Sertraline Hydrochloride

U.S. Food and Drug Administration requests additional Phase 3 study Issues raised in CRL echo those discussed in FDA Advisory Committee hearing The Company intends to pursue all available regulatory pathways to expeditiously bring a potential new treatment to the 13 million Americans who live with PTSD, a condition that has not had new treatments available for nearly 25 years1,2 SAN JOSE, Calif., Aug. 9, 2024 /PRNewswire/ -- Lykos Therapeutics ("Lykos"), a company dedicated to transforming mental healthcare, announced that the U.S. Food and Drug Administration ("FDA") has issued a complete response letter ("CRL") for the new drug application ("NDA") for midomafetamine capsules for the treatment of post-traumatic stress disorder ("PTSD") in adults. The FDA communicated that it had completed its review of the NDA and determined that it could not be approved based on data submitted to date. The FDA has requested that Lykos conduct an additional Phase 3 trial to further study the safety and efficacy of midomafetamine. Lykos plans to request a meeting with the FDA to ask for reconsideration of the decision and to further discuss the agency's recommendations for a resubmission seeking regulatory approval for midomafetamine capsules. The issues expressed in the CRL echo those raised during the FDA Advisory Committee meeting on June 4, 2024. The Company and other stakeholders have expressed concerns around the structure and conduct of the Advisory Committee meeting, including the limited number of subject matter experts on the panel and the nature of the discussion, which at times veered beyond the scientific content in the briefing documents. FDA itself has acknowledged potential problems with the Advisory Committee process and has opened a public docket seeking comments on how it can be improved. Lykos has previously published its response to the substantive issues discussed at the Advisory Committee hearing. Among others, this included concerns that Lykos' clinical data were insufficient to demonstrate durability along with questions about expectancy bias stemming primarily from participants with prior MDMA use. Lykos believes that the data included in the NDA provide sufficient evidence of efficacy and durability in line with the relevant FDA guidance. FDA's draft guidance for industry on psychedelic drugs3 indicates that endpoint data should be collected at 12 weeks; Lykos' Phase 3 studies collected endpoint data at 18 weeks, with additional exploratory endpoints collected six months or more later. In addition, Lykos had aligned with the FDA in the Special Protocol Assessment ("SPA") in 2017 on a variety of bias minimization measures in the study design. Prior MDMA use among participants was not previously viewed as detrimental. As an example, nearly 30% of participants in Lykos' Phase 2 studies reported prior use, which was shared with FDA before establishing the inclusion and exclusion criteria in the Phase 3 trial design. The Advisory Committee panelists also raised psychotherapy as a concern, with some recommending to further characterize the extent to which psychotherapy contributes to treatment benefit and if it is even necessary. Lykos acknowledges that midomafetamine-assisted therapy represents a novel combination of drug and therapy that raises unique research questions and will continue to engage the FDA as appropriate on these challenges. Lykos remains committed to continuing development of this integrated approach. "The FDA request for another study is deeply disappointing, not just for all those who dedicated their lives to this pioneering effort, but principally for the millions of Americans with PTSD, along with their loved ones, who have not seen any new treatment options in over two decades," said Amy Emerson, Chief Executive Officer of Lykos Therapeutics. "While conducting another Phase 3 study would take several years, we still maintain that many of the requests that had been previously discussed with the FDA and raised at the Advisory Committee meeting can be addressed with existing data, post-approval requirements or through reference to the scientific literature." Lykos will work diligently in the coming months to address FDA's concerns and to take advantage of agency processes to resolve scientific disagreements. Following the FDA meeting, Lykos expects to provide an update on next steps for the resubmission. Emerson added, "Our heart breaks for the millions of military veterans, first responders, victims of sexual and domestic abuse and countless others suffering from PTSD who may now face more years without access to new treatment options. We intend to work tirelessly and use all available regulatory pathways to find a reasonable and expeditious path forward for patients who deserve access to midomafetamine-assisted therapy for PTSD." As noted above, Lykos negotiated a SPA with the FDA in 2017. Breakthrough Therapy designation was granted that same year. On February 9, 2024, the FDA accepted the company's NDA for midomafetamine used in combination with psychological intervention for adults with PTSD and granted the application Priority Review. "Developing the first-ever clinical trial design to assess the safety and efficacy of midomafetamine-assisted therapy with patients suffering from moderate to severe PTSD is an enormously complex undertaking," said Jennifer Mitchell, Ph.D., Professor of Neurology and Psychiatry and Behavioral Sciences at UCSF. "Over the course of many years, the researchers, with the support of our sponsor, Lykos, developed and executed Phase 3 studies that we believe demonstrated the approvability of this treatment. We did so in consultation with the FDA and with an agreed Special Protocol Assessment in place. The FDA's decision to request another Phase 3 study is a major setback for the field." Midomafetamine capsules have not been approved by any regulatory agency. The safety and efficacy of midomafetamine have not been established for the treatment of PTSD. Investigational midomafetamine is also being studied in other indications. About PTSD Prevalence and symptoms PTSD is a serious mental health condition that can develop when a person experiences or witnesses a traumatic event.4 PTSD affects approximately 13 million Americans each year with women and disadvantaged or marginalized groups more likely to be affected.5,6 Military personnel also have a greater prevalence of PTSD than the general population.7 However, it may not be as widely known that the largest cause of PTSD is non-combat-related trauma (e.g., sexual violence, unexpected death of a loved one, life-threatening traumatic event or interpersonal violence).8 PTSD results in debilitating symptoms including nightmares and intrusive thoughts related to the trauma, mental and/or physical distress in response to trauma-related stimuli, avoidant behaviors, negative thoughts and feelings, and hyperarousal.9 These symptoms can impact nearly all aspects of a person's life, including their interpersonal relationships.4 PTSD can also be a chronic condition with a World Health Organization study showing that after ten years post-trauma, nearly a quarter of people had not recovered.10 Co-morbidities and economic impact People with PTSD frequently experience anxiety, depression, substance use disorder and suicidal ideation.11,12 They also may have a greater incidence of medical conditions that impact their physical health, including heart disease, metabolic syndrome and asthma.13,14,15,16 U.S. Army veterans who developed PTSD after military service have been shown to have approximately two times greater risk of mortality than U.S. Army veterans who did not develop PTSD after military service.15 In addition to the significant personal impact, PTSD has an enormous economic impact, resulting in an estimated annual cost of over $232 billion in the United States.13 PTSD treatment Trauma-focused talk therapy, which concentrates on memories of the traumatic event or thoughts and feelings associated with the traumatic event is first-line treatment for PTSD, which can be used alone or in combination with medication.17 There are two SSRIs approved for the treatment of PTSD (sertraline and paroxetine).18 Studies have shown talk therapy lessens the severity of PTSD symptoms, however, improvements in functioning and quality of life have been modest.19,20 Trauma-focused talk therapy is associated with a high risk of dropout and lingering symptoms which occur in as many as two-thirds of people who complete treatment.21,22 Current treatments for PTSD are "reasonably efficacious" (Bryant, 2019, p.265), however many people don't respond to treatment or stop treatment early, underscoring the urgent need for new evidence-based therapies and approaches to address this important public health issue.2 While there have been advancements in the management of PTSD, there have been no new drug treatments approved by the FDA in over twenty years.23 About Midomafetamine-Assisted Therapy Midomafetamine (MDMA) is commonly known to mental health professionals. In the 1970s and early 1980s, MDMA was used in conjunction with talk therapy by mental health providers to help enhance patients' access, processing and communication of difficult emotions and experiences.24 MDMA is an entactogen— a class of psychoactive compounds that are differentiated from classic psychedelics (i.e., psilocybin, mescaline and LSD) and are defined based on their mechanism and demonstrated effects of increasing self-awareness leading to introspection and personal reflection.25,26 In 1985, the U.S. Drug Enforcement Administration ("DEA") made MDMA a Schedule I drug under the Controlled Substances Act, preventing it from being used for recreational or medical use.27 Since then, research has suggested that MDMA may have potential as a catalyst to support psychotherapy by helping diminish the brain's fear response, allowing people to access and process painful memories without being overwhelmed.28 Lykos, with longstanding roots in advocacy for psychedelic medicine, was the first company to pioneer randomized, double-blind, placebo-controlled clinical trials evaluating the efficacy and safety of MDMA-assisted therapy as an investigational modality using midomafetamine (MDMA) in combination with psychological intervention and submit an NDA to the FDA seeking approval for the treatment of PTSD in adults. Lykos Therapeutics At Lykos Therapeutics, a public benefit corporation ("PBC") founded by the Multidisciplinary Association for Psychedelic Studies ("MAPS"), our mission is to transform mental healthcare. We're applying decades of evidence-based research to develop investigational psychedelics to catalyze therapeutic approaches for mental health conditions. We are relentlessly exploring and reimagining novel approaches to address unmet needs in the mental healthcare space, with an initial focus on PTSD. As a PBC, we are focused on delivering positive impact on our people, communities and society. To learn more visit us at and on LinkedIn, X, Instagram and Facebook. 1 VA National Center for PTSD. US Department of Veterans Affairs. Accessed August 9, 2024. 2 Stein MB, Rothbaum BO. 175 Years of progress in PTSD therapeutics: Learning from the past. Am J Psychiatry. 2018 Jun 1;175(6):508-516. doi: 10.1176/appi.ajp.2017.17080955 3 Psychedelic Drugs: Considerations for Clinical Investigations. Guidance for Industry (Draft Guidance). 4 The Mayo Clinic, PTSD, symptoms and causes. Accessed February 14, 2024. 5 VA National Center for PTSD. US Department of Veterans Affairs. Accessed May 13, 2024. 6 Goldstein RB et al. The epidemiology of DSM-5 posttraumatic stress disorder in the United States: results from the National Epidemiologic Survey on Alcohol and Related Conditions-III. Soc Psychiatry Psychiatr Epidemiol. 2016; 51(8):1137–1148. 7 Lehavot K et al. Post-traumatic stress disorder by gender and veteran status. Am J Prev Med. 2018 Jan;54(1):e1-e9. doi: 10.1016/j.amepre.2017.09.008 8 Kessler RC, Rose S, Koenen KC, et al. How well can post-traumatic stress disorder be predicted from pre-trauma risk factors? An exploratory study in the WHO World Mental Health Surveys. World Psychiatry. 2014 Oct;13(3):265-74. doi: 10.1002/wps.20150 9 Bryant RA. Post-traumatic stress disorder: a state-of-the-art review of evidence and challenges. World Psychiatry. 2019;18(3):259–269. 10 Rosellini AJ et al. Recovery from DSM-IV post-traumatic stress disorder in the WHO World Mental Health surveys. Psychol Med. 2018 Feb;48(3):437-450. doi: 10.1017/S0033291717001817 11 Grinage B.D. Diagnosis and management of post-traumatic stress disorder. Am Fam Physician. (2003);68(12):2401-2409. PMID: 14705759. 12 Rojas SM et al. Understanding PTSD comorbidity and suicidal behavior: associations among histories of alcohol dependence, major depressive disorder, and suicidal ideation and attempts. J Anxiety Disord. 2014 Apr;28(3):318-25. doi: 10.1016/j.janxdis.2014.02.004 13 Edmondson D, von Känel R. Post-traumatic stress disorder and cardiovascular disease. Lancet Psychiatry. 2017 Apr;4(4):320-329. doi: 10.1016/S2215-0366(16)30377-7 14 Krantz DS, Shank LM, Goodie JL. Post-traumatic stress disorder (PTSD) as a systemic disorder: Pathways to cardiovascular disease. Health Psychol. 2022 Oct;41(10):651-662. doi: 10.1037/hea0001127 15 Boscarino JA. Posttraumatic stress disorder and mortality among U.S. Army veterans 30 years after military service. Ann Epidemiol. 2006 Apr;16(4):248-56. doi: 10.1016/j.annepidem.2005.03.009 16 Nichter B, Norman S, Haller M, Pietrzak RH. Physical health burden of PTSD, depression, and their comorbidity in the U.S. veteran population: Morbidity, functioning, and disability. J Psychosom Res. 2019 Sep;124:109744. doi: 10.1016/j.jpsychores.2019.109744 17 Watkins LE, Sprang KR, Rothbaum BO. Treating PTSD: A Review of Evidence-Based Psychotherapy Interventions. Front Behav Neurosci. 2018 Nov 2;12:258. doi: 10.3389/fnbeh.2018.00258. PMID: 30450043; PMCID: PMC6224348. 18 American Psychological Association. Clinical Practice Guidelines for the Treatment of PTSD. Medications (apa.org) Accessed May 17, 2024. 19 Cusack K, et al. Psychological treatments for adults with posttraumatic stress disorder: A systematic review and meta-analysis. Clin Psychol Rev. 2016;43:128-141. 20 Bonfils, KA et al, Functional outcomes from psychotherapy for people with posttraumatic stress disorder: A meta-analysis. J Anxiety Disorders. 2022;89:102576. 21 Lewis, C., Roberts, N. P., Gibson, S., & Bisson, J. I. (2020). Dropout from psychological therapies for post-traumatic stress disorder (PTSD) in adults: systematic review and meta-analysis. European Journal of Psychotraumatology, 11(1). 22 Steenkamp, M. M., Litz, B. T., Hoge, C. W., & Marmar, C. R. (2015). Psychotherapy for Military-Related PTSD. JAMA, 314(5), 489. 23 Stein MB, Rothbaum BO. 175 Years of Progress in PTSD Therapeutics: Learning From the Past. Am J Psychiatry. 2018 Jun 1;175(6):508-516. doi: 10.1176/appi.ajp.2017.17080955 24 Wagner MT, Mithoefer MC, Mithoefer AT, MacAulay RK, Jerome L, Yazar-Klosinski B, Doblin R. Therapeutic effect of increased openness: Investigating mechanism of action in MDMA-assisted psychotherapy. J Psychopharmacol. 2017 Aug;31(8):967-974. doi: 10.1177/0269881117711712 25 Nichols, David E. Entactogens: How the name for a novel class of psychoactive agents originated. Frontiers in Psychiatry. 2022 Mar 25;13:863088. doi:10.3389/fpsyt.2022.863088 26 Vollenweider, Franz X.,Dialogues Clin Neurosci. 2001 Dec; 3(4): 265–279.doi: 10.31887/DCNS.2001.3.4/fxvollenweider 27 National Institute on Drug Abuse (NIDA) (nih.gov) What is the history of MDMA? . Accessed, January 17, 2024. What is the history of MDMA? | National Institute on Drug Abuse (NIDA) (nih.gov) 28 Yazar-Klosinski B, Mithoefer MC. Potential psychiatric uses for MDMA. Clinical Pharmacology & Therapeutics. 2017 Feb;101(2):194-196. doi: 10.1002/cpt.565 SOURCE Lykos Therapeutics

Company launching independent advisory board to inform key elements of a potential commercial launch, including therapy training, ethics and healthcare integration Company plans to work with select top-tier behavioral health centers that can meet FDA-proposed patient monitoring requirements and provide integrated quality care Company will collaborate with other institutions around therapy training SAN JOSE, Calif., Aug. 1, 2024 /PRNewswire/ -- Lykos Therapeutics ("Lykos"), a company dedicated to transforming mental healthcare, announced new initiatives and measures for additional oversight for midomafetamine capsules in combination with psychological intervention ("midomafetamine-assisted therapy") for the treatment of post-traumatic stress disorder ("PTSD") in adults, if approved by the U.S. Food and Drug Administration ("FDA"). The new drug application ("NDA") included results from numerous studies, including two randomized, double-blind, placebo-controlled Phase 3 studies (MAPP1 and MAPP2) evaluating the efficacy and safety of midomafetamine-assisted therapy versus placebo with therapy in participants diagnosed with moderate or moderate and severe PTSD, respectively. Both MAPP1 and MAPP2 studies met their primary and secondary endpoints and were published in Nature Medicine.1,2 Lykos' NDA is the first to combine a drug and psychological intervention. While not regulated by the FDA, the practice of psychotherapy is already a regulated field with mandatory reporting requirements and oversight provided by licensing boards and professional societies. The healthcare professionals providing psychological intervention with midomafetamine, if approved, will utilize their clinical judgment to effectively deliver treatment, with appropriate oversight from these governing bodies. This will be in addition to controls and requirements set forth in the product labeling and the Risk Evaluation and Mitigation Strategy ("REMS") program. "Given the novelty of this approach, we are taking steps to help ensure additional oversight for this drug plus therapy modality, if FDA approved, and to help integrate into the real-world healthcare setting," said Amy Emerson, Chief Executive Officer at Lykos Therapeutics. "It is critical for the millions of people suffering with PTSD, including veterans and survivors of physical and sexual assault, to have access to a potential new treatment option. To this end, we will work with external experts on an independent advisory board, focus our initial commercial rollout on centers of care where there are multiple layers of oversight and collaborate with others around therapy training. This process will establish a strong foundation to ultimately reach more patients in need of access to new treatment options." The new initiatives and measures of additional oversight include: Establishing an independent advisory board comprised of external experts in corporate and medical ethics, innovation, psychiatry, and military and veteran health to inform the Company's plans for the potential commercial launch of midomafetamine, if approved by the FDA. Advisory Board Members will include Barbara O. Rothbaum, Ph.D., Professor of Psychiatry, Emory University School of Medicine, Brigadier General (Ret) Loree Sutton, M.D., the highest-ranking psychiatrist to serve in the U.S. Army for twenty years who was awarded the Bronze Star, Robert Chesnut, former Assistant U.S. Attorney and author of the book "Intentional Integrity: How Smart Companies Can Lead an Ethical Revolution," and others. Working with top behavioral health facilities to help ensure these sites are prepared to implement the measures utilized in Lykos' clinical trials. Midomafetamine, if approved, would only be commercially available at centers of care that meet all the FDA and Drug Enforcement Administration ("DEA") requirements, such as nationally accredited centers, veteran healthcare facilities and academic medical centers that have coordinated medical and behavioral health care and layers of oversight. The REMS program will ensure the drug is administered only in certified healthcare facilities that meet the FDA's proposed requirements. Emory University, Sheppard Pratt, Hackensack Meridian Health, Pacific Neuroscience Institute and Sunstone Therapies are some of the centers that plan to be among the first to deliver midomafetamine-assisted therapy, if approved by the FDA. Collaborating on training to leverage Lykos' clinical trial experience developing MDMA-assisted therapy combined with the external perspective of institutions and health systems, if approved. Lykos is in dialogue with others on how to begin transitioning training to appropriately support the needs of institutions planning to deliver this new investigational treatment. The independent Advisory Board that we are establishing will advise on the approach to therapist training and how it can be delivered, including opportunities to transfer to others. "PTSD patients deserve the most effective treatments we can offer, and we want to make sure that we are well positioned to meet their needs," said Dr. Rothbaum. "Given the promise of midomafetamine-assisted therapy, we have been preparing our center to be an early leader in this potential science-driven combination treatment." Midomafetamine capsules have not been approved by any regulatory agency. The safety and efficacy of midomafetamine have not been established for the treatment of PTSD. Investigational midomafetamine is also being studied in other indications. If approved, the FDA will require a REMS program, which is generally designed to prevent, monitor and/or manage a specific serious risk by informing, educating and/or reinforcing actions to reduce the frequency and/or severity of the event. About PTSD Prevalence and symptoms PTSD is a serious mental health condition that can develop when a person experiences or witnesses a traumatic event.4 PTSD affects approximately 13 million Americans each year with women and disadvantaged or marginalized groups more likely to be affected.1,2 Military personnel also have a greater prevalence of PTSD than the general population.3 However, it may not be as widely known that the largest cause of PTSD is non-combat-related trauma (e.g., sexual violence, unexpected death of a loved one, life-threatening traumatic event or interpersonal violence).4 PTSD results in debilitating symptoms, including nightmares and intrusive thoughts related to the trauma, mental and/or physical distress in response to trauma-related stimuli, avoidant behaviors, negative thoughts and feelings, and hyperarousal.5 These symptoms can impact nearly all aspects of a person's life, including their interpersonal relationships.4 PTSD can also be a chronic condition, with a World Health Organization study showing that after ten years post-trauma, nearly a quarter of people had not recovered.6 Co-morbidities and economic impact People with PTSD frequently experience anxiety, depression, substance use disorder and suicidal ideation.7,8 They may also have a greater incidence of medical conditions that impact their physical health, including heart disease, metabolic syndrome and asthma.9,10,11,12 U.S. Army Veterans who developed PTSD after military service have been shown to have an approximately two times greater risk of mortality than U.S. Army Veterans who did not develop PTSD after military service.15 In addition to the significant personal impact, PTSD has an enormous economic impact, resulting in an estimated annual cost of over $232 billion in the United States.13 PTSD treatment Trauma-focused talk therapy, which concentrates on memories of the traumatic event or thoughts and feelings associated with the traumatic event, is first-line treatment for PTSD, which can be used alone or in combination with medication. 14 There are two SSRIs approved for the treatment of PTSD—sertraline and paroxetine.15 Studies have shown that talk therapy lessens the severity of PTSD symptoms, however, improvements in functioning and quality of life have been modest.16,17 Trauma-focused talk therapy is associated with a high risk of dropout and lingering symptoms, which occur in as many as two-thirds of people who complete treatment.18,19 Current treatments for PTSD are "reasonably efficacious"5, however, many people don't respond to treatment or stop treatment early, underscoring the urgent need for new evidence-based therapies and approaches to address this important public health issue.2 While there have been advancements in the management of PTSD, there have been no new drug treatments for PTSD approved by the FDA in over 20 years.20 About Midomafetamine-Assisted Therapy Midomafetamine (MDMA) is commonly known to mental health professionals. In the 1970s and early 1980s MDMA was used in conjunction with talk therapy by mental health providers to help enhance patients' access, processing and communication of difficult emotions and experiences.21 MDMA is an entactogen— a class of psychoactive compounds that are differentiated from classic psychedelics (i.e., psilocybin, mescaline and LSD) and are defined based on their mechanism and demonstrated effects of increasing self-awareness, leading to introspection and personal reflection.22,23 In 1985, the DEA made MDMA a Schedule I drug under the Controlled Substances Act, preventing it from being used for recreational or medical use.24 Since then, research has suggested that MDMA may have potential as a catalyst to support psychotherapy by helping diminish the brain's fear response, allowing people to access and process painful memories without being overwhelmed.25 Lykos, with longstanding roots in advocacy for psychedelic medicine, was the first company to pioneer randomized, double-blind, placebo-controlled clinical trials evaluating the efficacy and safety of midomafetamine-assisted therapy as an investigational modality using midomafetamine in combination with psychological intervention. Lykos submitted an NDA to the FDA seeking approval of midomafetamine for the treatment of PTSD in adults. If approved by the FDA, the DEA would be required to reschedule midomafetamine to make it available for prescription medical use. Lykos Therapeutics At Lykos, a public benefit corporation (PBC) founded by the Multidisciplinary Association for Psychedelic Studies ("MAPS"), our mission is to transform mental healthcare. We're applying decades of evidence-based research to develop investigational psychedelics to catalyze therapeutic approaches for mental health conditions. We are relentlessly exploring and reimagining novel approaches to address unmet needs in the mental healthcare space, with an initial focus on PTSD. As a PBC, we are focused on making a positive impact on our people, communities and society. To learn more, visit us at and on LinkedIn, X, Instagram and Facebook. ____________________________ 1 VA National Center for PTSD. US Department of Veterans Affairs. Accessed May 13, 2024. 2 Goldstein RB et al. The epidemiology of DSM-5 posttraumatic stress disorder in the United States: results from the National Epidemiologic Survey on Alcohol and Related Conditions-III. Soc Psychiatry Psychiatr Epidemiol. 2016; 51(8):1137–1148. 3 Lehavot K et al. Post-traumatic stress disorder by gender and veteran status. Am J Prev Med. 2018 Jan;54(1):e1-e9. doi: 10.1016/j.amepre.2017.09.008 4 American Psychiatric Association. (2022). Diagnostic and statistical manual of mental disorders (5th ed., text rev.). 5 Bryant RA. Post-traumatic stress disorder: a state-of-the-art review of evidence and challenges. World Psychiatry. 2019;18(3):259–269. 6 Rosellini AJ et al. Recovery from DSM-IV post-traumatic stress disorder in the WHO World Mental Health surveys. Psychol Med. 2018 Feb;48(3):437-450. doi: 10.1017/S0033291717001817 7 Grinage B.D. Diagnosis and management of post-traumatic stress disorder. Am Fam Physician. (2003);68(12):2401-2409. PMID: 14705759. 8 Rojas SM et al. Understanding PTSD comorbidity and suicidal behavior: associations among histories of alcohol dependence, major depressive disorder, and suicidal ideation and attempts. J Anxiety Disord. 2014 Apr;28(3):318-25. doi: 10.1016/j.janxdis.2014.02.004 9 Edmondson D, von Känel R. Post-traumatic stress disorder and cardiovascular disease. Lancet Psychiatry. 2017 Apr;4(4):320-329. doi: 10.1016/S2215-0366(16)30377-7 10 Krantz DS, Shank LM, Goodie JL. Post-traumatic stress disorder (PTSD) as a systemic disorder: Pathways to cardiovascular disease. Health Psychol. 2022 Oct;41(10):651-662. doi: 10.1037/hea0001127 11 Boscarino JA. Posttraumatic stress disorder and mortality among U.S. Army veterans 30 years after military service. Ann Epidemiol. 2006 Apr;16(4):248-56. doi: 10.1016/j.annepidem.2005.03.009 12 Nichter B, Norman S, Haller M, Pietrzak RH. Physical health burden of PTSD, depression, and their comorbidity in the U.S. veteran population: Morbidity, functioning, and disability. J Psychosom Res. 2019 Sep;124:109744. doi: 10.1016/j.jpsychores.2019.109744 13 Davis LL. The economic burden of posttraumatic stress disorder in the United States from a societal perspective. J Clin Psychiatry. (2022) Apr 25;83(3):21m14116. doi: 10.4088/JCP.21m14116 14 Watkins LE, Sprang KR, Rothbaum BO. Treating PTSD: A Review of Evidence-Based Psychotherapy Interventions. Front Behav Neurosci. 2018 Nov 2;12:258. doi: 10.3389/fnbeh.2018.00258. PMID: 30450043; PMCID: PMC6224348. 15 Schlenger WE, Corry NH, Williams CS, et al. A prospective study of mortality and trauma-related risk factors among a nationally representative sample of Vietnam Veterans. Am J Epidemiol. 2015;182 (12):980–990. 16 Cusack K, et al. Psychological treatments for adults with posttraumatic stress disorder: A systematic review and meta-analysis. Clin Psychol Rev. 2016;43:128-141. 17 Bonfils, KA et al, Functional outcomes from psychotherapy for people with posttraumatic stress disorder: A meta-analysis. J Anxiety Disorders. 2022;89:102576. 18 Lewis, C., Roberts, N. P., Gibson, S., & Bisson, J. I. (2020). Dropout from psychological therapies for post-traumatic stress disorder (PTSD) in adults: systematic review and meta-analysis. European Journal of Psychotraumatology, 11(1). 19 Steenkamp, M. M., Litz, B. T., Hoge, C. W., & Marmar, C. R. (2015). Psychotherapy for Military-Related PTSD. JAMA, 314(5), 489. 20 Stein MB, Rothbaum BO. 175 Years of Progress in PTSD Therapeutics: Learning From the Past. Am J Psychiatry. 2018 Jun 1;175(6):508-516. doi: 10.1176/appi.ajp.2017.17080955 21 Wagner MT, Mithoefer MC, Mithoefer AT, MacAulay RK, Jerome L, Yazar-Klosinski B, Doblin R. Therapeutic effect of increased openness: Investigating mechanism of action in MDMA-assisted psychotherapy. J Psychopharmacol. 2017 Aug;31(8):967-974. doi: 10.1177/0269881117711712 22 Nichols, David E. Entactogens: How the name for a novel class of psychoactive agents originated. Frontiers in Psychiatry. 2022 Mar 25;13:863088. doi:10.3389/fpsyt.2022.863088 23 Vollenweider, Franz X.,Dialogues Clin Neurosci. 2001 Dec; 3(4): 265–279.doi: 10.31887/DCNS.2001.3.4/fxvollenweider 24 National Institute on Drug Abuse (NIDA) (nih.gov) What is the history of MDMA? . Accessed, January 17, 2024. What is the history of MDMA? | National Institute on Drug Abuse (NIDA) (nih.gov) 25 Yazar-Klosinski B, Mithoefer MC. Potential psychiatric uses for MDMA. Clinical Pharmacology & Therapeutics. 2017 Feb;101(2):194-196. doi: 10.1002/cpt.565 SOURCE Lykos Therapeutics