments.

The Relationship Between the Therapeutic Alliance and Treatment Outcome in Two Distinct Psychotherapies for Chronic Depression


Journal of Consulting and Clinical Psychology, 2014


Abstract: This study tested whether the quality of the patient-rated working alliance, measured early in treatment, predicted subsequent symptom reduction in chronically depressed patients. Secondarily, the study assessed whether the relationship between early alliance and response to treatment differed between patients receiving Cognitive Behavioral Analysis System of Psychotherapy (CBASP) versus Brief Supportive Psychotherapy (BSP)…A more positive early working alliance was associated with lower subsequent symptom ratings in both the CBASP and BSP…. In addition, the interaction between alliance and psychotherapy type was significant, such that alliance quality was more strongly associated with symptom ratings among those in the CBASP treatment group.

Goal consensus and collaboration


Psychotherapy, 2011


Abstract: This article updates our previous article in this journal by examining via meta-analyses results of recent studies, published from 2000 through 2009, that relate goal consensus and collaboration to treatment outcome. Specifically, 15 studies with a total sample size of 1,302 yielded a goal consensus-psychotherapy outcome effect size of .34 (SD = .19, p < .0001, 95% confidence interval = .23-.45), indicating that better outcomes can be expected when patient and therapist agree on therapeutic goals and the processes to achieve these goals. The collaboration-outcome meta-analysis based on 19 studies with a total sample of 2,260 patients yielded a mean correlation of .33 (SD = .17, p < .0001, 95% confidence interval = .25-.42), suggesting that psychotherapy outcome appears to be considerably enhanced when patient and therapist are actively involved in a cooperative relationship. 

The Role of the Therapeutic Alliance in Psychotherapy and Pharmacotherapy Outcome


Journal of Lifelong Living Psychotherapy, 2011


Abstract: The relationship between therapeutic alliance and treatment outcome was examined for depressed outpatients who received interpersonal psychotherapy, cognitive-behavior therapy, imipramine with clinical management, or placebo with clinical management. Clinical raters scored videotapes of early, middle, and late therapy sessions for 225 cases (619 sessions). Outcome was assessed from patients’ and clinical evaluators’ perspectives and from depressive symptomatology. Therapeutic alliance was found to have a significant effect on clinical outcome for both psychotherapies and for active and placebo pharmacotherapy. Ratings of patient contribution to the alliance were significantly related to treatment outcome; ratings of therapist contribution to the alliance and outcome were not significantly linked. These results indicate that the therapeutic alliance is a common factor with significant influence on outcome.


By providing our clinicians and patients a shared platform to adapt goals and connect outside of sessions, our technology enhances clinical collaboration and therapeutic alliance to further improve outcomes.

Adherence supported by technology

Behavioral technology is the most accessible and effective way to strengthen therapeutic alliance, goal consensus, accountability — and ultimately lead to better clinical outcomes. A growing body of research indicates the benefits of mental health apps for treatment adherence, symptom reduction, and care accessibility.

Managing Emotions: The Effects of Online Mindfulness Meditation on Mental Health and Economic Behavior


MIT Economics Job Market Paper, 2022


Abstract: Emotions and worries can reduce individuals’ available attention and affect economic decisions. In a four-week experiment with 2,384 US adults, offering free access to a popular mindfulness meditation app that costs $13 per month improves mental health, productivity and decision making. First, it causes a 0.44 standard deviation reduction in symptoms of stress, anxiety, and depression, comparable to the impacts of expensive in-person therapy, with improvements even among participants with minimal or mild symptoms at baseline. Second, it increases earnings on a proofreading task by 1.9 percent. Third, it makes decision-making more stable across emotional states, reducing the interference of personal worries with risk choices. Overall, our results demonstrate the potential of affordable mindfulness meditation apps to improve mental health, productivity, and the impact of emotions on economic decisions.

Can smartphone mental health interventions reduce symptoms of anxiety? A meta-analysis of randomized controlled trials


Journal of Affective Disorders, 2017


Abstract: Various psychological interventions are effective for reducing symptoms of anxiety when used alone, or as an adjunct to anti-anxiety medications…This meta-analysis shows that psychological interventions delivered via smartphone devices can reduce anxiety. Future research should aim to develop pragmatic methods for implementing smartphone-based support for people with anxiety, while also comparing the efficacy of these interventions to standard face-to-face psychological care.


The efficacy of smartphone-based mental health interventions for depressive symptoms: a meta-analysis of randomized controlled trials


World Psychiatry, 2017


Abstract: The rapid advances and adoption of smartphone technology presents a novel opportunity for delivering mental health interventions on a population scale. Despite multi-sector investment along with wide-scale advertising and availability to the general population, the evidence supporting the use of smartphone apps in the treatment of depression has not been empirically evaluated. Thus, we conducted the first meta-analysis of smartphone apps for depressive symptoms. An electronic database search in May 2017 identified 18 eligible randomized controlled trials of 22 smartphone apps, with outcome data from 3,414 participants. Depressive symptoms were reduced significantly more from smartphone apps than control conditions (g=0.38, 95% CI: 0.24-0.52, p<0.001), with no evidence of publication bias…Overall, these results indicate that smartphone devices are a promising self-management tool for depression. Future research should aim to distill which aspects of these technologies produce beneficial effects, and for which populations. 

The use of mobile telephones as adjuncts to cognitive behavioral psychotherapy


Professional Psychiatry Research and Practice, 2008


Abstract: Despite the rapid proliferation of technological adjuncts in cognitive behavior therapy (CBT), much of this development appears to have occurred on an ad hoc basis and in many cases has resulted in applications that are beyond the resources of most practicing clinicians. The authors delineate the specific areas in which CBT can be augmented through use of technology and outline the characteristics of an ideal therapy augmentor. Mobile telephones are identified as a low-cost and accessible device whose use has been largely untapped to date. The existing literature on use of the mobile phone is reviewed, and potential areas for its application in CBT are examined.


With technology connecting to patients’ personal devices, we can provide patients daily tracking, reminders, and an ongoing connection with their clinician for improved adherence and outcomes.

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