Childhood Adversities and Complex PTSD: Psychedelic Therapy

Adverse Childhood Experiences and Complex PTSD: A Theoretical Model Exploring Psychedelic Substances as a Therapeutic Treatment A thesis submitted in partial fulfillment of the requirements for graduation with Honors in Psychology. 2022 PSYCHEDELIC SUBSTANCES AS cPTSD TREATMENT ________________________ ii PSYCHEDELIC SUBSTANCES AS cPTSD TREATMENT Table of Contents Acknowledgements ............................................................................................................. v Abstract .............................................................................................................................. vi List of Tables & Figures ................................................................................................... vii Chapter 1: Introduction ....................................................................................................... 1 Chapter 2: Adverse Childhood Experiences ....................................................................... 4 Definition and Frequency of ACEs................................................................................. 4 Externalizing and Internalizing Problems ....................................................................... 6 Physical Health Issues..................................................................................................... 7 Substance Use ................................................................................................................. 9 Toxic Stress Theory and LHPA Axis Activation ........................................................... 9 Conclusion .................................................................................................................... 12 Chapter 3: Complex Posttraumatic Stress Disorder.......................................................... 13 Background on cPTSD ................................................................................................. 14 Symptoms of PTSD and cPTSD ................................................................................... 14 Validity of cPTSD vs. PTSD ........................................................................................ 18 cPTSD vs. Borderline Personality Disorder (BPD) ...................................................... 21 Current Treatments ....................................................................................................... 22 Cognitive Therapies ................................................................................................... 23 Pharmacological Supplementation............................................................................ 24 Cannabis-Based Treatment ....................................................................................... 27 Conclusion .................................................................................................................... 28 Chapter 4: Psychedelics .................................................................................................... 30 Psychedelic Classification ............................................................................................ 30 DMT ........................................................................................................................... 31 LSD ............................................................................................................................ 33 MDMA ....................................................................................................................... 36 Historical Context ......................................................................................................... 38 Psychedelics and Anxiety Disorders ............................................................................. 41 Psychedelics and PTSD ................................................................................................ 43 Psychedelics and cPTSD............................................................................................... 45 DMT ........................................................................................................................... 46 LSD ............................................................................................................................ 48 MDMA ....................................................................................................................... 49 Usage Concerns ............................................................................................................ 50 Hallucinogen Persisting Perception Disorder (HPPD) ............................................ 50 Comorbidities ............................................................................................................ 51 Looping and Ego Death ............................................................................................. 52 Conclusion .................................................................................................................... 54 Chapter 5: Future Directions ............................................................................................. 55 Guidelines for Psychedelic Use .................................................................................... 55 Set & Setting .............................................................................................................. 55 Guides ........................................................................................................................ 57 Frequency of Sessions ............................................................................................... 58 Patient Check-Ins ...................................................................................................... 59 iii PSYCHEDELIC SUBSTANCES AS cPTSD TREATMENT Guidelines for Future Research .................................................................................... 60 Design ........................................................................................................................ 60 Control Groups .......................................................................................................... 61 Participants ............................................................................................................... 62 Procedure .................................................................................................................. 63 Conclusion .................................................................................................................... 64 References ......................................................................................................................... 66 iv PSYCHEDELIC SUBSTANCES AS cPTSD TREATMENT Acknowledgements This thesis would not have been possible without the love, support, and encouragement I received from my best friends. Only now am I beginning to realize just how interwoven our lives have become, and just how much we all have sacrificed to watch one another flourish. I do not have adequate enough words to describe my deep gratitude for all they have provided me, though I hope to show them in the years to come. v PSYCHEDELIC SUBSTANCES AS cPTSD TREATMENT Abstract Complex posttraumatic stress disorder (cPTSD) is associated with several detrimental outcomes, including severe anxiety, emotional detachment, mood irregularities, and vivid flashbacks to trauma. In many cases, cPTSD can be linked back to adverse childhood experiences (ACEs). Treatments for cPTSD that involve psychedelic drugs are potentially beneficial, but unfortunately, they are understudied in psychology labs due to their classification as a Schedule I substance. Thus, theoretical work is needed to propose potential mechanisms involved in treatment programs. Toxic stress theory (Murray, 2017) posits that exposure to extreme, frequent, and persistent ACEs without the presence of a supportive caretaker chronically activates the stress response system (Jones et al., 2021). Toxic stress results in dysregulation of the limbichypothalamic-pituitary-adrenal (LHPA) axis, elevating levels of catecholamines, cortisol, and proinflammatory cytokines (Thermo Fisher Scientific, n.d.). The toxic stress induced by ACEs causes cPTSD due to the persistent exposure to multiple adverse events leading to re-experience of the traumatic events, avoidance behaviors, and paranoia. Psychedelic drugs engage positively with negative self-concept and dysregulated emotions, which are both characteristic of the Disturbances of Self-Organization symptom cluster of cPTSD. In the new theoretical model presented in this thesis, I clarify the mechanistic links between ACEs and cPTSD and then examine why psychedelic drugs may be an ideal therapeutic tool for the treatment of cPTSD. This theoretical model may promote the public recognition of the potential benefits of this treatment and further exploration into this topic. Keywords: cPTSD, ACEs, psychedelics, toxic stress theory, LHPA axis vi PSYCHEDELIC SUBSTANCES AS cPTSD TREATMENT List of Tables & Figures Figure 1 .............................................................................................................................. 1 Table 1 .............................................................................................................................. 62 vii Chapter 1: Introduction Rates of individuals experiencing mental illness have never been higher than they are today, with estimates reaching over 1 in 5 U.S. adults experiencing mental illness in 2020 (National Alliance on Mental Illness, 2020). With this rise in cases, the call for effective, efficient treatment is louder than ever. Among these mental illnesses is complex Post Traumatic Stress Disorder (cPTSD), which is correlated with the intersection of various traumas and is thought to lead to a wide variety of occupational, relational, social, and functional issues that negatively affect daily life (Haselgruber et al., 2020; Jowett et al., 2020; Karatzias et al., 2019a; Karatzias et al., 2019b). cPTSD affects millions of individuals globally, and with little empirical support for effective, longlasting current forms of treatment, the need for effective therapy and care is critical (American Psychiatric Association, 2017; American Psychological Association, 2017; Gnaulati, 2019; Phan et al., 2008). Figure 1 Theoretical Model Depicting the Use of Psychedelic Substances as a Treatment for cPTSD The goal of the current project was to explore whether psychedelic-assisted therapy might be an effective treatment for cPTSD by examining prior research to PSYCHEDELIC SUBSTANCES AS cPTSD TREATMENT develop a theoretical model explaining the use of psychedelic-assisted therapy for cPTSD treatment. Figure 1 contains the proposed model for treatment of cPTSD using psychedelic-assisted therapy. Consistent with research on symptom clusters of cPTSD, the model highlights the hypothesized role of toxic stress theory and limbichypothalamic-pituitary-adrenocortical (LHPA) axis activation in explaining the mechanism through which ACEs can lead to the development of cPTSD. Chapter 2 focuses on adverse childhood experiences, or ACEs. ACEs tend to appear in clusters (Springer et al., 2007; Widom et al., 2006) and place children at risk for negative physical and psychological consequences in adulthood (Murray, 2017). Chapter 2 also provides an overview of the theory of toxic stress (Murray, 2017). This theory proposes that exposure to extreme, frequent, and persistent adverse events without the presence of a supportive caretaker chronically activates the stress response system, and that persons who experience more than one ACE are at risk for worse negative outcomes (Jones et al., 2021; Murray, 2017). One of the ways cPTSD can develop is when individuals undergo several ACEs, especially of varied types (Ben-Ezra et al., 2018); this is thought to lead to complex, multidimensional traumas that present with the symptoms that define cPTSD as a separate diagnosis from single-incident PTSD (Ben-Ezra et al., 2018; Haselgruber et al., 2020). These symptoms can result from experiencing multiple ACEs because the complex nature of experiencing a variety of ACEs leads to increased mental health issues, a lack of safety and security throughout adolescence, and the development of poor interpersonal skills that make it difficult for the individual to communicate effectively (Elder, 1985; Fothergill et al., 2016; Kendall-Tackett, 2002; Springer et al., 2007). These ideas are unpacked in Chapter 3. 2 PSYCHEDELIC SUBSTANCES AS cPTSD TREATMENT When cPTSD develops, the physical and psychological consequences are thought to be detrimental due to the activation of the LHPA axis. The toxic stress an individual experiences as a result of complex childhood traumas appears to lead to dysregulation of the LHPA axis. This elevates levels of various hormones and neurotransmitters, including catecholamines, which trigger the fight or flight response; cortisol, which helps slow nonessential functions in fight-or-flight scenarios; and proinflammatory cytokines, which oversee immune cell growth, activation, and movement to sites of infection for pathogen eradication (Thermo Fisher Scientific, n.d.). This is critical for examining the link between ACEs and cPTSD because the fight-or-flight response is frequently triggered in children due to the complex, stressful nature of the events they are experiencing (Shonkoff et al., 2012). The activation of the LHPA axis can lead to the development of cPTSD. In Chapter 3, I then proceed to outline the current treatments for cPTSD and their limitations. Chapter 4 proposes why the use of psychedelic-assisted therapy could be a more effective, longer-lasting treatment choice. Potential concerns about this treatment, as presented by prior literature, are also addressed. In outlining the use of psychedelicassisted therapy, Chapter 4 describes the use of three specific substances. Chapter 5 outlines a set of preliminary guidelines for psychedelic use and future research to guide future researchers in ethically evaluating and conducting this treatment. 3 PSYCHEDELIC SUBSTANCES AS cPTSD TREATMENT Chapter 2: Adverse Childhood Experiences ACEs are well-studied in psychological research. This chapter will define ACEs, outline their frequency, and explain the documented correlation between ACEs and several varied harmful outcomes. Then, the chapter addresses how toxic stress is correlated with detrimental, life-long effects, as demonstrated by toxic stress theory (Murray, 2017). Finally, this chapter outlines how ACEs activate the LHPA axis. Definition and Frequency of ACEs ACEs are potentially traumatic events that occur in childhood (0-17 years; Centers for Disease Control and Prevention, n.d.). When research into ACEs began, ten were defined: physical abuse, sexual abuse, verbal abuse, physical neglect, emotional neglect, having a family member who is diagnosed with mental illness, having a family member who is addicted to alcohol or another substance, having a family member who is in prison, witnessing a mother being abused, and losing a parent to separation, divorce or death (Felitti et al., 1998). There is generally agreement that childhood sexual assault (CSA) and childhood physical abuse (CPA) are also acceptable examples of ACEs, with CPA affecting approximately 1 in 20 children (American Academy of Pediatrics, 2021). Experiences like cumulative life poverty, emotional neglect, natural disasters, community violence, and parental figures with substance abuse issues can also constitute ACEs (Gaias et al., 2022; Huang et al., 2020; Jones et al., 2021). Researchers have asserted just how detrimental all manner of ACEs are. Thus, ACEs are now often defined more broadly as any traumatic events that occur during formative childhood years (Centers for Disease Control and Prevention, n.d.; Felitti et al., 4 PSYCHEDELIC SUBSTANCES AS cPTSD TREATMENT 1998); they encompass a wide variety of experiences, including, but not limited to: experiencing violence, abuse, or neglect; witnessing violence in the home or community; having a family member attempt or die by suicide; substance abuse or mental health problems pertaining to the child themselves or someone in their immediate social support group; instability due to parental separation; members of the child’s immediate circle being in jail or prison; and poverty (Centers for Disease Control and Prevention, 2021). ACEs are thought to impact millions of children worldwide every year. Estimates from adult-reported data place the number of children experiencing ACEs as low as 14% (Herrenkohl et al., 2016) and as high as 61% (Centers for Disease Control and Prevention, 2021). The reason for this range is due to a lack of consensus among field experts as to what constitutes an ACE. To fully gauge the frequency of ACEs in U.S. children, the CDC-Kaiser Pemanente group conducted one of the first studies on the topic (Felitti, 1998). The CDC-Kaiser Permanente ACEs study is one of the original, largest analyses of childhood abuse, maltreatment, and neglect. Conducted at Kaiser Permanente over the span of three years (1995-1997), the investigators gathered two waves of data from over 17,000 Health Maintenance Organization (HMO) members from Southern California to gauge the frequency of ACEs. HMO members received physical exams and responded to surveys regarding their childhood experiences, including ACES,1 and current health status and behaviors (Centers for Disease Control and Prevention, 2021; Felitti, 1998). 1 To measure ACEs, the Kaiser Permanente group defined seven categories of ACEs: psychological abuse, physical abuse, sexual abuse, violence against the mother in the home, living with household members who were substance abusers, living with household members who were mentally ill or suicidal, and living with household members who were ever imprisoned. 5 PSYCHEDELIC SUBSTANCES AS cPTSD TREATMENT More than 50% of respondents reported experiencing at least one ACE, and 25% reported experiencing more than two. These rates demonstrate the widespread impact that ACEs have on U.S. citizens. Externalizing and Internalizing Problems ACEs predict externalizing problems later in life. Having at least one ACE is associated with increased rates of externalizing problems, including rule-breaking, aggression, and paranoia/distrust of authority (Gaias et al., 2022; Timmermans et al., 2010). Prior research has demonstrated that distrust of authority due to childhood maltreatment at the hands of an adult that is supposedly trustworthy often results in paranoia and aggression as an adult. This further elucidates the notion that ACEs negatively affect children throughout much of their lives (Timmermans et al., 2010). As an example, CPA often takes place at the hands of parents, guardians, or other authority figures in a child’s life (Peterson, 2018). This is one reason that CPA may cause children to not trust authority figures; if they experience abuse at the hands of a parent, guardian, or other authority figure, they are less likely to trust other individuals also fitting into these categories. Distrust of authority figures, especially of those actively involved in raising the child, causes a child to lose a sense of safety and stability in their life, much of which is meant to be provided by a parent. In addition, self-reported data has elucidated that CPA predicts a graded increase in aggressive behaviors (Springer et al., 2007; Watters & Martin, 2021). ACEs from ages 10-17 are also related to rates of internalizing problems later in life, including depression, anxiety, withdrawn behaviors, and somatic complaints (Timmermans et al., 2010). CPA specifically predicts a linear increase in depression, 6 PSYCHEDELIC SUBSTANCES AS cPTSD TREATMENT anxiety, and feelings of anger, and other symptoms of poor mental health (Springer et al., 2007). Experiencing CPA often does not occur as a single ACE; experiencing multiple forms of abuse increases risk for detrimental effects on adult mental health (Murray, 2007; Springer et al., 2007). Based on longitudinal studies, experiences with CSA and CPA are associated with greater risks of mental disorders later in life, including depression, anxiety, poor emotional regulation, and substance abuse disorders; in these studies, CSA presented a higher risk for development of these mental health conditions than CPA (Fergusson et al., 2008; Herrenkohl et al., 2016). The model presented by Watters & Martin (2021) also demonstrates that ACEs are correlated with detrimental mental health effects, often correlated with a lack of stability and inability to form social connections with others. Childhood maltreatment has a positive correlation with depression, and a negative correlation with subjective wellbeing, decreased life satisfaction, and positive life events (Watters & Martin, 2021). In addition, adults who self-report experiencing ACEs had significantly greater emotional reactivity than adults who did not report experiencing ACEs, suggesting that there is a link between early childhood trauma and midlife mental health (Fagundes & Way, 2014; Springer, 2009). Physical Health Issues In addition to being correlated with detrimental mental health issues, ACEs are correlated with detrimental physical health effects, including a greater risk for cardiovascular diseases, cancer, and Type II diabetes (Fagundes & Way, 2014; Springer et al., 2007). Childhood maltreatment is related to higher cortisol levels and more detrimental physical symptoms (such as stress-induced muscle tension) and behaviors 7 PSYCHEDELIC SUBSTANCES AS cPTSD TREATMENT (such as injury-prone behaviors) for both men and women (Watters & Martin, 2021). Childhood maltreatment also has a negative correlation with subjective physical wellbeing, measured through self-report questionnaires of how the subject is experiencing their current physical health (Watters & Martin, 2021). From self-reported data on longitudinal studies, it is apparent that CPA predicts a graded increase in negative physical symptoms (such as joint damage due to stress) and medical diagnoses characteristic of severe ill health. (Springer et al., 2007; Watters & Martin, 2021). There are physical effects of stress from childhood maltreatment. Autonomic, epigenetic, neuroendocrine, and psychological responses to a stressful childhood environment are correlated with tissue inflammation in adulthood. Stress and ACEs can enhance inflammation by upregulating the transcription of a molecule that regulates expression of proinflammatory-cytokines (Fagundes & Way, 2014). Both the frequency of ACEs and intensity of ACEs affect this. It appears that early life stress caused by ACEs promotes disease by causing systemic inflammation and a weakened immune response. The Kaiser Permanente group (1998) also discovered a graded relationship between the number of categories of ACEs experienced and each of the adult health risk behaviors and diseases that were studied; the list of health risk behaviors was extensive, including smoking, severe obesity, physical inactivity, depressed mood, suicide attempts, and more. Persons with multiple categories of childhood exposure were also likely to have multiple health risk factors later in life. Persons who had experienced four or more of the seven studied categories of childhood exposure had a 12-fold increase in health risks, compared to a control group who had experienced no childhood maltreatment. The 8 PSYCHEDELIC SUBSTANCES AS cPTSD TREATMENT number of categories of ACEs also showed a graded relationship to the presence of adult diseases and poor adult health (Centers for Disease Control and Prevention, 2021; Felitti et al., 1998). These results highlight the potential detrimental relationship between ACEs and a variety of physical health issues. Substance Use ACEs predict adult drug use, which is associated with physical safety issues (Fothergill et al., 2016; Widom et al., 2006). Childhood adversity increases the risk for illicit drug use and substance abuse in adulthood; in addition, experiencing one or multiple ACEs is correlated with a higher chance of becoming a repeat drug user, according to one longitudinal study (Widom et al., 2006). ACEs were associated with higher levels of current drug use and drug-related problems in middle adulthood (Widom et al., 2006). In addition, the culture of illicit drug use can include potentially physically harmful behaviors, including sharing needles (Centers for Disease Control, 2021), unclean living environments (Addiction Center, 2021), homelessness (National Coalition for the Homeless, 2009), and disease contraction (Degenhardt & Hall, 2012). This demonstrates that there is a relationship between ACEs and the unsafe nature of illicit adult drug use. Toxic Stress Theory and LHPA Axis Activation Toxic stress theory states that the exposure to extreme, frequent, and persistent adverse events without the presence of a supportive caretaker chronically activates the stress response system (Jones et al., 2021; Murray, 2017). The unfortunate reality of ACEs is that a person experiencing one ACE is more likely to experience multiple 9 PSYCHEDELIC SUBSTANCES AS cPTSD TREATMENT between the ages of 0-17 (Springer et al., 2007; Widom et al., 2006). In fact, 15.6% of adults aged 18-25 in a survey taken between 2015-2017 reported experiencing more than one ACE (Jones et al., 2021). Persons who experience more than one ACE are at risk for negative outcomes, according to the theory of toxic stress (Murray, 2017). Experiencing four or more ACEs during childhood (0-17 years of age) places children at more risk for severely negative consequences than children who experience fewer ACEs, both physical and psychological (Murray, 2017). ACEs appear to undermine an individual’s sense of safety and stability by disrupting their immediate social support systems. In situations when an individual’s experience of childhood trauma occurs in the general family or friend context, the individual often feels as though their immediate support system has been compromised (Fothergill et al., 2016). A compromised support system can leave an individual feeling helpless, alone, distrusting of authority figures, and lacking direction, all of which may contribute to the detrimental outcomes seen as a result of toxic stress (Kong et al., 2019; Lyu & Agrigoroaei, 2017; Watters & Martin, 2021). Toxic stress is thought to result in dysregulation of the LHPA axis, elevating levels of catecholamines, which are responsible for the fight or flight response; cortisol, which increases blood glucose levels to help slow nonessential functions in fight-or-flight scenarios; and proinflammatory cytokines, which oversee immune cell growth, activation, and movement to sites of infection for pathogen eradication (Thermo Fisher Scientific, n.d.). This leads to cascading effects on the nervous, endocrine, and immune systems. Toxic stress also changes development of the amygdala, prefrontal cortex, and hippocampus, thereby affecting memory and leading to memory repression of traumatic childhood events (Shonkoff et al., 2012). The fight-or-flight response, which is in place 10 PSYCHEDELIC SUBSTANCES AS cPTSD TREATMENT as a physiological, evolutionary, automatic reaction to stress, is often activated in children experiencing ACEs, due to the stressful nature of the event they are experiencing (Shonkoff et al., 2012). These changes can affect attention and other executive functioning, impulsive behavior, brain reward systems, decision-making, and response to stress throughout the lifespan. The effects of the activation of the LHPA axis can be seen in the manner in which children choose to respond to childhood maltreatment. As described above, adult survivors of ACEs who do not receive treatment frequently adopt either an avoidant or intrusive set of behavior patterns, often depending on how their fight-or-flight response initiated and operated while experiencing their ACEs (Kendall-Tackett, 2002; Murray, 2017). Once the LHPA axis is activated, corticotropin-releasing hormone (CRH) is secreted into the bloodstream and increases the activity of the sympathetic nervous system; this perpetuates effects like elevated heart rate (Herman et al., 2016). CRH also signals the pituitary gland to secrete adrenocorticotropic hormone (ACTH), which is also released into the bloodstream; the hormone then travels down to the adrenal cortex, leading to a series of intracellular events that result in the adrenal glands secreting glucocorticoids like the hormone cortisol (Herman et al., 2016). This increased secretion of glucocorticoids acts on multiple organ systems to redirect energy resources to meet real or anticipated demand. Glucocorticosteroids increase blood pressure, cardiac output, and circulating glucose levels, providing more blood to skeletal muscles and preparing your body for a fight-or-flight situation during stressful situations (Chrousos, 2009; Herman et al., 2016). Mobilization of the sympathetic nervous system accounts for the presentation of fight-or-flight responses often seen in persons who experience trauma, 11 PSYCHEDELIC SUBSTANCES AS cPTSD TREATMENT wherein triggers and stressors of traumatic events initiate a response that encourages traumatized individuals to either confront or flee from the source of the traumatic event (Cloitre, 2020). Conclusion This chapter outlines information on ACEs, which are the first step in understanding the model presented in Figure 1. ACEs are pervasive and have become commonplace in today’s society (Centers for Disease Control and Prevention, 2021; Felitti, 1998; Herrenkohl et al., 2016). There are a variety of types, ranging from CPA and CSA to cumulative life poverty or having a family member in jail (Felitti et al., 1998; Gaias et al., 2022; Huang et al., 2020; Jones et al., 2021). ACEs are correlated with detrimental effects such as externalizing problems, internalizing problems, physical health issues, and substance use issues. The toxic stress of experiencing more than one ACE often activates the LHPA axis. The next chapter will outline information on cPTSD, including its symptom presentation, validity, and current treatments. 12 PSYCHEDELIC SUBSTANCES AS cPTSD TREATMENT Chapter 3: Complex Posttraumatic Stress Disorder Presentation of cPTSD can occur as a result of ACEs, as demonstrated by Figure 1. Though not every individual who experiences ACEs will develop cPTSD, it is correlated with a higher prevalence of a greater number of childhood-based traumas (Elliot et al., 2021). This chapter will outline the symptom profile of cPTSD, elaborate on the validity of its diagnosis, and outline the issues with current cPTSD treatments. In 1980, the American Psychiatric Association added PTSD to the third edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-3; American Psychiatric Association, 2013). For several years following this announcement, this was seen as a controversial decision (National Institute of Mental Health, 2017; World Health Organization, 2019). From a historical perspective, the addition of PTSD to the DSM ushered in significant change and controversy because the cause of the disorder was presumed to be outside the individual (e.g., a traumatic event) rather than a factor of the individual (e.g., having a traumatic neurosis; Friedman, 2007; National Institute of Mental Health, 2017). The foundation of PTSD is rooted in the concept of trauma (Friedman, 2007). Trauma is an individual’s behavioral, cognitive, and emotional response to a devastating event, such as assault, rape, or natural disaster (American Psychological Association, n.d.). To be diagnosed with PTSD, a person must have experienced at least one traumatic event. This can happen by experiencing the trauma directly, witnessing the traumatic event occurring to others, or learning that a loved one experienced a traumatic event. In addition, it must be coupled with distress or dissociation, avoidance behaviors, alterations in cognitions and moods, alterations in arousal and reactivity, and duration of this disturbance lasting one month or more 13 PSYCHEDELIC SUBSTANCES AS cPTSD TREATMENT (American Psychiatric Association, 2013). This chapter will outline the symptoms of cPTSD, the validity of this diagnosis, and the current treatment methods. Background on cPTSD The term cPTSD was first presented in Trauma and Recovery, a book dedicated to the complex difficulties of recovering from trauma (Herman, 1992). cPTSD is a disorder that may develop following exposure to an event or series of events of an extremely threatening or horrific nature, most commonly prolonged or repetitive events from which escape is difficult or impossible (World Health Organization, 2018). The diagnosis of cPTSD was introduced to the 11th edition of the International Classification of Diseases (ICD-11) for the first time in 2018 (World Health Organization, 2018). The WHO published ICD-11 for review in 2018, and it was formally adopted by the World Health Assembly on May 25, 2019; it became effective beginning January 1, 2022 (National Committee on Vital and Health Statistics, 2019). The recognition of cPTSD is controversial because some researchers argue that there is insufficient evidence to conclude that cPTSD is distinct from PTSD, which ultimately led to the decision to omit cPTSD from DSM-5. Symptoms of PTSD and cPTSD In the third edition of the DSM, PTSD was characterized by five major symptoms: having been exposed to severe stress; re-experiencing the trauma through intrusive recollections, nightmares or flashbacks; persistently avoiding emotionally charged stimuli through numbing of responsiveness, avoidance of charged stimuli, or psychogenic amnesia; having persistent hyperarousal, as indicated by insomnia, 14 PSYCHEDELIC SUBSTANCES AS cPTSD TREATMENT irritability, hypervigilance and increased startle response; and at least one month’s duration of symptoms (American Psychological Association, 1987). However, in publication of the fourth edition of the DSM (DSM-4), the criteria for diagnosis and symptom presentation were changed, and PTSD was characterized by the modern symptom clusters used today. PTSD was characterized as an anxiety disorder in DSM-4 by a set of three major symptom clusters (American Psychological Association, 1994). The first is re-experiencing of the traumatic event in the present (RE), which includes spontaneous memories of the traumatic event, recurrent distressing dreams related to it, flashbacks, and other intense or prolonged psychologically distressing experiences pertaining to memory of the event(s). The second symptom cluster is avoidance of traumatic reminders (AV), which refers to poor behavior patterns completed in order to avoid the distressing memories, thoughts, feelings or external reminders pertaining to the event. The third symptom cluster is arousal leading to a sense of current threat (TH), which is marked by aggressive, reckless, and/or self-destructive behavior; sleep disturbances; and hyper-vigilance, all of which leads to the interpretation that the individual is being threatened by the same or a similar traumatic experience as before (American Psychiatric Association, 1994). When the most recent edition of the DSM, DSM-5, was published, the arousal symptom cluster was emphasized through a renewed focus on the “flight” aspect in the fight-or-flight response commonly seen in PTSD (American Psychiatric Association, 2013; Cloitre, 2020). DSM-5 adds an additional symptom cluster characterized by negative cognition and mood (CM), which represents a variety of cognitions pertaining to a persistent and distorted sense of blame of self or others, estrangement from others, 15 PSYCHEDELIC SUBSTANCES AS cPTSD TREATMENT markedly diminished interest in activities, an inability to remember key aspects of the event. The criteria of DSM-5 also account for the “fight” reaction often seen as a result of sympathetic nervous system activation (Cloitre, 2020; Mayo Foundation for Medical Education and Research, 2018). DSM-5 lists PTSD in a new chapter on Trauma- and Stress- or-Related Disorders, rather than as an anxiety disorder (American Psychiatric Association, 2013). Immediately after the traumatic event, shock and denial are common responses. In long-term settings, reactions can include unpredictable emotions, emotional outbursts, flashbacks to the devastating event, strained relationships, and a variety of physical symptoms such as migraines and dizziness (American Psychological Association, n.d.; Mayo Foundation for Medical Education and Research, 2018). PTSD diagnosis is only made if problems pertaining to the experience of the traumatic event persist for more than one month and impair one’s ability to function in social, vocational, and romantic settings (Mayo Foundation for Medical Education and Research, 2018). A diagnosis of cPTSD requires the presence of the same symptom clusters as PTSD, with the addition of disturbances in self-organization (DSO) as reflected in: (1) excessive deficits in modulating emotions (ME), (2) negative self-concept (SC), and (3) dysfunctions in interpersonal relations (IR; American Psychiatric Association, 2013; BenEzra et al., 2018; World Health Organization, 2019). The World Health Organization expects that the addition of cPTSD as distinct from PTSD will provide greater precision in the diagnosis of trauma populations and more personalized and effective treatment (Cloitre, 2020; World Health Organization, 2019). Due to the additional symptoms experienced with the DSO symptom cluster as part of the cPTSD diagnosis, persons with cPTSD also often experience increased 16 PSYCHEDELIC SUBSTANCES AS cPTSD TREATMENT loneliness and emotional dysregulation. These symptoms interact iteratively, meaning that experiencing one makes the other worse, and vice versa (Bromberg, 2011; Dagan & Yager, 2019); these symptoms often stem from ACEs, and can incur a diagnosis of cPTSD. Symptoms of emotional dysregulation, such as intense reactivity, requiring long periods of time to calm down, easily hurt feelings, feelings of uncontrollable anger, and numbness, express a deactivation pattern in hippocampal memory storage, which causes increased memory avoidance (Bryant et al., 2021). Emotional dysregulation also contributes to adversities in interpersonal relationships that lead to loneliness (Dagan & Yager, 2019). Compared to PTSD, cPTSD patients report a higher number of more severely traumatic events earlier in life. Persons diagnosed with cPTSD also reported more multitype, multi-event childhood trauma due to adverse childhood experiences than persons diagnosed with PTSD (Haselgruber et al., 2020; Jowett et al., 2020; Karatzias et al., 2019a; Karatzias et al., 2019b). In addition, there is support for the notion that childhoodbased, multi-type trauma necessitates a diagnosis separate from the standard presentation of PTSD (Haselgruber et al, 2020). Furthermore, persons diagnosed with cPTSD exhibited high functional impairment, further demonstrating support for the idea that patients who experience more, prolonged, interpersonal traumas at a younger age have a higher correlation of developing cPTSD (Jowett et al., 2020). Childhood maltreatment may account for the differences seen in activation of the amygdala, ventromedial prefrontal cortex, and anterior cingulate cortex that are seen in persons with cPTSD (Teicher et al., 2014). 17 PSYCHEDELIC SUBSTANCES AS cPTSD TREATMENT It is worth noting that experiencing ACEs does not immediately lead to the development of cPTSD; there are moderating factors that can reduce the likelihood of this development. The presence of safety and stability in the form of a warm bond with a loving caretaker(s) in children’s lives can moderate the relationship between ACEs and perceptions of loss, poor adult physical health, and poor adult mental health. With those bonds present, children often suffer much less than with them absent (Herrenkohl et al., 2016; Kendall-Tackett, 2002; Murthi & Espelage, 2005; Springer, 2009). A lack of these socially supportive bonds for children reflects the absence of positive mentoring from adult role models, which is critical to helping them develop skills and competencies conducive to physical and mental well-being (Springer, 2009). The presence of role models or other strong social bonds in a child’s life can moderate the effects of ACEs, thus lessening the likelihood of developing cPTSD. Validity of cPTSD vs. PTSD Given the controversial nature of the introduction of cPTSD to ICD-11, the debate over the necessity for two separate PTSD and cPTSD diagnoses has been prevalent since Herman (1992) first proposed the term cPTSD. However, a variety of studies support the need for separate PTSD and cPTSD diagnoses due to the differences in prevalence, causal factors, biological differences, and symptom presentation. One assessment of the factorial validity of PTSD and cPTSD diagnoses was conducted on a sample of 1003 Israeli citizens, and results demonstrated prevalence of 9.0% for PTSD and 2.6% for cPTSD, in addition to multidimensional, rather than hierarchical, symptom clusters; this demonstrates support for factorial validity (Ben-Ezra et al., 2018). There is a distinct relationship between various types of trauma and types of difficulties in emotional 18 PSYCHEDELIC SUBSTANCES AS cPTSD TREATMENT regulation (Bennett et al., 2015). This is important because it suggests that, for a general measure of an individual’s responses to a traumatic event, evaluating various aspects of emotional dysregulation is necessary when assessing cPTSD in populations, given that individuals with cPTSD are often exposed to varied and multiple types of traumas (BenEzra et al., 2018; Haselgruber et al., 2020). Evaluation of emotional dysregulation as it relates to trauma response is accomplished through the set of multidimensional, rather than hierarchical, symptom clusters laid down by the World Health Organization (World Health Organization, 2019). As many as 20% of adults diagnosed with PTSD may actually be experiencing cPTSD because of repetitive trauma related to ACEs (Karam et al., 2014); this demonstrates a need for consistent evaluation and re-evaluation of patients diagnosed with PTSD, particularly older patients who were diagnosed before ICD-11 was officially published. Researchers have used fMRI research to investigate biological differences associated with PTSD and cPTSD. One study assessed the differences between neural processing data in persons who met the criteria for PTSD, cPTSD, and trauma-exposed control patients (Bryant et al., 2021). Results demonstrated reduced supraliminal right dorsolateral prefrontal cortex activation and increased subliminal amygdala and insula activation as common dysfunction for both cPTSD and PTSD groups relative to trauma controls. Results also demonstrated greater bilateral insula and right amygdala activation in cPTSD participants relative to PTSD participants during supraliminal presentations of threat stimuli (Bryant et al., 2021). The functional significance of insula activation in cPTSD can be understood in terms of the disruptions often seen in cPTSD in selforganization, which leads to an impoverished sense of self, low self-esteem, and poor 19 PSYCHEDELIC SUBSTANCES AS cPTSD TREATMENT monitoring of one’s bodily health; this is also characteristic of the emotion dysregulation symptoms of cPTSD. The right amygdala activation was greater in cPTSD than PTSD participants, which reflects the more extreme emotion dysregulation that occurs in cPTSD, leading to stronger fear expression and threat detection. This emphasizes the hypothesis that cPTSD is distinguished from PTSD by disturbances in emotion regulation and self-concept, thus warranting that cPTSD be classified as a separate diagnosis, as it is in the ICD (Bryant et al., 2021; Cloitre, 2020; World Health Organization, 2018). In terms of variations in symptom presentation, persons with cPTSD present with more dissociative symptoms than persons diagnosed with PTSD (Eilers et al., 2020); this can be understood as a reflection of the DSO symptom cluster seen in cPTSD but not PTSD, as dissociation and derealization symptoms reflect an inability to modulate emotions (ME) properly. In one study, a high proportion of psychiatric patients reporting post-traumatic responses presented with complex symptom profiles including a variety of emotional dysregulation factors, justifying a more complex symptom response. This extends previous studies’ findings that populations of individuals with lower functioning and exposure to multiple traumatic experiences have a higher prevalence of cPTSD than PTSD due to the complex symptom response demonstrated by these psychiatric patients (Moller et al., 2020). Receiving a diagnosis of cPTSD is likely to be infrequent following singleincident trauma; however, deeper investigation of some cPTSD features, notably affect dysregulation and interpersonal difficulties, may be warranted in younger people following a single-incident trauma. This means that single-incident trauma experienced at a young age could be more highly correlated with cPTSD symptoms than PTSD 20 PSYCHEDELIC SUBSTANCES AS cPTSD TREATMENT symptoms (Elliot et al., 2021). cPTSD, compared to PTSD, is independently associated with younger age, interpersonal trauma in childhood, and interpersonal trauma in adulthood (Karatzias et al., 2019a). This leads to the development of the DSO symptoms cluster that differentiates cPTSD from PTSD. Multivariate meta-regression suggested childhood-onset trauma was associated with a poorer outcome, furthering the notion that childhood-based trauma leads to worse functional impairment, poorer interpersonal skills, and more severe onset of cPTSD (Karatzias et al., 2019b). Complex features and symptoms like the ones seen in cPTSD cannot be attributed to comorbid anxiety or depression alone, as was thought to be the case for many years before the introduction of cPTSD to ICD-11 (Elliot et al., 2021); rather, addition of cPTSD into ICD-11 allows for recognition of the differences between cPTSD and PTSD. cPTSD vs. Borderline Personality Disorder (BPD) Theorists have also debated the differences between cPTSD and Borderline Personality Disorder (BPD). Since depersonalization and derealization are common and central features of Borderline Personality Disorder (BPD), there has been much debate in the community on the necessity and validity of a separate cPTSD and BPD diagnosis. In cPTSD, the disturbance to one’s sense of self is defined as a stable, deeply negative selfperception. As such, there is debate as to whether and how cPTSD is distinct from PTSD comorbid with BPD. BPD is characterized by an ongoing pattern of varying moods, selfimage, and behavior, often resulting in impulsive actions, problems in relationships, experiencing mood swings, and displaying uncertainty self-image and one’s role in the world (Mayo Foundation for Medical Education and Research, 2019a; National Institute of Mental Health, 2017). Emotional, physical, and sexual abuse during childhood is 21 PSYCHEDELIC SUBSTANCES AS cPTSD TREATMENT correlated with both BPD and cPTSD symptom profiles, specifically symptoms relating to depersonalization and derealization. However, PTSD and cPTSD frequently differ in terms of emotional expression. Although emotion regulation difficulties are central to both cPTSD and BPD, their expression can be quite different, with suicide attempts and gestures and self-injurious behaviors a core feature and a first target of treatment for BPD in contrast to cPTSD, which does not include either problem for diagnosis. Preliminary data indicate rates of these problems are substantially lower in cPTSD relative to BPD (Cloitre, 2020). Statistical analysis has also been conducted to demonstrate the differences between cPTSD and BPD. In one latent class analysis (LCA) study, chi-square tests were conducted on cPTSD and BPD symptoms presented by a sample of 195 highly traumatized, treatment-seeking adults in order to identify distinct profiles of cPTSD and BPD (Jowett et al., 2020). Results of the LCA suggested that some individuals presented with high symptom endorsement of cPTSD and moderate symptom endorsement of BPD. These findings support separate cPTSD and BPD diagnoses, even though symptoms of cPTSD and BPD can overlap (Jowett et al., 2020). Current Treatments Currently, cPTSD is treated with a variety of treatments and therapies, often combining medication use with some form of cognitive therapy. Almost every single patient diagnosed with cPTSD will undergo some form of psychotherapy (Center for Treatment of Anxiety and Mood Disorders, 2017; Gilles, 2018). Most patients diagnosed with PTSD take some combination of antidepressants, anxiolytics, and sleep-assist medications during their course of treatment (National Center for PTSD, 2018); this is 22 PSYCHEDELIC SUBSTANCES AS cPTSD TREATMENT similar for patients with cPTSD (Center for Treatment of Anxiety and Mood Disorders, 2017). Cognitive Therapies The American Psychiatric Association’s Guideline Developmental Panel for the Treatment of PTSD in Adults recommends two specific trauma-focused treatments (TFTs) with strong scientific merit: cognitive processing therapy (CPT), which involves clients learning to identify and alter unhelpful beliefs related to a traumatic event and its aftermath; and prolonged exposure (PE), a type of exposure-based therapy uses exposure techniques to gradually assist clients in overcoming the avoidance and fear associated with trauma-related memories, feelings, and situations (American Psychiatric Association, 2017; Lancaster, 2016). Other current treatments of PTSD use a phase-based model, which has three major steps: (1) stabilization through resources, (2) confrontation and acceptance of trauma memories through exposure therapy, and (3) reintegration of previous life goals (Ashfield et al., 2020; Corrigan et al., 2020). However, the phasebased model doesn’t address the shame that many patients feel in regard to their trauma. The presence of shame as a predominant PTSD symptom led to the development of compassion-focused therapy (CFT), a cross-diagnostic therapeutic approach that focuses on reducing shame and self-criticism by fostering an internal compassionate relationship (Ashfield et al., 2020). As researchers note, the active agent of phase-based models is unknown, and while it’s true that the results demonstrate positive effects, those effects vary from person to person, making it an ineffective first choice for treatment (Ashfield et al., 2020). Importantly, however, participants felt like CFT prepared them emotionally and mentally for exposure therapy. A patients’ emotional feelings of 23 PSYCHEDELIC SUBSTANCES AS cPTSD TREATMENT preparation and readiness for therapy are extremely critical for providing a stable emotional foundation on which successful therapy can be built. Current cognitive therapies for cPTSD also include exposure therapy and EMDR, with exposure therapy being the more common (Ashfield et al., 2020). Exposure therapy is rooted in traditional Pavlovian conditioning of conditioned stimuli and responses. The logic behind exposure therapy is that patients need to access the window of tolerance, which is the optimal level of emotional arousal for patients to properly confront past events (Ashfield et al., 2020). However, exposure therapy has a very low success rate, especially for childhood-based cPTSD, because people with cPTSD have trouble accessing and sustaining the window of tolerance and have increased feelings of shame made worse by exposure therapy. As such, exposure therapy can backfire, causing patients to emotionally regress and socially isolate (Ashfield et al., 2020; Corrigan et al., 2020). This can also make the patient more afraid of the conditioned response they are trying to extinguish. This is especially true for cPTSD, in which there are multiple stressors (Corrigan et al., 2020). There are major concerns about the APA’s recommended treatment patterns for PTSD (Gnaulati, 2019). Exposure therapy, TFTs, and phase-based treatments may trivialize the depth of individuals’ suffering and may not fully address the fragility of self that trauma survivors are afflicted with due to the violation of core values and beliefs at the center of the trauma they endured; this could account for the high dropout rate of trauma therapy (Gnaulati, 2019). Pharmacological Supplementation Research on pharmacological supplements to cognitive therapy as a treatment for cPTSD is limited; however, research on pharmacological treatments of PTSD suggests 24 PSYCHEDELIC SUBSTANCES AS cPTSD TREATMENT that there are two types of antidepressants that are common in PTSD treatment: selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors (SNRIs; Mayo Foundation for Medical Education and Research, 2019b). The three major SSRIs given to patients with PTSD are sertraline (brand name Zoloft), paroxetine (brand name Paxil), and fluoxetine (brand name Prozac). The major SNRI given to patients with PTSD is venlafaxine (brand name Effexor), although elevations in blood pressure have been noted with venlafaxine, so it is prescribed with caution (American Psychological Association, 2017; Mayo Foundation for Medical Education and Research, 2018; National Center for PTSD, 2018). Only sertraline and paroxetine are approved by the Food & Drug Administration for the treatment of PTSD (American Psychological Association, 2017). Use of pharmacological substances other than these two is done on a case-by-case basis, usually only due to patient diagnosis of comorbid disorders that would prevent the patient from taking sertraline or paroxetine. SSRIs and SNRIs are used to help treat PTSD more than monoamine oxidase inhibitors (MAOIs) because patients with PTSD taking MAOIs seem to have longer lasting, more continual symptoms than patients taking SSRIs and SNRIs (Asnis et al., 2004). MAOIs also present with more significant adverse effects, such as cardiovascular complications and safety issues, such as ease of overdose (Asnis et al., 2004). SSRIs have presented numerous detrimental side effects, including nausea, vomiting, diarrhea, headaches, exhaustion, dry mouth, insomnia, vision problems, nervousness, agitation, aggression, restlessness, dizziness, reduced sexual desire, difficulty reaching orgasm, erectile dysfunction, impact on appetite, reduced bone health, and suicidal thoughts (Mayo Foundation for Medical Education and Research, 2019c; 25 PSYCHEDELIC SUBSTANCES AS cPTSD TREATMENT Sansone & Sansone, 2012). One double-blind, placebo-controlled study on SSRIs and SNRIs found that the occurrence of suicidal thoughts and aggressive behavior doubled in children and adolescents who used these medications (Kwon, 2016). Research on antidepressants has also been a subject of controversy in recent years, as information regarding selective reporting of results has been unearthed (Jakobsen et al., 2017; Kwon, 2016). Pharmaceutical companies are often responsible for conducting the research on their medications. Thus, though antidepressants can be beneficial for certain individuals, it has recently come to light that increased negative side effects are more common than originally thought for antidepressants (Kwon, 2016). In addition, studies have demonstrated that SSRIs are often ineffective in or not tolerated by patients with PTSD (Alexander, 2012). Overall, it appears that antidepressant medications, while they do aid many people suffering from depression, are also accompanied by a variety of negative side effects (Jakobsen et al., 2017). Common anxiolytics used to help treat PTSD are alprazolam (brand name Xanax), chlordiazepoxide (brand name Librium), clonazepam (brand name Klonopin), diazepam (brand name Valium), and lorazepam (brand name Ativan; Mayo Foundation for Medical Education and Research, 2018). However, many anti-anxiety medications have the potential for abuse, so they are generally used only for a short time to help with the adjustment to pharmacotherapy and new psychotherapy. Finally, topiramate (brand name Topamax), an anti-epileptic medication thought to modulate glutamate neurotransmission and aid PTSD symptom reduction, is also given as a pharmacological supplement on occasion. However, the potential side effects and harms of topiramate are greater than they are for SSRI antidepressants due to the cognitive dulling side effect that 26 PSYCHEDELIC SUBSTANCES AS cPTSD TREATMENT often presents with topiramate use (American Psychological Association, 2017). Some research has suggested that neuroleptic medications could aid persons with trauma disorders (Adetunji et al., 2005); however, according to FDA treatment guidelines of PTSD has approved use of the SSRIs described above, not antipsychotic medications (American Psychological Association, 2017). Cannabis-Based Treatment There is an entire subfield of PTSD treatment that focuses exclusively on the effects of cannabis-based products as a potential aid for treatment, rather than using traditional pharmacological medications. Studies have examined the neurological effects of cannabis ingestion on anxiety levels through fMRI research. One hundred and twenty minutes after ingestion of 7.5 milligrams of ∆9-tetrahydrocannabinol (THC), participants filled out a variety of measures to examine the effects of the drugs on anxiety levels, feelings of being “high”, and pleasurable experiences (Phan et al., 2008). Cannabis was successfully able to reduce amygdala reactivity responses to aversive emotional stimuli, in addition to increasing neuronal activity in the vmPFC (Phan et al., 2008; Rabinak et al., 2014). Given that the amygdala is the part of the brain associated with fear responses to threats, this activity reduction could play a critical role in reducing classic threat- and paranoia-associated PTSD responses. In addition, cannabinoids can play a role in extinguishing the intensity of relived traumatic memories (Earlenbaugh, 2020; Raymundi et al., 2020). Case studies have been done to evaluate the benefits and harms of using cannabis to treat cPTSD (Earlenbaugh, 2020). Medical cannabis can be provided for patients with cPTSD who experience more severe symptoms in the DSO symptom cluster. Whereas 27 PSYCHEDELIC SUBSTANCES AS cPTSD TREATMENT some symptoms related to PTSD per se (e.g. anxiety, insomnia, nightmares) may be benefited by the addition of medical cannabis to the treatment profile (Rabinak et al., 2014; Raymundi et al., 2020), other symptoms that are more characteristic of cPTSD (e.g. dissociation, reckless behavior, and substance abuse associated with dysregulated affect) may be aggravated (Phan et al., 2008); as such, using cannabis as a treatment is still very new and is only used at the clinicians’ direction. Cannabinoids are involved in the modulation of the cortico-limbic system and the LHPA axis, both of which are disturbed in cPTSD (Dagan & Yager, 2020). In cPTSD, the vmPFC fails to inhibit the amygdala, leading to exaggerated responses to threat, which leads to enhanced fear responses and increased retention and impaired extinction of traumatic memories (Dagan & Yager, 2020). Cannabis can successfully reduce amygdala reactivity responses to aversive emotional stimuli, in addition to increasing neuronal activity in the vmPFC (Phan et al., 2008; Rabinak et al., 2014), thereby increasing negative memory extinction. Patients with cPTSD can also use cannabis to help manage affective dysregulation, which can aid them in calming down and coping with anger towards aversive, negative stimuli (Dagan & Yager, 2020). Conclusion This chapter examines the symptom profile of cPTSD, a pervasive condition that only just became a recognized disorder in 2018 in the ICD-11 (World Health Organization, 2019), as well as the validity of its diagnosis and its current treatments. Presentation of cPTSD can occur as a result of ACEs, as demonstrated by Figure 1. cPTSD presents with the same three symptom clusters as PTSD, with the addition of a fourth symptom cluster focusing on issues of self-organization (American Psychiatric 28 PSYCHEDELIC SUBSTANCES AS cPTSD TREATMENT Association, 2013; Ben-Ezra et al., 2018; World Health Organization, 2019). Prior literature has supported the validity of two separate cPTSD and PTSD diagnoses (BenEzra et al., 2018; Haselgruber et al., 2020) and the validity of two separate cPTSD and BPD diagnoses (American Psychiatric Association, 2013; Cloitre; 2020; Jowett et al., 2020). Current treatments for cPTSD include a combination of cognitive therapies and pharmacological supplementation but have demonstrated limited symptom relief and patient improvement. There is also a subfield of treatment examining cannabis-based treatments for trauma disorders, but these are not advised for cPTSD due to the possibility of aggravating cPTSD-specific symptoms. The next chapter will examine how psychedelic-assisted therapy could be used as a treatment option for cPTSD, given the nature of the therapy having limited negative side effects and increased patient wellbeing. Chapter 4 will outline the use of three specific substances, as demonstrated by Figure 1. 29 PSYCHEDELIC SUBSTANCES AS cPTSD TREATMENT Chapter 4: Psychedelics Psychedelics are a class of hallucinogenic drugs whose primary effect is to trigger non-ordinary states of consciousness, known as a “trip” (Nichols, 2016; Pollan, 2018). This chapter classifies psychedelics into various scientific categories and outlines the historical context of the end of that research. Then, there is a literature review of psychedelic-assisted therapy for treating both anxiety disorders and PTSD. A proposal is then made for the use of psychedelic-assisted therapy for cPTSD treatment. The chapter ends with a review of primary concerns presented by prior literature. Psychedelic Classification There are two primary classifications of psychedelic drugs: those that directly stimulate serotonin receptors (known as Direct Serotonin Agonists), and those that indirectly stimulate serotonin receptors (known as Indirect Serotonin Agonists). Direct serotonergic psychedelics are classified into two main groups: phenethylamines and tryptamines. Tryptamines can be further subdivided into two subgroups: simple tryptamines, which contain an indole ring and show substantial structural flexibility; and ergoline derivatives, such as LSD, which are fully synthetically produced tryptaminebased drugs (Hanks & González-Maeso, 2016a, 2016b). Though research on psychedelicassisted therapy has been conducted using several different psychedelic drugs, this theoretical model will outline the use of three specific psychedelics as potential treatment options for cPTSD, as demonstrated by Figure 1: N, N-Dimethyltryptamine (DMT), a simple tryptamine; Lysergic acid diethylamide (LSD), an ergoline derivative; and 3,4Methylenedioxymethamphetamine (MDMA), an indirect serotonin agonist. Most 30 PSYCHEDELIC SUBSTANCES AS cPTSD TREATMENT research on phenylethylamines has used mescaline, or synthetic derivatives of mescaline, as the primary pharmacological substance of interest; however, the amount of research available is limited (Nichols, 2016). As such, phenylethylamines will not be considered in this theoretical model due to the proportionally smaller amount of available research on their effects as mental health treatment options. DMT N,N-Dimethyltryptamine (DMT) is a derivative and structural analog of tryptamine (Carbonaro & Gatch, 2016). It is used recreationally as a fast-acting psychedelic drug and also by various cultures for entheogenic purposes; it is one of the primary components of the drink ayahuasca (McKenna et al., 1984). Its rapid onset of intense effects and short duration (5-15 minutes) allows users to experience a deep psychedelic experience in significantly less time than other psychoactive substances; for this reason, it became known colloquially as “the business trip” during the 1960s counterculture movement in the United States (Nelson et al., 2014). DMT is not generally active unless it is combined with an MAOI (McKenna et al., 1984); without one, the body will metabolize DMT quickly, thus eliminating the hallucinogenic effect (PubChem, 2005). DMT is an endogenous ligand of sigma-1 receptors (Sig-1Rs), which are responsible for the modulation of calcium ion (Ca2+) release and inhibition of voltage gated potassium ion (K+) channels (Monassier & Bousquet, 2002; Szabó et al., 2021). Voltage-gated potassium channels return a depolarized cell to a resting state after each nerve impulse, and as such, are important in modulating neuron excitability in the central and peripheral nervous systems (Aria, 2020). Regulating neuron excitation could play a 31 PSYCHEDELIC SUBSTANCES AS cPTSD TREATMENT critical role in treatment of cPTSD, as the activation of Sig-1Rs receptors by DMT is thought to play a role in depression, anxiety, and fear extinction (Rodrigues et al., 2019). Fear extinction is critically important when examining a person’s ability to confront and overcome traumatic memories. DMT is an agonist of the 5-HT2A receptor (5-HT2AR), a serotonin receptor involved in affect regulation and alternative thinking methods, such as increased openness (González-Maeso et al., 2007; Marona-Lewicka et al., 2002; Nichols, 2004, 2016); it is also an agonist of the 5-HT2C receptor (5-HT2CR), which is thought to play a role in its effects (Nichols, 2004; Smith et al., 1998). Through agonist binding to the 5HT2AR, DMT is capable of increasing neural plasticity, number of synapses, and improving their efficacy, as demonstrated by fluorescence microscopy and electrophysiology (Ly et al., 2018). The alternative thinking methods and increased neural plasticity could allow cPTSD patients to explore novel methods for confronting complex, traumatic memories that continue to negatively impact them, as well as learn new behavior patterns and coping mechanisms. DMT interrupts activity in parts of the brain that encode habits of thoughts and behavior (Carhart-Harris & Friston, 2019). Neuroimaging studies have shown that serotonergic psychedelics, like DMT, interrupt the default mode network (DMN), a part of the cerebral cortex that is active when a person is not focused on the outside world, during thoughts about external task performance, and when the individual is thinking about others, thinking about themselves, remembering the past, and planning for the future (Buckner et al., 2018; Nichols, 2004, 2016; Pasquini et al., 2020). This may be responsible for DMT’s potentially therapeutic benefit, as an emphasis on thinking about 32 PSYCHEDELIC SUBSTANCES AS cPTSD TREATMENT others and oneself in terms of the past and future could increase a user’s ability to evaluate traumatic events and plan accordingly using coping strategies for future circumstances. Even a single dose of DMT has been shown to facilitate the extinction of cued fear memory in rats (Cameron et al., 2018). LSD Lysergic acid diethylamide (LSD), colloquially known as acid, is a psychedelic drug falling in the ergoline derivative subcategory of tryptamines (Drugs.com, n.d.; Hanks & González-Maeso, 2016a). It was first synthesized by Swiss chemist Albert Hofmann in 1938 from lysergic acid (Pollan, 2018). Hofmann discovered its effects in humans in 1943, after accidentally ingesting an unknown amount of LSD (Hofmann, 1980; Pollan, 2018). Effects of LSD typically include intensified thoughts, emotions, and sensory perception, as well as increased blood pressure, body temperature, and dilated pupils (Drugs.com, n.d.; Nichols, 2016); at higher doses, effects can include auditory and visual hallucinations (Drugs.com, n.d.; Holze et al., 2020). These effects typically begin 30 minutes after ingestion and last for 8-10 hours but can last longer (European Monitoring Centre for Drugs and Drug Abuse, 2021). LSD is considered non-addictive and has a low potential for abuse (Lüscher & Ungless, 2006), making it an ideal choice for psychedelic-assisted therapy. Overdose from LSD has never been recorded; however, LSD can still cause injury as a result of accidents that occur when the user is less psychologically functional during the session (European Monitoring Centre for Drugs and Drug Abuse, 2021). Though the exact mechanism behind the effects of LSD is still unknown (Passie et al., 2008), it appears that four interconnected neurological mechanisms are at work. 33 PSYCHEDELIC SUBSTANCES AS cPTSD TREATMENT Through the interactions of these neurological mechanisms, LSD has been shown to reduce anxiety, enhance emotional empathy and prosociality, and decrease depressive behaviors and the recognition of fearful and sad faces both in research using rats and humans (Cameron et al., 2018; de la Fuente Revenga et al, 2021; Dolder et al., 2016; Schmid et al., 2015). Firstly, it is thought that the drug works by increasing release of the neurotransmitter glutamate in the cerebral cortex, therefore increasing excitation in this area of the brain (Nichols, 2004). Glutamate increases synaptic plasticity, and therefore is involved in learning and memory formation in the brain (McEntee & Crook, 1993). Long-term potentiation, a type of synaptic plasticity characterized by persistent strengthening of synapses based on frequent patterns of behavioral activity, takes place at glutamate synapses in the cerebral cortex (Okubo et al., 2010). This characteristic of the LSD mechanism could help patients with cPTSD learn positive new behavior patterns, such as coping mechanisms and exploration of traumatic memories. Secondly, LSD is thought to be an agonist of the 5-HT2A receptor (5-HT2AR), a serotonin receptor involved in affect regulation and increased flexible and divergent thinking methods, such as overall openness (González-Maeso et al., 2007; MaronaLewicka et al., 2002; Nichols, 2004, 2016). An LSD session that increases flexible and divergent thinking methods could allow cPTSD patients to explore novel methods for confronting complex, traumatic memories that continue to negatively impact them. LSD stays bound to this receptor, as well as other serotonin receptors, for several hours, and unbinds from the receptor very slowly; which may explain the long-lasting effects of a single session of LSD use (Chen & Tesmer, 2017; Wacker et al., 2017). The long-lasting 34 PSYCHEDELIC SUBSTANCES AS cPTSD TREATMENT effects of LSD could provide cPTSD patients more time to confront their multidimensional, traumatic memories. Thirdly, LSD, like DMT, disrupts activity in networks that encode habits of thoughts and behavior (Carhart-Harris & Friston, 2019). Neuroimaging studies have shown that serotonergic psychedelics disrupt the DMN, which is also associated with rumination (Nichols, 2004, 2016; Pasquini et al., 2020; Passie et al., 2008). This may be responsible for LSD’s therapeutic benefit, as decreasing rumination over negative experiences may improve self-relations and allow cPTSD patients to confront memories of traumatic events. Finally, in addition to binding to serotonin receptors, LSD binds to dopamine receptors D1 and D2; this could potentially account for the very stimulating nature of LSD (Marona-Lewicka et al., 2005). Most serotonergic psychedelics are not also dopaminergic, making LSD atypical in this regard (Marona-Lewicka et al., 2005; Nichols, 2016). LSD enhances signaling of the D2-5-HT2AR complex, which could contribute to the psychotic effects seen as a result of high-dose LSD consumption (Borroto-Escuela et al., 2014). Dopamine plays a major role in the motivational component of reward-motivated behavior, signaling the desirability or aversiveness of an outcome, which encourages the person’s behavior toward or away from achieving that outcome (Puglisi-Allegra & Ventura, 2012). This is the aspect of LSD that sets it apart from other tryptamines in terms of potential for cPTSD treatment; with the additional dopaminergic qualities, LSD holds the potential to not only provide the neurological state in which traumatic memories can be confronted, but also provides the user with the motivation to confront said memories. 35 PSYCHEDELIC SUBSTANCES AS cPTSD TREATMENT MDMA 3,4-Methylenedioxymethamphetamine (MDMA), colloquially known as ecstasy or molly, is a psychoactive drug characterized by effects of altered perceptual sensations and increased energy, empathy, openness, and pleasure (Drugs.com, n.d.; Meyer, 2013). Effects begin 30-45 minutes after ingestion and can last 3 to 6 hours (Drugs.com, n.d.; Freye, 2009). Originally synthesized in 1912, MDMA became a popular street drug in the 1980s, and is associated with electronic dance music and rave party culture (Drugs.com, n.d.); despite this, it is not commonly used, with only 0.3% of the population consuming it in 2016 (United Nations, 2018). Short-term adverse effects are blurry vision, increased body temperature, tiredness, and high heart rate; long-term adverse effects include addiction, paranoia, and sleeping difficulties. These effects are usually only seen after extended use of the drug (Drugs.com, n.d.). The neurological mechanism of MDMA acts by increasing the activity of three primary monoamine neurotransmitters: serotonin, dopamine, and norepinephrine (Drugs.com, n.d.). Unlike serotonergic psychedelics, MDMA’s principal mechanism is as an indirect serotonin agonist, increasing the release of these monoamine neurotransmitters by preventing their reuptake into the synaptic cleft of neurons in the brain (de la Torre et al., 2004). MDMA inhibition of neurotransmitter reuptake is highest for serotonin and norepinephrine, and less towards dopamine, meaning that more norepinephrine and serotonin remain in the synaptic cleft, thus leading to their excess binding to receptors and increased norepinephrine and serotonin effects (Oeri, 2021). MDMA has also been shown to increase connectivity between the amygdala and the hippocampus, elevate oxytocin levels, reduce amygdala and right insular activity in 36 PSYCHEDELIC SUBSTANCES AS cPTSD TREATMENT response to negative emotional stimuli, and increase superior frontal cortex activity (de la Torre et al., 2004; Kirkpatrick et al., 2014; Verrico et al., 2007; Walpola et al., 2017). With this reduced amygdala activity, MDMA can dampen the emotional response to traumatic memories, allowing people to relive their traumas in a safe and secure setting, and work through the difficult emotions and disturbances to self-organization seen in cPTSD (Kupferschmidt, 2017). In addition, MDMA has been reported to increase selfreported feelings of closeness to others, euphoria, empathy, and prosocial mood states; decrease anxiety and fear responses; blunt responses to social rejection; and facilitate fear extinction learning (Borissova et al., 2021; Feduccia et al., 2018; Kamilar-Britt & Bedi, 2015; Young et al., 2015). These effects can foster a strong therapeutic alliance between psychotherapist and patient and enable the patient to work with traumatic memories (Sarris et al., 2022). There are two enantiomers of MDMA: S-MDMA and R-MDMA. S-MDMA produces entactogenic effects, which are characterized by increased emotional communion, oneness, relatedness, empathy, and sympathy; these entactogenic effects are accomplished due to the S enantiomer more efficiently releasing serotonin, norepinephrine, and dopamine, as well as having a higher affinity for the 5-HT2C receptor (5-HT2CR; McGregor et al., 2010; Pitts et al., 2018). The R enantiomer demonstrates more agonistic behavior towards the 5-HT2A receptor (5-HT2AR), which is thought to contribute to the hallucinations experienced by individuals using psychedelic substances (Liechti & Vollenweider, 2001; Pitts et al., 2018). Due to the differences in these enantiomers, this model recommends use of pure S-MDMA for use in psychedelic-assisted psychotherapy. Many previous studies, as well 37 PSYCHEDELIC SUBSTANCES AS cPTSD TREATMENT as recreational use, have utilized a racemic mixture of MDMA, which can cause more hallucinogenic effects than necessary to accomplish the therapeutic benefits of cPTSD therapy (Pitts et al., 2018). Increased entactogenic effects without the occasionally frightening hallucinations could lead to easier confrontation of multidimensional, complex traumas, thus making them easier to unpack during the session and with a psychotherapist. This is especially critical for treatment of traumas that lead to the development of DSO symptoms. Symptoms in the DSO symptom cluster are often extremely internalized by the individual and are the result of different types of complex, pervasive traumas. As such, symptoms that are disturbing to self-organization would benefit from the increased openness, empathy, sympathy, and oneness seen in the entactogenic effects released by the S-enantiomer of MDMA. Historical Context The use of psychedelics, both recreationally and pharmacologically, was skyrocketing by the late 1960s and early 1970s (Bright & Williams, 2018; Gross, 2019; Leary, 1990). This was accomplished by the presence of the famous counterculture movement among youth as well as flourishing research by psychologists and psychiatrists that was exploring the use of psychedelic drugs as a therapeutic tool (Leary, 1990). The presence of the counterculture movement among youth led to a concerning rise in recreational use of psychedelic drugs, and eventually, former President Richard Nixon declared psychoactive drugs to be “public enemy number one” in a press conference on June 18th, 1971, claiming that psychoactive substances opposed U.S. patriotic values in the time of the Vietnam War (Bright & Williams, 2018; Hall, 2022). Thinking it would stabilize sociocultural and economic practices, Nixon banned the use of psychedelic 38 PSYCHEDELIC SUBSTANCES AS cPTSD TREATMENT drugs, much to the chagrin and outcry of psychiatrists and psychologists (Bright & Williams, 2018; Walsh & Grob, 2005). However, the War on Drugs initiated by President Nixon is not the only reason for the ceasement of research on psychedelics for therapeutic purposes. Research on psychedelic drugs as therapeutic tools was stopped for a plethora of reasons. One of these was that clinical research on these substances got swept up in a wave of tighter regulations and restrictions of pharmaceutical research after the Thalidomide disaster in the late 1950s and early 1960s (Hall, 2022). Thalidomide, an immunomodulatory drug, was introduced to the market in 1956 and was marketed under the trade name Contergan as a medication for pregnant women experiencing anxiety, trouble sleeping, and morning sickness, without having been tested on the target population (Vargesson, 2015). Issues of women ingesting Thalidomide and birthing children with birth defects began to appear in 1961, and the medication was removed from the market. The use of Thalidomide in 46 countries by women who were pregnant resulted in more than 10,000 children born with a range of severe deformities, such as phocomelia, as well as thousands of miscarriages (Hall, 2022; Vargesson, 2015). This pharmacological disaster led to tighter restrictions on research involving drugs, as well as the eventual passing of the Controlled Substances Act in 1970. Another major factor in abandoning research on psychedelic drugs was the passing of the Controlled Substances Act in 1970, which placed psychedelic drugs in the same classification category as heroin, methamphetamine, and crack cocaine. This classification is known as Schedule I; substances in this have no current accepted medical or therapeutic use and have large potential for addictiveness and abuse (Drug 39 PSYCHEDELIC SUBSTANCES AS cPTSD TREATMENT Enforcement Agency, n.d.). In addition, reports of “bad trips” began popping up across the Western United States, during which people experienced tremendous anxiety, psychosis, and even death. This led to public fear on the matter of psychedelic drugs (Hall, 2022). A major incident also occurred in 1969, when the media began reporting that Charles Manson was using LSD, also known colloquially as acid, to gather a group of followers and convince he was ‘the son of man’ (O’Neill & Piepenbring, 2019; Riley, 2019). Manson then encouraged these followers to murder several people in the Los Angeles area in 1969; this large murder trial led to an outburst of negative publicity for LSD, and psychedelic drugs in general (Lee & Shlain, 1985; Riley, 2019). Access to psychedelic drugs was also a concern. Sandoz is a global pharmaceutical company that originally produced LSD under the brand name Delysid and other psychedelic drugs and provided them to researchers free of charge for information on their mechanisms and effects (Time Magazine, 1954). When they stopped providing psychedelic drugs for research in 1965, research became significantly more difficult (Hall, 2022). Sandoz stopped providing psychedelic substances because they believed that their reputation was damaged by Leary’s advocacy of nonmedical use, as well as media reports of psychoses, accidental deaths, and suicides attributed to LSD (Hoffman, 1980). In addition, there was generally limited interest in funding these studies from the pharmaceutical industry due to mixed results. While most research on LSD in the 1950s was conducted in mental hospitals without the consent of the residing patients, research that began emerging during the 1960s on psychedelic drugs was conducted in comfortable, plushy living rooms by professors who had good relationships with the 40 PSYCHEDELIC SUBSTANCES AS cPTSD TREATMENT participants, often artists or graduate students, who were there in full consent, expecting a pleasant, meditative experience (Hartogsohn, 2020). This crucial divergence reflected the turbulent shift in the American society of the 1960s, and the lack of coherent results due to variety in samples and research methodology made pharmaceutical companies disinterested in providing funding for continued research (Hall, 2022). Overall, the eventual collapse of research on psychedelic drugs as a tool in therapeutic settings was brought about by an increased fear about the youth counterculture movement opposing U.S. wartime sentiments, tighter regulation of pharmaceutical research, lack of access to the drugs themselves, lack of interest in funding the research, and the eventual government intervention that made them illicit substances in 1970 (Hall, 2022). Psychedelics and Anxiety Disorders Although research on the effects of psychedelic drugs is difficult to conduct, some work has looked at their impact on individuals diagnosed with anxiety disorders. The methods of these studies varied; all of them used randomized design; some used placebo controlled, crossover design to compare the placebo versus active drug effects and some did not (Andersen et al., 2021). Although research on the use of psychedelic-assisted therapy is limited, prior research suggests that psychedelic drugs could be a beneficial treatment of anxiety disorders, as demonstrated by short- and long-term symptom reduction and improved patient well-being (Fauvel et al., 2021; Weston et al. 2020). Several studies have determined that therapeutic effects appeared to be long-lasting (on the order of weeks to months) after only 1 to 3 treatment session(s), with the potential for more sessions to lead to even longer-lasting relief (Andersen et al., 2021; Fauvel et al., 41 PSYCHEDELIC SUBSTANCES AS cPTSD TREATMENT 2021; Weston et al., 2020). In some cases, there are short-term effects such as immediate feelings of anxiety after the session, all of which were gone within one month (Aday et al., 2020; Weston et al., 2020). Psychological insights, which are achieved through therapeutic use of psychedelic substances, appear to help shift negative self-rumination toward positive self-compassion, which can decrease anxiety and improve patient well-being (Fauvel et al., 2021; Forstmann et al., 2021). Many patients using psychedelic drugs in a therapeutic setting report experiencing a subjectively pleasant psychedelic experience, which is reported to help reduce anxiety levels in long-term settings (Andersen et al., 2021; Fauvel et al., 2021; Studerus et al., 2021). Subjective pleasantness of a psychedelic experience is measured by two qualities: 1) presence (or lack of) an impactful mystical experience, and 2) number of adverse side effects (Fauvel et al., 2021). One study noted significant decreases in symptoms of depression, anxiety, and stress (DAS) after participants underwent a self-reported psychedelic experience, and level of psychological insights experienced during the psychedelic session was associated with a decrease in DAS (Fauvel et al., 2021). Researchers have reported that anxiety symptoms were reduced by enhancing emotional empathy and prosocial behaviors, which are brought about by therapeutic use of psychedelic substances, as well as by decreasing the recognition of fearful and sad faces (Dolder et al., 2016; Fauvel et al., 2021; Schmid et al., 2015). Enhancing emotional empathy and prosocial behaviors has been linked to increased understanding of the self and higher quality interpersonal relationships, which could reduce anxiety symptoms, 42 PSYCHEDELIC SUBSTANCES AS cPTSD TREATMENT especially those that are caused by social anxiety (Dolder et al., 2016; Schmid et al., 2015). Psychedelics and PTSD Although there are few studies on psychedelic-assisted therapy, the few that have been conducted on patients with single-incident PTSD have shown reduced PTSD symptoms following psychedelic-assisted therapy with few to no negative side effects (Bright & Williams, 2018; Mitchell et al., 2021; Sarris et al., 2022; Wheeler & Dyer, 2020). These results are significant, and the effect of treatment, as measured by Cohen’s d value d = 0.8, is substantial, according to one meta-analytical study (Wheeler & Dyer, 2020). This has resulted in expedited FDA Phase III studies to assess patient improval and well-being, as well as any long-term dangers of the drug (Mitchell et al., 2021). MDMA-assisted therapy has been highly effective in individuals with severe PTSD (Mitchell et al., 2021; Sarris et al., 2022; Wan, 2017). One breakthrough study on this topic began in November 2018, when research into FDA-approved Phase III trials on the use of 3,4-methylenedioxymethamphetamine (MDMA) to treat patients with PTSD (Mitchell et al., 2021). This research was based on six prior research studies that had been conducted during Phase II trial analysis of the drug’s benefits for MDMA-assisted PTSD therapy, and found positive results (Mithoefer et al., 2019). Participants (n = 90) in the Mitchell group had all psychiatric drugs cleared from their systems and were randomized to receive therapy with a placebo or with MDMA; both groups were given three preparatory and nine integrative sessions. PTSD symptoms were assessed at the baseline, throughout the process, and 2 months after the last session using the ClinicianAdministered PTSD Scale for DSM-5, or CAPS-5 (VA.gov, 2018); in addition, 43 PSYCHEDELIC SUBSTANCES AS cPTSD TREATMENT functional impairment and adverse effects to the medication (e.g., suicidal ideation) were assessed to determine longitudinal effects. No major safety issues were identified in the use of MDMA, and data suggest that MDMA has an equivalent, if not better, safety profile compared with that of SSRIs used in the treatment of PTSD (Mitchell et al., 2021). Other contemporary clinical studies with MDMA involving careful screening, preparation, monitoring, and follow-up have taken place with no serious adverse events reported (Sessa et al., 2019). The results demonstrated that MDMA significantly increased attenuation, decreased functional impairment over time compared to the placebo group, and did not induce any adverse effects, either short-term or long-term, when examining abuse potential or suicidal ideation (Mitchell et al., 2021). Results demonstrating increased attenuation, decreased functional impairment, and/or no adverse side effects have been confirmed by additional research (Bright & Williams, 2018; Sarris et al., 2022; Studerus et al., 2021; Wheeler & Dyer, 2020). Researchers have reported that patients suffering from PTSD experience fewer and less severe symptoms in both the short- and long-term after undergoing psychedelic therapy (Wheeler & Dyer, 2020). In addition, they also experience significant increases in openness, spirituality, mindfulness practices, acceptance, and processing of emotions, forgiveness, self-compassion, insights into the self, positive changes in worldview, motivation, and commitment to change (Aday et al., 2020; Borissova et al., 2021; Bright & Williams, 2018). In addition, if a patient was suffering from comorbid substance use disorder, prior literature suggests that they experience changes in the relationship to the substance of abuse and an overall decrease in substance use (Wheeler & Dyer, 2020). 44 PSYCHEDELIC SUBSTANCES AS cPTSD TREATMENT For several years, there was no recognized difference between PTSD and cPTSD. As such, no research yet exists on use of psychedelic drugs as a treatment for patients suffering from cPTSD. Below, I will develop a theoretical model for why psychedelicassisted therapy may be the best course of treatment for cPTSD patients. Psychedelics and cPTSD There are several reasons to suspect that psychedelic-assisted therapy may be a helpful treatment for cPTSD. Firstly, current treatment methods have demonstrated limited symptom relief for patients (e.g., Ashfield et al., 2020; Corrigan et al., 2020; Gnaulati, 2019). Secondly, psychedelic-assisted therapy has shown the potential to reduce PTSD symptoms, and individuals suffering from PTSD experience symptom reduction after just one psychedelic-assisted therapy session (Wheeler & Dyer, 2020). Thirdly, there is neurobiological evidence that suggests that these substances interact with the brain in ways that could promote healing through neurotransmitter release (e.g., Marona-Lewicka et al., 2002). Psychedelic substances may assist in the process of neurocircuitry rewiring, while also modulating an array of relevant neurochemical pathways (Magaraggia et al., 2021). This is often necessary in individuals experiencing cPTSD, as they demonstrate heightened and overly sensitized corticoamygdala neural circuitry, which is associated with the hypersensitivity and reactivity to threatening stimuli (Afifi & Asmundson, 2020; Nusslock & Miller, 2016). The amygdala is activated during fearful situations, like those that cause ACEs that can lead to the development of cPTSD. This triggers a stress response in the body, first mobilizing the sympathetic nervous system, and then activating the LHPA axis (Afifi & Asmundson, 2020). Modulation of neurochemical 45 PSYCHEDELIC SUBSTANCES AS cPTSD TREATMENT pathways can also help address negative emotional processing abilities and the generalized negative worldview commonly seen in cPTSD, which can lead to less negative rumination overall (Magaraggia et al., 2021). Examining the specific neurobiological and psychosocial effects of DMT, LSD, and MDMA would provide more clarity on the use of these substances in a therapeutic setting. DMT DMT is a structural analog of tryptamine and has been used by various Native cultures for entheogenic purposes, often through consumption of the drink ayahuasca (Carbonaro & Gatch, 2016; McKenna et al., 1984). As a shorter-acting (5-15 minutes), more intense psychoactive substance (Nelson et al., 2014), DMT-assisted psychedelic therapy would likely be most effective if there were several sessions (between 5-7, depending on the patient’s needs), each followed by sessions of non-DMT-assisted psychotherapy (3-4 sessions between each dosage of DMT). The standard dose of DMT, when ingested via inhalation (the most common route of administration), can range from 10-60 mg (The Drug Classroom, 2015). One benefit conferred by the use of DMT-assisted psychedelic therapy as opposed to using LSD or MDMA is that DMT is a shorter-acting substance. Even though it would likely take more sessions with the DMT to confront the individual’s negative traumatic experiences brought on by their cPTSD, each specific DMT session would be shorter. This means that each session could be focused on one specific area of trauma or concern, and the following psychotherapy sessions would be able to unpack that one experience more closely and target its negative effects. Having more sessions with the DMT included will allow the user to confront more of their traumatic, negative experiences, 46 PSYCHEDELIC SUBSTANCES AS cPTSD TREATMENT and the following psychotherapy sessions will be used to unpack those experiences and develop coping mechanisms and real-world applications. Since the body metabolizes DMT quickly and eliminates the hallucinogenic effects unless it is combined with an MAOI, inclusion of a small dose of an MAOI is also critical for the experience to proceed smoothly (McKenna et al., 1984; PubChem, 2005). As an agonist of the 5-HT2A receptor (5-HT2AR), DMT has the potential to regulate affect and thinking methods, increase openness, and change neural plasticity (González-Maeso et al., 2007; Ly et al., 2018; Marona-Lewicka et al., 2002). The feelings of openness and increased neural plasticity could allow cPTSD patients to explore novel methods for confronting complex, traumatic memories that continue to negatively impact them, as determined by the activation of the LHPA axis; in addition, participants could learn new behavior patterns and coping mechanisms through alternative thinking methods. Furthermore, agonism of the Sig-1Rs could play a critical role in treatment of cPTSD due to the receptors’ role in fear extinction, which is critically important when examining a person’s ability to confront and overcome traumatic memories (Rodrigues et al., 2019). This would address and reduce LHPA axis activation by decreasing the fightor-flight response seen as a result of increased cortisol levels. Given that a single dose of DMT has been shown to facilitate the extinction of cued fear memory in rats (Cameron et al., 2018), it is entirely plausible that several DMT sessions, each devoted to a specific incident of trauma or area in which the individual is struggling, could help extinguish fear memories in humans; when followed by psychotherapy to develop coping mechanisms, individuals could show great success in healing from cPTSD. 47 PSYCHEDELIC SUBSTANCES AS cPTSD TREATMENT LSD LSD, a psychedelic drug falling in the ergoline derivative subcategory of tryptamines (Hanks & González-Maeso, 2016a), has a longer effect time than DMT, lasting for 8-10 hours (European Monitoring Centre for Drugs and Drug Abuse, 2021). As a longer-acting psychoactive substance, LSD-assisted psychedelic therapy would likely be most effective if there were fewer sessions than DMT-assisted psychedelic therapy (between 3-5, depending on the patient’s needs), each followed by sessions of non-LSD-assisted psychotherapy (3-4 sessions between each dosage of LSD). The standard dose of LSD can range from 50-200 µg (Holze et al., 2020). The atypicality of LSD’s ability to bind to dopamine receptors also holds the potential to not only provide the neurological state in which traumatic memories can be confronted, but also provides the user with the motivation to confront said memories (Marona-Lewicka et al., 2005). One benefit conferred by the use of LSD-assisted psychedelic therapy as opposed to using DMT is that LSD is a longer-acting substance, meaning that it stays bound to the 5-HT2AR for a longer duration of time than DMT would (González-Maeso et al., 2007; Marona-Lewicka et al., 2002). More time bound to this receptor increases the amount of time the participant is investigating change in their affect regulation and increasing their flexible and divergent thinking methods, which could allow cPTSD patients to more thoroughly explore methods for confronting complex, traumatic memories that continue to negatively impact them. This means that it could take fewer sessions to confront the individual’s negative experiences brought on by the trauma from their cPTSD. Each session could therefore focus as intensely as necessary on any given issue, and the longer session would allow the participant to be guided through several different experiences 48 PSYCHEDELIC SUBSTANCES AS cPTSD TREATMENT and form opinions on their severity and connection to one another; the following psychotherapy sessions will be used to unpack those experiences, their severity and connection to one another, and develop coping mechanisms and real-world applications. The use of LSD-assisted psychedelic therapy also provides the advantage of increasing glutamate release and synaptic plasticity, which could help patients with cPTSD learn and solidify the coping mechanisms developed in the LSD session and the following psychotherapy sessions. Having intense focus on issues, as well as increasing glutamate release and synaptic plasticity, could address the LHPA axis activation in that it reduces the amount of CRH in the bloodstream released as a response to each traumatic event, thereby reducing the fight-or-flight response and allowing the body to restart all bodily functions while encountering trauma triggers. MDMA MDMA, a psychedelic drug that acts as an indirect serotonin agonist (de la Torre et al., 2004), has an effect time longer than DMT but shorter than LSD, lasting for 3-6 hours (Drugs.com, n.d.; Freye, 2009). As a slightly longer-acting psychoactive substance, MDMA-assisted psychedelic therapy would likely be most effective if there were fewer sessions than DMT-assisted psychedelic therapy but more than LSD-assisted psychedelic therapy (between 4-6, depending on the patient’s needs), each followed by sessions of non-MDMA-assisted psychotherapy (3-4 sessions between each dosage of MDMA). The standard dose of MDMA can range from 60-120 mg (National Institute on Drug Abuse, 2006). Use of S-MDMA could lead to easier confrontation of multidimensional, complex traumas, which is critical for treatment of cPTSD; symptoms in the DSO symptom cluster are often extremely internalized by the individual. As such, symptoms that are disturbing 49 PSYCHEDELIC SUBSTANCES AS cPTSD TREATMENT to self-organization would benefit from the increased openness, empathy, sympathy, and oneness seen in the entactogenic effects released by the S-enantiomer of MDMA. MDMA reduces amygdala and right insular activity in response to negative emotional stimuli and increases connectivity between the amygdala and the hippocampus (de la Torre et al., 2004; Walpola et al., 2017). With this reduced amygdalar activity, MDMA can lessen the severe emotional response to traumatic memories, allowing people to relive their traumas in a safe and secure setting, and work through the difficult emotions and disturbances to self-organization seen in cPTSD (Kupferschmidt, 2017). This could decrease the levels of catecholamines in the body, which would reduce the fight-or-flight response seen when encountering traumatic, triggering faces. Usage Concerns Hallucinogen Persisting Perception Disorder (HPPD) Hallucinogen persisting perception disorder (HPPD) is a rare, DSM-5-recognized disorder in which a person experiences lasting visual hallucinations and/or distortions of perception after previous use of a hallucinogenic drug; in order to be diagnosed with HPPD, the hallucinations and perceptual changes must cause daily distress (American Psychiatric Association, 2013; Halpern et al., 2018). The user’s experience while on the drug usually lacks the normal feelings of intoxication or mental alteration felt while using psychedelic drugs (Holland, 2021). HPPD usually resolves in a short time frame, on the order of a few weeks to several months; more severe cases can make the condition last for years, but cases this severe have rarely been reported (Holland, 2021). The hallucinations and perceptual changes consist of visual snow, tracers, after images (palinopsia), light fractals, and intensified perception of color (American Psychiatric 50 PSYCHEDELIC SUBSTANCES AS cPTSD TREATMENT Association, 2013; Hermle et al., 2012; Krebs & Johansen, 2013). Most reported cases of HPPD are temporary, resolving with little-to-no need for medication or other such treatments (Hermle et al., 2012; Holland, 2021). Research on HPPD is severely lacking in terms of cross-sectional and longitudinal studies that examine the long-term effects of this disorder and how it results from therapeutic use of psychedelic drugs versus recreational, unmonitored use (Halpern et al., 2018). However, the current research available suggests that HPPD is likely not a serious concern for psychedelic-assisted therapies. Comorbidities Concerns have been raised about the efficacy of treating comorbidity since the beginning of mental health treatment, and cPTSD is no exception (Back et al., 2009). Presenting with not only the traditional PTSD flashbacks, avoidance patterns, and paranoia symptoms, but also with a wide variety of self-concept and self-organization symptoms, cPTSD has high comorbidity with other mental health conditions (Back et al., 2009; Ben-Ezra et al., 2018; World Health Organization, 2019). As such, utilizing psychedelic drugs as a therapeutic tool requires extensive treatment and forethought in order to best improve patient well-being. One study examined MDMA effectiveness in participants with PTSD comorbid with other mental health conditions (Mitchell et al., 2021). The results demonstrated that MDMA was equally effective in participants with comorbidities as in participants with just a PTSD diagnosis, with both groups showing significant symptom reduction. The benefit of MDMA therapy was not affected by participants’ history of alcohol use disorder, history of substance use disorder, or severe childhood trauma (Mitchell et al., 2021). As such, use of psychedelic-assisted therapy as 51 PSYCHEDELIC SUBSTANCES AS cPTSD TREATMENT a treatment for cPTSD, though still requiring more research, holds great potential for treatment purposes. Looping and Ego Death Though limited psychological research has been done on the topic of poor psychedelic experiences, narrative reports have been released on the psychedelic phenomenon of Bad Trips, specifically pertaining to LSD and psilocybin (Ona, 2018); this phenomenon is colloquially known as Looping (Nahman, 2019). Most of the research on this topic has been done on psilocybin, though some has also been conducted on LSD (Ungerleider et al., 1968). Though the experience is said to vary from person to person, a Loop is said to feel like time slips away from the individual; the person may feel like they experience several days, weeks, or even years, while the rest of the world only experiences a couple of hours (Nahman, 2019). During those few hours, the individual experiences detrimental thought spirals, during which they are unable to control or guide their own thoughts and feelings; as a consequence, many people who experience a Loop often feel like they relive their worst nightmares and are forced to confront traumatic experiences they are not yet ready to process (Lucas, 2005; Nahman, 2019; Ona, 2018). Confronting these negative experiences can lead to the feeling that emotions are a problem that need to be solved rather than simply something everyone has and experiences (Nahman, 2019), as well as leading to the phenomenon of ego death, or ego dissolution. Ego death is the complete loss of subjective self-identity and sense of self, due to use of psychedelic drugs (Johnson et al., 2008; Leary, 1964). The term was first used by Timothy Leary and his team at Harvard to describe the first phase of an LSD session, in 52 PSYCHEDELIC SUBSTANCES AS cPTSD TREATMENT which a “complete transcendence” of the self occurs (Leary, 1964). Likening the use of psychedelic drugs, specifically LSD, to the death-and-rebirth cycle, Leary describes psychedelic usage as an experience that strips individuals of their ego defenses. The stripping of an individual’s ego is said to consist of three parts: 1) loss of ego feeling, or ego death; 2) a sense of separation of the observing subject from the body, during which time the body undergoes death; and 3) rebirth, during which the individual returns to normal, conscious thought; this final stage brings about cathartic feelings of relief that are said to lead to insightful notions about the self (Alnaes, 1964; Merkur, 1998). Though the notion of ego death is frightening due to the long-lasting effects it can bring (Johnson et al., 2008), psychedelic researchers have long thought that ego death was not something to be feared; rather, it was seen as a gateway to learning more about the self and as a path to “spiritual liberation” (Leary, 1964). It appears that individuals who take psychedelic drugs in therapeutic contexts are less likely to suffer a bad trip (Ona, 2018). Though populations with comorbid mental health conditions are more susceptible to bad trips, they are not necessarily discouraged from using these substances in a controlled environment (Ona, 2018; Ungerleider, 1968). Though research on the topic of psychedelic-assisted therapy was unsupported in its beginning, it has since shown promise in the treatment of a variety of mental health disorders and holds the potential for the treatment of cPTSD with few to no negative side effects and long-lasting treatment benefits. The three different psychedelic substances examined in this thesis have different neurological mechanisms to accomplish treatment goals, but any of these three substances could be beneficial for cPTSD treatment. Despite some concerns brought up in prior literature about the use of these substances causing 53 PSYCHEDELIC SUBSTANCES AS cPTSD TREATMENT long-term negative side effects, it seems that cases of these long-lasting side effects resolve on their own in a short timeframe and are not issues that should deter physicians and psychologists from utilizing this treatment method. Conclusion This chapter outlines prior research on the use of psychedelic-assisted therapy for treatment of anxiety disorders and PTSD. It then breaks down the neurobiological and psychosocial effects of the use of DMT, LSD, and MDMA for psychedelic-assisted therapy as a treatment for cPTSD, as demonstrated by Figure 1. It outlines the potential benefits conferred by the use of this treatment method and the lack of detrimental side effects. Finally, it outlines concerns of psychedelic-assisted therapy brought up in prior literature and addresses their relevance. Chapter 5 will address future directions of this research, including ethical guidelines for its completion and a description of what empirical research would look like. 54 PSYCHEDELIC DRUGS AS cPTSD TREATMENT Chapter 5: Future Directions Chapter four outlined the theoretical mechanism that explains why psychedelicassisted therapy a beneficial, long-lasting treatment option for cPTSD could be. However, theoretical models do not provide enough evidence to fully demonstrate the effectiveness of this treatment; empirical research is required. Having now described the mechanism behind the potential use of psychedelic-assisted therapy to treat cPTSD, this chapter outlines the future directions this research might take. This outline for future directions includes a list of primary recommendations for use of psychedelics, which may make the treatment more comfortable, effective, and less frightening to participants. It also includes an empirical map of this future research, including experiment design, participant recruiting, and how the procedure could be conducted. Guidelines for Psychedelic Use There are certain guidelines that must be followed for any and all therapeutic usage of psychedelic substances. I outline these guidelines for ethical research down below. Set & Setting Popularized by Timothy Leary in the early 1960s, the term “set and setting” describes the importance of one’s surroundings during a psychedelic experience (Hartogsohn, 2020; Leary, 1990). “Set” is the mental state a person is in when they arrive to their psychedelic experience, including their thoughts, feelings, attitude, and expectations. “Setting” is the physical and social environment of the session (Pollan, 2018). Social support networks have shown to be particularly important for patients 55 PSYCHEDELIC DRUGS AS cPTSD TREATMENT struggling with cPTSD (Fothergill et al., 2016; Kong et al., 2019; Lyu & Agrigoroaei, 2017), so surrounding oneself with a safe, supportive network would likely be critical to ensure a successful experience. The social network is able to help control or guide the course of the experience, both consciously and subconsciously. A relaxed, curious person in a safe, supportive, nurturing environment is often likely to have a pleasant experience. A curated musical playlist has been shown to be part of a positive setting (Strickland et al., 2020). Leary went as far as to claim that 99% percent of the specific response to LSD is determined by set-and-setting (Hartogsohn, 2020). Different societies had different set-and-setting conditions that shaped the character of the psychedelic experience in different ways; this means that one can differentiate between two types or levels of set-and-setting: individual and collective. Individual set-and-setting represents the concrete conditions under which an individual enters a psychedelic experience: the physical reality, expectations, and intentions of that individual, as well as the physical and social environment in which the experience takes place. However, collective set-and-setting represents the sociocultural and sociopolitical context under which the individual enters a psychedelic experience, including how society views the psychedelic experience, and therefore frames and sets up the individual set-and-setting in the most intimate of ways as a reflection of the society’s values and social structure (Hartogsohn, 2020). As a result, the set-and-setting conditions provided by the America of the 1950s (during which research on LSD was conducted in mental hospitals without the consent of the residing patients) and the America of the 1960s (during which research on LSD was conducted in comfortable, plushy living rooms by professors who had good relationships with the participants, often artists or graduate 56 PSYCHEDELIC DRUGS AS cPTSD TREATMENT students, who were there in full consent, expecting a pleasant, meditative experience) diverged crucially, reflecting the turbulent shift in the American counterculture society emerging in the 1960s. The set and setting of an individual’s psychedelic experience needs to be closely regulated. They must be in an open mindset, ready to undergo the psychedelic experience, and in a setting that they trust and know. This setting would, ideally, be more reflective of the LSD research conducted in the 1960s, wherein participants have a preestablished, positive relationship with their guide and therapist, the experience takes place in a comfortable room with music and soft lighting, and the individual is expecting a tough but well-intentioned experience. Guides Several studies of the impact of psychedelic-assisted therapy on mental health conditions have utilized psychedelic therapists and spiritual leaders, individuals known as “trip guides”, or just “guides”, to assist participants as they undergo their psychedelic experiences (Aday et al., 2020; Andersen et al., 2021). The use of guides during a session has been highly recommended since the beginning of this research in the 1960s, and potentially improves the quality of research (Leary, 1964; Walsh & Grob, 2005). Guides can help negate negative experiences during a trip (Walsh & Grob, 2005). Similarly, clinical psychologist and LSD researcher Timothy Leary states that the attitudes and behaviors of a guide are absolutely critical in determining the nature of the session, referring to the guide as the “ground control of the airport tower” and “a liberator, one who provides illumination, one who frees men from their life-long internal bondage” (Leary, 1964, p. 47-48). Leary’s research led him and his team at Harvard University to 57 PSYCHEDELIC DRUGS AS cPTSD TREATMENT the conclusion that most negative experiences due to LSD use stemmed from fear of losing control, an issue that the guide can help prevent from occurring (Leary, 1964). Given the qualifications a guide must meet and behavioral patterns they must exude, scientists and psychologists from the foundational days of this research have made their opinions on these qualifications very clear. Guides must be able to provide nondirective and directive support when needed (Andersen et al., 2021). Guides behave openly and honestly with the session participants and are ready to actively participate as much or as little as the participants require (Leary, 1964; Walsh & Grob, 2005). Guides can also choose to read aloud from certain psychedelic guiding books, such as those written by Leary (1964). These books provide an established set of questions and ideas for the participant to consider as they undergo their experience. It is also highly recommended that the guide has prior experience with psychedelic experiences, whether from personal experience or learned experience as a guide (Leary, 1964). Leary (1964) also recommended that guides take a low dose of the psychedelic drug with the participant, but more modern research does not support this notion, suggesting that a guide’s sobriety could help clearly steer the direction of the session for the patient’s best interest (Aday et al., 2020). Frequency of Sessions The majority of modern psychedelic research utilizes post-session, nonpsychedelic psychotherapy to unpack the psychedelic experience (Andersen et al., 2021; Bright & Williams, 2018; Nutt & Carhart-Harris, 2020). These psychotherapy sessions are designed to help the participants understand the visions and feelings they experienced during the psychedelic session (Leary, 1964). Leary (1964) likened the psychedelic 58 PSYCHEDELIC DRUGS AS cPTSD TREATMENT experience to the death-rebirth cycle and believed that non-psychedelic psychotherapeutic follow-up sessions would allow the participants to be more successful in their healing journeys and understand the impacts that prior experiences had had on their mental health. Therapeutic effects of psychedelic-assisted therapy with subsequent psychotherapy were long-lasting (weeks-months) after only 1 to 3 treatment session(s), with the potential for more sessions to lead to even longer-lasting relief (Andersen et al., 2021; Mitchell et al., 2021). Patients diagnosed with single-incident PTSD demonstrated significant increases in openness, spirituality, mindfulness practices, and reduced symptoms, all of which were long-lasting, after being exposed to frequent sessions (Bright & Williams, 2018). Post-session, non-psychedelic psychotherapy can also decrease fear of loss of control often experienced by many participants (Leary, 1964). In general, use of post-session, non-psychedelic psychotherapy has demonstrated enormous potential for improving the effectiveness of psychedelic-assisted therapy. Patient Check-Ins The success of any therapeutic treatment examines patient well-being in terms of occupational, relational, social, familial, and financial success and progress. Examination into patient well-being can be conducted one of two ways: by psychotherapist check-ins or by self-reported data (Andersen et al., 2021). However, in the wake of an intense psychedelic experience, it is critical that patients have check-ins with their psychotherapists, rather than just providing self-report data on symptom relief and progressive well-being (Andersen et al., 2021). Psychedelic experiences can be powerfully persuasive, shocking experiences on the psyche, and not having a mental health professional evaluate participant well-being in the aftermath of such an experience 59 PSYCHEDELIC DRUGS AS cPTSD TREATMENT could prove detrimental to participant health. Self-report data minimizes internal validity of an experiment and makes it more difficult to evaluate effectiveness of a study in any longitudinal manner (Fauvel et al., 2021). Studies that have incorporated psychotherapist evaluations have demonstrated long-term progress in the form of relief from PTSD and other mental health condition symptoms, as well as general patient personality improvements in terms of increased openness, spirituality, self-compassion, and selfacceptance, and decreased negative self-rumination (Andersen et al., 2021; CarhartHarris et al., 2018; Fauvel et al. 2021). Some studies have utilized self-report data to report psychedelic experiences and subsequent patient improvement over time; while these studies have not reported an increased proportion of negative side effects compared to studies that use psychotherapist evaluation, they do not provide as much insight into patient improval, thus limiting their external validity and usefulness to the mental health community, as well as limiting benefit to the patients. Guidelines for Future Research Future research on use of psychedelic-assisted therapy to treat cPTSD needs to be thorough, ethical, and carefully conducted in order to properly evaluate the efficacy of this treatment. Below, I outline possible methodological strategies for conducting this research. Design A double-blind experimental between-groups design should be utilized to compare three groups: a passive placebo group, in which participants are given a placebo that does not mimic the effects of psychedelic substances; an active placebo group, in which participants are given a placebo that does mimic the effects of psychedelic 60 PSYCHEDELIC DRUGS AS cPTSD TREATMENT substances but does not actually contain any of the substance in question; and an experimental group, in which participants are given the actual substance being tested. The experimental group should include three levels of different dosages of the psychedelic substance being tested (see Table 1); this will help evaluate the effectiveness of each substance and the amount needed to demonstrate symptom relief and patient well-being. Using a double-blind study will ensure that there is minimized researcher bias. Control Groups Several studies examining trauma disorders have used control groups of nontraumatized individuals (see Weston et al., 2020). However, this is insufficient when examining the effects of psychedelic-assisted therapy as a treatment for cPTSD because it does not provide the full scope of how the addition of psychedelic substances aids the patients suffering from cPTSD. Two studies utilized trauma-exposed persons who had not received a cPTSD or PTSD diagnosis as the control group (Andersen et al., 2021; Bryant et al., 2021); this is inadequate to properly examine the effects of psychedelicassisted therapy. Control groups and experimental groups should consist of individuals with cPTSD, with the only difference between the two groups being the treatment group they are exposed to. Treatment levels should include a passive placebo, an active placebo, and the psychedelic of the study. The use of both active and passive placebos allows for examination into the true benefits of psychedelic-assisted therapy on persons suffering from specific cPTSD symptoms. As such, utilizing these criteria will be necessary moving forward with more studies on psychedelic-assisted therapy. 61 PSYCHEDELIC DRUGS AS cPTSD TREATMENT Table 1 Recommended Dosage Levels for Experimental Groups in Future Research, Based on Scientific Data from Prior Literature Participants All participants in the study should have a cPTSD diagnosis to maintain internal validity of the study. In order to achieve a power of 0.9 at an alpha value of 0.05 with the field standard effect size of d = 0.8 (Wheeler & Dyer, 2020), an a priori power measure recommends that 138 participants are included in future research. Participants should be randomly assigned to the passive placebo group, the active placebo group, or the experimental group. One weakness of this research is that obtaining such a large sample size of participants with a specific mental health condition is difficult; using smaller sample sizes, or participants with cPTSD comorbid with other mental health conditions, may be necessary to continue research in this field. To recruit participants, psychotherapists and psychiatrists in the surrounding areas should be contacted and informed about the study; they can inform their patients about the study and give them the opportunity to learn more about the process of psychedelicassisted therapy and meet with the researchers to determine if they are a good fit for research. All participants should be over the age of 18. 62 PSYCHEDELIC DRUGS AS cPTSD TREATMENT Procedure All participants should be given information about the research they are participating in and give their informed consent to continue. A physician should administer the dose according to which group the participant is in. Once the dose has been administered and no immediate side effects have occurred, the physician should catalog which group the participant is in, and if they are in the experimental group, what dose level was given. The physician should then leave the room, and the participant’s psychotherapist and guide should enter. As the participant continues through their session, the psychotherapist and guide should ask relevant, guiding questions in order to gauge the participant’s mental state and lead them through the session. Sessions should last for a varied time period, depending on the dosage level given and which substance is being used (since different substances last different lengths of time). After the psychedelic session has ended, the participant should be given 30 minutes to destress and relax in a comfortable, lowly-lit, calm environment. They should be free to leave the session facility after those 30 minutes. Each participant should return one week after the psychedelic session for the first non-psychedelic psychotherapy session, and every week thereafter for four weeks (for a total of four total nonpsychedelic psychotherapy sessions). Each week, participants should spend two hours with the psychotherapist unpacking their session and exploring traumatic experiences and developing coping skills. Dependent variables would be assessed each week. Dependent variables should include symptom relief, patient well-being (assessed by the psychotherapist, not using self-reported data), effectiveness and frequency of use of coping mechanisms, feelings of openness, and emotional anxiety. On the sixth week, the 63 PSYCHEDELIC DRUGS AS cPTSD TREATMENT patient should begin the four-week process again. The five-week process should be repeated four times, for a total of a 20-week experiment for each participant. This presents another limiting factor for this research, as many people do not have two hours per week, plus transportation time, to spend in therapy. Other than the limiting factors already stated regarding sample size and weekly participant availability, there are other limitations to this research. Some persons with cPTSD may be employed at jobs that perform random drug testing; as such, participating in this research presents a complication for those individuals. Conclusion Prior research has demonstrated that ACEs are extremely detrimental to individuals, both in the short-term and long-term. The lack of safety and stability, coupled with detrimental physical health effects, can lead to both short-term fear and lifelong negative consequences in terms of one's physical and mental health (Fagundes & Way, 2014; Lyu & Agrigoroaei, 2017; Springer et al., 2007). As shown in Figure 1, one of these potential negative consequences is the development of cPTSD, a more multidimensional, complex version of single-incident PTSD. cPTSD is often brought about due to experiencing more than one ACE, and prior literature has supported the hypothesis that cPTSD is significantly different from single-incident PTSD and BPD (Ben-Ezra et al., 2018; Bryant et al., 2021; Cloitre, 2020; Eilers et al., 2020; Elliot et al., 2021; Haselgruber et al., 2020). Prior research on the current treatments for cPTSD has demonstrated limited symptom reduction and long-term patient well-being improvement (Ashfield et al., 2020; Alexander, 2012; Corrigan et al., 2020; Mayo Foundation for 64 PSYCHEDELIC DRUGS AS cPTSD TREATMENT Medical Education and Research, 2019c; Jakobsen et al., 2017; Kwon, 2016; Phan et al., 2008; Sansone & Sansone, 2012). Psychedelic-assisted therapy, though a new and under-researched field, has already demonstrated several potential benefits in the treatment of anxiety disorders and PTSD (e.g., Andersen et al., 2021; Dolder et al., 2016; Fauvel et al., 2021; Mitchell et al., 2021; Sarris et al., 2022; Weston et al., 2020). This thesis furthers the existing literature on psychedelic-assisted therapy by also elucidating the potential benefits for treating cPTSD through the use of DMT-assisted, LSD-assisted, or MDMA-assisted therapy. The potential benefits of these treatments could be explored with empirical, between-groups research that follows a specific set of ethical guidelines to assess the efficacy of the treatment. 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