Expectancy and Hope in MDMA-Assisted Therapy

Abstract: An FDA decision to delay the approval of MDMA-assisted Therapy (MDMA-AT) in 2024 came as a surprise to many. Phase III research data had demonstrated that more than two-thirds of participants who received MDMA with therapy no longer qualified for a PTSD diagnosis at the end of the treatment protocol. Among the reasons for the FDA’s decision to deny approval was concern for heightened positive expectations from participants, potentially biasing reported treatment outcomes. Community activists and ethicists have expressed an additional yet related concern that the cultural phenomenon of psychedelic hype (see Petranker et al., 2020; Yaden, Potash, 2022) may have further contributed to inflated expectations and placed undue pressure on MDMA-AT participants to report positive experiences. As Phase III MDMA-AT research practitioners, we affirm the need for additional inquiry into the influence of expectancy on MDMA-AT research in future Phase III trials. In considering expectancy, we also advocate for a deeper consideration of the role of hope in psychedelic therapy as distinct from expectancy. While potential expectancy bias on the part of the researchers relies on a belief in a positive endpoint, hope is a broader act of care and an ethical imperative in MDMA research. Developing an authentically caring therapeutic alliance requires aligning with participants’ hopes and dreams and striving to support conditions for their best outcome. Our reflection on the role of hope within MAT draws from spiritual, existential, religious, and theological sources and discusses the Inner Healing Intelligence method (O'Donnell et al., 2023) utilized in Phase II and Phase III MDMA-AT research protocols.

Post-traumatic stress disorder (PTSD) is a devastating and widespread psychiatric condition.¹ PTSD includes psychological, spiritual, and neurobiological symptoms and physical comorbidities² and can develop in response to a severe threat, abuse, sexual assault, near-death experiences, and other traumatic experiences.³ An estimated 3.6% of U.S. adults have PTSD, and the disorder occurs at higher rates within marginalized populations and among veterans.⁴ PTSD treatment is psychologically arduous and requires intensive, long-term commitment. Treatment has a high dropout rate, and standard PTSD treatments demonstrate minimal efficacy for many PTSD sufferers.⁵   

In recent years, MDMA⁶ in combination with therapeutic support has emerged as a novel and promising treatment for PTSD. Research suggests that MDMA’s unique pharmacological action, when offered in a supportive context with skilled therapy, supports a temporary state of reduced fear and increased safety—enabling an optimal and less arduous psychological state for processing traumatic memories. While research on MDMA-Assisted Psychotherapy (MAT) has been promising, this research, like other psychedelic trials, has struggled to control for how participants’ expectations about treatment outcomes impact study results. This has hampered scientific progress, and just as critically, has caused hope—a necessary therapeutic and spiritual emotion—to be conflated with expectation. 

As therapists in Phase III MAT trials, we affirm the importance of investigating expectancy effects in MAT research and psychedelic research more broadly.⁷ We also contend that expectancy is best considered separately from hope—a broader, existentially meaningful, and ethically grounded act of solidarity and care. In this essay, we call upon MAT researchers to distinguish between hope and expectancy in psychedelic research. These concepts have been conflated in clinical trials and deserve further elucidation. Drawing from our clinical research experience, we argue that honoring the therapeutic and, indeed, spiritual value of hope within clinical trials enhances participants’ well-being and does not conflict with a commitment to evaluating and minimizing unrealistic expectations. 

Hope is often incorporated as a dimension of care in psychotherapeutic treatment⁸, and definitions of hope are broad in scope, emerging from diverse cultural and language contexts.⁹ In psychological literature, hope is considered distinct from optimism or positive expectations. Although hope is a complex concept with multivalent meanings, psychologists define it as a combination of agency, or the motivation to act, and cognitive pathways that enable a person to identify possible routes to a goal.¹⁰ A recent prospective study demonstrated that an individual's level of hope is a significant factor in predicting how well they will cope and recover following a traumatic event.¹¹ Additionally, increased hope can predict post-trauma resilience.¹² Interventions aimed at enhancing hopefulness are present within many psychotherapeutic approaches, reflecting broad recognition of the role of hope in treatment.¹³ In their meta-analytic review of hope in PTSD treatment, Gallagher and colleagues conclude that researchers should examine hope as a mechanism of change in therapy.¹⁴  

In religious and philosophical contexts, hope is a positive catalyst for resilience and well-being. It is the capacity to affirm and make meaning of life, even in dire circumstances. Victor Frankl (1905-1997), a twentieth-century psychologist, philosopher, and Jewish Holocaust survivor, defines hope as the conviction that life has meaning and purpose regardless of adversities and devastating circumstances. Hope is a defiant choice to find meaning in suffering—a uniquely human capacity that gives purpose to one’s life. As a durable force that cannot be disproven by unfavorable circumstances, hope contrasts with false expectation—a state of mind that is inherently fragile and easily broken.¹⁵ Howard Thurman (1899-1981), an African-American theologian, philosopher, and civil rights leader, articulates a spirituality of hope rooted in divinity and cultivated through a faithful and active participation in a just and loving community.¹⁶ Thurman's hope is received from a divine source and realized through communal justice, while hope for Frankl is an individual’s response to an immutable circumstance. For bell hooks (b1952), a contemporary feminist theorist who was heavily influenced by Thurman, hope is more directly political. For hooks, “beloved community” only exists when people join together in spirit as well as through action and active resistance to the combined forces of racism, imperialism, capitalism, and sexism.¹⁷ These views of hope affirm human dignity in the face of adversity without a reliance on false expectations of a positive outcome.  

As a catalyst for healing, hope is deeply rooted in the human capacity for transformation and an affirmation of dignity, even in the face of extreme suffering. The intersections of expectancy and hope in MAT present both challenges and opportunities for advancing the treatment of severe PTSD. While the FDA’s concern about expectancy bias (discussed below) highlights the need for rigorous methodological safeguards, it also underscores the importance of distinguishing between expectancy as a cognitive belief in specific outcomes and hope, which is a broader spiritual/existential resource that fosters resilience, agency, meaning-making, and belonging. Hope is not merely a byproduct of treatment but an ethical imperative toward solidarity with study participants’ resilience and desires for healing. Hope supports the spiritual health of both the therapist and client, regardless of what the future may hold. 

Aligning with participants’ hope while attending to rigorous and ongoing informed consent processes can increase adherence to treatment without encouraging exaggerated expectations.¹⁸ Furthermore, a robust body of empirical evidence has established hope as a significant predictor of positive mental health treatment outcomes, a key mechanism of change within various therapeutic modalities, and a valid, measurable indicator of recovery.¹⁹ 

The gold standard for evaluating the efficacy of medical interventions is the double-blind, placebo-controlled randomized controlled trial (RCT).²⁰ A critical feature of RCTs is the masking (or blinding) of treatment allocation, which ensures that neither participants nor researchers know whether an individual has received the active treatment or a placebo. Due to the intense subjective effects of psychedelic treatment, it is highly unlikely for participants to truly be blinded to their assigned treatment group, presenting the hard problem of “functional unblinding” in psychedelic research.²¹ When study participants are aware of having received the treatment under investigation, the placebo effect is presumed to be strengthened and can threaten the internal validity of data outcomes.²²  

Functional unblinding may have influenced outcomes in the recent Lykos Therapeutics’ Phase III MAT trials. The trials demonstrated positive outcomes and a significant reduction in PTSD symptoms for many participants.²³ At the one-year follow-up assessment, between 67% to 73.5% of participants in these studies no longer met the criteria for PTSD.²⁴ Despite such promising study results, the U.S. Food and Drug Administration (FDA) declined to approve the sponsor’s new drug application after a public hearing in 2024.²⁵  

The FDA cited concern over functional unblinding and the potential impact of positive expectancy on study results. Expectancy effects occur when there is a bias (either positive or negative) regarding the efficacy of the treatment under investigation. This problem is especially acute in psychedelic research. Expectancy effects and functional unblinding are considered “hard problems” of psychedelic science. Participants and researchers are often able to identify whether they were assigned to the treatment group or the control (placebo) arm of the study.²⁶ In one Lykos Phase III study, 94.2% of MDMA-group participants and 74.6% of placebo-group participants correctly identified the arm of the study to which they were assigned.²⁷ Expectancy effects among these participants who identified their study arm were not monitored, and FDA committee members were concerned that a positive bias may have led to false reporting of positive outcomes.  

A failure of adequate blinding and the immense amount of optimistic “hype” in the broader culture may have contributed to some expectancy bias in the MAT trial results.²⁸ In our experience with study participants, many but not all participants who believed they had received MDMA also believed they would be helped by the investigational treatment, which may have influenced their reports of positive outcomes. Additionally, some participants felt let down at the end of their treatment when their PTSD conditions did not improve as quickly as they had expected. 

Hope and expectancy intersect in these trials. As study therapists, we supported hope by helping participants rediscover their agency and confidence in life through making sense of and integrating their traumatic experiences. Yet, we took great care not to encourage false expectations for recovery from PTSD. Though expectancy should remain a concern in psychedelic research, we urge future MAT research to distinguish between expectancy bias and hope, in order to more thoroughly understand the ways that facilitating hope in MAT can positively impact PTSD. 

Despite concerns around expectancy bias, hope remains a critical dimension of PTSD treatment. Acute and chronic trauma can profoundly disrupt an individual’s existential, spiritual, and/or religious sense of reality, resulting in feelings of profound hopelessness–experienced as disconnection and spiritual loss. Trauma disrupts neurobiological and existential frameworks, creating a dual crisis of meaning and identity.²⁹ When a survivor’s sense of being in the world is existentially destabilized, they are often left with feelings of alienation, fragmentation, existential dread, and hopelessness.³⁰ Persistent hopelessness that is experienced as a lack of a meaningful future or as a fragmented self can be devastating and can increase the risk of suicidal ideation and suicidality, even when accounting for changes in depressive symptoms.³¹  

MAT Phase III study participants entered the research trials having experienced devastating traumas, including sexual assault, childhood abuse, combat violence, terrible accidents, and violent crimes. For some, these traumas left them in what theologian Serene Jones refers to as a “middle space” of liminal suspension.³² Patients in this middle space may feel as though they are stuck between the past and the future, resulting in a spiritually distressing feeling of liminality that can impede their capacity to heal. Profound traumas can fracture the narrative coherence of the PTSD sufferer’s life, leading to meaninglessness and necessitating the co-creating of pathways for reconnecting with hope as a rediscovery of a future worth living.  

Many of our study participants were burdened with moral injury. Moral injury is felt as existential hopelessness that results from a profound violation of one’s core moral values and beliefs.³³ In the Phase III trial, moral injury was often the result of participants making choices during a traumatic event that conflicted with their inner sense of morality. For example, one study participant’s PTSD was the result of his time in the military and a particular experience in combat. In MAT sessions, the young man reflected on how he had acted in self-defense to ensure his own survival and how he felt he had failed to protect his companions. This left him racked with guilt. He felt he lacked permission to continue living beyond the moment his fellow soldiers died. He related how his decision at the time to counterattack and kill the enemy combatants had severed his sense of connection to a meaningful world and a moral future. This left him unable to move forward with purpose or hope, which resulted in decreased agency and disconnection from his core values and motivations. 

MAT helped lower the participant’s fear responses and allowed him to re-evaluate these traumatic memories with a new perspective. He reported that he was able to release feelings of meaninglessness and shame stemming from combat. He began to discover a renewed source of meaning and a purposeful future. The study treatment did not resolve the young veteran’s PTSD symptoms. Nevertheless, he expressed an increased capacity to envision a positive future and experienced increased self-compassion, as well as a reappraisal of his role in the traumatic events. He rediscovered a sense of belonging to the community of soldiers with whom he felt a deep spiritual connection and rediscovered a new identity as an honorable veteran. This process, though not curative, is indicative of the restoration of renewed agency that can occur during MAT that supports positive therapeutic outcomes.  

MDMA’s pharmacological effects enable participants to revisit traumatic memories with reduced fear and greater clarity. While the exact mechanisms are still under investigation, MDMA’s ability to enhance synaptic plasticity, emotional learning, and prosocial effects underscores its potential as a transformative treatment for PTSD.³⁴ Another participant experienced sexual abuse as self-alienation, resulting in a low degree of agency and existential disconnection. Her co-therapists supported her to recover a sense of belonging and internal congruence by supporting her as she processed the profound impacts the trauma had on her spiritual health, her beliefs, values, and religious belonging. Through remembering the past and reframing traumatic events during MAT, the participant was able to release unrealistic feelings of responsibility for the violence she was subjected to, while also honoring the intelligence of shame as a necessary survival strategy in response to overwhelming trauma. The co-therapists served as witnesses for this participant’s experience and were able to offer compassion and skilled intervention that helped her remember and reframe otherwise devastating memories. The combination of MDMA and therapy allowed the participant to reconnect with a sense of agency and a look to the future with both a sense of control and hope.

For study therapists, cultivating our own capacities for hope empowered us to support study participants as they reconnected with their capacities for hope. Affirming hope was not always easeful, and we were sometimes personally impacted by the traumatic stories we witnessed in the study sessions. Rather than an expectation toward wholeness, hope in our work with MAT participants emphasized agency and resilience for moving forward with confidence in life, despite setbacks and challenges. We aimed to hold onto this type of agentic hope, even when a participant could not connect with hopefulness themselves. Over time, many of our participants gradually and firmly internalized feelings of hope as an expression of personal agency and authentic choice in their own stance toward life, despite tragic losses.  

Hope emerges from a therapeutic commitment to respecting participants’ innate, protective intelligence in response to traumatic events. The concept of Inner Healing Intelligence (IHI) is a foundational theory for MAT therapists in the Phase III studies. IHI is a resilience-based therapeutic approach that affirms the capacity within each person to naturally move toward post-traumatic growth and a resolution of PTSD symptoms, when supported by the right conditions.³⁵  

MAT requires a clinician to support participants’ hope without feeding unrealistic expectations or biasing study results. Aligning with hope is part of an ethical imperative to do no harm. It reflects a necessity in all research involving human subjects, striking a balance between research validity and obligations to the participant. Affirming hope can be a tricky balance. For example, encouraging unrealistic hope in a clinical context can be a subtle form of coercion, leading participant to change their behavior to please or accommodate their care providers. In the MAT Phase III study, we avoided undermining participant autonomy and trust by not encouraging false or exaggerated hope. We took a measured and realistic stance toward projected treatment outcomes to balance therapeutic hope with realistic expectations. We acknowledge that an abundance of excitement about MAT as a promising novel therapy may have influenced our assessment of the benefits of MAT for specific participants. Yet, no one can be completely neutral, and we were committed to cultivating clinical equipoise and avoiding biasing participants, especially around matters of hope and expectations.  

When discussing potential treatment outcomes, we did not shy away from expressing our uncertainty because the outcomes were truly uncertain. As research therapists, we honestly informed participants of the knowns and unknowns of MAT. Through ongoing informed consent processes, we addressed unrealistic or unsupported expectations. We sought to balance realistic expectations with support for the participants’ capacity to look hopefully on life regardless of whether the future would include unburdening from debilitating symptoms of persistent PTSD. Ultimately, this allowed participants to cultivate a more realistic and enduring form of hope.

When grounded in hope, MAT represents not just a novel therapeutic intervention but an enduring act of care and solidarity with the care seeker’s resilience and post-traumatic growth. As psychedelic research continues, future trials will benefit from more robust differentiation between hope and expectancy. By honoring hope as a fundamental and enduring foundation for healing, researchers and clinicians can align scientific rigor with the ethical imperative to affirm the dignity of the human spirit. This integrated approach ensures that the pursuit of data does not come at the cost of the human connection that best supports transformative healing. 

¹ The National Center for PTSD, a division of the U.S. Department of Veterans Affairs reports that approximately 6% of the U.S. population will have PTSD at some point in their lives. About 3.6% of the U.S. adult population had PTSD in the past year, and in any given year, over 9 million American adults will live with PTSD. [Return to Section]

² M. L. Pacella, B. Hruska, and D. L. Delahanty, “The Physical Health Consequences of PTSD and PTSD Symptoms: A Meta-Analytic Review,” Journal of Anxiety Disorders 27, no. 1 (2013): 33–46. [Return to Section]

³ Diagnostic and Statistical Manual of Mental Disorders, 5th ed., Text Revision (DSM-5-TR) (Washington, DC: American Psychiatric Association Publishing, 2022), https://doi.org/10.1176/appi.books.9780890425787.x07_Trauma_and_Stresso… [Return to Section]

⁴ Kimberly Matheson, et al., “Traumatic Experiences, Perceived Discrimination, and Psychological Distress Among Members of Various Socially Marginalized Groups,” Frontiers in Psychology 10 (2019): 416, https://doi.org/10.3389/fpsyg.2019.00416; Andrea L. Roberts et al., “Race/Ethnic Differences in Exposure to Traumatic Events, Development of Post-Traumatic Stress Disorder, and Treatment-Seeking for Post-Traumatic Stress Disorder in the United States,” Psychological Medicine 45, no. 1 (2015): 71–83, https://doi.org/10.1017/S0033291714000869. [Return to Section]

⁵ Lisa Burback et al., “Treatment of Posttraumatic Stress Disorder: A State-of-the-Art Review,” Current Neuropharmacology 22, no. 4 (2024): 557–635, https://doi.org/10.2174/1570159X22666240110120747. [Return to Section]

⁶ 3,4-Methylenedioxymethamphetamine (MDMA), a psychoactive compound generally categorized as a psychedelic or entactogen. [Return to Section]

⁷ See L. Jacob Flameling, Jacob S. Aday, and Michiel van Elk, “Expectancy Effects Cannot Be Neglected in MDMA-Assisted Therapy Research,” ACS Chemical Neuroscience 14, no. 23 (2023): 4062–4063, https://doi.org/10.1021/acschemneuro.3c00676. [Return to Section]

⁸ Matthew W. Gallagher et al., “Examining Hope as a Transdiagnostic Mechanism of Change Across Anxiety Disorders and CBT Treatment Protocols,” Behavior Therapy 51, no. 1 (2020): 190–202; Charles Snyder, Scott Michael, and Jennifer S. Cheavens, “Hope as a psychotherapeutic foundation of common factors, placebos, and expectancies,” in The heart and soul of change: What works in therapy, eds. M. A. Hubble, B. L. Duncan, & S. D. Miller (American Psychological Association: 1999);179–200; Guy H. Montgomery, Daniel David, Terry DiLorenzo, and Joel Erblich, “Is Hoping the Same as Expecting? Discrimination Between Hopes and Response Expectancies for Nonvolitional Outcomes,” Personality and Individual Differences 35, no. 2 (2003): 399–409. [Return to Section]

⁹ A. M. Krafft, C. Martin-Krumm, and F. Fenouillet, “Adaptation, Further Elaboration, and Validation of a Scale to Measure Hope as Perceived by People: The HOPE Scale,” Journal of Well-Being Assessment 3, no. 1 (2019): 37–60. [Return to Section]

¹⁰ Laura J. Long, “Hope and PTSD,” Current Opinion in Psychology 48 (2022). [Return to Section]

¹¹ Ibid. [Return to Section]

¹² Matthew W. Gallagher and Patricia A. Resick, “Mechanisms of Change in Cognitive Processing Therapy and Prolonged Exposure Therapy for PTSD: Preliminary Evidence for the Differential Effects of Hopelessness and Habituation,” Cognitive Therapy and Research 36, no. 6 (2012): 750–55. [Return to Section]

¹³ Examples of approaches to psychotherapy that integrate hope as a resource include Traumatic Recovery Capacity (Bonanno 2004), Core State (Fosha 2000), Psychological Flexibility (Hayes et al. 2012), Actualizing Tendency (Rogers 1959), Intrinsic Motivation (Deci and Ryan 2000), Self-energy (Schwartz 1995), Organicity (Perls 1969), Authentic Self (Winnicott 1960), and Wise Mind (Linehan 1993) are all concepts that nod to hope either directly or by implication. While originating from diverse theoretical traditions, these frameworks emphasize the individual's innate capacity for growth, resilience, and transformation, which are inherently tied to hope as a catalyst for healing. Gallagher et al., “Examining Hope.” 2020; George A. Bonanno, “Loss, Trauma, and Human Resilience: Have We Underestimated the Human Capacity to Thrive After Extremely Aversive Events?” American Psychologist 59, no. 1 (2004): 20–28, https://doi.org/10.1037/0003-066X.59.1.20; Diana Fosha, The Transforming Power of Affect: A Model for Accelerated Change (New York: Basic Books, 2000); Steven C. Hayes et al., “Acceptance and Commitment Therapy: Model, Processes, and Outcomes,” Behaviour Research and Therapy 44, no. 1 (2012): 1–25, https://doi.org/10.1016/j.brat.2005.06.006; Carl R. Rogers, “A Theory of Therapy, Personality, and Interpersonal Relationships, as Developed in the Client-Centered Framework,” in Psychology: A Study of a Science, ed. Sigmund Koch (McGraw-Hill, 1959), 184–256; Edward L. Deci and Richard M. Ryan, “The ‘What’ and ‘Why’ of Goal Pursuits: Human Needs and the Self-Determination of Behavior,” Psychological Inquiry 11, no. 4 (2000): 227–268, https://doi.org/10.1207/S15327965PLI1104_01; Richard C. Schwartz, Internal Family Systems Therapy (Guilford Press, 1995); Frederick S. Perls, Gestalt Therapy Verbatim (Real People Press, 1969); Donald W. Winnicott, “Ego Distortion in Terms of True and False Self,” in The Maturational Processes and the Facilitating Environment (International Universities Press, 1960), 140–152; Marsha M. Linehan, Cognitive-Behavioral Treatment of Borderline Personality Disorder (Guilford Press, 1993). [Return to Section]

¹⁴ Matthew W. Gallagher, Laura J. Long, and Colleen A. Phillips, “Hope, Optimism, Self-Efficacy, and Posttraumatic Stress Disorder: A Meta-Analytic Review of the Protective Effects of Positive Expectancies,” Journal of Clinical Psychology 76, no. 3 (2020): 329–55, https://doi.org/10.1002/jclp.22882 [Return to Section]

¹⁵ Viktor E. Frankl, “Logotherapy and Existentialism,” Psychotherapy: Theory, Research & Practice 4, no. 3 (1967): 138. [Return to Section]

¹⁶ Howard Thurman, Jesus and the Disinherited (Beacon Press, 1949). [Return to Section]

¹⁷ bell hooks, All About Love: New Visions (New York: William Morrow and Company, 2000). [Return to Section]

¹⁸ Ö. Kısaoğlu and H. Tel, “The Impact of Hope Levels on Treatment Adherence in Psychiatric Patients,” Acta Psychologica 244 (2024). [Return to Section]

¹⁹ M. W. Gallagher and S. J. Lopez, eds., The Oxford Handbook of Hope (Oxford University Press, 2018); B. Schrank et al., “Evaluation of a Positive Psychotherapy Group Intervention for People with Psychosis: Pilot Randomised Controlled Trial,” Epidemiology and Psychiatric Sciences 25, no. 3 (2016): 235–46. [Return to Section]

²⁰ U.S. Food and Drug Administration, Considerations for Open-Label Clinical Trials: Design, Conduct, and Analysis (Silver Spring, MD: Center for Drug Evaluation and Research, 2019), https://www.fda.gov/media/168664/download; L. E. Bothwell and S. H. Podolsky, “The Emergence of the Randomized, Controlled Trial,” New England Journal of Medicine 375, no. 6 (2016): 501–504. [Return to Section]

21 missing

²² Michiel van Elk and Eiko I. Fried, “History Repeating: Guidelines to Address Common Problems in Psychedelic Science,” Therapeutic Advances in Psychopharmacology 13 (2023). [Return to Section]

²³ Lykos Therapeutics was recently renamed “Resilient Pharmaceuticals.” Jennifer M. Mitchell et al., “MDMA-Assisted Therapy for Severe PTSD: A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study,” Nature Medicine 27, no. 6 (2021): 1025–33, https://doi.org/10.1038/s41591-021-01336-3; Jennifer M. Mitchell et al., “MDMA-Assisted Therapy for Moderate to Severe PTSD: A Randomized, Placebo-Controlled Phase 3 Trial,” Nature Medicine 29, no. 10 (2023): 2473–80, https://doi.org/10.1038/s41591-023-02565-4. [Return to Section]

²⁴ Mitchell et al., 2021; Mitchell et al., 2023. [Return to Section]

²⁵ For a further discussion see Josh Hardman, “Analysis: FDA Advisory Committee Snubs MDMA-Assisted Therapy for PTSD in Overwhelming ‘No’ Vote,” Psychedelic Alpha, accessed February 1, 2025, https://psychedelicalpha.com/news/analysis-fda-advisory-committee-snubs…. [Return to Section]

²⁶ L. Jacob Flameling, Jacob S. Aday, and Michiel van Elk, “Expectancy Effects Cannot Be Neglected in MDMA-Assisted Therapy Research,” ACS Chemical Neuroscience 14, no. 23 (2023): 4062–63; T. F. Monaghan et al., “Blinding in Clinical Trials: Seeing the Big Picture,” Medicina 57, no. 7 (2021): 647. [Return to Section]

²⁷ Flameling et al., 2023 note that in Lykos-sponsored Phase III MDMA research, blinding survey data showed that not all participants correctly identified the treatment that they received. However, 94% of participants in the treatment group and 75% in the placebo group guessed their treatment condition correctly. Had blinding been perfect, the percentages in both groups should have been approximately 50%. See also Mitchell et al., 2021. [Return to Section]

²⁸ See David Yaden, James B. Potash, and Roland R. Griffiths, “Preparing for the Bursting of the Psychedelic Hype Bubble,” JAMA Psychiatry 79 (10) (2022): 943–944. https://doi.org/10.1001/jamapsychiatry.2022.2549. [Return to Section]

²⁹ Barbara Paraniak-Gieszczyk and Ewa Alicja Ogłodek, “Neurobiological and Existential Profiles in Posttraumatic Stress Disorder: The Role of Serotonin, Cortisol, Noradrenaline, and IL-12 Across Chronicity and Age,” International Journal of Molecular Sciences 26, no. 19 (2025): 9636; Kelly C. O’Donnell et al., “The Conceptual Framework for the Therapeutic Approach Used in Phase 3 Trials of MDMA-Assisted Therapy for PTSD,” Frontiers in Psychology 15 (2024): 1427531, https://doi.org/10.3389/fpsyg.2024.1427531. [Return to Section]

³⁰ See Robert D. Stolorow, Trauma and Human Existence: Autobiographical, Psychoanalytic, and Philosophical Reflections (New York: Routledge, 2011). [Return to Section]

³¹ Joseph W. Boffa, Sherry L. King, Gustavo Turecki, and Norman B. Schmidt, “Investigating the Role of Hopelessness in the Relationship Between PTSD Symptom Change and Suicidality,” Journal of Affective Disorders 225 (2018): 298–301, https://doi.org/10.1016/j.jad.2017.08.047. [Return to Section]

³² Serene Jones, Trauma and Grace: Theology in a Ruptured World (Westminster John Knox Press, 2019). [Return to Section]

³³ Victoria Williamson, S. A. M. Stevelink, and N. Greenberg, “Occupational Moral Injury and Mental Health: Systematic Review and Meta-Analysis,” British Journal of Psychiatry 212, no. 6 (2018): 339–46. [Return to Section]

³⁴ Allison A. Feduccia and Michael C. Mithoefer, “MDMA-Assisted Psychotherapy for PTSD: Are Memory Reconsolidation and Fear Extinction Underlying Mechanisms?,” Progress in Neuro-Psychopharmacology and Biological Psychiatry 84 (2018): 221–28. [Return to Section]

³⁵ Kelly C. O’Donnell et al., “The Conceptual Framework for the Therapeutic Approach Used in Phase 3 Trials of MDMA-Assisted Therapy for PTSD,” Frontiers in Psychology 15 (2024): 1427531, https://doi.org/10.3389/fpsyg.2024.1427531. [Return to Section]

Boffa, Joseph W., Sherry L. King, Gustavo Turecki, and Norman B. Schmidt. “Investigating the Role of Hopelessness in the Relationship Between PTSD Symptom Change and Suicidality.” Journal of Affective Disorders 225 (2018): 298–301. https://doi.org/10.1016/j.jad.2017.08.047. 

Bonanno, George A. “Loss, Trauma, and Human Resilience: Have We Underestimated the Human Capacity to Thrive After Extremely Aversive Events?” American Psychologist 59, no. 1 (2004): 20–28. https://doi.org/10.1037/0003-066X.59.1.20. 

Bothwell, L. E., and S. H. Podolsky. “The Emergence of the Randomized, Controlled Trial.” New England Journal of Medicine 375, no. 6 (2016): 501–504. 

Burback, Lisa, Simone Brult-Phillips, Mirjam J. Nijdam, Alexander McFarlane, and Eric Vermetten. “Treatment of Posttraumatic Stress Disorder: A State-of-the-Art Review.” Current Neuropharmacology 22, no. 4 (2024): 557–635. https://doi.org/10.2174/1570159X22666240110120747. 

Erikson, Erik H. Childhood and Society. New York: W. W. Norton & Company, 1950. 

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